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Protected areas (PAs) are the cornerstones of global biodiversity conservation efforts, but to fulfil this role they must be effective at conserving the ecosystems and species that occur within their boundaries. Adequate monitoring datasets that allow comparing biodiversity between protected and unprotected sites are lacking in tropical regions. Here we use the largest citizen science biodiversity dataset – eBird – to quantify the extent to which protected areas in eight tropical forest biodiversity hotspots are effective at retaining bird diversity. We find generally positive effects of protection on the diversity of bird species that are forest-dependent, endemic to the hotspots, or threatened or Near Threatened, but not on overall bird species richness. Furthermore, we show that in most of the hotspots examined this benefit is driven by protected areas preventing both forest loss and degradation. Our results provide evidence that, on average, protected areas contribute measurably to conserving bird species in some of the world’s most diverse and threatened terrestrial ecosystems., Assessing the effectiveness of protected areas requires sufficient monitoring data inside and outside of protected areas; such data are lacking in many tropical regions. Here the authors use robust citizen science data on bird occupancy to show that protected areas are effective in maintaining bird species diversity across eight tropical biodiversity hotspots.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

Monitoring of animal populations is essential for conservation management. Various techniques are available to assess spatiotemporal patterns of species distribution and abundance. Nest surveys are often used for monitoring great apes. Quickly developing technologies, including unmanned aerial vehicles (UAVs) can be used to complement these ground-based surveys, especially for covering large areas rapidly. Aerial surveys have been used successfully to detect the nests of orang-utans. It is unknown if such an approach is practical for African apes, which usually build their nests at lower heights, where they might be obscured by forest canopy. In this 2-month study, UAV-derived aerial imagery was used for two distinct purposes: testing the detectability of chimpanzee nests and identifying fruiting trees used by chimpanzees in Loango National Park (Gabon). Chimpanzee nest data were collected through two approaches: we located nests on the ground and then tried to detect them in UAV photos and vice versa. Ground surveys were conducted using line transects, reconnaissance trails, and opportunistic sampling during which we detected 116 individual nests in 28 nest groups. In complementary UAV images we detected 48% of the individual nests (68% of nest groups) in open coastal forests and 8% of individual nests (33% of nest groups) in closed canopy inland forests. The key factor for nest detectability in UAV imagery was canopy openness. Data on fruiting trees were collected from five line transects. In 122 UAV images 14 species of trees (N = 433) were identified, alongside 37 tree species (N = 205) in complementary ground surveys. Relative abundance of common tree species correlated between ground and UAV surveys. We conclude that UAVs have great potential as a rapid assessment tool for detecting chimpanzee presence in forest with open canopy and assessing fruit tree availability. UAVs may have limited applicability for nest detection in closed canopy forest.

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80–150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor forα -MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.

Recent evidence suggests that neuropeptide Y (NPY), originating in neurons in the hypothalamic arcuate nucleus, is an important mediator of the effects of leptin on the central nervous system. As these NPY neurons innervate hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN) that produce the tripeptide, TRH, we raised the possibility that NPY may be responsible for resetting of the hypothalamic-pituitary-thyroid (HPT) axis during fasting. To test this hypothesis, the effects of intracerebroventricularly administered NPY on circulating thyroid hormone levels and proTRH messenger RNA in the PVN were studied by RIA and in situ hybridization histochemistry, respectively. NPY administration suppressed circulating levels of thyroid hormone (T(3) and T(4)) and resulted in an inappropriately normal or low TSH. These alterations were associated with a significant suppression of proTRH messenger RNA in the PVN, indicating that NPY infusion had resulted in a state of central hypothyroidism. Similar observations were made in NPY-infused animals pair fed to the vehicle-treated controls. These data are reminiscent of the effect of fasting on the thyroid axis and indicate that NPY may play a major role in the inhibition of HPT axis during fasting.

Recent studies have reinforced the view that the lateral hypothalamic area (LHA) regulates food intake and body weight. We identified leptin-sensitive neurons in the arcuate nucleus of the hypothalamus (Arc) that innervate the LHA using retrograde tracing with leptin administration. We found that retrogradely labeled cells in the Arc contained neuropeptide Y (NPY) mRNA or proopiomelanocortin (POMC) mRNA. Following leptin administration, NPY cells in the Arc did not express Fos but expressed suppressor of cytokine signaling-3 (SOCS-3) mRNA. In contrast, leptin induced both Fos and SOCS-3 expression in POMC neurons, many of which also innervated the LHA. These findings suggest that leptin directly and differentially engages NPY and POMC neurons that project to the LHA, linking circulating leptin and neurons that regulate feeding behavior and body weight homeostasis.

The adipocyte-derived hormone leptin decreases body weight in part by activating the sympathetic nervous system, resulting in increased thermogenesis and energy expenditure. We investigated hypothalamic pathways underlying leptin’s effects on stimulating the sympathetic nervous system. We found that leptin activates neurons in the retrochiasmatic area (RCA) and lateral arcuate nucleus (Arc) that innervate the thoracic spinal cord and also contain cocaine- and amphetamine-regulated transcript (CART). We also found that most CART-containing neurons in the RCA and Arc of the hypothalamus also contain proopiomelanocortin (POMC) mRNA. The finding that leptin activates CART/POMC neurons innervating sympathetic preganglionic neurons in the thoracic spinal cord suggests that this pathway may contribute to the increased thermogenesis and energy expenditure and decreased body weight observed following leptin administration.

The cochlear spiral ligament is a connective tissue that plays diverse roles in normal hearing. Spiral ligament fibrocytes are classified into functional sub-types that are proposed to carry out specialized roles in fluid homeostasis, the mediation of inflammatory responses to trauma, and the fine tuning of cochlear mechanics. We derived a secondary sub-culture from guinea pig spiral ligament, in which the cells expressed protein markers of type III or “tension” fibrocytes, including non-muscle myosin II (nmII), α-smooth muscle actin (αsma), vimentin, connexin43 (cx43), and aquaporin-1. The cells formed extensive stress fibers containing αsma, which were also associated intimately with nmII expression, and the cells displayed the mechanically contractile phenotype predicted by earlier modeling studies. cx43 immunofluorescence was evident within intercellular plaques, and the cells were coupled via dye-permeable gap junctions. Coupling was blocked by meclofenamic acid (MFA), an inhibitor of cx43-containing channels. The contraction of collagen lattice gels mediated by the cells could be prevented reversibly by blebbistatin, an inhibitor of nmII function. MFA also reduced the gel contraction, suggesting that intercellular coupling modulates contractility. The results demonstrate that these cells can impart nmII-dependent contractile force on a collagenous substrate, and support the hypothesis that type III fibrocytes regulate tension in the spiral ligament-basilar membrane complex, thereby determining auditory sensitivity.

We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB2 receptor ligands with excellent selectivity over the CB1 receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB2 potency, selectivity and rat exposure.

The vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine kinase (RTK) signaling pathway plays a pivotal role in tumor angiogenesis. Neovascularization promotes increased tumor cell proliferation, survival and metasasis. Many antiangiogenic agents including multi-RTK inhibitors are either approved or are undergoing testing in clinical trials. Axitinib is a potent and selective inhibitor of VEGF RTK 1, 2, and 3. This chapter discusses the stucture of axitinib as well as its toxicities and drug interactions. Important preclinical and clinical data for axitinib are presented including findings from phase II studies in many tumor types including malignant melanoma and renal, pancreatic, thyroid, breast, lung and colorectal carcinomas. Ongoing phase III studies in pancreatic and metastatic renal cell carcinoma will ultimately define the therapeutic role of this targeted agent.

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.

Ciliary neurotrophic factor (CNTF) and leptin decrease food intake and body weight. Lipopolysaccharide (LPS) is a potent exogenous pyrogen and produces anorexia via cytokine production. CNTF-, leptin-, and LPS-induced cytokines all act on type I cytokine receptors. However, it is not known if these cytokines engage similar central nervous system (CNS) pathways to exert their effects. To assess mechanisms by which these cytokines act, we examined the patterns of immediate early gene expression (SOCS-3, c-fos, and tis-11) in the brain following intravenous administration. CNTF and LPS induced gene expression in circumventricular organs; ependymal cells of the ventricles, meninges, and choroid plexus; and the arcuate nucleus of the hypothalamus. CNTF administration also induced fever and cyclooxygenase-2 mRNA expression. In contrast, we found no evidence of leptin-induced inflammation. CNTF and leptin are being assessed as potential therapeutic antiobesity agents, and both potently reduce food intake. Our findings support the hypothesis that CNTF and leptin engage distinct CNS sites and CNTF possesses inflammatory properties distinct from leptin.

Cocaine- and amphetamine-regulated transcript (CART) is a recently described neuropeptide widely expressed in the rat brain. CART mRNA and peptides are found in hypothalamic sites such as the paraventricular nucleus (PVH), the supraoptic nucleus (SON), the lateral hypothalamic area (LHA), the dorsomedial nucleus of the hypothalamus (DMH), the arcuate nucleus (Arc), the periventricular nucleus (Pe), and the ventral premammillary nucleus (PMV). Intracerebroventricular administration of recombinant CART peptide decreases food intake and CART mRNA levels in the Arc are regulated by leptin. Leptin administration induces Fos expression in hypothalamic CART neurons in the PVH, the DMH, the Arc, and the PMV. In the current study, we used double label in situ hybridization histochemistry to investigate the potential direct action of leptin on hypothalamic CART neurons and to define the chemical identity of the hypothalamic CART neurons in the rat brain. We found that CART neurons in the Arc, DMH, and PMV express long form leptin-receptor mRNA, and the suppressor of cytokine signaling-3 (SOCS-3) mRNA after an acute dose of intravenous leptin. We also found that CART neurons in the parvicellular PVH, in the DMH and in the posterior Pe coexpress thyrotropin-releasing hormone (TRH) mRNA. CART neurons in the magnocellular PVH and in the SON coexpress dynorphin (DYN), and CART cell bodies in the LHA and in the posterior Pe coexpress melanin-concentrating hormone (MCH) and glutamic acid decarboxylase (GAD-67) mRNA. In the Arc, a few CART neurons coexpress neurotensin (NT) mRNA. In addition, we examined the distribution of CART immunoreactivity in the human hypothalamus. We found CART cell bodies in the PVH, in the SON, in the LHA, in the Arc (infundibular nucleus) and in the DMH. We also observed CART fibers throughout the hypothalamus, in the bed nucleus of the stria terminalis, and in the amygdala. Our results indicate that leptin directly acts on CART neurons in distinct nuclei of the rat hypothalamus. Furthermore, hypothalamic CART neurons coexpress neuropeptides involved in energy homeostasis, including MCH, TRH, DYN, and NT. The distribution of CART cell bodies and fibers in the human hypothalamus indicates that CART may also play a role in the regulation of energy homeostasis in humans.

Because cocaine- and amphetamine-regulated transcript (CART) coexists with α-melanocyte stimulating hormone (α-MSH) in the arcuate nucleus neurons and we have recently demonstrated that α-MSH innervates TRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), we raised the possibility that CART may also be contained in fibers that innervate hypophysiotropic thyrotropin-releasing hormone (TRH) neurons and modulate TRH gene expression. Triple-labeling fluorescentin situhybridization and immunofluorescence were performed to reveal the morphological relationships between pro-TRH mRNA-containing neurons and CART- and α-MSH-immunoreactive (IR) axons. CART-IR axons densely innervated the majority of pro-TRH mRNA-containing neurons in all parvocellular subdivisions of the PVN and established asymmetric synaptic specializations with pro-TRH neurons. However, whereas all α-MSH-IR axons in the PVN contained CART-IR, only a portion of CART-IR axons in contact with pro-TRH neurons were immunoreactive for α-MSH. In the medial and periventricular parvocellular subdivisions of the PVN, CART was co-contained in ∼80% of pro-TRH neuronal perikarya, whereas colocalization with pro-TRH was found in 80% of TRH/CART neurons in the periventricular and medial parvocellular subdivisions accumulated Fluoro-Gold after systemic administration, suggesting that CART may serve as a marker for hypophysiotropic TRH neurons. CART prevented fasting-induced suppression of pro-TRH in the PVN when administered intracerebroventricularly and increased the content of TRH in hypothalamic cell cultures. These studies establish an anatomical association between CART and pro-TRH-producing neurons in the PVN and demonstrate that CART has a stimulatory effect on hypophysiotropic TRH neurons by increasing pro-TRH gene expression and the biosynthesis of TRH.

Knife cuts ventral or medial to the striatum were used to interrupt some of the principal connections of this structure. All of the cuts depleted striatal dopamine and produced aphagia and adipsia but there was no indication that the two classes of effects were always correlated. Cuts medial to the striatum produced the most severe DA depletions, persistent aphagia and adipsia, and the full complement of deficits in responding to glucoprivic and hydrational challenges that characterize rats that have recovered from lateral hypothalamic lesions. Cuts ventral to posterior portions of the striatum produced comparable periods of aphagia and adipsia (but few of the persisting impairments in responsiveness to regulatory challenges) even though their effect on striatal DA was relatively small (the average depletion was 51% compared to 89% for rats with cuts medial to the striatum). A second group of rats with cuts below more anterior aspects of the striatum sustained severe DA depletions (70%) but only very brief periods of aphagia and adipsia and only slight deficits in responding to osmotic challenges. The effects of the DA depleting cuts were compared with the behavioral consequences of coronal cuts in the midbrain tegmentum which selectively depleted hypothalamic norepinephrine. These cuts did not produce reliable effects on either food or water intake but abolished the normal feeding response to 2-deoxy-d-glucose without affecting the response to insulin. A correlational analysis of the biochemical and behavioral results of our cuts indicated a significant positive relationship between drinking in response to cellular thirst stimuli and hypothalamic NE as well as striatal DA. The postoperative body weights of our experimental animals were positively correlated with striatal dopamine and negatively related to hypothalamic norepinephrine.

Parasagittal knife cuts along the lateral border of the diencephalon (PS), coronal cuts accross the lateral (LMFB) or medial (MMFB) components of the medial forebrain bundle reproduce most of the persisting deficits in responding to glucoprivic and hydrational challenges that characterize rats with lateral hypothalamic lesions or intracranial injections of 6-hydroxydopamine (60HDA). Each of these cuts produced a different pattern of regulatory deficits, suggesting that individual components of the LH syndrome may be mediated by different neural substrates. This interpretation is supported by the results of our correlational analysis of the relationships between specific behavioral and biochemical effects of our cuts. For example, feeding responses to insulin were reliably correlated with striatal DA concentrations but feeding responses to 2-deoxy-d-glucose (2DG) were not. Water intake during periods of food deprivation was reliably correlated with striatal DA but water intake after an experimental osmotic challenge was not. Only one of the common persisting deficits (impaired feeding response to peripheral injections of insulin) was positively correlated with the duration of aphagia and adipsia.

Knife cuts were made that preferentially interrupted (a) the nigrostriatal pathway; (b) pallidofugal projections to the lower brainstem; (c) caudate-pallidal interconnections; and (d) fibers entering or leaving the striatum ventrally. The effects of these cuts on conditioned (shuttle box) avoidance, passive avoidance, swimming escape, sucrose-rewarded alley running, locomotor activity, and various measures of sensory-motor function were examined. The norepinephrine, dopamine and serotonin content of the striatum, residual forebrain and hypothalamus were determined following the completion of behavioral testing. The pattern of results suggests that striatal functions which are significantly influenced by several afferent and efferent connections are essential for the acquisition and, perhaps, execution of complex behavior in appetitive as well as aversive test paradigms. A special role for the dopaminergic afferents to the striatum was not established in these tests.

Aphagia and adipsia of equivalent duration were produced by knife cuts along the lateral border of the hypothalamus (PH cuts), or the medial surface of the globus pallidus (MP cuts) in male albino rats. Striatal dopamine (DA) was reduced by 75% in animals with PH cuts but only 50% by MP cuts. Hypothalamic norepinephrine was reduced 25% by PH cuts and was unaffected by MP cuts. Aphagia and adipsia were positively correlated with DA depletions only in rats with PH cuts. Presurgical catecholamine depletions produced by chronic injections of alpha-methyl-p-tyrosine did not alter the duration of aphagia or adipsia resulting from these knife cuts. However, following recovery of ingestive behavior, rats with PH and MP cuts were supersensitive to the anorexic effects of the dopamine-beta-hydroxylase inhibitor, diethyldithiocarbamate. Exaggerated anorexia was also observed after DA blockade by haloperidol or alpha-adrenergic blockade by phenoxybenzamine. The most pronounced effects of catecholamine blockade were observed in rats with PH cuts.

The raphe-spinal pathway, which contains co-localized serotonin (5-HT), thyrotropin-releasing hormone (TRH), and several TRH-prohormone-derived non-TRH peptides, projects to the ventral horn of the spinal cord. Pharmacologic ablation of this pathway with the 5-HT neurotoxin, 5, 7-dihydroxytryptamine, in neonatal rats resulted in deficient recovery of plantar foot muscles, functionally denervated with botulinum toxin type A. Failure of reinnervation was suggested by slower and incomplete recovery of the plantar foot compound muscle action potential amplitude and by a reduced mean diameter of plantar foot muscle fibers in ablated rats. These findings indicate that deprivation of alpha motor neurons from descending raphe-spinal input interferes with their ability to respond to muscle-derived signals for reinnervation.