Self-medication by orang-utans (Pongo pygmaeus) using bioactive properties of Dracaena cantleyi

This is the final version of the article. Available from Springer Nature via the DOI in this record.Animals self-medicate using a variety of plant and arthropod secondary metabolites by either ingesting them or anointing them to their fur or skin apparently to repel ectoparasites and treat skin diseases. In this respect, much attention has been focused on primates. Direct evidence for self-medication among the great apes has been limited to Africa. Here we document self-medication in the only Asian great ape, orang-utans (Pongo pygmaeus), and for the first time, to our knowledge, the external application of an anti-inflammatory agent in animals. The use of leaf extracts from Dracaena cantleyi by orang-utan has been observed on several occasions; rubbing a foamy mixture of saliva and leaf onto specific parts of the body. Interestingly, the local indigenous human population also use a poultice of these leaves for the relief of body pains. We present pharmacological analyses of the leaf extracts from this species, showing that they inhibit TNFα-induced inflammatory cytokine production (E-selectin, ICAM-1, VCAM-1 and IL-6). This validates the topical anti-inflammatory properties of this plant and provides a possible function for its use by orang-utans. This is the first evidence for the deliberate external application of substances with demonstrated bioactive potential for self-medication in great apes.We thank our financial supporters: the Wildlife Conservation Society, the U.S. Fish and Wildlife Service Great Apes Conservation Fund, Primate Conservation Inc., Foundation UMI – Saving of Pongidae, the L.S.B. Leakey Foundation, NERC (Natural Environmental Research Council) and the University of Exeter. L.R. and K.D. were supported by the Ministry of Education Youth and Sports, Czech Republic (grant LO1204 from the National Program of Sustainability and Agricultural Research). We are also very grateful to grant No. P505/11/1163 from The Grant Agency of The Czech Republic and to Prof. Jitka Ulrichová for the kind gift of HUVEC cells

Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS

Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases

Assessing the impact of forest structure disturbances on the arboreal movement and energetics of orangutans—An agent-based modeling approach

This is the final version. Available from Frontiers Media via the DOI in this record. Data availability statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary material.Agent-based models have been developed and widely employed to assess the impact of disturbances or conservation management on animal habitat use, population development, and viability. However, the direct impacts of canopy disturbance on the arboreal movement of individual primates have been less studied. Such impacts could shed light on the cascading effects of disturbances on animal health and fitness. Orangutans are an arboreal primate that commonly encounters habitat quality deterioration due to land-use changes and related disturbances such as forest fires. Forest disturbance may, therefore, create a complex stress scenario threatening orangutan populations. Due to forest disturbances, orangutans may adapt to employ more terrestrial, as opposed to arboreal, movements potentially prolonging the search for fruiting and nesting trees. In turn, this may lead to changes in daily activity patterns (i.e., time spent traveling, feeding, and resting) and available energy budget, potentially decreasing the orangutan's fitness. We developed the agent-based simulation model BORNEO (arBOReal aNimal movEment mOdel), which explicitly describes both orangutans' arboreal and terrestrial movement in a forest habitat, depending on distances between trees and canopy structures. Orangutans in the model perform activities with a motivation to balance energy intake and expenditure through locomotion. We tested the model using forest inventory data obtained in Sebangau National Park, Central Kalimantan, Indonesia. This allowed us to construct virtual forests with real characteristics including tree connectivity, thus creating the potential to expand the environmental settings for simulation experiments. In order to parameterize the energy related processes of the orangutans described in the model, we applied a computationally intensive evolutionary algorithm and evaluated the simulation results against observed behavioral patterns of orangutans. Both the simulated variability and proportion of activity budgets including feeding, resting, and traveling time for female and male orangutans confirmed the suitability of the model for its purpose. We used the calibrated model to compare the activity patterns and energy budgets of orangutans in both natural and disturbed forests. The results confirm field observations that orangutans in the disturbed forest are more likely to experience deficit energy balance due to traveling to the detriment of feeding time. Such imbalance is more pronounced in males than in females. The finding of a threshold of forest disturbances that affects a significant change in activity and energy budgets suggests potential threats to the orangutan population. Our study introduces the first agent-based model describing the arboreal movement of primates that can serve as a tool to investigate the direct impact of forest changes and disturbances on the behavior of species such as orangutans. Moreover, it demonstrates the suitability of high-performance computing to optimize the calibration of complex agent-based models describing animal behavior at a fine spatio-temporal scale (1-m and 1-s granularity).UKR

Recent Surveys in the Forests of Ulu Segama Malua, Sabah, Malaysia, Show That Orang-utans (P. p. morio) Can Be Maintained in Slightly Logged Forests

BACKGROUND: Today the majority of wild great ape populations are found outside of the network of protected areas in both Africa and Asia, therefore determining if these populations are able to survive in forests that are exploited for timber or other extractive uses and how this is managed, is paramount for their conservation. METHODOLOGY/PRINCIPAL FINDINGS: In 2007, the "Kinabatangan Orang-utan Conservation Project" (KOCP) conducted aerial and ground surveys of orang-utan (Pongo pygmaeus morio) nests in the commercial forest reserves of Ulu Segama Malua (USM) in eastern Sabah, Malaysian Borneo. Compared with previous estimates obtained in 2002, our recent data clearly shows that orang-utan populations can be maintained in forests that have been lightly and sustainably logged. However, forests that are heavily logged or subjected to fast, successive coupes that follow conventional extraction methods, exhibit a decline in orang-utan numbers which will eventually result in localized extinction (the rapid extraction of more than 100 m(3) ha(-1) of timber led to the crash of one of the surveyed sub-populations). Nest distribution in the forests of USM indicates that orang-utans leave areas undergoing active disturbance and take momentarily refuge in surrounding forests that are free of human activity, even if these forests are located above 500 m asl. Displaced individuals will then recolonize the old-logged areas after a period of time, depending on availability of food sources in the regenerating areas. CONCLUSION/SIGNIFICANCE: These results indicate that diligent planning prior to timber extraction and the implementation of reduced-impact logging practices can potentially be compatible with great ape conservation

Accounting for seedling performance from nursery to outplanting when reforesting degraded tropical peatlands

This is the final version. Available on open access from Wiley via the DOI in this recordData availability: The full datasets supporting this study are deposited in the UK CEH Environmental Information Data Centre (Harrison et al. 2023). No novel code was used to generate these findings, and the code used is freely available as part of packages or existing published sources referenced in the text.Reforestation is promoted to address the dual global climate and biodiversity crises. This is particularly relevant for carbon-rich, biodiverse tropical peatlands, for which active reforestation typically involves two post-germination stages: nursery rearing of seedlings, then outplanting. Yet, linkages between these stages and cumulative seedling performance are rarely quantified during tropical peatland reforestation. By monitoring tree seedling survival and growth, we investigate factors influencing seedling performance (species identity, seedling source, treatments, and climate), whether nursery performance predicts outplanting performance, and calculate cumulative survival (nursery plus outplanting) in Sebangau National Park, Indonesian Borneo. Standardized survival at 2 years was higher in the nursery (mean 67% across 40 species) than outplanting (44% across 24 species). For nursery and outplanting, species identity was the main source of variation in survival and height growth. Seedling source, treatments, site condition, and precipitation had no significant impact on survival but did influence growth in some cases. Nursery survival did not predict outplanting survival, but nursery height did predict outplanting height. Across species, around a quarter of seedlings survived from nursery to outplanting over 4 years. Cumulative survival represents a more realistic basis for assessing the genetic and other resource costs of tropical peatland reforestation. Our two-phase approach identified outplanting as the greater bottleneck to cumulative seedling survivability. We argue that the nursery stage may be used to harden seedlings for degraded peatland conditions by selecting more relevant treatments (e.g. flooding) and screening for resilience to common disturbances (e.g. fire) to enhance outplanted, and thus cumulative, seedling survival.The Orangutan ProjectArcus FoundationDarwin InitiativeSave the OrangutanOrangutan Land TrustU.S. Fish and Wildlife Service Great Apes Conservation FundOcean Parks Conservation Foundation Hong KongEuropean Outdoor Conservation AssociationRufford Small Grants For NatureTaronga ZooEuropean Association of Zoos and AquariaFundacion BioparcUKRISingaporean Ministry of Educatio

Unexpected Ecological Resilience in Bornean Orangutans and Implications for Pulp and Paper Plantation Management

Ecological studies of orangutans have almost exclusively focused on populations living in primary or selectively logged rainforest. The response of orangutans to severe habitat degradation remains therefore poorly understood. Most experts assume that viable populations cannot survive outside undisturbed or slightly disturbed forests. This is a concern because nearly 75% of all orangutans live outside protected areas, where degradation of natural forests is likely to occur, or where these are replaced by planted forests. To improve our understanding of orangutan survival in highly altered forest habitats, we conducted population density surveys in two pulp and paper plantation concessions in East Kalimantan, Indonesia. These plantations consist of areas planted with fast-growing exotics intermixed with stands of highly degraded forests and scrublands. Our rapid surveys indicate unexpectedly high orangutan densities in plantation landscapes dominated by Acacia spp., although it remains unclear whether such landscapes can maintain long-term viable populations. These findings indicate the need to better understand how plantation-dominated landscapes can potentially be incorporated into orangutan conservation planning. Although we emphasize that plantations have less value for overall biodiversity conservation than natural forests, they could potentially boost the chances of orangutan survival. Our findings are based on a relatively short study and various methodological issues need to be addressed, but they suggest that orangutans may be more ecologically flexible than previously thought

The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers

Therapies for hormone-independent prostate and breast cancer are limited, with the effectiveness of the taxanes compromised by toxicity, lack of oral bioavailability and drug resistance. This study aims to identify and characterise new microtubule disruptors, which may have improved efficacy relative to the taxanes in hormone-independent cancer. 2-Methoxy-3-O-sulphamoyl-17β-cyanomethyl-oestra-1,3,5(10)-triene (STX641), 2-methoxy-3-hydroxy-17β-cyanomethyl-oestra-1,3,5(10)-triene (STX640) and 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140) were all potent inhibitors of cell proliferation in a panel of prostate and breast cancer cell lines. STX641 and STX640 significantly inhibited tumour growth in the MDA-MB-231 xenograft model. STX641 inhibited both in vitro and in vivo angiogenesis. Despite good in vivo activity, STX641 was not as potent in vivo as STX140. Therefore, STX140 was evaluated in the prostate hormone-independent PC-3 xenograft model. STX140 had superior efficacy to docetaxel, 2-MeOE2 and bevacizumab. In contrast to vinorelbine, no significant toxicity was observed. Furthermore, STX140 could be dosed daily over a 60-day period leading to tumour regression and complete responses, which were maintained after the cessation of dosing. This study demonstrates that STX641 and STX140 have considerable potential for the treatment of hormone-independent breast and prostate cancer. In contrast to the taxanes, STX140 can be dosed orally, with no toxicity being observed even after prolonged daily dosing

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized

BCRP expression does not result in resistance to STX140 in vivo, despite the increased expression of BCRP in A2780 cells in vitro after long-term STX140 exposure

The anti-proliferative and anti-angiogenic properties of the endogenous oestrogen metabolite, 2-methoxyoestradiol (2-MeOE2), are enhanced in a series of sulphamoylated derivatives of 2-MeOE2. To investigate possible mechanisms of resistance to these compounds, a cell line, A2780.140, eightfold less sensitive to the 3,17-O,O-bis-sulphamoylated derivative, STX140, was derived from the A2780 ovarian cancer cell line by dose escalation. Other cell lines tested did not develop STX140 resistance. RT–PCR and immunoblot analysis demonstrated that breast cancer resistance protein (BCRP) expression is dramatically increased in A2780.140 cells. The cells are cross-resistant to the most structurally similar bis-sulphamates, and to BCRP substrates, mitoxantrone and doxorubicin; but they remain sensitive to taxol, an MDR1 substrate, and to all other sulphamates tested. Sensitivity can be restored using a BCRP inhibitor, and this pattern of resistance is also seen in a BCRP-expressing MCF-7-derived cell line, MCF-7.MR. In mice bearing wild-type (wt) and BCRP-expressing tumours on either flank, both STX140 and mitoxantrone inhibited the growth of the MCF-7wt xenografts, but only STX140 inhibited growth of the MCF-7.MR tumours. In conclusion, STX140, a promising orally bioavailable anti-cancer agent in pre-clinical development, is highly efficacious in BCRP-expressing xenografts. This is despite an increase in BCRP expression in A2780 cells in vitro after chronic dosing with STX140