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

Temozolomide and cisplatin in relapsed/refractory acute leukemia

Cisplatin depletes MGMT and increases the sensitivity of leukemia cells to temozolomide. We performed a phase I study of cisplatin and temozolomide in patients with relapsed and refractory acute leukemia. Fifteen patients had AML, 3 had ALL, and 2 had biphenotypic leukemia. The median number of prior chemotherapy regimens was 3 (1–5). Treatment was well tolerated up to the maximal doses of temozolomide 200 mg/m2/d times 7 days and cisplatin 100 mg/m2 on day 1. There was one complete remission in this heavily pretreated patient population. Five of 20 (25%) patients demonstrated a significant reduction in bone marrow blasts

Insights for restoration: Reconstructing the drivers of long-term local fire events and vegetation turnover of a tropical peatland in Central Kalimantan

This is the final version. Available on open access from Elsevier via the DOI in this record. Data availability: Data will be made available on request.Fire events in tropical peatlands often relate to dry peat conditions associated with climate variability (drought) and anthropogenic-driven ecosystem degradation. However, drought is not the only driver of long-term fire events and peatland ecosystem changes. This study used palaeoecological and geochemical proxies to investigate the long-term drivers of charcoal influx to identify local fires and examine the associated responses to the tropical peatland ecosystem in Central Kalimantan, Indonesia. The results showed local fire events increased after 756 cal. yr BP, and possible drivers of charcoal influx include changes in sea level, increased frequency of El Niño events, increased biomass, and anthropogenically-driven ecosystem degradation. However, the vegetation composition showed changes since ∼2300 cal. yr BP from a mix of peat swamp forest (PSF) and open vegetation (OV) during the late Holocene (∼2300 to 1129 cal. yr BP), to predominantly PSF from 1128 to 375 cal. yr BP, dry lowland mixed with swamp forest (LMS) and open vegetation (OV) from 374 to 135 cal. yr BP, and predominantly OV and freshwater swamp forest (FSF) from 134 to −62 cal. yr BP. The possible drivers of the vegetation turnover were hydrological conditions and the availability of peat nutrients, while the vegetation turnover affected the accumulation and decomposition of recalcitrant organic matter in peat. The thresholds of the peatland ecosystems over longer-term timeframes provided the following restoration insights: 1) PSF species (i.e. Eurya and Ilex) showed high fire tolerance and increased in abundance up to charcoal influx threshold of ∼23 grains mm−2 cm−3 yr−1 while LMS and OV species increased up to a lower threshold of ∼13 grains mm−2 cm−3 yr−1before declining; 2) PSF species expanded during periods of wet conditions and high peat nutrients (i.e. TN - enriched); and 3) Future revegetation in the region can focus on tree taxa such as Euphorbiaceae, Arenga, Ficus, and Trema as they were historically able to thrive in fire events and dry hydrological conditions.Natural Environment Research Council (NERC)European Research Council (ERC)Ministry of Research and Technology/National Research and Innovation Agency (RISTEK-BRIN)Universitas Jamb

Post-Transcriptional Regulation of BCL2 mRNA by the RNA-Binding Protein ZFP36L1 in Malignant B Cells

The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3′ untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the ‘maximum information coefficient’ (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3′ untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3′ untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells

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

A redox switch in angiotensinogen modulates angiotensin release.

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child

Selective Deletion of PTEN in Dopamine Neurons Leads to Trophic Effects and Adaptation of Striatal Medium Spiny Projecting Neurons

The widespread distribution of the tumor suppressor PTEN in the nervous system suggests a role in a broad range of brain functions. PTEN negatively regulates the signaling pathways initiated by protein kinase B (Akt) thereby regulating signals for growth, proliferation and cell survival. Pten deletion in the mouse brain has revealed its role in controlling cell size and number. In this study, we used Cre-loxP technology to specifically inactivate Pten in dopamine (DA) neurons (Pten KO mice). The resulting mutant mice showed neuronal hypertrophy, and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon. Interestingly, quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum, despite a significant increase in total DA tissue levels. Striatal dopamine receptor D1 (DRD1) and prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while dopamine receptor D2 (DRD2) and preproenkephalin (PPE) mRNA levels remained unchanged. In addition, PTEN inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion. These results provide further evidence about the role of PTEN in the brain and suggest that manipulation of the PTEN/Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson's disease, and other neurodegenerative disorders