mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression.

Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of mdm2 was fully rescued in the background of p535KR/5KR , but not p534KR/4KR background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in p53-5KR cells. Notably, the early-onset tumor formation observed in p535KR/5KR and p53-null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors.

Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROS-detoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

Refining greenhouse gas emission factors for Indonesian peatlands and mangroves to meet ambitious climate targets.

For countries' emission-reduction efforts under the Paris Agreement to be effective, baseline emission/removals levels and reporting must be as transparent and accurate as possible. For Indonesia, which holds among the largest area of tropical peatlands and mangrove forest in the world, it is particularly important for these high-carbon ecosystems to produce high-accuracy greenhouse gas inventory and to improve national forest reference emissions level/forest reference level. Here, we highlight the opportunity for refining greenhouse gas emission factors (EF) of peatlands and mangroves and describe scientific challenges to support climate policy processes in Indonesia, where 55 to 59% of national emission reduction targets by 2030 depend on mitigation in Forestry and Other Land Use. Based on the stock-difference and flux change approaches, we examine higher-tier EF for drained and rewetted peatland, peatland fires, mangrove conversions, and mangrove on peatland to improve future greenhouse gas flux reporting in Indonesia. We suggest that these refinements will be essential to support Indonesia in achieving Forest and Other Land Use net sink by 2030 and net zero emissions targets by 2060 or earlier.

Carbon emissions reductions from Indonesia's moratorium on forest concessions are cost-effective yet contribute little to Paris pledges.

International initiatives for reducing carbon emissions from deforestation and forest degradation (REDD+) could make critical, cost-effective contributions to tropical countries' nationally determined contributions (NDCs). Norway, a key donor of such initiatives, had a REDD+ partnership with Indonesia, offering results-based payments in exchange for emissions reductions calculated against a historical baseline. Central to this partnership was an area-based moratorium on new oil palm, timber, and logging concessions in primary and peatland forests. We evaluate the effectiveness of the moratorium between 2011 and 2018 by applying a matched triple difference strategy to a unique panel dataset. Treated dryland forest inside moratorium areas retained, at most, an average of 0.65% higher forest cover compared to untreated dryland forest outside the moratorium. By contrast, carbon-rich peatland forest was unaffected by the moratorium. Cumulative avoided dryland deforestation from 2011 until 2018 translates into 67.8 million to 86.9 million tons of emissions reductions, implying an effective carbon price below Norway's US$5 per ton price. Based on Norway's price, our estimated cumulative emissions reductions are equivalent to a payment of US$339 million to US$434.5 million. Annually, our estimates suggest a 3 to 4% contribution to Indonesia's NDC commitment of a 29% emissions reduction by 2030. Despite the Indonesia-Norway partnership ending in 2021, reducing emissions from deforestation remains critical for meeting this commitment. Future area-based REDD+ initiatives could build on the moratorium's outcomes by reforming its incentives and institutional arrangements, particularly in peatland forest areas.

Dual-agent dose-finding in Phase I clinical trial-An extension of rapid enrollment design.

Dual-agent treatment has become more and more popular in clinical trials. We have developed an approach called rapid enrollment dual-agent design (REDD) for dose-finding in Phase I clinical trials. This approach aims to administer treatment to patients using a dose combination that is highly probable to be the target dose combination. Unlike other non-model-based designs, rapid enrollment designs (RED and REDD) do not require waiting for all patients to complete an assessment before the assignment of the next participant. Simulations showed that across several scenarios, the average performance of REDD is comparable to that of the Bayesian optimal interval (BOIN) design and the partial order continual reassessment method (POCRM). The simulation results of REDD for late-onset toxicity assessments demonstrated that assigning patients to a dose combination as they are being enrolled, without waiting for the most recent cohort of patients to complete their follow-up, does not significantly compromise the quality of the maximum tolerated dose (MTD) estimation. Instead, it saves a considerable amount of time in clinical trial enrollment. User-friendly online applications have also been created to further facilitate the adoption of rapid enrollment designs in Phase I trials. In summary, being similar to BOIN and POCRM in performance, REDD is an approach that is easily comprehensible, straightforward to implement and offers an advantage of enrolling patients without having to wait for all current patients to complete their follow-ups for toxicity.

Land cover changes and carbon dynamics in Central India's dry tropical forests: A 25-year assessment and nature-based eco-restoration approaches.

Anthropogenic land use and land cover changes are major drivers of environmental degradation and declining soil health across heterogeneous landscapes in Central India. To examines the land cover changes and spatio-temporal variations in forest carbon stock and soil organic carbon (SOC) over the past 25 years in central India. Geospatial techniques, coupled with ground measurements were employed to detect changes in land cover, carbon stocks in vegetation, and soil carbon in various vegetation types. The results indicate that forested areas have decreased, while agriculture and habitation have expanded between 1997 and 2022. Vegetation C stocks varied significantly (P < 0.05) from 39.42 to 139.95 Mg ha-1 and the SOC varied from 7.02 to 17.98 Mg ha-1 under different soil profiles across vegetation types, which decreased with soil depth, while the pH and bulk density increased. The maximum bulk density in the soil was found at a depth of 40-60 cm (lower profile) in Bamboo Brake, while the minimum was observed under Dense Mixed Forest at a depth of 0-20 cm (top profile). The topsoil profile contributed 33.6%-39%, the middle profile (20-40 cm) was 33.6%-34.4%, and the lower profile was 26.5%-30.8% of soil organic carbon. The study site has experienced rapid carbon losses due to changes in land cover, such as illegal expansion of agriculture, encroachments into forest fringes, and activities like selective logging and overgrazing, which have degraded dense forests. The ecological engineering of degraded ecosystems poses a great challenge and application of complex biological, mechanical and engineering measures is highly cumbersome, expensive, uneconomical and practically not feasible for upscaling. Nevertheless, proposed nature-based solutions mimic natural reparation and processes provide sustainable interventions for the reclamation of ruined landscapes besides improving ecological integrity and rendering many co-benefits to ecosystems and human societies.

Implication of the new VCS jurisdictional and nested REDD methodology on baselines of existing avoided deforestation projects.

A changing climate is poised to inflict massive-scale damage through extreme weather events. Preserving Earth's forests stands out as a critical resource in our battle to mitigate climate change. One pivotal approach for this endeavour is the Reduction of Emissions from Deforestation and Forest Degradation (REDD), a climate change mitigation solution currently being enacted through locally-based projects certified by the Verified Carbon Standard (VCS) Association. Nevertheless, these REDD projects have recently faced severe scrutiny for potentially overemphasizing their effectiveness. To address these concerns, the VCS has put forth a new jurisdictional and nested REDD methodology. This study, therefore, aims to assess the impact of the new REDD methodology on the baseline measurements of existing REDD projects within the VCS registry. For this assessment, we selected four REDD projects, each spanning across four continents and encompassing two major forest types. An in-depth analysis of these four projects reveals a noteworthy trend: under the new methodology, three of them are projected to experience a substantial reduction in the number of issued credits compared to the previous methodologies. Consequently, it appears that the new REDD methodology holds promise in generating higher-quality credits by reducing the potential for an inflated baseline.

Actor Perceptions of the Governance Framework and Non-Carbon Benefits from the Ghana Cocoa Forest REDD+ Program: An Extended Q-Study of the Juabuso-Bia Hotspot Intervention Area.

The expansion of cocoa farms is a major driver of deforestation and emissions in Ghana's high forest zone. The Ghana Cocoa Forest Reducing Emissions from Deforestation and Forest Degradation Program (REDD+) was launched as the world's first commodity-based initiative to address emissions from deforestation caused by cocoa production and generate non-carbon benefits. Hotspot Intervention Areas were established to implement the Ghana Cocoa REDD+ program. This study combines Q-methodology with focus group discussions and interviews to assess stakeholder perceptions in the Juabuso-Bia cocoa landscape regarding the capacity of the Hotspot Intervention Area to facilitate the generation of governance and economic non-carbon benefits to sustain emission reductions. We found that introducing the Hotspot Intervention Area has re-centralized landscape governance, which, coupled with weak collaboration among stakeholders, has led to poor generation of non-carbon benefits. Furthermore, efforts to include women in the leadership structure of the Hotspot Intervention Area can be described as tokenism, and little has been done to improve land and tree tenure for vulnerable groups. This, combined with the low adoption of climate-smart cocoa practices, is likely to negatively affect the generation of economic non-carbon benefits. To overcome these challenges, we recommend reforming the Hotspot Intervention Area, bolstering community-level sensitization, improving access to decision-making spaces that will enhance the participation of women and minority groups in landscape governance, and improving farmers' tenure security through a registration scheme for land and trees. These recommendations can ensure the efficient generation of non-carbon benefits, which are key to the success of REDD+.

Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.

Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In WT cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (IκB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of IκB by enhancing both K63-ubiquitination and auto-phosphorylation of IκB kinase complex. In contrast with STZ-diabetic REDD1+/+ mice, IκB kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.

REDD1 (regulated in development and DNA damage 1) modulates the glucocorticoid receptor function in keratinocytes.

Glucocorticoids (GCs) are widely used for the treatment of inflammatory skin diseases despite significant adverse effects including skin atrophy. Effects of GCs are mediated by the glucocorticoid receptor (GR), a well-known transcription factor. Previously, we discovered that one of the GR target genes, REDD1, is causatively involved in skin atrophy. Here, we investigated its role in GR function using HaCaT REDD1 knockout (KO) keratinocytes. We found large differences in transcriptome of REDD1 KO and control Cas9 cells in response to glucocorticoid fluocinolone acetonide (FA): both the scope and amplitude of response were significantly decreased in REDD1 KO. The status of REDD1 did not affect GR stability/degradation during self-desensitization, and major steps in GR activation-its nuclear import and phosphorylation at activating Ser211. However, the amount of GR phosphorylated at Ser226 that may play negative role in GR signalling, was increased in the nuclei of REDD1 KO cells. GR nuclear import and transcriptional activity also depend on the composition of GR chaperone complex: exchange of chaperone FKBP51 (FK506-binding protein 5) for FKBP52 (FK506-binding protein 4) being a necessary step in GR activation. We found the increased expression and abnormal nuclear translocation of FKBP51 in both untreated and FA-treated REDD1 KO cells. Overall, our results suggest the existence of a feed-forward loop in GR signalling mediated by its target gene REDD1, which has translational potential for the development of safer GR-targeted therapies.

Practical guide to coproduction in conservation science.

We considered a series of conservation-related research projects on the island of Pemba, Tanzania, to reflect on the broad significance of Beier et al.'s recommendations for linking conservation science with practical conservation outcomes. The implementation of just some of their suggestions can advance a successful coproduction of actionable science by small research teams. Key elements include, first, scientists and managers working together in the field to ensure feedback in real time; second, questions jointly identified by managers and researchers to facilitate engaged collaboration; third, conducting research at multiple sites, thereby broadening managers' abilities to reach multiple stakeholders; and fourth, establishing a multidisciplinary team because most of the concerns of local managers require input from multiple disciplines.

Consideramos una serie de proyectos de investigación relacionados con la conservación en la isla de Pemba, Tanzania, para reflexionar sobre la importancia de las recomendaciones de Beier et al. para vincular las ciencias de la conservación con sus resultados prácticos. La implementación de sólo algunas de sus sugerencias puede impulsar una coproducción exitosa de ciencia práctica hecha por pequeños equipos de investigación. Los elementos clave incluyen, primero, a los científicos y administrados trabajando juntos en el campo para asegurar respuestas en tiempo real; segundo, preguntas identificadas en conjunto por los administradores y los investigadores para facilitar la colaboración participativa; tercero, realizar investigaciones en sitios diferentes y ampliar con esto las habilidades de los administradores para llegar a múltiples actores; y cuarto, establecer un equipo multidisciplinario ya que la mayoría de los intereses de los administradores locales requieren información de múltiples disciplinas.

Decreasing REDD1 expression protects against high glucose-induced apoptosis, oxidative stress and inflammatory injury in podocytes through regulation of the AKT/GSK-3ß/Nrf2 pathway.

OBJECTIVE: Our goal in this work was to investigate the possible role and mechanism of regulated in development and DNA damage response 1 (REDD1) in mediating high glucose (HG)-induced podocyte injury in vitro. MATERIALS AND METHODS: Mouse podocytes were stimulated with HG to establish HG injury model. Protein expression was examined by Western blotting. Cell viability was measured by cell counting kit-8 assay. Cell apoptosis was assessed by annexin V-FITC/propidium iodide and TUNEL apoptotic assays. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were quantified by commercial kits. Concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß were measured by ELISA. RESULTS: A marked increase in REDD1 expression was observed in podocytes stimulated with HG. Reduced REDD1 expression strikingly restrained HG-induced increases in apoptosis, oxidative stress, and inflammation response in cultured podocytes. Decreasing REDD1 expression enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) activation in HG-exposed podocytes via regulation of the AKT/glycogen synthase kinase-3 beta (GSK-3ß) pathway. Inhibition of AKT or reactivation of GSK-3ß prominently abolished Nrf2 activation induced by decreasing REDD1 expression. Pharmacological repression of Nrf2 markedly reversed the protective effects of decreasing REDD1 expression in HG-injured podocytes. CONCLUSION: Our data demonstrate that decreasing REDD1 expression protects cultured podocytes from HG-induced injuries by potentiating Nrf2 signaling through regulation of the AKT/GSK-3ß pathway. Our work underscores the potential role of REDD1-mediated podocyte injury during the development of diabetic kidney disease.

Community evaluation of forest and REDD+ governance quality in the Democratic Republic of the Congo.

The Democratic Republic of Congo (DRC) has over 100 million Ha of forest and has significant potential to benefit from these forests, including through REDD+ if they are managed effectively. Effective governance of forest landscapes is essential for environmental management and equitable harnessing of ecosystem service benefits for communities. Poor governance, political instability, and capacity limitations in the DRC are widely highlighted. However, there have been few, if any, attempts to evaluate forest governance in the DRC, especially at the community level. This paper reports a community-level evaluation of forest governance in the DRC, using a survey method. The results suggest that REDD+ projects have the ability to improve forest governance as perceived by the community. The research shows that building the right capacity, consulting and accessing the needs of the community and building long-term projects and partnerships a key success factors. These findings and the novel approach to supporting communities to evaluate their governance are applicable to similar community-level forest governance contexts.

Pathways of REDD+ Piloting in Enhancing Sustainable Forest Management: The Case of Masito-Ugalla Ecosystem, Western Tanzania.

In Tanzania, the piloting phase for the Reduced Emission from Deforestation and forest Degradation lasted for almost 8 years, between 2008 and 2016. REDD+ pilot projects were implemented to document critical lessons that would inform the development of REDD policy in the country, including the development of REDD strategy and Action Plan that the government endorsed in March 2013. Major thematic areas for piloting were to understand the drivers of deforestation and forest degradation, community engagement approaches, alternative livelihoods in the context of REDD+, measurement, reporting and verification of carbon issues in the context of REDD+ and financing questions. In western Tanzania, REDD+ was implemented in the same vein, with several activities employed with the involvement of state and non-state actors. This study evaluated the success and failure of the REDD+ mechanism in the Masito-Ugalla Ecosystem to draw lessons for future REDD+ implementation. This study employed a cross-sectional design that applied a mixed methods approach in collecting primary and secondary data, including 528 questionnaires, eight focus group discussions and data from direct observations. Before the REDD+ pilot, results indicate the existence of different forms of forest management, both traditional and modern, with traditional approaches being stricter than conventional and whose strength lost over time. The rise of conventional approaches was to alleviate deforestation that started in the aftermath that necessitated the development and implementation of conservation projects, whereby the REDD+ pilot is credited for stakeholder involvement and awareness creation programmes. However, it was challenging to balance conservation under REDD+ and community socio-economic development to achieve sustainable forest management targets, including alleviating shifting cultivation. The lack of completion of REDD+ activities such as the sale of carbon credits due to its short lifespan was an indication of REDD+ failure to achieve its milestones. Results illustrate further that transparency in planning for benefits distribution among actors, community empowerment, equity and equality and community responsiveness are necessary to foster community participation in SFM processes. Unless the transfer of tenure rights from the government (especially in JFM) to communities surrounding forests, it will be hard for local communities to effectively participate in future SFM activities. Findings highlight the need to clearly define how local communities surrounding forests can sustainably be engaged in management and conservation and benefit from their engagement in such processes.

Carbon stocks of tree plantations in a Western Ghats landscape, India: influencing factors and management implications.

Biomass and carbon stock assessments in data-deficient plantations and identifying the factors influencing tree growth, distribution, and carbon stocks are extremely important for implementing sound silvicultural management and monitoring practices to achieve REDD+ goals. We conducted carbon stock assessments in five major plantation types in a regional landscape in the central Western Ghats, India, by establishing fifty 0.1-ha plots across the landscape. We quantified the overall carbon stocks by summing the carbon pools across mature trees, deadwood, and soil (0 -15 cm) components. Allometric equations were compared to address the uncertainty in the tree biomass carbon. The tree biomass carbon and soil organic carbon varied significantly across the plantation types (F = 55.23, p < 0.00). The present study yielded the highest carbon stocks in Pinus plantation (201.91 ± 9.52 Mg ha-1) and the least in Eucalyptus (122.63 ± 9.73 Mg ha-1). The correlation analysis displayed a strong influence of mean annual precipitation and edaphic factors on soil organic carbon, while basal area and elevation were good predictors of tree biomass carbon. The principal component analysis revealed an association of predictor variables in the distribution of plantation types. We found a strong association between mean annual precipitation on Pinus plantation and mean annual temperature on Eucalyptus and Acacia plantations. On the other hand, teak pure plantation was associated with structural and topographic variables, while edaphic factors mainly influenced the distribution of teak mixed plantations. The findings of the present study conclude substantial carbon storage ability of the plantations in the studied landscape which can play a significant role in mitigating the effects of climate change and reaching carbon neutrality.

REDD1 interacts with AIF and regulates mitochondrial reactive oxygen species generation in the keratinocyte response to UVB.

Non-melanoma skin cancer (NMSC) incidence is rising, especially in high-risk, immunocompromised groups such as organ transplant patients, who often develop numerous, aggressive cutaneous squamous cell carcinomas. Identifying the pathways that support NMSC development will result in new approaches for prevention and therapy. Our goal is to define the function of REDD1 (Regulated in DNA Damage and Development 1) in the UVB stress response. REDD1 is rapidly induced by a variety of stressors to repress mechanistic target of rapamycin complex I (mTORC1), and it has been reported that REDD1 loss causes dysfunctional mitochondria with increased reactive oxygen species (ROS) and impaired oxidative phosphorylation (OXPHOS). We now show that knockout of REDD1 in human keratinocytes sensitizes them to UVB-induced apoptosis in an mTORC1-independent manner and intensifies mitochondrial ROS generation. Upon REDD1 knockout, we observe reduced levels of apoptosis inducing factor (AIF), a mitochondrial intermembrane space NADH oxidase that is required for electron transport chain Complex I biogenesis. Further, we show that keratinocyte REDD1 interacts with both AIF and the mitochondrial import protein CHCHD4, a direct binding partner of AIF that ensures functional OXPHOS. Our results support the hypothesis that REDD1 is part of a mitochondrial complex that protects cells from UVB-induced ROS toxicity and suggest novel therapeutic targets for prevention and therapy of NMSC.

Active fires show an increasing elevation trend in the tropical highlands.

As an inherent element of the Earth's ecosystem, forest, and vegetation fires are one of the key contributors to and direct consequences of climate change. Given that topography is one of the key drivers of forest landscapes and fire behavior, it is important to clarify what the topographical characteristics and trends of global fire events are, particularly in the tropics. Here, we have investigated the variations in elevation of active fires at the continental to a global scale, including the tropics, the extra-tropics, the lowlands, and the highlands (greater than 200 m above sea level [asl]), using the available MODIS Collection 6 active fire products (2001-2019). The main conclusions are: (1) the annual totality (average of 4.5 million) of global active fire events decreased and over 97% of them occurred frequently below 1500 m asl. (2) The tropics and the highlands accounted for ~74% (±3%) and 71% (±2%) of global active fires, respectively, and 77% (±2%) were observed in the tropical highlands. (3) From the beginning of the 21st century, active fires in the highlands displayed an upward elevational trend, particularly in the tropics, while the opposite trend was observed for the lowlands. More importantly, the rate of the increasing elevation in the highlands had a greater magnitude than that of decreasing elevation in the lowlands. (4) Finally, the United Nations collaborative program on Reducing Emissions from Deforestation and Forest Degradation (UN-REDD) in Developing Countries seemed to slow down or even result in a reversal of the upward elevational trend of fire occurrences in the tropics for the partner countries, especially in the lowlands. In the context of global climate change and rampant fires, the trend of rising elevation for active fire occurrences, particularly in the tropical highlands, indicates that more vegetation burning events occur or will occur in hilly to mountainous areas, thus posing further threats to tropical forests and some important biodiversity refuges. More sustained efforts should be made by governments and the scientific community to instigate enhanced fire management practices and to conduct in-depth research programs.

The role of the PTEN/mTOR axis in clinical response of rectal cancer patients.

BACKGROUND: Preoperative chemoradiotherapy has long been accepted as a method to improve survival and lifetime quality of rectal cancer patients. However, physiologic effects of these therapies largely depend on the resistance of cells to the radiation, type of chemotherapeutic agents and individual responses. As one of the signaling cascades involved in chemo- or radiation- resistance, the present study focused on several proteins involved in pTEN/Akt/mTOR pathway to explore their prognostic significance. MATERIALS AND METHODS: Samples from advanced stage rectal cancer patients were analyzed to detect expression levels of pTEN/Akt/mTOR pathway related proteins pTEN, mLST8, REDD1, BNIP3, SAG and NOXA, together with p53, by RT-qPCR. Kaplan-Meier analysis was used to assess expression-survival relation and correlations among all proteins and clinicopathological features were statistically analyzed. RESULTS: Except p53, none of the proteins showed prognostic significance. High p53 expression presented clear impact on overall survival and disease free survival. It was also significantly related to pathologic complete response. p53 showed high correlation to local recurrence as well. On the other hand, strong correlation was observed with PTEN expression and tumor response, but not with survival. High associations were also observed between mLST8/REDD1, PTEN and NOXA, confirming their role in the same cascade. CONCLUSION: The contentious role of p53 as a prognostic biomarker in colorectal cancer was further affirmed, while PTEN and REDD1 could be suggested as potential candidates. Additionally, NOXA emerges as a conjunctive element for different signaling pathways.

Modeling trade-offs across carbon sequestration, biodiversity conservation, and equity in the distribution of global REDD+ funds.

The program on Reducing Emissions from Deforestation and Forest Degradation (REDD+) is one of the major attempts to tackle climate change mitigation in developing countries. REDD+ seeks to provide result-based incentives to promote emission reductions and increase carbon sinks in forest land while promoting other cobenefits, such as the conservation of biodiversity. We model different scenarios of international REDD+ funds distribution toward potential recipient countries using 2 carbon emission reduction targets (20% and 50% compared to the baseline scenario, i.e., deforestation and forest degradation without REDD+) by 2030. The model combines the prioritization of environmental outcomes in terms of carbon sequestration and biodiversity conservation and social equity, accounting for the equitable distribution of international REDD+ funds. Results highlight the synergy between carbon sequestration and biodiversity conservation under alternative fund allocation criteria, especially for scenarios of low carbon emission reduction. Trade-offs increase when distributional equity is considered as an additional criterion, especially under higher equity requirements. The analysis helps to better understand the inherent trade-offs between enhancing distributional equity and meeting environmental targets under alternative REDD+ fund allocation options.

Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?

Regulated in Development and DNA Damage Response 1 (REDD1)/DNA Damage-Induced Transcript 4 (DDIT4) is an immediate early response gene activated by different stress conditions, including growth factor depletion, hypoxia, DNA damage, and stress hormones, i.e., glucocorticoids. The most known functions of REDD1 are the inhibition of proliferative signaling and the regulation of metabolism via the repression of the central regulator of these processes, the mammalian target of rapamycin (mTOR). The involvement of REDD1 in cell growth, apoptosis, metabolism, and oxidative stress implies its role in various pathological conditions, including cancer and inflammatory diseases. Recently, REDD1 was identified as one of the central genes mechanistically involved in undesirable atrophic effects induced by chronic topical and systemic glucocorticoids widely used for the treatment of blood cancer and inflammatory diseases. In this review, we discuss the role of REDD1 in the regulation of cell signaling and processes in normal and cancer cells, its involvement in the pathogenesis of different diseases, and the approach to safer glucocorticoid receptor (GR)-targeted therapies via a combination of glucocorticoids and REDD1 inhibitors to decrease the adverse atrophogenic effects of these steroids.