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Abstract Land‐use change is a major driver of biodiversity loss, affecting tropical forests and savannas at an unprecedented rate. To protect these ecosystems and their biodiversity, national conservation areas and international conservation funding have increased considerably in these regions. Understanding of how conservation funding allocation relates to dynamics in deforestation and conservation areas is crucial to identifying what mobilizes and distributes conservation funding. By applying fixed‐effect models on 30 years of dynamics in forest cover, conservation areas and conservation funding in the main deforestation regions of South America, we analysed the conservation funding allocation strategies in relation to deforestation (proactive vs. reactive), conservation areas (expanding or consolidating) and previous investment (agglomerating or not). We also assessed whether allocation strategies vary across regions and the stages of deforestation and conservation. We found that funding allocation followed conservation areas and higher prior funding levels over space and over time, across all regions and deforestation stages. This highlights the important role of recognized conservation areas (including protected areas and Indigenous territories) in mobilizing financial support for conservation. The allocation strategies relating to forest dynamics, however, varied depending on the scale of analysis, whether we look at the temporal or spatial dimension, and in which regions we assessed the allocation patterns. Capturing region‐level biases and within‐region dynamics is crucial for more effective and equitable conservation. As public and private actors commit to mobilizing more conservation funding and conserving more areas of the Earth, our insights on the relations between forest change and conservation efforts can help improve the allocation of conservation areas and conservation funding. Read the free Plain Language Summary for this article on the Journal blog.

Summary: Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Land-use expansion is linked to major sustainability concerns including climate change, food security and biodiversity loss. This expansion is largely concentrated in so-called ‘frontiers’, defined here as places experiencing marked transformations owing to rapid resource exploitation. Understanding the mechanisms shaping these frontiers is crucial for sustainability. Previous work focused mainly on explaining how active frontiers advance, in particular, into tropical forests. Comparatively, our understanding of how frontiers emerge in territories considered marginal in terms of agricultural productivity and global market integration remains weak. We synthesize conceptual tools explaining resource and land-use frontiers, including theories of land rent and agglomeration economies, of frontiers as successive waves, spaces of territorialization, friction and opportunities, anticipation and expectation. We then propose a new theory of frontier emergence, which identifies exogenous pushes, legacies of past waves and actors’ anticipations as key mechanisms by which frontiers emerge. Processes of differential rent creation and capture and the built-up of agglomeration economies then constitute key mechanisms sustaining active frontiers. Finally, we discuss five implications for the governance of frontiers for sustainability. Our theory focuses on agriculture and deforestation frontiers in the tropics but can be inspirational for other frontier processes including for extractive resources, such as minerals.

Abstract Carbon offsets are widely promoted as a strategy to lower the cost of emission reductions, but recent findings suggest that offsets may not causally reduce emissions by the amount claimed. In a compliance market, offsets increase net emissions if they do not reflect real emission reductions beyond the baseline scenario. Few studies have examined the additionality of forest carbon offsets within California’s U.S. Forest Projects compliance offset protocol, one of the largest forest offset programs in the world. Here we examine additionality in California’s offset protocol. Since 2012, most of California’s offset credits (84%) have been awarded to improved forest management projects. Using a database of improved forest management project characteristics, locations, and remotely sensed forest disturbance data indicative of management activity, we find that projects have been primarily allocated to forests with high carbon stocks (127% higher than regional averages) and low historical disturbance (28% less disturbance than regional averages since 1985). A matching and panel regression analysis failed to show additionality, as project creation did not significantly lower disturbance rates 3 and 5 years after project implementation relative to similar non-project lands. These results indicate that California’s forest offset protocol may contribute to an increasingly large carbon debt.

Abstract Background Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored. Methods EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo. Results In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3β, and transcription factors, including HIF1α, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo. Conclusions Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored.

A G protein-coupled receptors (GPCRs) phosphorylation assay for cell culture plates can be used for ligand profiling and inhibitor screening, as evidenced by the identification of two GRK inhibitor compounds.

Abstract Background The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months. Methods SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM). Results Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score. Conclusion Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Commodity agriculture continues to spread into tropical dry forests globally, eroding their social-ecological integrity. Understanding where deforestation frontiers expand, and which impacts this process triggers, is thus important for sustainability planning. We reconstructed past land-system change (1985–2015) and simulated alternative land-system futures (2015–2045) for the Gran Chaco, a 1.1 million km ^2 global deforestation hotspot with high biological and cultural diversity. We co-developed nine plausible future land-system scenarios, consisting of three contrasting policy narratives (Agribusiness, Ecomodernism, and Integration) and three agricultural expansion rates (high, medium, and low). We assessed the social-ecological impacts of our scenarios by comparing them with current biodiversity, carbon density, and areas used by forest-dependent people. Our analyses revealed four major insights. First, intensified agriculture and mosaics of agriculture and remaining natural vegetation have replaced large swaths of woodland since 1985. Second, simulated land-system futures until 2045 revealed potential hotspots of natural vegetation loss (e.g. western and southern Argentinian Chaco, western Paraguayan Chaco), both due to the continued expansion of existing agricultural frontiers and the emergence of new ones. Third, the strongest social-ecological impacts were consistently connected to the Agribusiness scenarios, while impacts were lower for the Ecomodernism and Integration scenarios. Scenarios based on our Integration narrative led to lower social impacts, while Ecomodernism had lower ecological impacts. Fourth, comparing recent land change with our simulations showed that 10% of the Chaco is on a pathway consistent with our Agribusiness narrative, associated with adverse social-ecological impacts. Our results highlight that much is still at stake in the Chaco. Stricter land-use and conservation planning are urgently needed to avoid adverse social-ecological outcomes, and our results charting the option space of plausible land-system futures can support such planning.

Syrian agriculture recovered after the 2007-2009 drought, before the 2011 civil conflict, according to remotely sensed data on agricultural activity in Syria, which calls into question the influence of climate stress on migration and conflict risk.

The leak tightness of the sealing system rotary shaft seal is based on the formation of an active back-pumping effect of the sealing ring. Here, the sealing ring pumps the fluid in the sealing gap back into the housing. However, this active sealing mechanism is disturbed by so-called “lead structures”. Lead structures include all types of directional structures on the sealing counterface which create rotation-dependent axial fluid pumping. Lead-affected sealing counterfaces can thus cause leakage or insufficient lubrication of the sealing contact. To ensure leak tightness, lead must be avoided or tolerated. This article investigates how different structural characteristics of lead affect the amount of fluid pumped by the shaft surface. For this purpose, 26 shafts are subjected to surface analyzing methods and an experimental pumping rate test. The interaction of various geometric features of the lead structures and their combined effect on the pumping capacity is modeled based on the measured data. Appropriated correlation models are discussed and relationships between shaft lead and its pumping effect are shown. The aim is to estimate shaft pumping rates based on surface measurements in future. The results contribute to the derivation of measurable tolerance values for lead and to the prevention of leakage.

Radial lip seals are a common seal type for various industrial applications. In retarder breaking systems for commercial vehicles, radial lip seals are exposed to very fast changing oil sump temperatures. Due to increasing demands, the elastomer seals are increasingly failing premature in such applications. It is assumed that this is caused in particular by the very high temperature gradients, that result from the fact that a lot of braking power is dissipated within a short time. This is the case, for example, when braking while driving downhill with heavy loads. Since the temperature gradient is of minor importance in many applications, there are no publications regarding the specific influence of high temperature gradients on the function of radial shaft seals. Therefore, a test rig with advanced heating and cooling capacities is developed. A comprehensive test series is carried out, with the main focus on the influence of high temperature gradients on the wear behavior of the seals. Test results show, that different temperature levels lead to a significant change of the wear behavior. Additionally, fast changing temperatures are adding additional tribological stress to the sealing system.

The function of radial sealing systems depends significantly on the shaft counterface. External cylindrical plunge grinding is considered the standard for the manufacturing of suitable shaft counterfaces. It creates a stochastic surface texture with many anisotropic groove-like grinding structures, oriented in the circumferential direction of the shaft. The structures are created by the grain engagement into the workpiece during the grinding process. This surface characteristic exhibits optimal properties for hydrodynamic lubrication between the seal and the shaft. Although there is no axial relative movement between grinding wheel and workpiece in plunge grinding, under unfavorable conditions grinding structures can be produced that deviate from the circumferential direction. These structures then transport fluid through the sealing during rotation. Structures, that cause fluid transportation because of inclined orientation to the circumferential direction, are referred to as micro lead. Especially for high rotational speeds, e.g. in electric powertrains, micro lead causes high pumping effects and therefore leakage and following failure of products. This publication presents findings on the influence of the dressing parameters on the formation of micro lead during external cylindrical plunge grinding. The experimental investigations show that especially negative dressing speed ratios lead to the formation of micro lead structures.

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb’s farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2-null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells.

Abstract Background New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). Objective To describe systematically the CSF profile in children with MOG-EM. Material and methods Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF l-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. Results Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6–256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all

Forest loss in the tropics affects large areas, but whereas full forest conversions are routinely assessed, forest degradation patters remain often unclear. This is particularly so for the world’s tropical dry forests, where remote sensing of forest disturbances is challenging due to high canopy complexity, strong phenology and climate variability, and diverse degradation drivers. Here, we used the full depth of the Landsat archive and devised an approach to detect disturbances related to forest degradation across the entire Argentine Dry Chaco (about 489,000 km2) over a 30-year timespan. We used annual time series of different spectral indices, summarized for three seasonal windows, and applied LandTrendr to temporally segment each time series. The resulting pixel-level forest disturbance metrics then served as input for a Random Forests classification which we used to produce an area-wide disturbance map, and associated yearly area estimates of disturbed forest. Finally, we evaluated disturbance trends in relation to climate and soil conditions. Our best model produced a disturbance map with an overall accuracy of 79%, with a balanced error distribution. A total of 8% (24,877 ± 860 km2) of the remaining forest in the Argentine Dry Chaco have been affected by forest disturbances between 1990 and 2017. Diverse spatial patterns of forest disturbances indicate a variety of agents driving disturbances. We also found the disturbed area to vary strongly between years, with larger areas being disturbed during drought years. Our approach shows that it is possible to robustly map forest disturbances in tropical dry forests using Landsat time series, and demonstrates the value of ensemble approaches to capture spectrally-complex and heterogeneous land-change processes. For the Chaco, a global deforestation hotspot, our analyses provide the first Landsat-based assessment of forest disturbance in remaining forests, highlighting the need to better consider such disturbances in assessments of carbon budgets and biodiversity change.

Summary: Neuroinflammation is a hallmark of neurological disorders and is accompanied by the production of neurotoxic agents such as nitric oxide. We used stem cell-based phenotypic screening and identified small molecules that directly protected neurons from neuroinflammation-induced degeneration. We demonstrate that inhibition of CDK5 is involved in, but not sufficient for, neuroprotection. Instead, additional inhibition of GSK3β is required to enhance the neuroprotective effects of CDK5 inhibition, which was confirmed using short hairpin RNA-mediated knockdown of CDK5 and GSK3β. Quantitative phosphoproteomics and high-content imaging demonstrate that neurite degeneration is mediated by aberrant phosphorylation of multiple microtubule-associated proteins. Finally, we show that our hit compound protects neurons in vivo in zebrafish models of motor neuron degeneration and Alzheimer's disease. Thus, we demonstrate an overlap of CDK5 and GSK3β in mediating the regulation of the neuronal cytoskeleton and that our hit compound LDC8 represents a promising starting point for neuroprotective drugs. : Neuroinflammation is a hallmark of many neurological disorders and can be neurotoxic. Sterneckert and colleagues perform a phenotypic screening campaign identifying compounds protecting motor neurons from inflammation. Compound profiling demonstrates that dual inhibition of CDK5 and GSK3β mediates neuroprotection. Quantitative phosphoproteomics demonstrates that neuroprotection is linked to alterations in microtubule dynamics mediated by phosphorylation of microtubule-associated proteins. Keywords: neurodegeneration, neuroinflammation, stem cell-based phenotypic screening, CDK5, GSK3β, induced pluripotent stem cells, ALS

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort.Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ

Background: Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory demyelinating disorders of the central nervous system mainly characterized by recurrent episodes of uni- or bilateral optic neuritis (ON), transverse myelitis (TM) and brainstem syndromes (BS). The majority of adult patients has serum antibodies directed against the water channel protein aquaporin 4 (AQP4-abs). In pediatric patients, AQP4-abs are less, while antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) are more frequently detectable than in adults. Some children with NMOSD have neither AQP4- nor MOG-ab (double-seronegative).Objective: Evaluation of epidemiological data regarding incidence and prevalence of pediatric NMOSD in Germany and Austria.Methods: We recruited pediatric NMOSD patients between 1 March 2017 and 28 February 2019 with five different tools: (1) ESPED (Surveillance Unit for Rare Pediatric Disorders in Germany), (2) ESNEK (Surveillance for Rare Neurological Disorders during Childhood), (3) pediatric neurology working group within the Austrian Society of Pediatrics and Adolescent Medicine, (4) BIOMARKER Study and (5) NEMOS (Neuromyelitis optica Study Group). We requested data regarding clinical symptoms, antibody status, therapy regimen and response via a standardized questionnaire.Results: During the 2-year recruitment period, 46 (both incidental and prevalent) patients with a suspected diagnosis of NMOSD were brought to our attention. Twenty-two of these patients did not fulfill the inclusion criteria. Of the remaining 24 children, 22 had a median age at onset of 11 (range 3–17) years and 16/22 were female (72.7%) (no data in two patients). Sixteen of 24 patients were AQP4-ab positive (67%), 4/24 MOG-ab positive (16.7%), three children were double-seronegative and in one patient no antibody testing was done. We calculated an incidence rate of 0.022 per 100,000 person-years for Germany, while there was no incidental case in Austria during the recruitment period. The prevalence rate was 0.147 and 0.267 per 100,000 persons in Germany and Austria, respectively.Conclusion: Pediatric NMOSD, with and without associated antibodies, are very rare even considering the different limitations of our study. An unexpected finding was that a considerable proportion of patients was tested neither for AQP4- nor MOG-abs during diagnostic work-up, which should prompt to establish and disseminate appropriate guidelines.

Agricultural expansion into tropical and subtropical forests often leads to major social-ecological trade-offs. Yet, despite ever-more detailed information on where deforestation occurs, how agriculture expands into forests remains unclear, which is hampered by a lack of spatially and temporally detailed reconstruction of agricultural expansion. Here, we developed and mapped a novel set of metrics that quantify agricultural frontier processes at unprecedented spatial and temporal detail. Specifically, we first derived consistent annual time series of land-use/cover to, second, describe archetypical patterns of frontier expansion, pertaining to the speed, the diffusion and activity of deforestation, as well as post-deforestation land use. We exemplify this approach for understanding agricultural frontier expansion across the entire South American Chaco (1.1 million km ^2 ), a global deforestation hotspot. Our study provides three major insights. First, agricultural expansion has been rampant in the Chaco, with more than 19.3 million ha of woodlands converted between 1985 and 2020, including a surge in deforestation after 2019. Second, land-use trajectories connected to frontier processes have changed in major ways over the 35 year study period we studied, including substantial regional variations. For instance, while ranching expansion drove most of the deforestation in the 1980s and 1990s, cropland expansion dominated during the mid-2000s in Argentina, but not in Paraguay. Similarly, 40% of all areas deforested were initially used for ranching, but later on converted to cropping. Accounting for post-deforestation land-use change is thus needed to properly attribute deforestation and associated environmental impacts, such as carbon emissions or biodiversity loss, to commodities. Finally, we identified major, recurrent frontier types that may be a useful spatial template for land governance to match policies to specific frontier situations. Collectively, our study reveals the diversity of frontier processes and how frontier metrics can capture and structure this diversity to uncover major patterns of human–nature interactions, which can be used to guide spatially-targeted policies.

Activation of Toll-like receptor 9 (TLR9) is known to foster innate and adaptive immune responses and thus improve immune-mediated control of malignant disease. Lefitolimod is a potent TLR9 agonist without chemical modification developed for immunotherapeutic strategies. Modulation of the tumor microenvironment (TME) is a crucial requirement for the response to various immunotherapies: Immunogenic (“hot”) tumors, characterized by their T cell-infiltrated TME, respond better compared to non-immunogenic (“cold”) tumors. It has been speculated that the mode-of-action of lefitolimod provides the necessary signals for activation of immune cells, their differentiation into anti-tumor effector cells and their recruitment into the TME. We investigated the effect of lefitolimod on TME, and its potency to induce synergistic anti-tumor effects when combined with immune checkpoint inhibitory antibodies (CPI) in a murine model. Indeed, we could show that treatment with single-agent lefitolimod beneficially modulated the TME, via infiltration of activated CD8+ cells and a shift in the macrophage population toward M1 phenotype. The result was a pronounced anti-tumor effect correlated with the magnitude of infiltrated immune cells and tumor-specific T cell responses. In line with this, lefitolimod led to persistent anti-tumor memory in the EMT-6 model after tumor re-challenge. This was accompanied by an increase of tumor-specific T cell responses and cross-reactivity against different tumor cells. Lefitolimod clearly augmented the limited anti-tumor effect of the CPI anti-PD1 in an A20 and anti-PD-L1 in a CT26 model. These properties of potent immune surveillance reactivation render lefitolimod an ideal candidate as therapeutic agent for immuno-oncology, e.g. improving CPI strategies.

Olaptesed pegol (NOX-A12) is a pegylated structured L-oligoribonucleotide that binds and neutralizes CXCL12, a chemokine tightly regulating the life cycle of chronic lymphocytic leukemia cells. The resulting inhibition of CXCR4 and CXCR7 signaling reduces the protective activity of the bone marrow and lymph node microenvironment. CXCL12 inhibition mobilizes chronic lymphocytic leukemia cells into the circulation and prevents their homing into the protective niches. In this phase I/II study, 28 patients with relapsed/refractory chronic lymphocytic leukemia were treated with olaptesed pegol in combination with bendamustine and rituximab. Combination treatment was preceded by single escalating pilot doses of olaptesed pegol in the first ten patients for evaluation of safety and pharmacokinetics. Peak concentrations and systemic exposure of olaptesed pegol were dose-linear; plasma elimination was monophasic with a 53.2 h half-life. A rapid increase in circulating chronic lymphocytic leukemia cells was observed already 1 h after administration of olaptesed pegol and lasted for at least 72 h. Single-agent treatment was well tolerated and no dose-limiting toxicity was observed. The combination regimen yielded an overall response rate of 86%, with 11% of patients achieving a complete response and 75% a partial response. Notably, all ten high-risk patients, including four with a 17p deletion, responded to treatment. The median progression-free survival was 15.4 (95% confidence interval: 12.2, 26.2) months while the median overall survival was not reached with >80% of patients alive after a median follow-up of 28 months. Olaptesed pegol was well tolerated and did not result in additional toxicity when combined with bendamustine and rituximab (ClinicalTrials.gov identifier: NCT01486797). Further clinical development of this novel CXCL12 inhibitor is thus warranted.

Water treadmill exercise has become popular in recent years for the training and rehabilitation of equine athletes. In 2019, an equine hydrotherapy working group was formed to establish what was commonly considered to be best practice in the use of the modality. This article describes the process by which general guidelines for the application of water treadmill exercise in training and rehabilitation programmes were produced by the working group. The guidelines describe the consensus reached to date on (1) the potential benefits of water treadmill exercise, (2) general good practice in water treadmill exercise, (3) introduction of horses to the exercise, (4) factors influencing selection of belt speed, water depth and duration of exercise, and (5) monitoring movement on the water treadmill. The long-term goal is to reach a consensus on the optimal use of the modality within a training or rehabilitation programme. Collaboration between clinicians, researchers and experienced users is needed to develop research programmes and further guidelines regarding the most appropriate application of the modality for specific veterinary conditions.

PDEδ is a widely expressed factor that sustains the spatial organization and signalling of Ras family proteins. Here the authors describe the activity of Deltazinone 1, a new highly selective PDEδ inhibitor of KRAS-dependent cancer cell growth with low cytotoxic side effects.

Objectives: Hirayama disease is a rare myelopathy, occurring predominantly in males with onset in the teens. Methods and results: Here, we report a young female patient who developed the first signs of Hirayama disease at 10.5 years of age. Prior to onset, she had experienced a growth spurt and grew about 8 cm. The disease progressed over 3 years and the typical clinical, electrophysiological, and neuroimaging signs of Hirayama disease were found. After this period and achievement of her final height, no further progression was noticed. Conclusions: This case highlights that pediatric neurologists should be aware of Hirayama disease, which can also occur in girls in early adolescence.

The world’s grasslands, both natural and managed, provide food and many non-provisioning ecosystem services. Although most grasslands today are used for livestock grazing or fodder production, little is known about the spatial patterns of grassland management intensity, especially at broad geographic scales. Using the European Union as a case study, we mapped mowing frequency as a key indicator of grassland management intensity. We used MODIS NDVI time series from 2000–2012 to map mowing frequency using a spline-fitting algorithm that detects up to five mowing events within a single growing season. We combined mowing frequency maps with existing maps of livestock distribution and grassland management frequency to identify clusters of similar grassland management intensity across Europe. Our results highlight generally high mowing frequency in areas of high grassland productivity, especially in Ireland, northern and central France, and the Netherlands. Our analyses also show distinct clusters of similar grassland management, representing different grassland-management intensity regimes. High intensity clusters occurred particularly in western and southern Europe, especially in Ireland, in the northern and central parts of France and Spain, and the Netherlands but also in northern and southern Germany and eastern Poland. Low intensity clusters were found mainly in central and eastern Europe and in mountainous regions but also in Extremadura in Spain, Wales and western England (UK). Generally, our analyses emphasize the usefulness of jointly using satellite time series and agricultural statistics to monitor grassland intensity across broad geographic extents. Our maps allow for a new, spatially-detailed view of management intensity in grassland systems and may help to improve regionally targeted land-use and conservation policies.

On agricultural frontiers, minimal regulation and potential windfall profits drive opportunistic land use that often results in environmental damage. Cannabis, an increasingly decriminalized agricultural commodity in many places throughout the world, may now be creating new agricultural frontiers. We examined how cannabis frontiers have boomed in northern California, one of the United States’ leading production areas. From 2012–2016 cannabis farms increased in number by 58%, cannabis plants increased by 183%, and the total area under cultivation increased by 91%. Growth in number of sites (80%), as well as in site size (56% per site) contributed to the observed expansion. Cannabis expansion took place in areas of high environmental sensitivity, including 80%–116% increases in cultivation sites near high-quality habitat for threatened and endangered salmonid fish species. Production increased by 40% on steep slopes, sites more than doubled near public lands, and increased by 44% in remote locations far from paved roads. Cannabis farm abandonment was modest, and driven primarily by farm size, not location within sensitive environments. To address policy and institutions for environmental protection, we examined state budget allocations for cannabis regulatory programs. These increased six-fold between 2012–2016 but remained very low relative to other regulatory programs. Production may expand on frontiers elsewhere in the world, and our results warn that without careful policy and institutional development these frontiers may pose environmental threats, even in locations with otherwise robust environmental laws and regulatory institutions.

Background. The causes of cerebral venous thrombosis (CVT) are manifold as is its clinical presentation. Case. We report the case of a CVT following lumbar puncture and intravenous glucocorticosteroid therapy in a female adolescent with a clinically isolated syndrome and risk factors for thrombosis. Conclusion. In adolescent patients with acute inflammatory disease undergoing lumbar puncture followed by intravenous high-dose glucocorticosteroid therapy, one should be aware of the elevated risk for thrombosis. A persistent headache with change in the headache pattern and loss of a postural component might be a sign for CVT, requiring emergency imaging of the brain.

This study was conducted according to GCP criteria as a prospective randomized cross-over study. The primary goal of the study was to determine clinical findings and patient satisfaction with postoperative treatment. 29 patients with a distal radius fracture that was surgically stabilized from volar and who met the inclusion criteria were enrolled over a 12-month period. Each patient randomly received either a dorsal plaster splint or a vacuum-fit flexible but blocked orthosis applied postoperatively in the operating theatre to achieve postoperative immobilization. After one week all patients were crossed over to the complementary device maintaining the immobilization until end of week 2. After week 2 both groups were allowed to exercise wrist mobility with a physiotherapist, in the orthosis group the device was deblocked, thus allowing limited wrist mobility. After week 4 the devices were removed in both groups. Follow-up exams were performed after postoperative weeks 1, 2, 4 and 12.Results were determined after week 1 and 2 using SF 36 and a personally compiled questionnaire; after weeks 4 and 12 with a clinical check-up, calculation of ROM and the DASH Score. Comparison of the two groups showed a significant difference in ROM for volar flexion after 4 weeks, but no significant differences in DASH Score, duration of disability or x-ray findings. With regard to satisfaction with comfort and hygiene, patients were significantly more satisfied with the dynamic orthosis, and 23 of the 29 patients would prefer the flexible vacuum orthosis in future.German Clinical Trials Register (DRKS) DRKS00006097.

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune-mediated demyelinating disease affecting mainly children and young adults. Differentiation to multiple sclerosis is not always possible, due to overlapping clinical symptoms and recurrent and multiphasic forms. Until now, immunoglobulins reactive to myelin oligodendrocyte glycoprotein (MOG antibodies) have been found in a subset of patients with ADEM. However, there are still patients lacking autoantibodies, necessitating the identification of new autoantibodies as biomarkers in those patients. Therefore, we aimed to identify novel autoantibody targets in ADEM patients. Sixteen ADEM patients (11 seronegative, 5 seropositive for MOG antibodies) were analysed for potential new biomarkers, using a protein microarray and immunohistochemistry on rat brain tissue to identify antibodies against intracellular and surface neuronal and glial antigens. Nine candidate antigens were identified in the protein microarray analysis in at least two patients per group. Immunohistochemistry on rat brain tissue did not reveal new target antigens. Although no new autoantibody targets could be found here, future studies should aim to identify new biomarkers for therapeutic and prognostic purposes. The microarray analysis and immunohistochemistry methods used here have several limitations, which should be considered in future searches for biomarkers.

Rising global demand for agricultural products results in agricultural expansion and intensification, with substantial environmental trade-offs. The South American Dry Chaco contains some of the fastest expanding agricultural frontiers worldwide, and includes diverse forms of land management, mainly associated with different land tenure regimes; which in turn are segregated along environmental gradients (mostly rainfall). Yet, how these regimes impact the environment and how trade-offs between production and environmental outcomes varies remains poorly understood. Here, we assessed how biodiversity, biomass stocks, and agricultural production, measured in meat-equivalents, differ among land tenure regimes in the Dry Chaco. We calculated a land-use outcome index (LUO) that combines indices comparing actual vs. potential values of ‘preservation of biodiversity’ (PI), ‘standing biomass’ (BI) and ‘meat production’ (MI). We found land-use outcomes to vary substantially among land-tenure regimes. Protected areas showed a biodiversity index of 0.75, similar to that of large and medium-sized farms (0.72 in both farming systems), and higher than in the other tenure regimes. Biomass index was similar among land tenure regimes, whereas we found the highest median meat production index on indigenous lands (MI = 0.35). Land-use outcomes, however, varied more across different environmental conditions than across land tenure regimes. Our results suggest that in the Argentine Dry Chaco, there is no single land tenure regime that better minimizes the trade-offs between production and environmental outcomes. A useful approach to manage these trade-offs would be to develop geographically explicit guidelines for land-use zoning, identifying the land tenure regimes more appropriate for each zone.

Higher biodiversity leads to more productive ecosystems which, in turn, supports more biodiversity. Ongoing global changes affect ecosystem productivity and, therefore, are expected to affect productivity-biodiversity relationships. However, the magnitude of these relationships may be affected by baseline biodiversity and its lifeforms. Cork oak (Quercus suber) woodlands are a highly biodiverse Mediterranean ecosystem managed for cork extraction; as a result of this management cork oak woodlands may have both tree and shrub canopies, just tree and just shrub canopies, and just grasslands. Trees, shrubs, and grasses may respond differently to climatic variables and their combination may, therefore, affect measurements of productivity and the resulting productivity-biodiversity relationships. Here, we asked whether the relationship between productivity and climate is affected by the responses of trees, shrubs, and grasses in cork oak woodlands in Southern Portugal. To answer this question, we linked a 15-year time series of Enhanced Vegetation Index (EVI) derived from Landsat satellites to micrometeorological data to assess the relationship between trends in EVI and climate. Between 2000 and 2013 we observed an overall decrease in EVI. However, EVI increased over cork oaks and decreased over shrublands. EVI trends were strongly positively related to changes in relative humidity and negatively related to temperature. The intra-annual EVI cycle of grasslands and sparse cork oak woodland without understorey (savannah-like ecosystem) had higher variation than the other land-cover types. These results suggest that oaks and shrubs have different responses to changes in water availability, which can be either related to oak physiology, to oaks being either more resilient or having lagged responses to changes in climate, or to the fact that shrublands start senesce earlier than oaks. Our results also suggest that in the future EVI could improve because the rate of increase in minimum EVI is greater than the rate of decrease in maximum EVI, and that this is contingent on management of the shrub understorey as it affects the rate of decrease in maximum EVI. This will be the challenge for the persistence of cork oak woodlands, their associated biodiversity and social-ecological system.

Global agricultural production will likely need to increase in the future due to population growth, changing diets, and the rising importance of bioenergy. Intensifying already existing cropland is often considered more sustainable than converting more natural areas. Unfortunately, our understanding of cropping patterns and intensity is weak, especially at broad geographic scales. We characterized and mapped cropping systems in Europe, a region containing diverse cropping systems, using four indicators: (a) cropping frequency (number of cropped years), (b) multi-cropping (number of harvests per year), (c) fallow cycles, and (d) crop duration ratio (actual time under crops) based on the MODIS Normalized Difference Vegetation Index (NDVI) time series from 2000 to 2012. Second, we used these cropping indicators and self-organizing maps to identify typical cropping systems. The resulting six clusters correspond well with other indicators of agricultural intensity (e.g., nitrogen input, yields) and reveal substantial differences in cropping intensity across Europe. Cropping intensity was highest in Germany, Poland, and the eastern European Black Earth regions, characterized by high cropping frequency, multi-cropping and a high crop duration ratio. Contrarily, we found lowest cropping intensity in eastern Europe outside the Black Earth region, characterized by longer fallow cycles. Our approach highlights how satellite image time series can help to characterize spatial patterns in cropping intensity—information that is rarely surveyed on the ground and commonly not included in agricultural statistics: our clustering approach also shows a way forward to reduce complexity when measuring multiple indicators. The four cropping indicators we used could become part of continental-scale agricultural monitoring in order to identify target regions for sustainable intensification, where trade-offs between intensification and the environmental should be explored.

The wealth of complementary data available from remote sensing missions can hugely aid efforts towards accurately determining land use and quantifying subtle changes in land use management or intensity. This study reviewed 112 studies on fusing optical and radar data, which offer unique spectral and structural information, for land cover and use assessments. Contrary to our expectations, only 50 studies specifically addressed land use, and five assessed land use changes, while the majority addressed land cover. The advantages of fusion for land use analysis were assessed in 32 studies, and a large majority (28 studies) concluded that fusion improved results compared to using single data sources. Study sites were small, frequently 300–3000 km 2 or individual plots, with a lack of comparison of results and accuracies across sites. Although a variety of fusion techniques were used, pre-classification fusion followed by pixel-level inputs in traditional classification algorithms (e.g., Gaussian maximum likelihood classification) was common, but often without a concrete rationale on the applicability of the method to the land use theme being studied. Progress in this field of research requires the development of robust techniques of fusion to map the intricacies of land uses and changes therein and systematic procedures to assess the benefits of fusion over larger spatial scales.

The demand for agricultural products continues to grow rapidly, but further agricultural expansion entails substantial environmental costs, making recultivating currently unused farmland an interesting alternative. The collapse of the Soviet Union in 1991 led to widespread abandonment of agricultural lands, but the extent and spatial patterns of abandonment are unclear. We quantified the extent of abandoned farmland, both croplands and pastures, across the region using MODIS NDVI satellite image time series from 2004 to 2006 and support vector machine classifications. Abandoned farmland was widespread, totaling 52.5 Mha, particularly in temperate European Russia (32 Mha), northern and western Ukraine, and Belarus. Differences in abandonment rates among countries were striking, suggesting that institutional and socio-economic factors were more important in determining the amount of abandonment than biophysical conditions. Indeed, much abandoned farmland occurred in areas without major constraints for agriculture. Our map provides a basis for assessing the potential of Central and Eastern Europe’s abandoned agricultural lands to contribute to food or bioenergy production, or carbon storage, as well as the environmental trade-offs and social constraints of recultivation.