Application of a Coupled Vegetation Competition and Groundwater Simulation Model to Study Effects of Sea Level Rise and Storm Surges on Coastal Vegetation

Global climate change poses challenges to areas such as low-lying coastal zones, where sea level rise (SLR) and storm-surge overwash events can have long-term effects on vegetation and on soil and groundwater salinities, posing risks of habitat loss critical to native species. An early warning system is urgently needed to predict and prepare for the consequences of these climate-related impacts on both the short-term dynamics of salinity in the soil and groundwater and the long-term effects on vegetation. For this purpose, the U.S. Geological Survey’s spatially explicit model of vegetation community dynamics along coastal salinity gradients (MANHAM) is integrated into the USGS groundwater model (SUTRA) to create a coupled hydrology–salinity–vegetation model, MANTRA. In MANTRA, the uptake of water by plants is modeled as a fluid mass sink term. Groundwater salinity, water saturation and vegetation biomass determine the water available for plant transpiration. Formulations and assumptions used in the coupled model are presented. MANTRA is calibrated with salinity data and vegetation pattern for a coastal area of Florida Everglades vulnerable to storm surges. A possible regime shift at that site is investigated by simulating the vegetation responses to climate variability and disturbances, including SLR and storm surges based on empirical information

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President\u27s Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report

Generating operative workflows for vestibular schwannoma resection: a two-stage Delphi consensus in collaboration with British Skull Base Society. Part 1: the retrosigmoid approach

Objective: An operative workflow systematically compartmentalises operations into hierarchal components of phases, steps, instrument, technique errors and event errors. Operative workflow provides a foundation for education, training, and understanding of surgical variation. In Part 1 we present a codified operative workflow for the retrosigmoid approach to vestibular schwannoma resection. / Methods: A mixed-method consensus process of literature review, small group Delphi consensus, followed by a national Delphi consensus was performed in collaboration with British Skull Base Society (BSBS). Each Delphi round was repeated until data saturation and over 90% consensus was reached. / Results: Eighteen consultant skull base surgeons (10 neurosurgeons; 8 ENT) with median 17.9 years of experience (IQR 17.5 years) of independent practice participated. There was a 100% response rate across both Delphi rounds. The operative workflow for the retrosigmoid approach contained 3 phases and 40 unique steps: Phase 1: approach and exposure; Phase 2: tumour debulking and excision; Phase 3: closure. For the retrosigmoid approach, technique and event error for each operative step was also described. / Conclusions: We present Part 1 of a national, multi-centre, consensus-derived codified operative workflow for the retrosigmoid and approach to vestibular schwannomas that encompasses phases, steps, instruments, technique errors, and event errors. The codified retrosigmoid approach presented in this manuscript can serve as foundational research for future work, such as operative workflow analysis or neurosurgical simulation and education

Generating Operative Workflows for Vestibular Schwannoma Resection: A Two-Stage Delphi's Consensus in Collaboration with the British Skull Base Society. Part 2: The Translabyrinthine Approach

Objective An operative workflow systematically compartmentalizes operations into hierarchal components of phases, steps, instrument, technique errors, and event errors. Operative workflow provides a foundation for education, training, and understanding of surgical variation. In this Part 2, we present a codified operative workflow for the translabyrinthine approach to vestibular schwannoma resection. Methods A mixed-method consensus process of literature review, small-group Delphi's consensus, followed by a national Delphi's consensus was performed in collaboration with British Skull Base Society (BSBS). Each Delphi's round was repeated until data saturation and over 90% consensus was reached. Results Seventeen consultant skull base surgeons (nine neurosurgeons and eight ENT [ear, nose, and throat]) with median of 13.9 years of experience (interquartile range: 18.1 years) of independent practice participated. There was a 100% response rate across both the Delphi rounds. The translabyrinthine approach had the following five phases and 57 unique steps: Phase 1, approach and exposure; Phase 2, mastoidectomy; Phase 3, internal auditory canal and dural opening; Phase 4, tumor debulking and excision; and Phase 5, closure. Conclusion We present Part 2 of a national, multicenter, consensus-derived, codified operative workflow for the translabyrinthine approach to vestibular schwannomas. The five phases contain the operative, steps, instruments, technique errors, and event errors. The codified translabyrinthine approach presented in this manuscript can serve as foundational research for future work, such as the application of artificial intelligence to vestibular schwannoma resection and comparative surgical research

Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

Thyroid hormones (THs) 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) are important regulators of the metabolism and physiology of most normal tissues.Cytochrome P450 family 3A members are drug metabolizing enzymes involved in theactivation and detoxification of several drugs. CYP3A4 is the major enzyme involvedin the metabolism of chemotherapeutic drugs. In this work, we demonstrate thatTHs induce a significant increase in CYP3A4 mRNA levels, protein expression andmetabolic activity through the membrane receptor integrin αvβ3 and the activation ofsignalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4modulation may act as an important regulator in the metabolism of doxorubicin(Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, noTH-mediated chemosensitivity to Doxo was observed. We also found that THs modulatethese functions by activating the membrane receptor integrin αvβ3. In addition, weshowed that the thyroid status can modulate CYP450 mRNA levels in tumor and livertissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxotreatment in hypothyroid mice was associated with lower tumors, displaying lowerlevels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYPenzymes were found in livers from Doxo treated hypothyroid mice respect to control.These results present a new mechanism by which TH could modulate chemotherapyresponse. These findings highlight the importance of evaluating thyroid status inpatients during application of T-cell lymphoma therapeutic regimens.Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Aschero, María del Rosario. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Isse, Blanca Alicia de Los Angeles G.. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; ArgentinaFil: Farias, Ricardo Norberto. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados UnidosFil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

PGE2 alters chromatin through H2A.Z-variant enhancer nucleosome modification to promote hematopoietic stem cell fate

Prostaglandin E2 (PGE2) and 16,16-dimethyl-PGE2 (dmPGE2) are important regulators of hematopoietic stem and progenitor cell (HSPC) fate and offer potential to enhance stem cell therapies [C. Cutler et al. Blood 122, 3074–3081(2013); W. Goessling et al. Cell Stem Cell 8, 445–458 (2011); W. Goessling et al. Cell 136, 1136–1147 (2009)]. Here, we report that PGE2-induced changes in chromatin at enhancer regions through histone-variant H2A.Z permit acute inflammatory gene induction to promote HSPC fate. We found that dmPGE2-inducible enhancers retain MNase-accessible, H2A.Z-variant nucleosomes permissive of CREB transcription factor (TF) binding. CREB binding to enhancer nucleosomes following dmPGE2 stimulation is concomitant with deposition of histone acetyltransferases p300 and Tip60 on chromatin. Subsequent H2A.Z acetylation improves chromatin accessibility at stimuli-responsive enhancers. Our findings support a model where histone-variant nucleosomes retained within inducible enhancers facilitate TF binding. Histone-variant acetylation by TF-associated nucleosome remodelers creates the accessible nucleosome landscape required for immediate enhancer activation and gene induction. Our work provides a mechanism through which inflammatory mediators, such as dmPGE2, lead to acute transcriptional changes and modify HSPC behavior to improve stem cell transplantation

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma

Are specialists at risk under environmental change? Neoecological, paleoecological and phylogenetic approaches

The question ‘what renders a species extinction prone’ is crucial to biologists. Ecological specialization has been suggested as a major constraint impeding the response of species to environmental changes. Most neoecological studies indicate that specialists suffer declines under recent environmental changes. This was confirmed by many paleoecological studies investigating longer-term survival. However, phylogeneticists, studying the entire histories of lineages, showed that specialists are not trapped in evolutionary dead ends and could even give rise to generalists. Conclusions from these approaches diverge possibly because (i) of approach-specific biases, such as lack of standardization for sampling efforts (neoecology), lack of direct observations of specialization (paleoecology), or binary coding and prevalence of specialists (phylogenetics); (ii) neoecologists focus on habitat specialization; (iii) neoecologists focus on extinction of populations, phylogeneticists on persistence of entire clades through periods of varying extinction and speciation rates; (iv) many phylogeneticists study species in which specialization may result from a lack of constraints. We recommend integrating the three approaches by studying common datasets, and accounting for range-size variation among species, and we suggest novel hypotheses on why certain specialists may not be particularly at risk and consequently why certain generalists deserve no less attention from conservationists than specialists

Detecting ‘poachers’ with drones: Factors influencing the probability of detection with TIR and RGB imaging in miombo woodlands, Tanzania

Conservation biologists increasingly employ drones to reduce poaching of animals. However, there are no published studies on the probability of detecting poachers and the factors influencing detection. In an experimental setting with voluntary subjects, we evaluated the influence of various factors on poacher detection probability: camera (visual spectrum: RGB and thermal infrared: TIR), density of canopy cover, subject distance from the image centreline, subject contrast against the background, altitude of the drone and image analyst. We manually analysed the footage and marked all recorded subject detections. A multilevel model was used to analyse the TIR image data and a general linear model approach was used for the RGB image data. We found that the TIR camera had a higher detection probability than the RGB camera. Detection probability in TIR images was significantly influenced by canopy density, subject distance from the centreline and the analyst. Detection probability in RGB images was significantly influenced by canopy density, subject contrast against the background, altitude and the analyst. Overall, our findings indicate that TIR cameras improve human detection, particularly at cooler times of the day, but this is significantly hampered by thick vegetation cover. The effects of diminished detection with increased distance from the image centreline can be improved by increasing the overlap between images although this requires more flights over a specific area. Analyst experience also contributed to increased detection probability, but this might cease being a problem following the development of automated detection using machine learning

A HIF-independent, CD133-mediated mechanism of cisplatin resistance in glioblastoma cells

Purpose Glioblastoma Multiforme (GBM) is the commonest brain tumour in adults. A population of cells, known as cancer stem cells (CSCs), is thought to mediate chemo/radiotherapy resistance. CD133 is a cell surface marker to identify and isolate CSCs. However, its functional significance and the relevant microenvironment in which to study CD133 remain unknown. We examined the influence of hypoxia on CD133 expression and the potential functional significance of CD133 in glioblastoma chemoresistance. Methods Gene expression was analysed by qRT-PCR. siRNA technique was used to downregulate genes and confirmed by flow cytometry. IC50 values was evaluated with the Alamar blue assay. Results CD133 expression was upregulated in hypoxia in 2D and 3D models. There was increased resistance to chemotherapeutics, cisplatin, temozolomide and etoposide, in cells cultured in hypoxia compared to normoxia. siRNA knockdown of either HIF1a or HIF2a resulted in reduced CD133 mRNA expression with HIF2a having a more prolonged effect on CD133 expression. HIF2a downregulation sensitized GBM cells to cisplatin to a greater extent than HIF1a but CD133 knockdown had a much more marked effect on cisplatin sensitisation than knockdown of either of the HIFs suggesting a HIF-independent mechanism of cisplatin resistance mediated via CD133. The same mechanism was not involved in temozolomide resistance since downregulation of HIF1a but not HIF2a or CD133 sensitized GBM cells to temozolomide. Conclusion Knowledge of the mechanisms involved in the novel hypoxia-induced CD133-mediated resistance to cisplatin observed might lead to identification of new strategies that enable more effective use of current therapeutic agents