Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy

Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellent target during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect of radiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes of HIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cells were reoxygenated 6 h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1α and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1α accumulated in the reoxygenated regions 24 h postirradiation. Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increase in tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressed the effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation of HIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation of HIF-1 activity is important for the best therapeutic benefit

Differential Effects of HIF-1 Inhibition by YC-1 on the Overall Outcome and Blood-Brain Barrier Damage in a Rat Model of Ischemic Stroke

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular adaptation to hypoxia and has been suggested as a potent therapeutic target in cerebral ischemia. Here we show in an ischemic stroke model of rats that inhibiting HIF-1 and its downstream genes by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) significantly increases mortality and enlarges infarct volume evaluated by MRI and histological staining. Interestingly, the HIF-1 inhibition remarkably ameliorates ischemia-induced blood-brain barrier (BBB) disruption determined by Evans blue leakage although it does not affect brain edema. The result demonstrates that HIF-1 inhibition has differential effects on ischemic outcomes and BBB permeability. It indicates that HIF-1 may have different functions in different brain cells. Further analyses show that ischemia upregulates HIF-1 and its downstream genes erythropoietin (EPO), vascular endothelial growth factor (VEGF), and glucose transporter (Glut) in neurons and brain endothelial cells and that YC-1 inhibits their expression. We postulate that HIF-1-induced VEGF increases BBB permeability while certain other proteins coded by HIF-1's downstream genes such as epo and glut provide neuroprotection in an ischemic brain. The results indicate that YC-1 lacks the potential as a cerebral ischemic treatment although it confers certain protection to the cerebral vascular system

Phase II Trial of Concurrent Sunitinib and Image-Guided Radiotherapy for Oligometastases

BACKGROUND: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. METHODS: Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). RESULTS: The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. CONCLUSIONS: Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00463060

Human Telomerase Reverse Transcriptase (hTERT) Q169 Is Essential for Telomerase Function In Vitro and In Vivo

BACKGROUND:Telomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA-binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS:To understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non-conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function. CONCLUSIONS/SIGNIFICANCE:We provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention

Monitoring and Scoring Counter-Diffusion Protein Crystallization Experiments in Capillaries by in situ Dynamic Light Scattering

In this paper, we demonstrate the feasibility of using in situ Dynamic Light Scattering (DLS) to monitor counter-diffusion crystallization experiments in capillaries. Firstly, we have validated the quality of the DLS signal in thin capillaries, which is comparable to that obtained in standard quartz cuvettes. Then, we have carried out DLS measurements of a counter-diffusion crystallization experiment of glucose isomerase in capillaries of different diameters (0.1, 0.2 and 0.3 mm) in order to follow the temporal evolution of protein supersaturation. Finally, we have compared DLS data with optical recordings of the progression of the crystallization front and with a simulation model of counter-diffusion in 1D

Contrasting patterns of evolutionary constraint and novelty revealed by comparative sperm proteomic analysis in Lepidoptera

Background: Rapid evolution is a hallmark of reproductive genetic systems and arises through the combined processes of sequence divergence, gene gain and loss, and changes in gene and protein expression. While studies aiming to disentangle the molecular ramifications of these processes are progressing, we still know little about the genetic basis of evolutionary transitions in reproductive systems. Here we conduct the first comparative analysis of sperm proteomes in Lepidoptera, a group that exhibits dichotomous spermatogenesis, in which males produce a functional fertilization-competent sperm (eupyrene) and an incompetent sperm morph lacking nuclear DNA (apyrene). Through the integrated application of evolutionary proteomics and genomics, we characterize the genomic patterns potentially associated with the origination and evolution of this unique spermatogenic process and assess the importance of genetic novelty in Lepidopteran sperm biology. Results: Comparison of the newly characterized Monarch butterfly (Danaus plexippus) sperm proteome to those of the Carolina sphinx moth (Manduca sexta) and the fruit fly (Drosophila melanogaster) demonstrated conservation at the level of protein abundance and post-translational modification within Lepidoptera. In contrast, comparative genomic analyses across insects reveals significant divergence at two levels that differentiate the genetic architecture of sperm in Lepidoptera from other insects. First, a significant reduction in orthology among Monarch sperm genes relative to the remainder of the genome in non-Lepidopteran insect species was observed. Second, a substantial number of sperm proteins were found to be specific to Lepidoptera, in that they lack detectable homology to the genomes of more distantly related insects. Lastly, the functional importance of Lepidoptera specific sperm proteins is broadly supported by their increased abundance relative to proteins conserved across insects. Conclusions: Our results identify a burst of genetic novelty amongst sperm proteins that may be associated with the origin of heteromorphic spermatogenesis in ancestral Lepidoptera and/or the subsequent evolution of this system. This pattern of genomic diversification is distinct from the remainder of the genome and thus suggests that this transition has had a marked impact on lepidopteran genome evolution. The identification of abundant sperm proteins unique to Lepidoptera, including proteins distinct between specific lineages, will accelerate future functional studies aiming to understand the developmental origin of dichotomous spermatogenesis and the functional diversification of the fertilization incompetent apyrene sperm morph

Stochastic upscaling of hydrodynamic dispersion and retardation factor in a physically and chemically heterogeneous tropical soil

[EN] Stochastic upscaling of flow and reactive solute transport in a tropical soil is performed using real data collected in the laboratory. Upscaling of hydraulic conductivity, longitudinal hydrodynamic dispersion, and retardation factor were done using three different approaches of varying complexity. How uncertainty propagates after upscaling was also studied. The results show that upscaling must be taken into account if a good reproduction of the flow and transport behavior of a given soil is to be attained when modeled at larger than laboratory scales. The results also show that arrival time uncertainty was well reproduced after solute transport upscaling. This work represents a first demonstration of flow and reactive transport upscaling in a soil based on laboratory data. It also shows how simple upscaling methods can be incorporated into daily modeling practice using commercial flow and transport codes.The authors thank the financial support by the Brazilian National Council for Scientific and Technological Development (CNPq) (Project 401441/2014-8). The doctoral fellowship award to the first author by the Coordination of Improvement of Higher Level Personnel (CAPES) is acknowledged. The first author also thanks the international mobility grant awarded by CNPq, through the Sciences Without Borders program (Grant Number: 200597/2015-9). The international mobility grant awarded by Santander Mobility in cooperation with the University of Sao Paulo is also acknowledged. DHI-WASI is gratefully thanked for providing a FEFLOW license.Almeida De-Godoy, V.; Zuquette, L.; Gómez-Hernández, JJ. (2019). Stochastic upscaling of hydrodynamic dispersion and retardation factor in a physically and chemically heterogeneous tropical soil. Stochastic Environmental Research and Risk Assessment. 33(1):201-216. https://doi.org/10.1007/s00477-018-1624-zS201216331Ahuja LR, Naney JW, Green RE, Nielsen DR (1984) Macroporosity to characterize spatial variability of hydraulic conductivity and effects of land management. Soil Sci Soc Am J 48:699. https://doi.org/10.2136/sssaj1984.03615995004800040001xBellin A, Lawrence AE, Rubin Y (2004) Models of sub-grid variability in numerical simulations of solute transport in heterogeneous porous formations: three-dimensional flow and effect of pore-scale dispersion. Stoch Environ Res Risk Assess 18:31–38. https://doi.org/10.1007/s00477-003-0164-2Brent RP (1973) Algorithms for minimization without derivatives. Prentice Hall, Englewood CliffsBrusseau ML (1998) Non-ideal transport of reactive solutes in heterogeneous porous media: 3. model testing and data analysis using calibration versus prediction. J Hydrol 209:147–165. https://doi.org/10.1016/S0022-1694(98)00121-8Brusseau ML, Srivastava R (1999) Nonideal transport of reactive solutes in heterogeneous porous media: 4. Analysis of the cape cod natural-gradient field experiment. Water Resour Res 35:1113–1125. https://doi.org/10.1029/1998WR900019Brutsaert W (1967) Some methods of calculating unsaturated permeability. Trans ASAE 10:400–404Cadini F, De Sanctis J, Bertoli I, Zio E (2013) Upscaling of a dual-permeability Monte Carlo simulation model for contaminant transport in fractured networks by genetic algorithm parameter identification. Stoch Environ Res Risk Assess 27:505–516. https://doi.org/10.1007/s00477-012-0595-8Cambardella CA, Moorman TB, Parkin TB, Karlen DL, Novak JM, Turco RF, Konopka AE (1994) Field-scale variability of soil properties in central iowa soils. Soil Sci Soc Am J 58:1501. https://doi.org/10.2136/sssaj1994.03615995005800050033xCapilla JE, Rodrigo J, Gómez-Hernández JJ (1999) Simulation of non-Gaussian transmissivity fields honoring piezometric data and integrating soft and secondary information. Math Geol 31:907–927. https://doi.org/10.1023/A:1007580902175Cassiraga EF, Fernàndez-Garcia D, Gómez-Hernández JJ (2005) Performance assessment of solute transport upscaling methods in the context of nuclear waste disposal. Int J Rock Mech Min Sci 42:756–764. https://doi.org/10.1016/j.ijrmms.2005.03.013Corey AT (1977) Mechanics of heterogeneous fluids in porous media. Water Resources Publications, Fort Collins, CO, p 259Dagan G (1989) Flow and transport in porous formations. Springer, Berlin. https://doi.org/10.1007/978-3-642-75015-1Dagan G (2004) On application of stochastic modeling of groundwater flow and transport. Stoch Environ Res Risk Assess. https://doi.org/10.1007/s00477-004-0191-7de Azevedo AAB, Pressinotti MMN, Massoli M (1981) Sedimentological studies of the Botucatu and Pirambóia formations in the region of Santa Rita do Passa Quatro (In portuguese). Rev do Inst Geológico 2:31–38. https://doi.org/10.5935/0100-929X.19810003Deng H, Dai Z, Wolfsberg AV, Ye M, Stauffer PH, Lu Z, Kwicklis E (2013) Upscaling retardation factor in hierarchical porous media with multimodal reactive mineral facies. Chemosphere 91:248–257. https://doi.org/10.1016/j.chemosphere.2012.10.105Diersch H-JG (2014) Finite element modeling of flow, mass and heat transport in porous and fractured media. Springer, Berlin. https://doi.org/10.1007/978-3-642-38739-5Dippenaar MA (2014) Porosity reviewed: quantitative multi-disciplinary understanding, recent advances and applications in vadose zone hydrology. Geotech Geol Eng 32:1–19. https://doi.org/10.1007/s10706-013-9704-9Fagundes JRT, Zuquette LV (2011) Sorption behavior of the sandy residual unconsolidated materials from the sandstones of the Botucatu Formation, the main aquifer of Brazil. Environ Earth Sci 62:831–845. https://doi.org/10.1007/s12665-010-0570-yFenton GA, Griffiths DV (2008) Risk assessment in geotechnical engineering. Wiley, p 463Fernàndez-Garcia D, Gómez-Hernández JJ (2007) Impact of upscaling on solute transport: Traveltimes, scale dependence of dispersivity, and propagation of uncertainty. Water Resour Res. https://doi.org/10.1029/2005WR004727Fernàndez-Garcia D, Llerar-Meza G, Gómez-Hernández JJ (2009) Upscaling transport with mass transfer models: mean behavior and propagation of uncertainty. Water Resour Res. https://doi.org/10.1029/2009WR007764Feyen L, Gómez-Hernández JJ, Ribeiro PJ, Beven KJ, De Smedt F (2003a) A Bayesian approach to stochastic capture zone delineation incorporating tracer arrival times, conductivity measurements, and hydraulic head observations. Water Resour Res. https://doi.org/10.1029/2002WR001544Feyen L, Ribeiro PJ, Gómez-Hernández JJ, Beven KJ, De Smedt F (2003b) Bayesian methodology for stochastic capture zone delineation incorporating transmissivity measurements and hydraulic head observations. J Hydrol 271:156–170. https://doi.org/10.1016/S0022-1694(02)00314-1Forsythe GE, Malcolm MA, Moler CB (1976) Computer methods for mathematical computations. Prentice-Hall, Englewood Cliffs, p 259Freeze R, Cherry J (1979) Groundwater. PrenticeHall Inc, Englewood cliffs, p 604Frippiat CC, Holeyman AE (2008) A comparative review of upscaling methods for solute transport in heterogeneous porous media. J Hydrol 362:150–176. https://doi.org/10.1016/j.jhydrol.2008.08.015Fu J, Gómez-Hernández JJ (2009) Uncertainty assessment and data worth in groundwater flow and mass transport modeling using a blocking Markov chain Monte Carlo method. J Hydrol 364:328–341. https://doi.org/10.1016/j.jhydrol.2008.11.014Gelhar LW, Axness CL (1983) Three-dimensional stochastic analysis of macrodispersion in aquifers. Water Resour Res 19:161–180. https://doi.org/10.1029/WR019i001p00161Gelhar LW, Welty C, Rehfeldt KR (1992) A critical review of data on field-scale dispersion in aquifers. Water Resour Res 28:1955–1974. https://doi.org/10.1029/92WR00607Giacheti HL, Rohm SA, Nogueira JB, Cintra JCA (1993) Geotechnical properties of the Cenozoic sediment (in protuguese). In: Albiero JH, Cintra JCA (eds) Soil from the interior of São Paulo. ABMS, Sao Paulo, pp 143–175Gómez-Hernandez JJ (1990) A stochastic approach to the simulation of block conductivity fields conditional upon data measured at a smaller scale. Stanford University, StanfordGómez-Hernández JJ, Gorelick SM (1989) Effective groundwater model parameter values: influence of spatial variabiity of hydraulic conductivity, leackance, and recharge. Water Resour Res 25:405–419Gómez-Hernández JJ, Journel A (1993) Joint sequential simulation of multigaussian fields. In: Geostatistics Tróia’92. pp 85–94. https://doi.org/10.1007/978-94-011-1739-5_8Gómez-Hernández JJ, Wen X-H (1994) Probabilistic assessment of travel times in groundwater modeling. Stoch Hydrol Hydraul 8:19–55. https://doi.org/10.1007/BF01581389Gómez-Hernández JJ, Fu J, Fernandez-Garcia D (2006) Upscaling retardation factors in 2-D porous media. In: Bierkens MFP, Gehrels JC, Kovar K (eds) Calibration and reliability in groundwater modelling: from uncertainty to decision making: proceedings of the ModelCARE 2005 conference held in The Hague, The Netherlands, 6–9 June, 2005. IAHS Publication, pp 130–136Goovaerts P (1999) Geostatistics in soil science: state-of-the-art and perspectives. Geoderma 89:1–45. https://doi.org/10.1016/S0016-7061(98)00078-0Jarvis NJ (2007) A review of non-equilibrium water fl ow and solute transport in soil macropores: principles, controlling factors and consequences for water quality. Eur J Soil Sci 58:523–546. https://doi.org/10.4141/cjss2011-050Jellali S, Diamantopoulos E, Kallali H, Bennaceur S, Anane M, Jedidi N (2010) Dynamic sorption of ammonium by sandy soil in fixed bed columns: evaluation of equilibrium and non-equilibrium transport processes. J Environ Manag 91:897–905. https://doi.org/10.1016/j.jenvman.2009.11.006Journel AG, Gomez-Hernandez JJ (1993) Stochastic imaging of the wilmington clastic sequence. SPE Form Eval 8:33–40. https://doi.org/10.2118/19857-PAJournel A, Deutsch C, Desbarats A (1986) Power averaging for block effective permeability. Proc SPE Calif Reg Meet. https://doi.org/10.2118/15128-MSKronberg BI, Fyfe WS, Leonardos OH, Santos AM (1979) The chemistry of some Brazilian soils: element mobility during intense weathering. Chem Geol 24:211–229. https://doi.org/10.1016/0009-2541(79)90124-4Lake LW (1988) The origins of anisotropy (includes associated papers 18394 and 18458). J Pet Technol 40:395–396. https://doi.org/10.2118/17652-PALawrence AE, Rubin Y (2007) Block-effective macrodispersion for numerical simulations of sorbing solute transport in heterogeneous porous formations. Adv Water Resour 30:1272–1285. https://doi.org/10.1016/j.advwatres.2006.11.005Lemke LD, Barrack WA II, Abriola LM, Goovaerts P (2004) Matching solute breakthrough with deterministic and stochastic aquifer models. Groundwater 42:920–934Li L, Zhou H, Gómez-Hernández JJ (2011a) A comparative study of three-dimensional hydraulic conductivity upscaling at the macro-dispersion experiment (MADE) site, Columbus Air Force Base, Mississippi (USA). J Hydrol 404:278–293. https://doi.org/10.1016/j.jhydrol.2011.05.001Li L, Zhou H, Gómez-Hernández JJ (2011b) Transport upscaling using multi-rate mass transfer in three-dimensional highly heterogeneous porous media. Adv Water Resour 34:478–489. https://doi.org/10.1016/j.advwatres.2011.01.001Logsdon Keller KE, Moorman TB (2002) Measured and predicted solute leaching from multiple undisturbed soil columns. Soil Sci Soc Am J 66:686–695. https://doi.org/10.2136/sssaj2002.6860Lourens A, van Geer FC (2016) Uncertainty propagation of arbitrary probability density functions applied to upscaling of transmissivities. Stoch Environ Res Risk Assess 30:237–249. https://doi.org/10.1007/s00477-015-1075-8Mahapatra IC, Singh KN, Pillai KG, Bapat SR (1985) Rice soils and their management. Indian J Agron 30:R1–R41Morakinyo JA, Mackay R (2006) Geostatistical modelling of ground conditions to support the assessment of site contamination. Stoch Environ Res Risk Assess 20:106–118. https://doi.org/10.1007/s00477-005-0015-4Moslehi M, de Barros FPJ, Ebrahimi F, Sahimi M (2016) Upscaling of solute transport in disordered porous media by wavelet transformations. Adv Water Resour 96:180–189. https://doi.org/10.1016/j.advwatres.2016.07.013Osinubi KJ, Nwaiwu CM (2005) Hydraulic conductivity of compacted lateritic soil. J Geotech Geoenviron Eng 131:1034–1041. https://doi.org/10.1061/(ASCE)1090-0241(2005)131:8(1034)Remy N (2004) SGeMS: stanford geostatistical modeling software. Softw Man. https://doi.org/10.1007/978-1-4020-3610-1_89Renard P, de Marsily G (1997) Calculating equivalent permeability: a review. Adv Water Resour 20:253–278. https://doi.org/10.1016/S0309-1708(96)00050-4Robin MJL, Sudicky EA, Gillham RW, Kachanoski RG (1991) Spatial variability of strontium distribution coefficients and their correlation with hydraulic conductivity in the Canadian forces base borden aquifer. Water Resour Res 27:2619–2632. https://doi.org/10.1029/91WR01107Salamon P, Fernàndez-Garcia D, Gómez-Hernández JJ (2007) Modeling tracer transport at the MADE site: the importance of heterogeneity. Water Resour Res. https://doi.org/10.1029/2006WR005522Sánchez-Vila X, Carrera J, Girardi JP (1996) Scale effects in transmissivity. J Hydrol 183:1–22. https://doi.org/10.1016/S0022-1694(96)80031-XScheibe T, Yabusaki S (1998) Scaling of flow and transport behavior in heterogeneous groundwater systems. Adv Water Resour 22:223–238. https://doi.org/10.1016/S0309-1708(98)00014-1Selvadurai PA, Selvadurai APS (2014) On the effective permeability of a heterogeneous porous medium: the role of the geometric mean. Philos Mag 94:2318–2338. https://doi.org/10.1080/14786435.2014.913111Shackelford CD (1994) Critical concepts for column testing. J Geotech Eng 120:1804–1828. https://doi.org/10.1016/0148-9062(95)96996-OŠimůnek J, van Genuchten MT, Šejna M, Toride N, Leij FJ (1999) The STANMOD computer software for evaluating solute transport in porous media using analytical solutions of convection-dispersion equation. Riverside, CaliforniaTaskinen A, Sirviö H, Bruen M (2008) Modelling effects of spatial variability of saturated hydraulic conductivity on autocorrelated overland flow data: linear mixed model approach. Stoch Environ Res Risk Assess 22:67–82. https://doi.org/10.1007/s00477-006-0099-5Tuli A, Hopmans JW, Rolston DE, Moldrup P (2005) Comparison of air and water permeability between disturbed and undisturbed soils. Soil Sci Soc Am J 69:1361. https://doi.org/10.2136/sssaj2004.0332Tyukhova AR, Willmann M (2016) Conservative transport upscaling based on information of connectivity. Water Resour Res 52:6867–6880. https://doi.org/10.1002/2015WR018331van Genuchten MTh (1980) Determining transport parameters from solute displacement experiments. Research Report 118. U.S. Salinity Lab., Riverside, CAVanderborght J, Timmerman A, Feyen J (2000) Solute transport for steady-state and transient flow in soils with and without macropores. Soil Sci Soc Am J 64:1305–1317. https://doi.org/10.2136/sssaj2000.6441305xVanmarcke E (2010) Random fields: analysis and synthesis. World Scientific. MIT Press, Cambridge, MA, p 364Vishal V, Leung JY (2017) Statistical scale-up of 3D particle-tracking simulation for non-Fickian dispersive solute transport modeling. Environ Res Risk Assess, Stoch. https://doi.org/10.1007/s00477-017-1501-1Wen X-H, Gómez-Hernández JJ (1996) Upscaling hydraulic conductivities in heterogeneous media: an overview. J Hydrol 183:ix–xxxii. https://doi.org/10.1016/S0022-1694(96)80030-8Wen XH, Gómez-Hernández JJ (1998) Numerical modeling of macrodispersion in heterogeneous media: a comparison of multi-Gaussian and non-multi-Gaussian models. J Contam Hydrol 30:129–156. https://doi.org/10.1016/S0169-7722(97)00035-1Wen XH, Capilla JE, Deutsch CV, Gómez-Hernández JJ, Cullick AS (1999) A program to create permeability fields that honor single-phase flow rate and pressure data. Comput Geosci 25:217–230. https://doi.org/10.1016/S0098-3004(98)00126-5Wilding LP, Drees LR (1983) Spatial variability and pedology. In: Wilding LP, Smeck NE, Hall GF (eds) Pedogenesis and soil taxonomy: the soil orders. Elsevier, Amsterdam, pp 83–116Willmann M, Carrera J, Guadagnini A (2006) Block-upscaling of transport in heterogeneous aquifers. h2ogeo.upc.edu 1–7Xu Z, Meakin P (2013) Upscaling of solute transport in heterogeneous media with non-uniform flow and dispersion fields. Appl Math Model 37:8533–8542. https://doi.org/10.1016/j.apm.2013.03.070Zech A, Attinger S, Cvetkovic V, Dagan G, Dietrich P, Fiori A, Rubin Y, Teutsch G (2015) Is unique scaling of aquifer macrodispersivity supported by field data? Water Resour Res 51:7662–7679. https://doi.org/10.1002/2015WR017220Zhou H, Li L, Gómez-Hernández JJ (2010) Three-dimensional hydraulic conductivity upscaling in groundwater modeling. Comput Geosci 36:1224–1235. https://doi.org/10.1016/j.cageo.2010.03.008Zhou H, Li L, Hendricks Franssen H-J, Gómez-Hernández JJ (2012) Pattern recognition in a bimodal aquifer using the normal-score ensemble Kalman filter. Math Geosci 44:169–185. https://doi.org/10.1007/s11004-011-9372-

Ocean acidification and temperature rise: effects on calcification during early development of the cuttlefish Sepia officinalis

This study investigated the effects of seawater pH (i.e., 8.10, 7.85 and 7.60) and temperature (16 and 19 °C) on (a) the abiotic conditions in the fluid surrounding the embryo (viz. the perivitelline fluid), (b) growth, development and (c) cuttlebone calcification of embryonic and juvenile stages of the cephalopod Sepia officinalis. Egg swelling increased in response to acidification or warming, leading to an increase in egg surface while the interactive effects suggested a limited plasticity of the swelling modulation. Embryos experienced elevated pCO2 conditions in the perivitelline fluid (>3-fold higher pCO2 than that of ambient seawater), rendering the medium under-saturated even under ambient conditions. The growth of both embryos and juveniles was unaffected by pH, whereas 45Ca incorporation in cuttlebone increased significantly with decreasing pH at both temperatures. This phenomenon of hypercalcification is limited to only a number of animals but does not guarantee functional performance and calls for better mechanistic understanding of calcification processes

Human telomerase activity regulation

Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control but also other factors contributing to the enzyme phosphorylation status, assembling or complex subunits transport. Thus, we show that the telomerase expression targeting cannot be the only possibility to shorten telomeres and induce cell apoptosis. It is important especially since the transcription expression is not always correlated with the enzyme activity which might result in transcription modulation failure or a possibility for the gene therapy to be overcome. This review summarizes the current state of knowledge of numerous telomerase regulation mechanisms that take place after telomerase subunits coding genes transcription. Thus we show the possible mechanisms of telomerase activity regulation which might become attractive anticancer therapy targets