A specific fungal transcription factor controls effector gene expression and orchestrates the establishment of the necrotrophic pathogen lifestyle on wheat

The fungus Parastagonospora nodorum infects wheat through the use of necrotrophic efector (NE) proteins that cause host-specifc tissue necrosis. The Zn2Cys6 transcription factor PnPf2 positively regulates NE gene expression and is required for virulence on wheat. Little is known about other downstream targets of PnPf2. We compared the transcriptomes of the P. nodorum wildtype and a strain deleted in PnPf2 (pf2-69) during in vitro growth and host infection to further elucidate targets of PnPf2 signalling. Gene ontology enrichment analysis of the diferentially expressed (DE) genes revealed that genes associated with plant cell wall degradation and proteolysis were enriched in down-regulated DE gene sets in pf2-69 compared to SN15. In contrast, genes associated with redox control, nutrient and ion transport were up-regulated in the mutant. Further analysis of the DE gene set revealed that PnPf2 positively regulates twelve genes that encode efector-like proteins. Two of these genes encode proteins with homology to previously characterised efectors in other fungal phytopathogens. In addition to modulating efector gene expression, PnPf2 may play a broader role in the establishment of a necrotrophic lifestyle by orchestrating the expression of genes associated with plant cell wall degradation and nutrient assimilation.Tis study was supported by the Centre for Crop and Disease Management, a joint initiative of Curtin University and the Grains Research and Development Corporation [research grant CUR00023 (Programme 3)]. EJ was supported by the Australian Government Research Training Program Scholarshi

Association of body mass index in midlife with morbidity burden in older adulthood and longevity

Importance: Abundant evidence links obesity with adverse health consequences. However, controversies persist regarding whether overweight status compared with normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is associated with longer survival and whether this occurs at the expense of greater long-term morbidity and health care expenditures. Objective: To examine the association of BMI in midlife with morbidity burden, longevity, and health care expenditures in adults 65 years and older. Design, Setting, and Participants: Prospective cohort study at the Chicago Heart Association Detection Project in Industry, with baseline in-person examination between November 1967 and January 1973 linked with Medicare follow-up between January 1985 and December 2015. Participants included 29 621 adults who were at least age 65 years in follow-up and enrolled in Medicare. Data were analyzed from January 2020 to December 2021. Exposures: Standard BMI categories. Main Outcomes and Measures: (1) Morbidity burden at 65 years and older assessed with the Gagne combined comorbidity score (ranging from -2 to 26, with higher score associated with higher mortality), which is a well-validated index based on International Classification of Diseases, Ninth Revision codes for use in administrative data sets; (2) longevity (age at death); and (3) health care costs based on Medicare linkage in older adulthood (aged ≥65 years). Results: Among 29 621 participants, mean (SD) age was 40 (12) years, 57.1% were men, and 9.1% were Black; 46.0% had normal BMI, 39.6% were overweight, and 11.9% had classes I and II obesity at baseline. Higher cumulative morbidity burden in older adulthood was observed among those who were overweight (7.22 morbidity-years) and those with classes I and II obesity (9.80) compared with those with a normal BMI (6.10) in midlife (P \u3c .001). Mean age at death was similar between those who were overweight (82.1 years [95% CI, 81.9-82.2 years]) and those who had normal BMI (82.3 years [95% CI, 82.1-82.5 years]) but shorter in those who with classes I and II obesity (80.8 years [95% CI, 80.5-81.1 years]). The proportion (SE) of life-years lived in older adulthood with Gagne score of at least 1 was 0.38% (0.00%) in those with a normal BMI, 0.41% (0.00%) in those with overweight, and 0.43% (0.01%) in those with classes I and II obesity. Cumulative median per-person health care costs in older adulthood were significantly higher among overweight participants ($12 390 [95$10 427 to $14 354]) and those with classes I and II obesity ($23 396 [95% CI, $18 474 to$28 319]) participants compared with those with a normal BMI (P \u3c .001). Conclusions and Relevance: In this cohort study, overweight in midlife, compared with normal BMI, was associated with higher cumulative burden of morbidity and greater proportion of life lived with morbidity in the context of similar longevity. These findings translated to higher total health care expenditures in older adulthood for those who were overweight in midlife

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Gene content evolution in the arthropods

Arthropods comprise the largest and most diverse phylum on Earth and play vital roles in nearly every ecosystem. Their diversity stems in part from variations on a conserved body plan, resulting from and recorded in adaptive changes in the genome. Dissection of the genomic record of sequence change enables broad questions regarding genome evolution to be addressed, even across hyper-diverse taxa within arthropods. Using 76 whole genome sequences representing 21 orders spanning more than 500 million years of arthropod evolution, we document changes in gene and protein domain content and provide temporal and phylogenetic context for interpreting these innovations. We identify many novel gene families that arose early in the evolution of arthropods and during the diversification of insects into modern orders. We reveal unexpected variation in patterns of DNA methylation across arthropods and examples of gene family and protein domain evolution coincident with the appearance of notable phenotypic and physiological adaptations such as flight, metamorphosis, sociality, and chemoperception. These analyses demonstrate how large-scale comparative genomics can provide broad new insights into the genotype to phenotype map and generate testable hypotheses about the evolution of animal diversity

Correlation and high-resolution timing for Paleo-tethys Permian-Triassic boundary exposures in Vietnam and Slovenia using geochemical, geophysical and biostratigraphic data sets

Two Permian-Triassic boundary (PTB) successions, Lung Cam in Vietnam, and Lukač in Slovenia, have been sampled for high-resolution magnetic susceptibility, stable isotope and elemental chemistry, and biostratigraphic analyses. These successions are located on the eastern (Lung Cam section) and western margins (Lukač section) of the Paleo-Tethys Ocean during PTB time. Lung Cam, lying along the eastern margin of the Paleo-Tethys Ocean provides an excellent proxy for correlation back to the GSSP and out to other Paleo-Tethyan successions. This proxy is tested herein by correlating the Lung Cam section in Vietnam to the Lukač section in Slovenia, which was deposited along the western margin of the Paleo-Tethys Ocean during the PTB interval. It is shown herein that both the Lung Cam and Lukač sections can be correlated and exhibit similar characteristics through the PTB interval. Using time-series analysis of magnetic susceptibility data, high-resolution ages are obtained for both successions, thus allowing relative ages, relative to the PTB age at ~252 Ma, to be assigned. Evaluation of climate variability along the western and eastern margins of the Paleo-Tethys Ocean through the PTB interval, using d18O values indicates generally cooler climate in the west, below the PTB, changing to generally warmer climates above the boundary. A unique Black Carbon layer (elemental carbon present by agglutinated foraminifers in their test) below the boundary exhibits colder temperatures in the eastern and warmer temperatures in the western Paleo-Tethys Ocean.ReferencesBalsam W., Arimoto R., Ji J., Shen Z, 2007. Aeolian dust in sediment: a re-examination of methods for identification and dispersal assessed by diffuse reflectance spectrophotometry. International Journal of Environment and Health, 1, 374-402.Balsam W.L., Otto-Bliesner B.L., Deaton B.C., 1995. Modern and last glacial maximum eolian sedimentation patterns in the Atlantic Ocean interpreted from sediment iron oxide content. Paleoceanography, 10, 493-507.Berggren W.A., Kent D.V., Aubry M-P., Hardenbol J., 1995. Geochronology, Time Scales and Global Stratigraphic Correlation. SEPM Special Publication #54, Society for Sedimentary Geology, Tulsa, OK, 386p.Berger A., Loutre M.F., Laskar J., 1992. Stability of the astronomical frequencies over the Earth's history for paleoclimate studies. Science, 255, 560-566.Bloemendal J., deMenocal P., 1989. Evidence for a change in the periodicity of tropical climate cycles at 2.4 Myr from whole-core magnetic susceptibility measurements. Nature, 342, 897-900.Chen J., Shen S-j., Li X-h., Xu Y-g., Joachimski M.M., Bowring S.A., Erwin D.H., Yuan D-x., Chen B., Zhang H., Wang Y., Cao C-q, Zheng Q-f., Mu L., 2016. High-resolution SIMS oxygen isotope analysis on conodont apatite from South China and implications for the end-Permian mass extinction. Palaeogeography, Palaeoclimatology, Palaeoecology, 448, 26-38.Da Silva A-C., Boulvain F., 2002. Sedimentology, magnetic susceptibility and isotopes of a Middle Frasnian carbonate platform: Tailfer Section, Belgium. Facies, 46, 89-102.Da Silva A.-C., Boulvain F., 2005. Upper Devonian carbonate platform correlations and sea level variations recorded in magnetic susceptibility. Palaeogeography, Palaeoclimatology, Palaeoecology, 240, 373-388.Dettinger M.D., Ghil M., Strong C.M., Weibel W., Yiou P., 1995. Software expedites singular-spectrum analysis of noisy time series. EOS. Transactions of the American Geophysical Union, 76, 12-21.Dinarès-Turell J., Baceta J.I., Bernaola G., Orue-Etxebarria X., Pujalte V., 2007. Closing the Mid-Palaeocene gap: Toward a complete astronomically tuned Palaeocene Epoch and Selandian and Thanetian GSSPs at Zumaia (Basque Basin, W Pyrenees). Earth Planetary Science Letters, 262, 450-467.Ellwood B.B., García-Alcalde J.L., El Hassani A., Hladil J., Soto F.M., Truyóls-Massoni M., Weddige K., Koptikova L., 2006. Stratigraphy of the Middle Devonian Boundary: Formal Definition of the Susceptibility Magnetostratotype in Germany with comparisons to Sections in the Czech Republic, Morocco and Spain. Tectonophysics, 418, 31-49.Ellwood B.B., Wang W.-H., Tomkin J.H., Ratcliffe K.T., El Hassani A., Wright A.M., 2013. Testing high resolution magnetic susceptibility and gamma gradiation methods in the Cenomanian-Turonian (Upper Cretaceous) GSSP and near-by coeval section. Palaeogeography, Palaeoclimatology, Palaeoecology, 378, 75-90.Ellwood B.B., Wardlaw B.R., Nestell M.K., Nestell G.P., Luu Thi Phuong Lan, 2017. Identifying globally synchronous Permian-Triassic boundary levels in successions in China and Vietnam using Graphic Correlation. Palaeogeography, Palaeoclimatology, Palaeoecology, 485, 561-571.Ghil M., Allen R.M., Dettinger M.D., Ide K., Kondrashov D., Mann M.E., Robertson A., Saunders A., Tian Y., Varadi F., Yiou P., 2002. Advanced spectral methods for climatic time series. Reviews of Geophysics, 40, 3.1-3.41. http://dx.doi.org/10.1029/2000RG000092.Gradstein F.M., Ogg J.G., Smith A.G., 2004. A geologic Time Scale 2004. Cambridge University Press, England, 589p.Hartl P., Tauxe L., Herbert T., 1995. Earliest Oligocene increase in South Atlantic productivity as interpreted from “rock magnetics” at Deep Sea drilling Site 522. Paleoceanography, 10, 311-326.Imbrie J., Hays J.D., Martinson D.G., McIntyre A., Mix A.C., Morley J.J., Pisias N.G., Prell W.L., Shackleton N.J., 1984. The Orbital Theory of Pleistocene Climate: Support from a Revised Chronology of the Marine Delta 18O Record. In Berger A.L., Imbrie J., Hays J., Kukla G., Saltzman B. (Eds.), Milankovitch and Climate, Part I, Kluwer Academic Publishers, 269-305.Mead G.A., Yauxe L., LaBrecque J.L., 1986. Oligocene paleoceanography of the South Atlantic: paleoclimate implications of sediment accumulation rates and magnetic susceptibility. Paleoceanography, 1, 273-284.Salvador A., (Ed.), 1994. International Stratigraphic Guide: The International Union of Geological Sciences and The Geological Society of America, Inc., 2nd Edition, 214p.Scotese C.R., 2001. Atlas of Earth History, Volume 1, Paleogeography, PALEOMAP Project, Arlington, Texas, 52p.Scotese C.R., 2013. Map Folio 49, Permo-Triassic Boundary (251 Ma), PALEOMAP PaleoAtlas for ArcGIS, Triassic and Jurassic Paleogeographic, Paleoclimatic and Plate Tectonic Reconstructions, PALEOMAP Project, Evanston, IL, 3.Shackleton N.J., Crowhurst S.J., Weedon G.P., Laskar J., 1999. Astronomical calibration of Oligocene-Miocene time. Philosophical Transactions of the Royal Society London, A357, 1907-1929.Shaw A.B., 1964. Time in Stratigraphy. New York, Mc Graw Hill, 365p.Shen S.-Z., Crowley J.L., Wang Y., Bowring S.A., Erwin D.H., Henderson C.M., Ramezani J., Zhang H., Shen Y.,Wang X.-D., Wang W., Mu L., Li W.-Z., Tang Y.-G., Liu X.-L., Liu X.-L., Zeng Y., Jiang Y.-F., Jin Y.-G., 2011a. High-precision geochronologic dating constrains probable causes of Earth’s largest mass extinction. Science, 334, 1367-1372. Doi:10.1126/science.1213454.Swartzendruber L.J., 1992. Properties, units and constants in magnetism. Journal of Magnetic Materials, 100, 573-575.Weedon G.P., Jenkyns H.C., Coe A.L., Hesselbo S.P., 1999. Astronomical calibration of the Jurassic time-scale from cyclostratigraphy in British mudrock formations. Philosophical Transactions of the Royal Society London, A357, 1787-1813.Weedon G.P., Shackleton N.J., Pearson P.N., 1997. The Oligocne time scale and cyclostratigraphy on the Ceara Rise, western equatorial Atlantic. In: Schackleton N.J., Curry W.B., Richter C., and Bralower T.J. (Eds.). Proceedings of the Ocean Drilling Program, Scientific Results, 154, 101-114.Whalen M.T., Day J.E., 2008. Magnetic Susceptibility, Biostratigraphy, and Sequence Stratigraphy: Insights into Devonian Carbonate Platform Development and Basin Infilling, Western Alberta. Papers on Phanerozoic Reef Carbonates in Honor of Wolfgang Schlager. SEPM (Society for Sedimentary Geology) Special Publication, 89, 291-314

Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells

Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence. Metabolically active senescent cells secrete multiple tumor promoting factors making their elimination a therapeutic priority. Viscum album is one of the most widely used alternative anti-cancer medicines facilitating chemotherapy tolerance of breast cancer patients. The aim of this study was to model and investigate how Viscum album extracts execute additive anti-tumor activity with low-dose Dox using ER + MCF7 breast cancer cells. We report that cotreatment of MCF7 with Viscum album and Dox abrogates G2/M cycle arrest replacing senescence with intrinsic apoptotic program. Mechanistically, this switch was associated with down-regulation of p21, p53/p73 as well as Erk1/2 and p38 activation. Our findings, therefore, identify a novel mechanistic axis of additive antitumor activity of Viscum album and low dose-Dox. In conclusion, ER + breast cancer patients may benefit from addition of Viscum album to low-dose Dox chemotherapy due to suppression of cancer cell senescence and induction of apoptosis