Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification

Filamentation induced by cyclic AMP (FIC)-domain enzymes catalyze adenylylation or other posttranslational modifications of target proteins to control their function. Recently, we have shown that Fic enzymes are autoinhibited by an α-helix (αinh) that partly obstructs the active site. For the single-domain class III Fic proteins, the αinh is located at the C terminus and its deletion relieves autoinhibition. However, it has remained unclear how activation occurs naturally. Here, we show by structural, biophysical, and enzymatic analyses combined with in vivo data that the class III Fic protein NmFic from Neisseria meningitidis gets autoadenylylated in cis, thereby autonomously relieving autoinhibition and thus allowing subsequent adenylylation of its target, the DNA gyrase subunit GyrB. Furthermore, we show that NmFic activation is antagonized by tetramerization. The combination of autoadenylylation and tetramerization results in nonmonotonic concentration dependence of NmFic activity and a pronounced lag phase in the progress of target adenylylation. Bioinformatic analyses indicate that this elaborate dual-control mechanism is conserved throughout class III Fic proteins

Soil resources and topography shape local tree community structure in tropical forests

Both habitat filtering and dispersal limitation influence the compositional structure of forest communities, but previous studies examining the relative contributions of these processes with variation partitioning have primarily used topography to represent the influence of the environment. Here, we bring together data on both topography and soil resource variation within eight large (24-50 ha) tropical forest plots, and use variation partitioning to decompose community compositional variation into fractions explained by spatial, soil resource and topographic variables. Both soil resources and topography account for significant and approximately equal variation in tree community composition (9-34% and 5-29%, respectively), and all environmental variables together explain 13-39% of compositional variation within a plot. A large fraction of variation (19-37%) was spatially structured, yet unexplained by the environment, suggesting an important role for dispersal processes and unmeasured environmental variables. For the majority of sites, adding soil resource variables to topography nearly doubled the inferred role of habitat filtering, accounting for variation in compositional structure that would previously have been attributable to dispersal. Our results, illustrated using a new graphical depiction of community structure within these plots, demonstrate the importance of small-scale environmental variation in shaping local community structure in diverse tropical forests around the globe. © 2012 The Author(s) Published by the Royal Society. All rights reserved

Stationary scalar clouds around a BTZ black hole

We establish the existence of stationary clouds of massive test scalar fields around BTZ black holes. These clouds are zero-modes of the superradiant instability and are possible when Robin boundary conditions (RBCs) are considered at the AdS boundary. These boundary conditions are the most general ones that ensure the AdS space is an isolated system, and include, as a particular case, the commonly considered Dirichlet or Neumann-type boundary conditions (DBCs or NBCs). We obtain an explicit, closed form, resonance condition, relating the RBCs that allow the existence of normalizable (and regular on and outside the horizon) clouds to the system's parameters. Such RBCs never include pure DBCs or NBCs. We illustrate the spatial distribution of these clouds, their energy and angular momentum density for some cases. Our results show that BTZ black holes with scalar hair can be constructed, as the non-linear realization of these clouds. (C) 2017 The Author(s). Published by Elsevier B.V

Image-based multiplex immune profiling of cancer tissues : translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer.Gilead Breast Cancer Research Grant; Breast Cancer Research Foundation; Susan G Komen Leadership; Interne Fondsen KU Leuven/Internal Funds KU Leuven; Swedish Society for Medical Research; Swedish Breast Cancer Association; Cancer Research Program; US Department of Defense; Mayo Clinic Breast Cancer; Marie Sklodowska Curie; NHMRC; National Institutes of Health; Cancer Research UK; Japan Society for the Promotion of Science; Horizon 2020 European Union Research and Innovation Programme National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Biomedical Imaging and Bioengineering; VA Merit Review Award; US Department of Veterans Affairs Biomedical Laboratory Research Breast Cancer Research Program; Prostate Cancer Research Program; Lung Cancer Research Program; Kidney Precision Medicine Project (KPMP) Glue Grant; EPSRC; Melbourne Research Scholarship; Peter MacCallum Cancer Centre; KWF Kankerbestrijding; Dutch Ministry of Health, Welfare and Sport the Breast Cancer Research Foundation; Agence Nationale de la Recherche; Q-Life; National Breast Cancer Foundation of Australia; National Health and Medical Council of Australia; All-Island Cancer Research Institute; Irish Cancer Society; Science Foundation Ireland Investigator Programme; Science Foundation Ireland Strategic Partnership Programme. Open access funding provided by IReL.https://pathsocjournals.onlinelibrary.wiley.com/journal/10969896hj2024ImmunologySDG-03:Good heatlh and well-bein

Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer

Sonographischer Nachweis von Hirntumoren im Säuglingsalter = Ultrasonographic Demonstration of Brain Tumors in Infancy

Using the open fontanelle as an acoustic window brain tumours were diagnosed by gray scale ultrasonography in 3 infants aged 1 day to 5 months. The tumours were characterized by their echo dense structure and their good delimination from the surrounding brain. In 2 children the tumour was localized infratentorially (medulloblastoma and unclassified neuroectodermal tumour) and had caused an occlusive hydrocephalus. Both children died aged 3 and 5 months in central nervous dysregulation. One child suffered from plexus papilloma which had caused a hypersecretory hydrocephalus. After resection of the tumour the hydrocephalus decreased without any further treatment. Comparison with axial computed tomography and autopsy findings showed, that gray scale ultrasonography is equally efficient in diagnosing brain tumours and associated hydrocephalus