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Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse
No full textProstate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making
Can nationally prescribed institutional arrangements enable community-based conservation? An analysis of conservancies and community forests in the Zambezi region of Namibia
No full textCommunity-based conservation is advocated as an idea that long-term conservation success requires engaging with, providing benefits for, and establishing institutions representing local communities. However, community-based conservation’s efficacy and impact in sustainable resource management varies depending on national natural resource policies and implications for local institutional arrangements. This paper analyses the significance of natural resource management policies and institutional design on the management of common pool resources (CPRs), by comparing Namibian conservancies and community forests. To meet this aim, we reviewed key national policies pertinent to natural resource governance and conducted 28 semi-structured interviews between 2012 and 2013. Key informants included conservancy and community forest staff and committee members, village headmen, NGO coordinators, regional foresters, wildlife officials (wardens), and senior government officials in the Ministry of Environment and Tourism and the Ministry of Agriculture, Water and Forestry. We explored the following questions: how do national natural resource management policies affect the operations of local common pool resource institutions? and how do external factors affect local institutions and community participation in CPRs decision-making? Our results show that a diversity of national policies significantly influenced local institutional arrangements. Formation of conservancies and community forests by communities is not only directly linked with state policies designed to increase wildlife numbers and promote forest growth or improve condition, but also formulated primarily for benefits from and control over natural resources. The often-assumed direct relationship between national policies and local institutional arrangements does not always hold in practice, resulting in institutional mismatch. We aim to advance theoretical and applied discourse on common pool resource governance in social-ecological systems, with implications for sustainable land management policies in Namibia and other landscapes across sub-Saharan Africa
The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes
No full textPost-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where “x” is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation
Aging and the (chemical) senses: Implications for food behaviour amongst elderly consumers
No full textThe growing aging population are increasingly suffering from the negative health consequences of the age-related decline in their senses, especially their chemical senses. Unfortunately, however, unlike for the higher senses of vision and hearing, there is currently nothing that can be done to bring back the chemical senses once they are lost (or have started their inevitable decline). The evidence suggests that such chemosensory changes can result in a range of maladaptive food behaviours, including the addition of more salt and sugar to food and drink in order to experience the same taste intensity while, at the same time, reducing their overall consumption because food has lost its savour. Here, though, it is also important to stress the importance of the more social aspects of eating and drinking, given the evidence suggesting that a growing number of older individuals are consuming more of their meals alone than ever before. Various solutions have been put forward in order to try to enhance the food experience amongst the elderly, including everything from optimising the product-intrinsic food inputs provided to the remaining functional senses through to a variety of digital interventions. Ultimately, however, the aim has to be to encourage healthier patterns of food consumption amongst this rapidly-growing section of the population by optimising the sensory, nutritional, social, and emotional aspects of eating and drinking. An experimental dinner with the residents of one such home where nostalgic-flavoured healthy ice-creams were served is described
Beam position detection of a short electron bunch in presence of a longer and more intense proton bunch for the AWAKE Experiment
No full textThe AWAKE experiment studies the acceleration of electrons to multi-GeV levels driven by the plasma wakefield generated by an ultra-relativistic and high intensity proton bunch. The proton beam, being considerably more intense than the co-propagating electron bunch, perturbs the measurement of the electron beam position achieved via standard techniques. This contribution shows that the electrons position monitoring is possible by frequency discrimination, exploiting the large bunch length difference between the electron and proton beams. Simulations and a beam measurement hint, the measurement has to be carried out in a frequency regime of a few tens of GHz, which is far beyond the spectrum produced by the 1ns long (4 σ Gaussian) proton bunch. As operating a conventional Beam Position Monitor (BPM) in this frequency range is problematic, an innovative approach based on the emission of coherent Cherenkov Diffraction Radiation (ChDR) in dielectrics is being studied. After describing the monitor concept and design, we will report about the results achieved with a prototype system at the CERN electron facility CLEAR
Restoration of multiphase salt tectonic deformation using passive strain markers
No full textSeveral salt basins globally have been subject to multi-phase deformation. The geometry of structures formed within a salt sheet during an early phase of deformation can be concealed by overprinting during later deformation phases, impeding an informed investigation into the early drivers for salt flow. The layered Messinian Evaporites in the deep basins of the Eastern Mediterranean have undergone a Late Messinian phase of deformation, punctuated by truncation of the top of the deformation structures, followed by a Late Pliocene-Recent phase of deformation. Seismic reflection data show that the Messinian Evaporites are internally dominated by contraction structures that verge basinward in the Late Pliocene-Recent flow direction, with several apparent detachments. Planform linear trails of fluid escape pipes, documented in the North Levant Basin, that cross-cut the Messinian Evaporites present natural passive markers for the internal flow kinematics of the salt sheet throughout the Late Pliocene-Recent phase of deformation. Using the Couette (simple shear) strain profile implied by the fluid escape pipes, we remove the effects of the Late Pliocene-Recent deformation through cross-section and map restorations. The subsequent geometries are far simpler, with upright folds that are now vertically aligned. Once apparently detached structures are demonstrably connected through the Messinian Evaporites. The vergence of the present day intra-salt folds can be taken as an indicator for the Late Pliocene-Recent flow direction and distinct deformation geometries that connect at various levels through the salt sequence once retro-deformed can assist when interpreting the salt flow profile. The retro-deformation is essential for how intra-Messinian deformation and its drivers are interpreted going forward. Furthermore, simple shear deformation results in erroneous apparent percentage shortening calculations as line length is not conserved, obscuring the strain from the pre-Pliocene deformational phase. The methodology employed here has important implications for all salt basins that have undergone multi-phase deformation
Image-based mechanical balancing of reservoir volumes during benchtop flow battery operation
No full textThe long-term maintenance of stable redox-flow-battery performance requires a strategy to manage dynamic volume imbalances between electrolyte reservoirs. Even with ion-selective membranes as separators, bulk liquid exchange can occur within the reactor because of pressure differences across its positive and negative chambers. Disproportionation chemistries, wherein both electrolyte reservoirs have identical composition in the discharged state, tolerate species crossover reversibly. These make possible the use of low-cost porous separators, but such materials are more hydraulically permeable. Here we propose an approach to mitigate reservoir imbalance, using the nonaqueous vanadium acetylacetonate disproportionation chemistry as a test platform. We demonstrate a benchtop-scale control scheme, which relies on a camera that monitors reservoir volumes linked to a microcontroller that regulates the differential flowrate between flow streams. The balancing apparatus introduces no extra wetted components and enables real-time measurements of intra-cycle imbalance due to electroosmosis. All software and firmware is made available for community use
Linear-time model checking branching processes
No full text(Multi-type) branching processes are a natural and well-studied model for generating random infinite trees. Branching processes feature both nondeterministic and probabilistic branching, generalizing both transition systems and Markov chains (but not generally Markov decision processes). We study the complexity of model checking branching processes against linear-time omega-regular specifications: is it the case almost surely that every branch of a tree randomly generated by the branching process satisfies the omega-regular specification? The main result is that for LTL specifications this problem is in PSPACE, subsuming classical results for transition systems and Markov chains, respectively. The underlying general model-checking algorithm is based on the automata-theoretic approach, using unambiguous Büchi automata
Ductal adenocarcinoma of the prostate: A systematic review and meta‐analysis of incidence, presentation, prognosis, and management
No full textContext
Ductal adenocarcinoma (DAC) is relatively rare, but is nonetheless the second most common subtype of prostate cancer. First described in 1967, opinion is still divided regarding its biology, prognosis, and outcome.
Objectives
To systematically interrogate the literature to clarify the epidemiology, diagnosis, management, progression, and survival statistics of DAC.
Materials and methods
We conducted a literature search of five medical databases from inception to May 04 2020 according to PRISMA criteria using search terms “prostate ductal adenocarcinoma” OR “endometriod adenocarcinoma of prostate” and variations of each.
Results
Some 114 studies were eligible for inclusion, presenting 2 907 170 prostate cancer cases, of which 5911 were DAC. [Correction added on 16 January 2021 after the first online publication: the preceding statement has been corrected in this current version.] DAC accounts for 0.17% of prostate cancer on meta‐analysis (range 0.0837%‐13.4%). The majority of DAC cases were admixed with predominant acinar adenocarcinoma (AAC). Median Prostate Specific Antigen at diagnosis ranged from 4.2 to 9.6 ng/mL in the case series.
DAC was more likely to present as T3 (RR1.71; 95%CI 1.53‐1.91) and T4 (RR7.56; 95%CI 5.19‐11.01) stages, with far higher likelihood of metastatic disease (RR4.62; 95%CI 3.84‐5.56; all P‐values < .0001), compared to AAC. Common first treatments included surgery (radical prostatectomy (RP) or cystoprostatectomy for select cases) or radiotherapy (RT) for localized disease, and hormonal or chemo‐therapy for metastatic disease. Few studies compared RP and RT modalities, and those that did present mixed findings, although cancer‐specific survival rates seem worse after RP.
Biochemical recurrence rates were increased with DAC compared to AAC. Additionally, DAC metastasized to unusual sites, including penile and peritoneal metastases. Where compared, all studies reported worse survival for DAC compared to AAC.
Conclusion
When drawing conclusions about DAC it is important to note the heterogenous nature of the data. DAC is often diagnosed incidentally post‐treatment, perhaps due to lack of a single, universally applied histopathological definition. As such, DAC is likely underreported in clinical practice and the literature. Poorer prognosis and outcomes for DAC compared to AAC merit further research into genetic composition, evolution, diagnosis, and treatment of this surprisingly common prostate cancer sub‐type.
Patient summary
Ductal prostate cancer is a rare but important form of prostate cancer. This review demonstrates that it tends to be more serious at detection and more likely to spread to unusual parts of the body. Overall survival is worse with this type of prostate cancer and urologists need to be aware of the presence of ductal prostate cancer to alter management decisions and follow‐up