Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphe neurones and cranial motoneurones

In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol(-/-) embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol(-/-) mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphe nucleus and the trochlear motor nucleus are absent in mol(-/-) embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins

Rigorous engineering for hardware security: Formal modelling and proof in the CHERI design and implementation process

The root causes of many security vulnerabilities include a pernicious combination of two problems, often regarded as inescapable aspects of computing. First, the protection mechanisms provided by the mainstream processor architecture and C/C++ language abstractions, dating back to the 1970s and before, provide only coarse-grain virtual-memory-based protection. Second, mainstream system engineering relies almost exclusively on test-and-debug methods, with (at best) prose specifications. These methods have historically sufficed commercially for much of the computer industry, but they fail to prevent large numbers of exploitable bugs, and the security problems that this causes are becoming ever more acute. In this paper we show how more rigorous engineering methods can be applied to the development of a new security-enhanced processor architecture, with its accompanying hardware implementation and software stack. We use formal models of the complete instruction-set architecture (ISA) at the heart of the design and engineering process, both in lightweight ways that support and improve normal engineering practice -- as documentation, in emulators used as a test oracle for hardware and for running software, and for test generation -- and for formal verification. We formalise key intended security properties of the design, and establish that these hold with mechanised proof. This is for the same complete ISA models (complete enough to boot operating systems), without idealisation. We do this for CHERI, an architecture with \emph{hardware capabilities} that supports fine-grained memory protection and scalable secure compartmentalisation, while offering a smooth adoption path for existing software. CHERI is a maturing research architecture, developed since 2010, with work now underway on an Arm industrial prototype to explore its possible adoption in mass-market commercial processors. The rigorous engineering work described here has been an integral part of its development to date, enabling more rapid and confident experimentation, and boosting confidence in the design.This work was supported by EPSRC programme grant EP/K008528/1 (REMS: Rigorous Engineering for Mainstream Systems). This work was supported by a Gates studentship (Nienhuis). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement 789108, ELVER). This work was supported by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 (CTSRD), HR0011-18-C-0016 (ECATS), and FA8650-18-C-7809 (CIFV)

Phenotypic and genotypic monitoring of Schistosoma mansoni in Tanzanian schoolchildren five years into a preventative chemotherapy national control programme

We conducted combined in vitro PZQ efficacy testing with population genetic analyses of S. mansoni collected from children from two schools in 2010, five years after the introduction of a National Control Programme. Children at one school had received four annual PZQ treatments and the other school had received two mass treatments in total. We compared genetic differentiation, indices of genetic diversity, and estimated adult worm burden from parasites collected in 2010 with samples collected in 2005 (before the control programme began) and in 2006 (six months after the first PZQ treatment). Using 2010 larval samples, we also compared the genetic similarity of those with high and low in vitro sensitivity to PZQ

Fast Protection-Domain Crossing in the CHERI Capability-System Architecture

Capability Hardware Enhanced RISC Instructions (CHERI) supplement the conventional memory management unit (MMU) with instruction-set architecture (ISA) extensions that implement a capability system model in the address space. CHERI can also underpin a hardware-software object-capability model for scalable application compartmentalization that can mitigate broader classes of attack. This article describes ISA additions to CHERI that support fast protection-domain switching, not only in terms of low cycle count, but also efficient memory sharing with mutual distrust. The authors propose ISA support for sealed capabilities, hardware-assisted checking during protection-domain switching, a lightweight capability flow-control model, and fast register clearing, while retaining the flexibility of a software-defined protection-domain transition model. They validate this approach through a full-system experimental design, including ISA extensions, a field-programmable gate array prototype (implemented in Bluespec SystemVerilog), and a software stack including an OS (based on FreeBSD), compiler (based on LLVM), software compartmentalization model, and open-source applications.This work is part of the CTSRD and MRC2 projects sponsored by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 and FA8750-11-C-0249. We also acknowledge the Engineering and Physical Sciences Research Council (EPSRC) REMS Programme Grant [EP/K008528/1], the EPSRC Impact Acceleration Account [EP/K503757/1], EPSRC/ARM iCASE studentship [13220009], Microsoft studentship [MRS2011-031], the Isaac Newton Trust, the UK Higher Education Innovation Fund (HEIF), Thales E-Security, and Google, Inc.This is the author accepted manuscript. The final version of the article can be found at: http://ieeexplore.ieee.org/document/7723791

Pathological and ecological host consequences of infection by an introduced fish parasite

The infection consequences of the introduced cestode fish parasite Bothriocephalus acheilognathi were studied in a cohort of wild, young-of-the-year common carp Cyprinus carpio that lacked co-evolution with the parasite. Within the cohort, parasite prevalence was 42% and parasite burdens were up to 12% body weight. Pathological changes within the intestinal tract of parasitized carp included distension of the gut wall, epithelial compression and degeneration, pressure necrosis and varied inflammatory changes. These were most pronounced in regions containing the largest proportion of mature proglottids. Although the body lengths of parasitized and non-parasitized fish were not significantly different, parasitized fish were of lower body condition and reduced weight compared to non-parasitized conspecifics. Stable isotope analysis (δ15N and δ13C) revealed trophic impacts associated with infection, particularly for δ15N where values for parasitized fish were significantly reduced as their parasite burden increased. In a controlled aquarium environment where the fish were fed ad libitum on an identical food source, there was no significant difference in values of δ15N and δ13C between parasitized and non-parasitized fish. The growth consequences remained, however, with parasitized fish growing significantly slower than non-parasitized fish, with their feeding rate (items s−1) also significantly lower. Thus, infection by an introduced parasite had multiple pathological, ecological and trophic impacts on a host with no experience of the parasite

The convective storm initiation project

Copyright @ 2007 AMSThe Convective Storm Initiation Project (CSIP) is an international project to understand precisely where, when, and how convective clouds form and develop into showers in the mainly maritime environment of southern England. A major aim of CSIP is to compare the results of the very high resolution Met Office weather forecasting model with detailed observations of the early stages of convective clouds and to use the newly gained understanding to improve the predictions of the model. A large array of ground-based instruments plus two instrumented aircraft, from the U.K. National Centre for Atmospheric Science (NCAS) and the German Institute for Meteorology and Climate Research (IMK), Karlsruhe, were deployed in southern England, over an area centered on the meteorological radars at Chilbolton, during the summers of 2004 and 2005. In addition to a variety of ground-based remote-sensing instruments, numerous rawin-sondes were released at one- to two-hourly intervals from six closely spaced sites. The Met Office weather radar network and Meteosat satellite imagery were used to provide context for the observations made by the instruments deployed during CSIP. This article presents an overview of the CSIP field campaign and examples from CSIP of the types of convective initiation phenomena that are typical in the United Kingdom. It shows the way in which certain kinds of observational data are able to reveal these phenomena and gives an explanation of how the analyses of data from the field campaign will be used in the development of an improved very high resolution NWP model for operational use.This work is funded by the National Environment Research Council following an initial award from the HEFCE Joint Infrastructure Fund

Complicated skin, skin structure and soft tissue infections - are we threatened by multi-resistant pathogens?

Tissue infections or skin, skin structure, and deep seated soft tissue infections are general terms for infections of the entire skin layer including the subcutaneous and muscle tissue layers and their respective fascia structures. Infections of the different mediastinal fascias (mediastinitis) and retroperitoneal fascia infections also belong to this category. Due to the variability of their clinical presentation, skin and soft tissue infections can be classified according to different features. The following aspects can be used for classification

CheriABI: Enforcing Valid Pointer Provenance and Minimizing Pointer Privilege in the POSIX C Run-time Environment

The CHERI architecture allows pointers to be implemented as capabilities (rather than integer virtual addresses) in a manner that is compatible with, and strengthens, the semantics of the C language. In addition to the spatial protections offered by conventional fat pointers, CHERI capabilities offer strong integrity, enforced provenance validity, and access monotonicity. The stronger guarantees of these architectural capabilities must be reconciled with the real-world behavior of operating systems, run-time environments, and applications. When the process model, user-kernel interactions, dynamic linking, and memory management are all considered, we observe that simple derivation of architectural capabilities is insufficient to describe appropriate access to memory. We bridge this conceptual gap with a notional \emph{abstract capability} that describes the accesses that should be allowed at a given point in execution, whether in the kernel or userspace. To investigate this notion at scale, we describe the first adaptation of a full C-language operating system (FreeBSD) with an enterprise database (PostgreSQL) for complete spatial and referential memory safety. We show that awareness of abstract capabilities, coupled with CHERI architectural capabilities, can provide more complete protection, strong compatibility, and acceptable performance overhead compared with the pre-CHERI baseline and software-only approaches. Our observations also have potentially significant implications for other mitigation techniques.This work was supported by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 (``CTSRD'') and HR0011-18-C-0016 (``ECATS''). The views, opinions, and/or findings contained in this report are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. We also acknowledge the EPSRC REMS Programme Grant (EP/K008528/1), the ERC ELVER Advanced Grant (789108), Arm Limited, HP Enterprise, and Google, Inc. Approved for Public Release, Distribution Unlimited

Expression of the inhibitor of DNA-binding (ID)-1 protein as an angiogenic mediator in tumour advancement of uterine cervical cancers

The ID protein, an inhibitor of basic helix-loop-helix (HLH) transcription factors, has been involved in multiple cellular processes. To investigate the association between tumour advancement and ID expressions of uterine cervical cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction and the histoscore with the localisation of ID-1 was determined by immunohistochemistry and patient survival in 60 patients. ID-1 histoscores and mRNA levels both significantly (P<0.05) increased in uterine cervical cancers according to clinical stage regardless of histopathological type or lymph node metastasis. Furthermore, the 36-month survival rate of the 30 patients with high ID-1 was poor (60%), whereas that of the other 30 patients with low ID-1 was significantly higher (83%). ID-1 histoscores and mRNA levels significantly (P<0.0001) correlated with microvessel counts in uterine cervical cancers. Tumour cells show mostly diffuse to strong cytoplasmic expression of ID-1 and also very faint expression in endothelial cells. Moreover, ID-1 expression not only correlated with microvessel counts but also correlated significantly with histoscore. Therefore, ID-1 might work on tumour advancement through angiogenic activity and is considered to be a candidate for a prognostic indicator in uterine cervical cancers