Herpes simplex virus blocks apoptosis by precluding mitochondrial cytochrome c release independent of caspase activation in infected human epithelial cells

Expression of HSV-1 genes leads to the induction of apoptosis in human epithelial HEp-2 cells but the subsequent synthesis of infected cell protein prevents the process from killing the cells. Thus, viruses unable to produce appropriate prevention factors are apoptotic. We now report that the addition of either a pancaspase inhibitor or caspase-9-specific inhibitor prevented cells infected with an apoptotic HSV-1 virus from undergoing cell death. This result indicated that HSV-1-dependent apoptosis proceeds through the mitochondrial apoptotic pathway. However, the pancaspase inhibitor did not prevent the release of cytochrome c from mitochondria, implying that caspase activation is not required for this induction of cytochrome c release by HSV-1. The release of cytochrome c was first detected at 9 hpi while caspase-9, caspase-3 and PARP processing were detected at 12 hpi. Finally, Bax accumulated at mitochondria during apoptotic, but not wild type HSV-1 infection. Together, these findings indicate that HSV-1 blocks apoptosis by precluding mitochondrial cytochrome c release in a caspase-independent manner and suggest Bax as a target in infected human epithelial cells

Carotid-cavernous fistula as a mimicker of myasthenia gravis

BACKGROUND: A carotid-cavernous fistula (CCF) is an abnormal communication between the carotid arterial system and the cavernous sinus. Common symptoms of CCFs include proptosis and ophthalmoplegia, but fluctuating diplopia and presence of ptosis are not typical. CASE DESCRIPTION: We present an unusual case of CCF with fluctuating binocular diplopia and ptosis, mimicking myasthenia gravis. Electrodiagnostic testing, which included repetitive nerve stimulation and single-fiber electromyography, was normal. Magnetic resonance imaging of the brain and orbits was initially normal, but later magnetic resonance angiography revealed enlargement of the left superior ophthalmic vein along with a left CCF. Patient underwent a successful left cavernous sinus embolization. CONCLUSION: Fluctuating ophthalmic symptoms are a typical presentation of myasthenia gravis; however, there may be an association of these symptoms with a CCF. Repetitive nerve stimulation and single-fiber electromyography played a key role in diagnosis of this case, as the normal result led to further investigations revealing a CCF

Presence of an anti-viral factor in peritoneal dialysis effluent

Presence of an anti-viral factor in peritoneal dialysis effluent. Viral peritonitis is an exceptionally rare occurrence in peritoneal dialysis. In fact, up to now, only one case report has been documented in the literature. In a prospective study, peritoneal dialysis effluent (PDE) was specifically cultured for the following viruses: the herpes group of viruses, including herpes simplex types I (HSV) and II, cytomegalovirus (CMV) and varicella-zoster (V-Z), and the enteroviruses group including coxsackie B-5 (Cox B), echo, enterovirus and polio. Cultures were performed under both basal conditions and in the presence of peritonitis. No viral growth was demonstrated. The possible existence of an anti-viral factor in the PDE was therefore raised. In order to investigate this hypothesis, the PDE of 16 patients undergoing intermittent peritoneal dialysis and of 24 patients on continuous ambulatory peritoneal dialysis were examined for anti-viral activity. The method used was analogous to that employed for testing the anti-viral effect of interferon (IFN). The inhibition of the cytopathic effect (CPE) of various viruses was examined in the following tissue cultures: Vero cells (a line of monkey kidney cells) incubated with HSV, vesicular stomatitis virus (VSV) and Cox B; human kidney cells incubated with parainfluenza 3 (Para-3); human foreskin fibroblasts incubated with CMV, HSV and VSV and L-929 (a line of mouse cells) incubated with VSV. As control, unused Dianeal (Travenol, Ashdod, Israel) 1.5 and 4.25 g/dl, normal saline and 5 g/dl dextrose solutions were tested under the same conditions using VSV on Vero. The PDE was also examined for the presence of specific anti-viral antibodies by microneutralization and ELISA tests. The presence of human IFN (β and γ) was evaluated by radioimmunoassay using anti IFN monoclonal antibodies. Human IFN a was tested by a bioassay using MBDK cells with VSV. PDE from both patients on intermittent peritoneal dialysis and continuous ambulatory peritoneal dialysis inhibited the cytopathic activity of all the viruses tested in the various tissue cultures, except for the mouse line of cells. No such inhibition was seen with the control solutions. Only antibodies to HSV were detected in the PDE and their titer did not correlate with the inhibition of cytopathic effect. Human IFN aα, β and γ were not detected. These studies suggest that PDE contains an anti-viral factor which is not a known IFN or an anti-viral antibody. This factor is active against both RNA and DNA viruses in both human and monkey cell cultures

SMARTER Teamwork: System for Management, Assessment, Research, Training, Education, and Remediation for Teamwork

The rapid adoption of Team-Maker and the Comprehensive Assessment of Team Member Effectiveness (CATME), tools for team formation and peer evaluation, make it possible to extend their success to have a significant impact on the development of team skills in higher education. The web-based systems are used by over 700 faculty at over 200 institutions internationally. This paper and its accompanying poster will describe strategies for broadening the scope of those tools into a complete system for the management of teamwork in undergraduate education. The System for the Management, Assessment, Research, Training, Education, and Remediation of Teamwork (SMARTER Teamwork) has three specific goals: 1) to equip students to work in teams by providing them with training and feedback, 2) to equip faculty to manage student teams by providing them with information and tools to facilitate best practices, and 3) to equip researchers to understand teams by broadening the system’s capabilities to collect additional types of data so that a wider range of research questions can be studied through a secure researcher interface. The three goals of the project support each other in hierarchical fashion: research informs faculty practice, faculty determine the students’ experience, which, if well managed based on research findings, equips students to work in teams. Our strategies for achieving these goals are based on a well-accepted training model that has five elements: information, demonstration, practice, feedback, and remediation. Different outcomes are expected for each group of people. For the students, both individual outcomes, such as student learning, and team outcomes, such as the development of shared mental models, are expected. For the faculty, individual outcomes such as faculty learning and faculty satisfaction are expected. The outcomes for researchers will be community outcomes, that is, benefits for stakeholders outside the research team, such as generating new knowledge for teaming theory and disseminating best practices. Measuring these outcomes is the basis for the project’s evaluation plan

Distinguishing sequences for partially specified FSMs

Distinguishing Sequences (DSs) are used inmany Finite State Machine (FSM) based test techniques. Although Partially Specified FSMs (PSFSMs) generalise FSMs, the computational complexity of constructing Adaptive and Preset DSs (ADSs/PDSs) for PSFSMs has not been addressed. This paper shows that it is possible to check the existence of an ADS in polynomial time but the corresponding problem for PDSs is PSPACE-complete. We also report on the results of experiments with benchmarks and over 8 * 106 PSFSMs. © 2014 Springer International Publishing

Sarcoidosis presenting as Wallenberg syndrome and panuveitis

© 2018 The Authors Sarcoidosis is a multi-system disease with neurological involvement being one of the more rare manifestations. We report a case of a patient who presented with the lateral medullary syndrome and panuveitis as her initial manifestation of sarcoidosis. The patient\u27s course was further complicated by renal involvement. Lacrimal gland and renal biopsies showed noncaseating granulomas without evidence of infection, establishing the diagnosis. Intracranial vertebral artery involvement was confirmed by brain imaging. Bilateral hilar lymphadenopathy with upper lobe predominant nodules on chest imaging was consistent with asymptomatic pulmonary involvement. Systemic steroid therapy is indicated for treatment of ocular sarcoidosis, with standard stroke management indicated for the treatment of lateral medullary syndrome

Isoforms of U1-70k control subunit dynamics in the human spliceosomal U1 snRNP

Most human protein-encoding genes contain multiple exons that are spliced together, frequently in alternative arrangements, by the spliceosome. It is established that U1 snRNP is an essential component of the spliceosome, in human consisting of RNA and ten proteins, several of which are post- translationally modified and exist as multiple isoforms. Unresolved and challenging to investigate are the effects of these post translational modifications on the dynamics, interactions and stability of the particle. Using mass spectrometry we investigate the composition and dynamics of the native human U1 snRNP and compare native and recombinant complexes to isolate the effects of various subunits and isoforms on the overall stability. Our data reveal differential incorporation of four protein isoforms and dynamic interactions of subunits U1-A, U1-C and Sm-B/B’. Results also show that unstructured post- ranslationally modified C-terminal tails are responsible for the dynamics of Sm-B/B’ and U1-C and that their interactions with the Sm core are controlled by binding to different U1-70k isoforms and their phosphorylation status in vivo. These results therefore provide the important functional link between proteomics and structure as well as insight into the dynamic quaternary structure of the native U1 snRNP important for its function.This work was funded by: BBSRC (OVM), BBSRC and EPSRC (HH and NM), EU Prospects (HH), European Science Foundation (NM), the Royal Society (CVR), and fellowship from JSPS and HFSP (YM and DAPK respectively)

SMARTER Teamwork: System for Management, Assessment, Research, Training, Education, and Remediation for Teamwork

SMARTER Teamwork: System for Management, Assessment, Research, Training, Education, and Remediation for TeamworkThe rapid adoption of Team-Maker and the Comprehensive Assessment of Team MemberEffectiveness (CATME) tools for team formation and peer evaluation make it possible to extendtheir success to have a significant impact on the development of team skills in higher education.The web-based systems have been used by more than 110,000 students of more than 2400faculty at more than 500 institutions internationally—the figure below shows the growth of theuser base. 2400 The system has had 113,373 unique student users. 2200 Fitted curves are third order. 2000 1800 Faculty and staff 1600 1400 1200 Number of 1000 users 800 Institutions 600 400 Aug Oct. 2005 2012 200 0 0 1 2 3 4 5 6 7 Years since software was releasedThis paper and its accompanying poster will describe strategies for broadening the scope of thosetools into a complete system for the management of teamwork in undergraduate education. TheSystem for the Management, Assessment, Research, Training, Education, and Remediation ofTeamwork (SMARTER Teamwork) has three specific goals: 1) to equip students to work inteams by providing them with training and feedback, 2) to equip faculty to manage student teamsby providing them with information and tools to facilitate best practices, and 3) to equipresearchers to understand teams by broadening the system’s capabilities to collect additionaltypes of data so that a wider range of research questions can be studied through a secureresearcher interface. The three goals of the project support each other in hierarchical fashion:research informs faculty practice, faculty determine the students’ experience, which, if wellmanaged based on research findings, equips students to work in teams. Our strategies forachieving these goals are based on a well-accepted training model that has five elements:information, demonstration, practice, feedback, and remediation.The paper that will be submitted and the poster presented at the conference will focus on newfeatures of the system, the development of training materials, and the deployment of a partnerwebsite that shares information about the SMARTER tools for teamwork and provides basicinformation about teamwork and team management