Immanence and Causation in Spinoza

I defend an expanded reading of immanent causation that includes both inherence and causal efficacy; I argue that the latter is required if God is to remain the immanent cause of finite modes

ATPase cycle and DNA unwinding kinetics of RecG helicase

The superfamily 2 bacterial helicase, RecG, is a monomeric enzyme with a role in DNA repair by reversing stalled replication forks. The helicase must act specifically and rapidly to prevent replication fork collapse. We have shown that RecG binds tightly and rapidly to four-strand oligonucleotide junctions, which mimic a stalled replication fork. The helicase unwinds such DNA junctions with a step-size of approximately four bases per ATP hydrolyzed. To gain an insight into this mechanism, we used fluorescent stopped-flow and quenched-flow to measure individual steps within the ATPase cycle of RecG, when bound to a DNA junction. The fluorescent ATP analogue, mantATP, was used throughout to determine the rate limiting steps, effects due to DNA and the main states in the cycle. Measurements, when possible, were also performed with unlabeled ATP to confirm the mechanism. The data show that the chemical step of hydrolysis is the rate limiting step in the cycle and that this step is greatly accelerated by bound DNA. The ADP release rate is similar to the cleavage rate, so that bound ATP and ADP would be the main states during the ATP cycle. Evidence is provided that the main structural rearrangements, which bring about DNA unwinding, are linked to these states

Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations

Epstein-Barr virus (EBV) is a highly successful herpesvirus, colonizing more than 90% of the adult human population worldwide, although it is also associated with various malignant diseases. Primary infection is usually clinically silent, and subsequent establishment of latency in the memory B lymphocyte compartment allows persistence of the virus in the infected host for life. EBV is so markedly B-lymphotropic when exposed to human lymphocytes in vitro that the association of EBV with rare but distinct types of T and NK cell lymphoproliferations was quite unexpected. Whilst relatively rare, these EBV-associated T and NK lymphoproliferations can be therapeutically challenging and prognosis for the majority of patients is dismal. In this review, we summarize the current knowledge on the role of EBV in the pathogenesis of these tumours, and the implications for treatment. \ud \u

Risk across design domains

Design processes involve risk: to life and limb if the product is unsafe, to the financial health of the company if the product is late, unsuccessful or simply the wrong product, as well as to the emotions and careers of the designers. Many of the risks are shared universally by all designers, but each different industry and each different project faces its own spectrum of serious and minor risks. Different industries have put their methodological effort into finding ways to mitigate the risks they recognise as important. As part of the Across Design project exploring similarities and differences between design processes in different industries, this paper examines how risks are perceived and handled in different types of design process, and proposes that designers and managers can usefully look to other industries for ways to handle risks that are more central for those other industries

The ATPase cycle of PcrA helicase and its coupling to translocation on DNA.

The superfamily 1 bacterial helicase PcrA has a role in the replication of certain plasmids, acting with the initiator protein (RepD) that binds to and nicks the double-stranded origin of replication. PcrA also translocates single-stranded DNA with discrete steps of one base per ATP hydrolyzed. Individual rate constants have been determined for the DNA helicase PcrA ATPase cycle when bound to either single-stranded DNA or a double-stranded DNA junction that also has RepD bound. The fluorescent ATP analogue 2'(3')-O-(N-methylanthraniloyl)ATP was used throughout all experiments to provide a complete ATPase cycle for a single nucleotide species. Fluorescence intensity and anisotropy stopped-flow measurements were used to determine rate constants for binding and release. Quenched-flow measurements provided the kinetics of the hydrolytic cleavage step. The fluorescent phosphate sensor MDCC-PBP was used to measure phosphate release kinetics. The chemical cleavage step is the rate-limiting step in the cycle and is essentially irreversible and would result in the bound ATP complex being a major component at steady state. This cleavage step is greatly accelerated by bound DNA, producing the high activation of this protein compared to the protein alone. The data suggest the possibility that ADP is released in two steps, which would result in bound ADP also being a major intermediate, with bound ADP.P(i) being a very small component. It therefore seems likely that the major transition in structure occurs during the cleavage step, rather than P(i) release. ATP rebinding could then cause reversal of this structural transition. The kinetic mechanism of the PcrA ATPase cycle is very little changed by potential binding to RepD, supporting the idea that RepD increases the processivity of PcrA by increasing affinity to DNA rather than affecting the enzymatic properties per se

HIV-positive status among surgeons - an ethical dilemma

HIV/AIDS is a manageable disease with a reasonable expectation that affected individuals might be able to experience both reduced mortality and morbidity. Within the socio-political context of the illness there has been a very strong emphasis on human rights issues, especially in relation to discrimination, which has seemingly been influenced more by emotion than science. This article explores and addresses the potential risk of an HIV-positive surgeon transmitting the virus to a patient. We argue that the Centers for Disease Control (CDC) and Health Professions Council of South Africa (HPCSA) guidelines are too restrictive, especially against a background of limited transmission risk, and hence that these guidelines could be more harmful than beneficial to our health systems

Programmable toys and free play in early childhood classrooms

This paper reports on a study that investigated the ways that young children interact with discrete programmable digital toys in a free play setting. One intention was to see whether this interaction would address some of the requirements of the Digital Technologies subject in the Australian Curriculum. The study was implemented in two phases in consecutive years involving teachers and students from two early childhood classes. Researchers worked with the teachers to provide the children with opportunities to use two types of digital toys - the Sphero and the Beebot. The children were observed as they interacted with these toys and their interactions analysed using a checklist of behaviours. It was found that without some explicit scaffolding the children did not tend to demonstrate any actions that could be associated with an understanding of ‘algorithms’. However, they did demonstrate motivation, engagement, and increased proficiency and recognition with using the hardware and software of these digital systems

Does heat or cold work better for acute muscle strain?

Cryotherapy is better than heat for treating acute muscle strain (strength of recommendation [SOR]: C, consensus, usual practice, and expert opinion). Insufficient patient-oriented evidence exists regarding use of heat to treat acute soft-tissue injuries