Mapping mammalian synaptic connectivity

Mapping mammalian synaptic connectivity has long been an important goal of neuroscientists since it is considered crucial for explaining human perception and behavior. Yet, despite enormous efforts, the overwhelming complexity of the neural circuitry and the lack of appropriate techniques to unravel it have limited the success of efforts to map connectivity. However, recent technological advances designed to overcome the limitations of conventional methods for connectivity mapping may bring about a turning point. Here, we address the promises and pitfalls of these new mapping technologies.     

Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis.

c-Abl, a non-receptor tyrosine kinase, is activated by agents that damage DNA. This activation results in either arrest of the cell cycle in phase G1 or apoptotic cell death, both of which are dependent on the kinase activity of c-Abl. p73, a member of the p53 family of tumour-suppressor proteins, can also induce apoptosis. Here we show that the apoptotic activity of p73alpha requires the presence of functional, kinase-competent c-Abl. Furthermore, p73 and c-Abl can associate with each other, andthis binding is mediated by a PxxP motif in p73 and the SH3 domain of c-Abl. We find that p73 is a substrate of the c-Abl kinase and that the ability of c-Abl to phosphorylate p73 is markedly increased by gamma-irradiation. Moreover, p73 is phosphorylated in vivo in response to ionizing radiation. These findings define a pro-apoptotic signalling pathway involving p73 and c-Abl.     

Pursuing frequency standards and control: the invention of quartz clock technologies

The quartz clock, the first to replace the pendulum as the time standard and later a ubiquitous and highly influential technology, originated in research on means for determining frequency for the needs of telecommunication and the interests of its users. This article shows that a few groups in the US, Britain, Italy and the Netherlands developed technologies that enabled the construction of the new clock in 1927–28. To coordinate complex and large communication networks, the monopolistic American Telephone and Telegraph Company, and national laboratories needed to determine and maintain a common ‘standard’ frequency measurement unit. Exploiting novel piezoelectric quartz methods and valve electronics techniques, researchers in these organizations constructed a new crystal-based frequency standard. To ensure its accuracy they compared it to an accepted absolute standard - an astronomical clock, constructing thereby the first quartz clock. Other groups, however, had different, though connected, technological aims, which originated from the diverse interests of the industrial, governmental and academic institutes to which they belonged, and for which they needed to measure, control and manipulate with frequencies of electric oscillations. The present article suggests a comparative examination of the research and development paths of these groups on their incentives, the technological and scientific resources they utilized, and the kind of research carried out in the various institutional settings.     

Functional genomics reveal that the serine synthesis pathway is essential in breast cancer

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets.     

Measuring constants of nature: confirmation and determination in piezoelectricity

Exact measurements are a central practice of modern physics. In certain cases, they are essential for determining values of coefficients, for confirming theories, and for detecting the existence of effects. The history of piezoelectricity at the end of the nineteenth century reveals two different methods of exact measurement: a mathematical versus an “artisanal” approach. In the former, a scientist first carried out the experiment and later employed mathematical methods to reduce error. In the latter, a scientist physically manipulated the experimental apparatus to bypass possible sources of error before its performance. These two approaches were related to German theoreticians and to French experimentalists, respectively. However, affiliation with a particular school rather than nationality was the decisive factor in the differences between the two approaches. Despite differences, adherents of both approaches sought to attain high precision and to eliminate even small experimental errors.This history exhibits the complexity and flexibility of experiments and their analysis. It supports the claim of the “New Experimentalism” that theory does not supply complete directions for practical experimental decisions. An example for this is found in the way an experimental error was discovered (after incorrect results had already been published) only by a comparison to an earlier experiment rather than to a theory.     

From ultrasonic to frequency standards: Walter Cady’s discovery of the sharp resonance of crystals

In 1918–1919 Walter G. Cady was the first to recognize the significant electrical consequences of the fact that piezoelectric crystals resonate at very sharp, precise and stable frequencies. Cady was also the first to suggest the employment of these properties, first as frequency standards and then to control frequencies of electric circuits—an essential component in electronic technology. Cady’s discovery originated in the course of research on piezoelectric ultrasonic devices for submarine detection (sonar) during World War I. However, for the discovery Cady had to change his research programme to crystal resonance. This change followed Cady’s experimental findings and the scientific curiosity that they raised, and was helped by the termination of the war. Cady’s transition was also a move from “applied” research, aimed at improving a specific technology, to “pure” research lacking a clear practical aim. This article examines how Cady reached the discovery and his early ideas for its use. It shows that the discovery was not an instantaneous but a gradual achievement. It further suggests that disinterested “scientific” research (rather than “engineering” research) was needed in this process, while research aimed at design was required for the subsequent development of technological devices. I am very grateful to Chris McGahey for providing me with his research notes taken from Walter Cady’s diaries kept by the Rhode Island Historical Society, henceforth Diaries. I would like to thank Aharon (Arkee) Eviatar for linguistic comments, Ido Yavetz for our helpful discussion and Jed Buchwald for his thoughtful comments and editorial work. I thank the Lemelson Center in the National Museum for American History for a grant that enabled me to study Walter Guyton Cady Papers, 1903–1974, Archives Center, National Museum of American History (henceforth, ACNMAH) and the staff of the center, especially Alison Oswald, for their help. The following abbreviations are used: NB—Cady’s research notebooks kept at ACNMAH, AIP - Niels Bohr Library, American Institute of Physics, Cady’s dossier.