Cytoarchitectonic and dynamic origins of giant positive local field potentials in the dentate gyrus.

To determine why some pathways but not others produce sizable local field potentials (LFPs) and how far from the source can these be recorded, complementary experimental analyses and realistic modeling of specific brain structures are required. In the present study, we combined multiple in vivo linear recordings in rats and a tridimensional finite element model of the dentate gyrus, a curved structure displaying abnormally large positive LFPs. We demonstrate that the polarized dendritic arbour of granule cells (GCs), combined with the curved layered configuration of the population promote the spatial clustering of GC currents in the interposed hilus and project them through the open side at a distance from cell domains. LFPs grow up to 20 times larger than observed in synaptic sites. The dominant positive polarity of hilar LFPs was only produced by the synchronous activation of GCs in both blades by either somatic inhibition or dendritic excitation. Moreover, the corresponding anatomical pathways must project to both blades of the dentate gyrus as even a mild decrease in the spatial synchronization resulted in a dramatic reduction in LFP power in distant sites, yet not in the GC domains. It is concluded that the activation of layered structures may establish sharply delimited spatial domains where synaptic currents from one or another input appear to be segregated according to the topology of afferent pathways and the cytoarchitectonic features of the target population. These also determine preferred directions for volume conduction in the brain, of relevance for interpretation of surface EEG recordings.

Shaping biomedical objects across history and philosophy:a conversation with Hans-Jörg Rheinberger.

Historical epistemology, according to the historian of science Hans-Jörg Rheinberger, is a space through which "to take experimental laboratory work into the realm of philosophy". This key concept, together with the crucial events and challenges of his career, were discussed in a public conversation which took place on the occasion of Rheinberger's retirement. By making sense of natural phenomena in the laboratory, the act of experimenting shapes the object; it is this shaping which became the core of Rheinberger's own research across biology and philosophy into history. For his intellectual agenda, a history of the life sciences so constructed became "epistemologically demanding".

Between mice and sheep: Biotechnology, agricultural science and animal models in late-twentieth century Edinburgh.

In this paper, we investigate the ways in which a group of scientists in Edinburgh worked across mice and sheep during the last quarter of the twentieth century. With this local episode, we show the utility of an interspecies perspective to investigate recent historical transformations in the life sciences. We argue that the emergence of animal biotechnology was the result of interactions between neoliberal policymakers, science administrators, molecular biologists, agricultural breeders, and the laboratory and farm organisms with which they worked. During the early 1980s, all these actors believed that the exportation of genetic engineering techniques from mice to farm animals would lead to more effective breeding programmes in the agricultural sciences. However, the circulation of people, money, expertise and infrastructures that the experiments required, as well as the practical constraints of working with mice and sheep, resisted a simple scaling-up from one organism to the other. This displaced the goals of the Edinburgh scientists from the production of transgenic sheep to stem cell research and human regenerative medicine. We account for this unexpected shift by looking at the interplay between science policy and its implementation via collective action and bench work across different organisms. The emergence of animal biotechnology in Edinburgh also provides historiographical insights on the birth of Dolly the sheep and, more generally, on the interactions between the molecular and the reproductive sciences at the fall of the twentieth century.

Polarizability of shelled particles of arbitrary shape in lossy media with an application to hematic cells.

We show that within the dipole approximation the complex polarizability of shelled particles of arbitrary shape can be written as the volume of the particle times a weighted average of the electric field in the particle, with weights determined by the differences in permittivities between the shells and the external, possibly lossy media. To calculate the electric field we use an adaptive-mesh finite-element method which is very effective in handling the irregular domains, material inhomogeneities, and complex boundary conditions usually found in biophysical applications. After extensive tests with exactly solvable models, we apply the method to four types of hematic cells: platelets, T-lymphocytes, erythrocytes, and stomatocytes. Realistic shapes of erythrocytes and stomatocytes are generated by a parametrization in terms of Jacobi elliptic functions. Our results show, for example, that if the average polarizability is the main concern, a confocal ellipsoid may be used as a model for a normal erythrocyte, but not for a stomatocyte. A comparison with experimental electrorotation data shows quantitatively the effect of an accurate geometry in the derivation of electrical cell parameters from fittings of theoretical models to the experimental data.

Mapping and sequencing information: the social context for the genomics revolution.

In 1983, after devoting some eight years of his life to the description of how a nematode worm develops from an embryo into an adult, molecular biologist John Sulston embarked on a remarkably different project: he decided to map the worm's genome. Sulston's impulsive desire to characterise this creature's DNA from start to finish offers only a partial explanation for this transition. Instead, a close examination of the wider social context for this 'moment' in molecular biology gives a more rewarding explanation of Sulston's intellectual leap. This reveals a world in which biotechnology gradually adapted to and integrated into an 'information society' increasingly dependent on the creation, distribution and manipulation of information. The application of computing to DNA during the first half of the 1980s was crucial for this integration, fostering the emergence of genomics and ultimately the Human Genome Project.

The proactive historian: Methodological opportunities presented by the new archives documenting genomics.

In this paper, I propose a strategy for navigating newly available archives in the study of late-twentieth century genomics. I demonstrate that the alleged 'explosion of data' characteristic of genomics-and of contemporary science in general-is not a new problem and that historians of earlier periods have dealt with information overload by relying on the 'perspective of time': the filtering effect the passage of time naturally exerts on both sources and memories. I argue that this reliance on the selective capacity of time results in inheriting archives curated by others and, consequently, poses the risk of reifying ahistorical scientific discourses. Through a preliminary examination of archives documenting early attempts at mapping and sequencing the human genome, I propose an alternative approach, in which historians proactively problematize and improve available sources. This approach provides historians with a voice in the socio-political management of scientific heritage and advances methodological innovations in the use of oral histories. It also provides a narrative framework in which to address big science initiatives by following second order administrators, rather than individual scientists. The new genomic archives thus represent an opportunity for historians to take an active role in current debates concerning 'big data' and critically embed the humanities in pressing global problems.

Erythrocyte rouleau formation under polarized electromagnetic fields.

We study the influence of an external electromagnetic field of 1.8 GHz in the formation or disaggregation of long rouleau of identical erythrocyte cells. In particular we calculate the variation of the transmembrane potential of an individual erythrocyte illuminated by the external field due to the presence of the neighboring erythrocytes in the rouleau, and compare the total electric energy of isolated cells with the total electric energy of the rouleau. We show that the polarization of the external electromagnetic field plays a fundamental role in the total energy variation of the cell system, and consequently in the formation or disaggregation of rouleau.

Animal breeding in the age of biotechnology: the investigative pathway behind the cloning of Dolly the sheep.

This paper addresses the 1996 cloning of Dolly the sheep, locating it within a long-standing tradition of animal breeding research in Edinburgh. Far from being an end in itself, the cell-nuclear transfer experiment from which Dolly was born should be seen as a step in an investigative pathway that sought the production of medically relevant transgenic animals. By historicising Dolly, I illustrate how the birth of this sheep captures a dramatic redefinition of the life sciences, when in the 1970s and 1980s the rise of neo-liberal governments and the emergence of the biotechnology market pushed research institutions to show tangible applications of their work. Through this broader interpretative framework, the Dolly story emerges as a case study of the deep transformations of agricultural experimentation during the last third of the twentieth century. The reorganisation of laboratory practice, human resources and institutional settings required by the production of transgenic animals had unanticipated consequences. One of these unanticipated effects was that the boundaries between animal and human health became blurred. As a result of this, new professional spaces emerged and the identity of Dolly the sheep was reconfigured, from an instrument for livestock improvement in the farm to a more universal symbol of the new cloning age.

Source analysis of spontaneous magnetoencephalograpic activity in healthy aging and mild cognitive impairment: influence of apolipoprotein E polymorphism.

The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for the development of late-onset Alzheimer's disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ε4 allele. Sources of spectral variations in these groups were calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEε4 carriers showed an increased relative power in the 4.5-6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5-6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEε4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD, and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space.

The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

The Default Mode Network is functionally and structurally disrupted in amnestic mild cognitive impairment - a bimodal MEG-DTI study.

Over the past years, several studies on Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) have reported Default Mode Network (DMN) deficits. This network is attracting increasing interest in the AD community, as it seems to play an important role in cognitive functioning and in beta amyloid deposition. Attention has been particularly drawn to how different DMN regions are connected using functional or structural connectivity. To this end, most studies have used functional Magnetic Resonance Imaging (fMRI), Positron Emission Tomography (PET) or Diffusion Tensor Imaging (DTI). In this study we evaluated (1) functional connectivity from resting state magnetoencephalography (MEG) and (2) structural connectivity from DTI in 26 MCI patients and 31 age-matched controls. Compared to controls, the DMN in the MCI group was functionally disrupted in the alpha band, while no differences were found for delta, theta, beta and gamma frequency bands. In addition, structural disconnection could be assessed through a decreased fractional anisotropy along tracts connecting different DMN regions. This suggests that the DMN functional and anatomical disconnection could represent a core feature of MCI.

Synchronization during an internally directed cognitive state in healthy aging and mild cognitive impairment: a MEG study.

Mild cognitive impairment (MCI) is a stage between healthy aging and dementia. It is known that in this condition the connectivity patterns are altered in the resting state and during cognitive tasks, where an extra effort seems to be necessary to overcome cognitive decline. We aimed to determine the functional connectivity pattern required to deal with an internally directed cognitive state (IDICS) in healthy aging and MCI. This task differs from the most commonly employed ones in neurophysiology, since inhibition from external stimuli is needed, allowing the study of this control mechanism. To this end, magnetoencephalographic (MEG) signals were acquired from 32 healthy individuals and 38 MCI patients, both in resting state and while performing a subtraction task of two levels of difficulty. Functional connectivity was assessed with phase locking value (PLV) in five frequency bands. Compared to controls, MCIs showed higher PLV values in delta, theta, and gamma bands and an opposite pattern in alpha, beta, and gamma bands in resting state. These changes were associated with poorer neuropsychological performance. During the task, this group exhibited a hypersynchronization in delta, theta, beta, and gamma bands, which was also related to a lower cognitive performance, suggesting an abnormal functioning in this group. Contrary to controls, MCIs presented a lack of synchronization in the alpha band which may denote an inhibition deficit. Additionally, the magnitude of connectivity changes rose with the task difficulty in controls but not in MCIs, in line with the compensation-related utilization of neural circuits hypothesis (CRUNCH) model.

Brain-wide slowing of spontaneous alpha rhythms in mild cognitive impairment.

The neurophysiological changes associated with Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) include an increase in low frequency activity, as measured with electroencephalography or magnetoencephalography (MEG). A relevant property of spectral measures is the alpha peak, which corresponds to the dominant alpha rhythm. Here we studied the spatial distribution of MEG resting state alpha peak frequency and amplitude values in a sample of 27 MCI patients and 24 age-matched healthy controls. Power spectra were reconstructed in source space with linearly constrained minimum variance beamformer. Then, 88 Regions of Interest (ROIs) were defined and an alpha peak per ROI and subject was identified. Statistical analyses were performed at every ROI, accounting for age, sex and educational level. Peak frequency was significantly decreased (p < 0.05) in MCIs in many posterior ROIs. The average peak frequency over all ROIs was 9.68 ± 0.71 Hz for controls and 9.05 ± 0.90 Hz for MCIs and the average normalized amplitude was (2.57 ± 0.59)·10(-2) for controls and (2.70 ± 0.49)·10(-2) for MCIs. Age and gender were also found to play a role in the alpha peak, since its frequency was higher in females than in males in posterior ROIs and correlated negatively with age in frontal ROIs. Furthermore, we examined the dependence of peak parameters with hippocampal volume, which is a commonly used marker of early structural AD-related damage. Peak frequency was positively correlated with hippocampal volume in many posterior ROIs. Overall, these findings indicate a pathological alpha slowing in MCI.

From the genetic to the computer program: the historicity of 'data' and 'computation' in the investigations on the nematode worm C. elegans (1963-1998).

This paper argues that the history of the computer, of the practice of computation and of the notions of 'data' and 'programme' are essential for a critical account of the emergence and implications of data-driven research. In order to show this, I focus on the transition that the investigations on the worm C. elegans experienced in the Laboratory of Molecular Biology of Cambridge (UK). Throughout the 1980s, this research programme evolved from a study of the genetic basis of the worm's development and behaviour to a DNA mapping and sequencing initiative. By examining the changing computing technologies which were used at the Laboratory, I demonstrate that by the time of this transition researchers shifted from modelling the worm's genetic programme on a mainframe apparatus to writing minicomputer programs aimed at providing map and sequence data which was then circulated to other groups working on the genetics of C. elegans. The shift in the worm research should thus not be simply explained in the application of computers which transformed the project from hypothesis-driven to a data-intensive endeavour. The key factor was rather a historically specific technology-in-house and easy programmable minicomputers-which redefined the way of achieving the project's long-standing goal, leading the genetic programme to co-evolve with the practices of data production and distribution.

From metaphor to practices: The introduction of "information engineers" into the first DNA sequence database.

This paper explores the introduction of professional systems engineers and information management practices into the first centralized DNA sequence database, developed at the European Molecular Biology Laboratory (EMBL) during the 1980s. In so doing, it complements the literature on the emergence of an information discourse after World War II and its subsequent influence in biological research. By the careers of the database creators and the computer algorithms they designed, analyzing, from the mid-1960s onwards information in biology gradually shifted from a pervasive metaphor to be embodied in practices and professionals such as those incorporated at the EMBL. I then investigate the reception of these database professionals by the EMBL biological staff, which evolved from initial disregard to necessary collaboration as the relationship between DNA, genes, and proteins turned out to be more complex than expected. The trajectories of the database professionals at the EMBL suggest that the initial subject matter of the historiography of genomics should be the long-standing practices that emerged after World War II and to a large extent originated outside biomedicine and academia. Only after addressing these practices, historians may turn to their further disciplinary assemblage in fields such as bioinformatics or biotechnology.

Academic and molecular matrices: a study of the transformations of connective tissue research at the University of Manchester (1947-1996).

This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations.

Electromechanical effects on multilayered cells in nonuniform rotating fields.

We use the Maxwell stress tensor to calculate the dielectrophoretic force and electrorotational torque acting on a realistic four-shelled model of the yeast Saccharomyces cerevisiae in a nonuniform rotating electric field generated by four coplanar square electrodes. The comparison of these results with numerical calculations of the dipolar and quadrupolar contributions obtained from an integral equation for the polarization charge density shows the effect of the quadrupole contribution in the proximity of the electrode plane. We also show that under typical experimental conditions the substitution of the multilayered cell by an equivalent cell with homogeneous permittivity underestimates the quadrupole contribution to the force and torque by 1 order of magnitude.

A new insight into Sanger's development of sequencing: from proteins to DNA, 1943-1977.

Fred Sanger, the inventor of the first protein, RNA and DNA sequencing methods, has traditionally been seen as a technical scientist, engaged in laboratory bench work and not interested at all in intellectual debates in biology. In his autobiography and commentaries by fellow researchers, he is portrayed as having a trajectory exclusively dependent on technological progress. The scarce historical scholarship on Sanger partially challenges these accounts by highlighting the importance of professional contacts, institutional and disciplinary moves in his career, spanning from 1940 to 1983. This paper will complement such literature by focusing, for the first time, on the transition of Sanger's sequencing strategies from degrading to copying the target molecule, which occurred in the late 1960s as he was shifting from protein and RNA to DNA sequencing, shortly after his move from the Department of Biochemistry to the Laboratory of Molecular Biology, both based in Cambridge (U.K.). Through a reinterpretation of Sanger's papers and retrospective accounts and a pioneering investigation of his laboratory notebooks, I will claim that sequencing shifted from the working procedures of organic chemistry to those of the emergent molecular biology. I will also argue that sequencing deserves a history in its own right as a practice and not as a technique subordinated to the development of molecular biology or genomics. My proposed history of sequencing leads to a reappraisal of current STS debates on bioinformatics, biotechnology and biomedicine.