Formalization of Transform Methods using HOL Light

Transform methods, like Laplace and Fourier, are frequently used for analyzing the dynamical behaviour of engineering and physical systems, based on their transfer function, and frequency response or the solutions of their corresponding differential equations. In this paper, we present an ongoing project, which focuses on the higher-order logic formalization of transform methods using HOL Light theorem prover. In particular, we present the motivation of the formalization, which is followed by the related work. Next, we present the task completed so far while highlighting some of the challenges faced during the formalization. Finally, we present a roadmap to achieve our objectives, the current status and the future goals for this project.Comment: 15 Pages, CICM 201

What we talk about when we talk about capacitance measured with the voltage-clamp step method

Capacitance is a fundamental neuronal property. One common way to measure capacitance is to deliver a small voltage-clamp step that is long enough for the clamp current to come to steady state, and then to divide the integrated transient charge by the voltage-clamp step size. In an isopotential neuron, this method is known to measure the total cell capacitance. However, in a cell that is not isopotential, this measures only a fraction of the total capacitance. This has generally been thought of as measuring the capacitance of the “well-clamped” part of the membrane, but the exact meaning of this has been unclear. Here, we show that the capacitance measured in this way is a weighted sum of the total capacitance, where the weight for a given small patch of membrane is determined by the voltage deflection at that patch, as a fraction of the voltage-clamp step size. This quantifies precisely what it means to measure the capacitance of the “well-clamped” part of the neuron. Furthermore, it reveals that the voltage-clamp step method measures a well-defined quantity, one that may be more useful than the total cell capacitance for normalizing conductances measured in voltage-clamp in nonisopotential cells

The Global Groundwater Crisis

Groundwater depletion the world over poses a far greater threat to global water security than is currently acknowledged

HERALD (Health Economics using Routine Anonymised Linked Data)

<b>Background</b> Health economic analysis traditionally relies on patient derived questionnaire data, routine datasets, and outcomes data from experimental randomised control trials and other clinical studies, which are generally used as stand-alone datasets. Herein, we outline the potential implications of linking these datasets to give one single joined up data-resource for health economic analysis.<p></p> <b>Method</b> The linkage of individual level data from questionnaires with routinely-captured health care data allows the entire patient journey to be mapped both retrospectively and prospectively. We illustrate this with examples from an Ankylosing Spondylitis (AS) cohort by linking patient reported study dataset with the routinely collected general practitioner (GP) data, inpatient (IP) and outpatient (OP) datasets, and Accident and Emergency department data in Wales. The linked data system allows: (1) retrospective and prospective tracking of patient pathways through multiple healthcare facilities; (2) validation and clarification of patient-reported recall data, complementing the questionnaire/routine data information; (3) obtaining objective measure of the costs of chronic conditions for a longer time horizon, and during the pre-diagnosis period; (4) assessment of health service usage, referral histories, prescribed drugs and co-morbidities; and (5) profiling and stratification of patients relating to disease manifestation, lifestyles, co-morbidities, and associated costs.<p></p> <b>Results</b> Using the GP data system we tracked about 183 AS patients retrospectively and prospectively from the date of questionnaire completion to gather the following information: (a) number of GP events; (b) presence of a GP 'drug' read codes; and (c) the presence of a GP 'diagnostic' read codes. We tracked 236 and 296 AS patients through the OP and IP data systems respectively to count the number of OP visits; and IP admissions and duration. The results are presented under several patient stratification schemes based on disease severity, functions, age, sex, and the onset of disease symptoms.<p></p> <b>Conclusion</b> The linked data system offers unique opportunities for enhanced longitudinal health economic analysis not possible through the use of traditional isolated datasets. Additionally, this data linkage provides important information to improve diagnostic and referral pathways, and thus helps maximise clinical efficiency and efficiency in the use of resources

Across-Channel Timing Differences as a Potential Code for the Frequency of Pure Tones

When a pure tone or low-numbered harmonic is presented to a listener, the resulting travelling wave in the cochlea slows down at the portion of the basilar membrane (BM) tuned to the input frequency due to the filtering properties of the BM. This slowing is reflected in the phase of the response of neurons across the auditory nerve (AN) array. It has been suggested that the auditory system exploits these across-channel timing differences to encode the pitch of both pure tones and resolved harmonics in complex tones. Here, we report a quantitative analysis of previously published data on the response of guinea pig AN fibres, of a range of characteristic frequencies, to pure tones of different frequencies and levels. We conclude that although the use of across-channel timing cues provides an a priori attractive and plausible means of encoding pitch, many of the most obvious metrics for using that cue produce pitch estimates that are strongly influenced by the overall level and therefore are unlikely to provide a straightforward means for encoding the pitch of pure tones

Epigenetic regulation of CD44 in Hodgkin and non-Hodgkin lymphoma

<p>Abstract</p> <p>Background</p> <p>Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a hallmark of cancer. To assay its extent in human lymphoma, methylation of 24 TSG was analyzed in lymphoma-derived cell lines as well as in patient samples.</p> <p>Methods</p> <p>We screened for TSG methylation using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in 40 lymphoma-derived cell lines representing anaplastic large cell lymphoma, Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin lymphoma and mantle cell lymphoma (MCL) as well as in 50 primary lymphoma samples. The methylation status of differentially methylated <it>CD44 </it>was verified by methylation-specific PCR and bisulfite sequencing. Gene expression of <it>CD44 </it>and its reactivation by DNA demethylation was determined by quantitative real-time PCR and on the protein level by flow cytometry. Induction of apoptosis by anti-CD44 antibody was analyzed by annexin-V/PI staining and flow cytometry.</p> <p>Results</p> <p>On average 8 ± 2.8 of 24 TSG were methylated per lymphoma cell line and 2.4 ± 2 of 24 TSG in primary lymphomas, whereas 0/24 TSG were methylated in tonsils and blood mononuclear cells from healthy donors. Notably, we identified that <it>CD44 </it>was hypermethylated and transcriptionally silenced in all BL and most FL and DLBCL cell lines, but was usually unmethylated and expressed in MCL cell lines. Concordant results were obtained from primary lymphoma material: <it>CD44 </it>was not methylated in MCL patients (0/11) whereas <it>CD44 </it>was frequently hypermethylated in BL patients (18/29). In cell lines with <it>CD44 </it>hypermethylation, expression was re-inducible at mRNA and protein levels by treatment with the DNA demethylating agent 5-Aza-2'-deoxycytidine, confirming epigenetic regulation of <it>CD44</it>. CD44 ligation assays with a monoclonal anti-CD44 antibody showed that CD44 can mediate apoptosis in CD44⁺lymphoma cells. <it>CD44 </it>hypermethylated, CD44^-lymphoma cell lines were consistently resistant towards anti-CD44 induced apoptosis.</p> <p>Conclusion</p> <p>Our data show that <it>CD44 </it>is epigenetically regulated in lymphoma and undergoes <it>de novo </it>methylation in distinct lymphoma subtypes like BL. Thus <it>CD44 </it>may be a promising new epigenetic marker for diagnosis and a potential therapeutic target for the treatment of specific lymphoma subtypes.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Incorporating the social dimension into hydrogeochemical investigations for rural development: the Bir Al-Nas approach for socio-hydrogeology

A replicable multidisciplinary approach is presented for science-based groundwater management practices: Bir Al-Nas (Bottom-up IntegRated Approach for sustainabLe grouNdwater mAnagement in rural areaS). This approach provides a practical example of the concept of “socio-hydrogeology”, a way of incorporating the social dimension into hydrogeological investigations, as reinforced by the translation of the Arabic bir al-nas: “the people’s well”. To achieve this, hydrogeologists act as “social hydrologists” during their monitoring activities, which often bring them into contact with local communities and end users (and polluters) of water. Not only can they retrieve reliable information about traditional know-how and local issues, but they can also change the public perception of science/scientists to create the basis for mutual collaboration and understanding in view of implementing improved integrated groundwater management. The final outcomes are expected to be an increased awareness of communities at the local level and a clear understanding of their water issues and needs from the very early stages of the investigation. Although the importance of using such methods in groundwater analysis and management is widely recognized, hydrogeological investigations are currently dominated by sectorial approaches that are easier to implement but less sustainable. The pressure of population growth, the shift towards more water-dependent economies, climate change and its impact on water availability will require scientists to use a more integrated approach, such as Bir Al-Nas, when dealing with increasing water pollution and water-scarcity issues.A replicable multidisciplinary approach is presented for science-based groundwater management practices: Bir Al-Nas (Bottom-up IntegRated Approach for sustainabLe grouNdwater mAnagement in rural areaS). This approach provides a practical example of the concept of "socio-hydrogeology", a way of incorporating the social dimension into hydrogeological investigations, as reinforced by the translation of the Arabic bir al-nas: "the people's well". To achieve this, hydrogeologists act as "social hydrologists" during their monitoring activities, which often bring them into contact with local communities and end users (and polluters) of water. Not only can they retrieve reliable information about traditional know-how and local issues, but they can also change the public perception of science/scientists to create the basis for mutual collaboration and understanding in view of implementing improved integrated groundwater management. The final outcomes are expected to be an increased awareness of communities at the local level and a clear understanding of their water issues and needs from the very early stages of the investigation. Although the importance of using such methods in groundwater analysis and management is widely recognized, hydrogeological investigations are currently dominated by sectorial approaches that are easier to implement but less sustainable. The pressure of population growth, the shift towards more water-dependent economies, climate change and its impact on water availability will require scientists to use a more integrated approach, such as Bir Al-Nas, when dealing with increasing water pollution and water-scarcity issues