β-adrenergic-mediated dynamic augmentation of sarcolemmal CaV 1.2 clustering and co-operativity in ventricular myocytes.

Key pointsPrevailing dogma holds that activation of the β-adrenergic receptor/cAMP/protein kinase A signalling pathway leads to enhanced L-type CaV 1.2 channel activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. However, the full mechanistic and molecular details underlying this phenomenon are incompletely understood. CaV 1.2 channel clusters decorate T-tubule sarcolemmas of ventricular myocytes. Within clusters, nanometer proximity between channels permits Ca2+ -dependent co-operative gating behaviour mediated by physical interactions between adjacent channel C-terminal tails. We report that stimulation of cardiomyocytes with isoproterenol, evokes dynamic, protein kinase A-dependent augmentation of CaV 1.2 channel abundance along cardiomyocyte T-tubules, resulting in the appearance of channel 'super-clusters', and enhanced channel co-operativity that amplifies Ca2+ influx. On the basis of these data, we suggest a new model in which a sub-sarcolemmal pool of pre-synthesized CaV 1.2 channels resides in cardiomyocytes and can be mobilized to the membrane in times of high haemodynamic or metabolic demand, to tune excitation-contraction coupling.AbstractVoltage-dependent L-type CaV 1.2 channels play an indispensable role in cardiac excitation-contraction coupling. Activation of the β-adrenergic receptor (βAR)/cAMP/protein kinase A (PKA) signalling pathway leads to enhanced CaV 1.2 activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. CaV 1.2 channels exhibit a clustered distribution along the T-tubule sarcolemma of ventricular myocytes where nanometer proximity between channels permits Ca2+ -dependent co-operative gating behaviour mediated by dynamic, physical, allosteric interactions between adjacent channel C-terminal tails. This amplifies Ca2+ influx and augments myocyte Ca2+ transient and contraction amplitudes. We investigated whether βAR signalling could alter CaV 1.2 channel clustering to facilitate co-operative channel interactions and elevate Ca2+ influx in ventricular myocytes. Bimolecular fluorescence complementation experiments reveal that the βAR agonist, isoproterenol (ISO), promotes enhanced CaV 1.2-CaV 1.2 physical interactions. Super-resolution nanoscopy and dynamic channel tracking indicate that these interactions are expedited by enhanced spatial proximity between channels, resulting in the appearance of CaV 1.2 'super-clusters' along the z-lines of ISO-stimulated cardiomyocytes. The mechanism that leads to super-cluster formation involves rapid, dynamic augmentation of sarcolemmal CaV 1.2 channel abundance after ISO application. Optical and electrophysiological single channel recordings confirm that these newly inserted channels are functional and contribute to overt co-operative gating behaviour of CaV 1.2 channels in ISO stimulated myocytes. The results of the present study reveal a new facet of βAR-mediated regulation of CaV 1.2 channels in the heart and support the novel concept that a pre-synthesized pool of sub-sarcolemmal CaV 1.2 channel-containing vesicles/endosomes resides in cardiomyocytes and can be mobilized to the sarcolemma to tune excitation-contraction coupling to meet metabolic and/or haemodynamic demands

Non-Locality and Theories of Causation

The aim of the paper is to investigate the characterization of an unambiguous notion of causation linking single space-llike separated events in EPR-Bell frameworks. This issue is investigated in ordinary quantum mechanics, with some hints to no collapse formulations of the theory such as Bohmian mechanics.Comment: Presented at the NATO Advanced Research Workshop on Modality, Probability and Bell's Theorems, Cracow, Poland, August 19-23, 200

Rethinking place and the social work office in the delivery of children's social work services

Limited attention has been given to the concept of place in social work research and practice. This paper draws on the national evaluation of social work practices (SWPs) in England undertaken between 2009 and 2012. SWPs were pilot organisations providing independent social work services for children in out-of-home care in five sites. One factor distinguishing some of these pilots was their attention to place. The evaluation employed a mixed methods approach and we use data from interviews with 121 children and young people in out-of-home care, 19 birth parents and 31 interviews with SWP staff which explored their views and experiences of the SWP offices. Children and young people were alert to the stigma which could attach to social work premises and appreciated offices which were planned and furnished to appear less institutional and more ‘normal’. Daily interactions with staff which conveyed a sense of recognition and value to service users also contributed to a view of some SWP offices as accessible and welcoming places. Both children and parents appreciated offices that provided fun activities that positioned them as active rather than passive. Staff valued opportunities for influencing planning decisions about offices and place was seen to confer a value on them as well as on service users. However, not all the SWPs were able to achieve these aspects of place, and engaging children and families in place was less likely when the service user population was widely dispersed. Recognising the importance of place and how place is constructed through relationships between people as well as through the physical environment appeared to be key to creating offices that combated the stigma attached to out-of-home care. Those leading and managing children’s services should explore ways of involving local communities in planning social work offices and turn attention to making these offices accessible, welcoming, places

Algebro-Geometric Solutions of the Boussinesq Hierarchy

We continue a recently developed systematic approach to the Bousinesq (Bsq) hierarchy and its algebro-geometric solutions. Our formalism includes a recursive construction of Lax pairs and establishes associated Burchnall-Chaundy curves, Baker-Akhiezer functions and Dubrovin-type equations for analogs of Dirichlet and Neumann divisors. The principal aim of this paper is a detailed theta function representation of all algebro-geometric quasi-periodic solutions and related quantities of the Bsq hierarchy.Comment: LaTeX, 48 page

Implications of the Partial Ring Design for a Clinical SPECT Insert

The INSERT system is a stationary SPECT insert designed for clinical SPECT/MRI. The system has been evaluated as a standalone SPECT scanner and here the image reconstruction is evaluated to determine the implications of its design. A two-step image acquisition can be implemented to overcome the limitations of the partial ring design. The image quality and activity linearity are evaluated through a set of point sources and vials of varying activity concentration. The evaluation highlighted areas where image reconstruction and data processing needed to improve before proceeding to simultaneous SPECT/MRI acquisitions. We have shown that the proposed dual acquisition method can produce improved image quality through the use of modified data acquisition and reconstruction protocols

PKS2250-41: a case study for triggering

We present the results of a multiwavelength study of the z = 0.31 radio source PKS2250-41. Integral field unit and long-slit spectroscopy obtained using VIMOS and FORS1 on the VLT, and archival HST optical imaging observations are used to study the morphology, kinematics and ionisation state of the extended emission line region (EELR) surrounding this source, and also a companion galaxy at a similar redshift. Near-infrared imaging observations obtained using the NTT are used to analyse the underlying galaxy morphologies. The EELR displays a complex variety of different gas kinematics and ionization states, consistent with a mixture of radio source shocks and AGN photoionization. The radio galaxy is likely to lie within a group environment, and is plausibly undergoing interactions with one or more other objects. The disk-like galaxy to the northeast of the radio source lies at a similar redshift to the radio galaxy itself, and has its major axis position angle aligned with the filamentary continuum and line emission extending outwards from the radio galaxy. This filamentary structure is most plausibly interpreted as a tidal structure associated with an interaction involving the radio source host galaxy and the aligned companion galaxy to the north-east; this encounter may have potentially triggered the current epoch of radio source activity. Overall, PKS2250-41 displays some of the best evidence that radio source activity can be triggered in this manner. [abridged]Comment: 16 pages, 13 figures (some colour). Accepted for publication in MNRAS. Abstract abridge

Fatal COVID-19 infection in a patient with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A case report

Long-chain fatty-acyl CoA dehydrogenase deficiency (LCHADD) is an inborn error of long chain fatty acid oxidation with various features including hypoketotic hypoglycemia, recurrent rhabdomyolysis, pigmentary retinopathy, peripheral neuropathy, cardiomyopathy, and arrhythmias. Various stresses trigger metabolic decompensation. Coronavirus disease 2019 (COVID-19) is a pandemic caused by the RNA virus SARS-CoV-2 with diverse presentations ranging from respiratory symptoms to myocarditis. We report a case of a patient with LCHADD who initially presented with typical metabolic decompensation symptoms including nausea, vomiting, and rhabdomyolysis in addition to mild cough, and was found to have COVID-19. She developed acute respiratory failure and refractory hypotension from severe cardiomyopathy which progressed to multiple organ failure and death. Our case illustrates the need for close monitoring of cardiac function in patients with a long-chain fatty acid oxidation disorder

Elliptic Solitons and Groebner Bases

We consider the solution of spectral problems with elliptic coefficients in the framework of the Hermite ansatz. We show that the search for exactly solvable potentials and their spectral characteristics is reduced to a system of polynomial equations solvable by the Gr\"obner bases method and others. New integrable potentials and corresponding solutions of the Sawada-Kotera, Kaup-Kupershmidt, Boussinesq equations and others are found.Comment: 18 pages, no figures, LaTeX'2