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Background: The purinergic ATP-gated P2X7 receptor (P2X7R) is increasingly recognized to contribute to pathological neuroinflammation and brain hyperexcitability. P2X7R expression has been shown to be increased in the brain, including both microglia and neurons, in experimental models of epilepsy and patients. To date, the cell type-specific downstream effects of P2X7Rs during seizures remain, however, incompletely understood. Methods: Effects of P2X7R signaling on seizures and epilepsy were analyzed in induced seizure models using male mice including the kainic acid model of status epilepticus and pentylenetetrazole model and in male and female mice in a genetic model of Dravet syndrome. RNA sequencing was used to analyze P2X7R downstream signaling during seizures. To investigate the cell type-specific role of the P2X7R during seizures and epilepsy, we generated mice lacking exon 2 of the P2rx7 gene in either microglia (P2rx7:Cx3cr1-Cre) or neurons (P2rx7:Thy-1-Cre). To investigate the protective potential of overexpressing P2X7R in GABAergic interneurons, P2X7Rs were overexpressed using adeno-associated virus transduction under the mDlx promoter. Results: RNA sequencing of hippocampal tissue from wild-type and P2X7R knock-out mice identified both glial and neuronal genes, in particular genes involved in GABAergic signaling, under the control of the P2X7R following seizures. Mice with deleted P2rx7 in microglia displayed less severe acute seizures and developed a milder form of epilepsy, and microglia displayed an anti-inflammatory molecular profile. In contrast, mice lacking P2rx7 in neurons showed a more severe seizure phenotype when compared to epileptic wild-type mice. Analysis of single-cell expression data revealed that human P2RX7 expression is elevated in the hippocampus of patients with temporal lobe epilepsy in excitatory and inhibitory neurons. Functional studies determined that GABAergic interneurons display increased responses to P2X7R activation in ex, European Commission, Ministerio de Ciencia e Innovación (España), Sección Deptal. de Farmacología y Toxicología (Veterinaria), Depto. de Optometría y Visión, Fac. de Veterinaria, Fac. de Óptica y Optometría, TRUE, pub

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Electrochemical jet processing techniques provide an efficient method for large area surface structuring and micro-milling, where the metallurgy of the near-surface is assured and not adversely affected by thermal loading. Here, doped electrolytes are specifically developed for jet techniques to exploit the Gaussian energy distribution as found in energy beam processes. This allows up to 26% reduction in dissolution kerf and enhancements of the defined precision metric of up to 284% when compared to standard electrolytes. This is achieved through the filtering of low energy at discrete points within the energy distribution curve. Two fundamental mechanisms of current filtering and refresh rate are proposed and investigated in order to underpin the performance enhancements found using this methodology. This study aims to demonstrate that a step change in process fidelity and flexibility can be achieved through optimisation of the electrochemistry specific to jet processes.

The increasing demand for optimised component surfaces with enhanced chemical and geometric complexity is a key driver in the manufacturing technology required for advanced surface production. Current methodologies cannot create complex surfaces in an efficient and scalable manner in robust engineering materials. Hence, there is a need for advanced manufacturing technologies which overcome this. Current technologies are limited by resolution, geometric flexibility and mode of energy delivery. By addressing the fundamental limitations of electrochemical jetting techniques through modulation of the current density distribution by mechanical design, significant improvements to the electrochemical jet process methods are presented. A simplified 2D stochastic model was developed with the ability to vary current density distribution to assess the effects of nozzle-tip shape changes. The simulation demonstrated that the resultant profile was found to be variable from that of a standard nozzle. These nozzle-tip modifications were then experimentally tested finding a high degree of variance was possible in the machined profile. Improvements such as an increase in side-wall steepness of 162% are achieved over a standard profile, flat bases to the cut profile and a reduction of profile to surface inter-section radius enable the process to be analogous to traditional milling profiles. Since electrode design can be rapidly modified EJP is shown to be a flexible process capable of varied and complex meso-scale profile creation. Innovations presented here in the modulation of resistance in-jet have enabled electrochemical jet processes to become a viable, top-down, single-step method for applying complex surfaces geometries unachievable by other means.

Traditional methods for achieving hierarchical surface structures include highly specified, deterministic approaches to create features to meet design intention. In this study microstructural alteration was undertaken using laser apparatus and secondary texturing was achieved via succeeding electrochemical processes. Electrochemical jet machining (EJM) was performed on mild steel subjected to laser pre-treatment using power densities of 4167 and 5556 W/cm2 with pulse durations from 0.3 - 1.5 seconds. Results show that in combination, laser pre-treatment and EJM can alter the exposed surface textures and chemistries. Here, machined surface roughness (Sa) was shown to increase from approximately 0.45 µm for untreated surfaces to approximately 18 µm for surfaces subjected to extreme laser pretreatments. After pre-treatments materials were characterised to appraise microstructural changes, shown to be martensite formation, reinforced by complementary simulation data, and significant increases in observable hardness from approximately 261 HV for the asreceived material to over 700 HV after pre-treatment. The greater hardness was retained after EJM. Exposed martensitic lath structures at machined surfaces are shown to be partially responsible for surface roughness increases. The surfaces were explored with energy dispersive X-ray spectroscopy (EDS) and Raman spectroscopy demonstrating changes in apparent surface chemistry. This analysis revealed increasing oxide formation at the surface of the pre-treated EJM surface, a further contributory factor to surface roughness increases. This new process chain will be of interest to manufacturers seeking to control surface morphology for applications including micro-injection mould/die manufacture. While demonstrated here for steel similar mechanisms are exploitable in other material systems. A new technique has been demonstrated, resulting from the models and processes presented to couple laser and electrolyte jet processing for

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Electrochemical jet processing techniques provide an efficient method for large area surface structuring and micro-milling, where the metallurgy of the near-surface is assured and not adversely affected by thermal loading. Here, doped electrolytes are specifically developed for jet techniques to exploit the Gaussian energy distribution as found in energy beam processes. This allows up to 26% reduction in dissolution kerf and enhancements of the defined precision metric of up to 284% when compared to standard electrolytes. This is achieved through the filtering of low energy at discrete points within the energy distribution curve. Two fundamental mechanisms of current filtering and refresh rate are proposed and investigated in order to underpin the performance enhancements found using this methodology. This study aims to demonstrate that a step change in process fidelity and flexibility can be achieved through optimisation of the electrochemistry specific to jet processes.

The increasing demand for optimised component surfaces with enhanced chemical and geometric complexity is a key driver in the manufacturing technology required for advanced surface production. Current methodologies cannot create complex surfaces in an efficient and scalable manner in robust engineering materials. Hence, there is a need for advanced manufacturing technologies which overcome this. Current technologies are limited by resolution, geometric flexibility and mode of energy delivery. By addressing the fundamental limitations of electrochemical jetting techniques through modulation of the current density distribution by mechanical design, significant improvements to the electrochemical jet process methods are presented. A simplified 2D stochastic model was developed with the ability to vary current density distribution to assess the effects of nozzle-tip shape changes. The simulation demonstrated that the resultant profile was found to be variable from that of a standard nozzle. These nozzle-tip modifications were then experimentally tested finding a high degree of variance was possible in the machined profile. Improvements such as an increase in side-wall steepness of 162% are achieved over a standard profile, flat bases to the cut profile and a reduction of profile to surface inter-section radius enable the process to be analogous to traditional milling profiles. Since electrode design can be rapidly modified EJP is shown to be a flexible process capable of varied and complex meso-scale profile creation. Innovations presented here in the modulation of resistance in-jet have enabled electrochemical jet processes to become a viable, top-down, single-step method for applying complex surfaces geometries unachievable by other means.

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Electrochemical jet processing techniques provide an efficient method for large area surface structuring and micro-milling, where the metallurgy of the near-surface is assured and not adversely affected by thermal loading. Here, doped electrolytes are specifically developed for jet techniques to exploit the Gaussian energy distribution as found in energy beam processes. This allows up to 26% reduction in dissolution kerf and enhancements of the defined precision metric of up to 284% when compared to standard electrolytes. This is achieved through the filtering of low energy at discrete points within the energy distribution curve. Two fundamental mechanisms of current filtering and refresh rate are proposed and investigated in order to underpin the performance enhancements found using this methodology. This study aims to demonstrate that a step change in process fidelity and flexibility can be achieved through optimisation of the electrochemistry specific to jet processes.

The increasing demand for optimised component surfaces with enhanced chemical and geometric complexity is a key driver in the manufacturing technology required for advanced surface production. Current methodologies cannot create complex surfaces in an efficient and scalable manner in robust engineering materials. Hence, there is a need for advanced manufacturing technologies which overcome this. Current technologies are limited by resolution, geometric flexibility and mode of energy delivery. By addressing the fundamental limitations of electrochemical jetting techniques through modulation of the current density distribution by mechanical design, significant improvements to the electrochemical jet process methods are presented. A simplified 2D stochastic model was developed with the ability to vary current density distribution to assess the effects of nozzle-tip shape changes. The simulation demonstrated that the resultant profile was found to be variable from that of a standard nozzle. These nozzle-tip modifications were then experimentally tested finding a high degree of variance was possible in the machined profile. Improvements such as an increase in side-wall steepness of 162% are achieved over a standard profile, flat bases to the cut profile and a reduction of profile to surface inter-section radius enable the process to be analogous to traditional milling profiles. Since electrode design can be rapidly modified EJP is shown to be a flexible process capable of varied and complex meso-scale profile creation. Innovations presented here in the modulation of resistance in-jet have enabled electrochemical jet processes to become a viable, top-down, single-step method for applying complex surfaces geometries unachievable by other means.

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Electrochemical jet processing techniques provide an efficient method for large area surface structuring and micro-milling, where the metallurgy of the near-surface is assured and not adversely affected by thermal loading. Here, doped electrolytes are specifically developed for jet techniques to exploit the Gaussian energy distribution as found in energy beam processes. This allows up to 26% reduction in dissolution kerf and enhancements of the defined precision metric of up to 284% when compared to standard electrolytes. This is achieved through the filtering of low energy at discrete points within the energy distribution curve. Two fundamental mechanisms of current filtering and refresh rate are proposed and investigated in order to underpin the performance enhancements found using this methodology. This study aims to demonstrate that a step change in process fidelity and flexibility can be achieved through optimisation of the electrochemistry specific to jet processes.

The increasing demand for optimised component surfaces with enhanced chemical and geometric complexity is a key driver in the manufacturing technology required for advanced surface production. Current methodologies cannot create complex surfaces in an efficient and scalable manner in robust engineering materials. Hence, there is a need for advanced manufacturing technologies which overcome this. Current technologies are limited by resolution, geometric flexibility and mode of energy delivery. By addressing the fundamental limitations of electrochemical jetting techniques through modulation of the current density distribution by mechanical design, significant improvements to the electrochemical jet process methods are presented. A simplified 2D stochastic model was developed with the ability to vary current density distribution to assess the effects of nozzle-tip shape changes. The simulation demonstrated that the resultant profile was found to be variable from that of a standard nozzle. These nozzle-tip modifications were then experimentally tested finding a high degree of variance was possible in the machined profile. Improvements such as an increase in side-wall steepness of 162% are achieved over a standard profile, flat bases to the cut profile and a reduction of profile to surface inter-section radius enable the process to be analogous to traditional milling profiles. Since electrode design can be rapidly modified EJP is shown to be a flexible process capable of varied and complex meso-scale profile creation. Innovations presented here in the modulation of resistance in-jet have enabled electrochemical jet processes to become a viable, top-down, single-step method for applying complex surfaces geometries unachievable by other means.

Traditional methods for achieving hierarchical surface structures include highly specified, deterministic approaches to create features to meet design intention. In this study microstructural alteration was undertaken using laser apparatus and secondary texturing was achieved via succeeding electrochemical processes. Electrochemical jet machining (EJM) was performed on mild steel subjected to laser pre-treatment using power densities of 4167 and 5556 W/cm2 with pulse durations from 0.3 - 1.5 seconds. Results show that in combination, laser pre-treatment and EJM can alter the exposed surface textures and chemistries. Here, machined surface roughness (Sa) was shown to increase from approximately 0.45 µm for untreated surfaces to approximately 18 µm for surfaces subjected to extreme laser pretreatments. After pre-treatments materials were characterised to appraise microstructural changes, shown to be martensite formation, reinforced by complementary simulation data, and significant increases in observable hardness from approximately 261 HV for the asreceived material to over 700 HV after pre-treatment. The greater hardness was retained after EJM. Exposed martensitic lath structures at machined surfaces are shown to be partially responsible for surface roughness increases. The surfaces were explored with energy dispersive X-ray spectroscopy (EDS) and Raman spectroscopy demonstrating changes in apparent surface chemistry. This analysis revealed increasing oxide formation at the surface of the pre-treated EJM surface, a further contributory factor to surface roughness increases. This new process chain will be of interest to manufacturers seeking to control surface morphology for applications including micro-injection mould/die manufacture. While demonstrated here for steel similar mechanisms are exploitable in other material systems. A new technique has been demonstrated, resulting from the models and processes presented to couple laser and electrolyte jet processing for

Electrolyte design for electrochemical jet processing (EJP) techniques can directly affect form and finish of machined structures. A newly developed, industrially focused, EJP machining centre was designed to incorporate complete control of all relevant machining parameters. A computer numerically controlled, electrolyte multiplexing system, was developed to allow rapid changes in electrolyte type and the ability to mix and fade between electrolytes to create roughing and finishing strategies, and functionally graded surfaces as part of the toolpath program. In this study, the use of three electrolytes (NaNO3, NaCl and a hybrid electrolyte NaI20) are used. Through dynamic electrolyte selection, applied in a sequential manner, it was demonstrated that a combination of NaCl / NaI20 achieved the best compromise of precision and performance, with an increase in depth of 10% over NaI and a 9% kerf reduction over NaCl. Surface finishes were demonstrated to be varied by 40% dependant on the sequence of electrolytes applied without effecting the form. It was shown that graduated surfaces can be created from a high lustre finish to matte by fading electrolyte types. For the first time, an automated method of electrolyte multiplexing is described and the flexibility and process enhancements that can be imparted by this methodology are demonstrated.

Traditional methods for achieving hierarchical surface structures include highly specified, deterministic approaches to create features to meet design intention. In this study microstructural alteration was undertaken using laser apparatus and secondary texturing was achieved via succeeding electrochemical processes. Electrochemical jet machining (EJM) was performed on mild steel subjected to laser pre-treatment using power densities of 4167 and 5556 W/cm2 with pulse durations from 0.3 - 1.5 seconds. Results show that in combination, laser pre-treatment and EJM can alter the exposed surface textures and chemistries. Here, machined surface roughness (Sa) was shown to increase from approximately 0.45 µm for untreated surfaces to approximately 18 µm for surfaces subjected to extreme laser pretreatments. After pre-treatments materials were characterised to appraise microstructural changes, shown to be martensite formation, reinforced by complementary simulation data, and significant increases in observable hardness from approximately 261 HV for the asreceived material to over 700 HV after pre-treatment. The greater hardness was retained after EJM. Exposed martensitic lath structures at machined surfaces are shown to be partially responsible for surface roughness increases. The surfaces were explored with energy dispersive X-ray spectroscopy (EDS) and Raman spectroscopy demonstrating changes in apparent surface chemistry. This analysis revealed increasing oxide formation at the surface of the pre-treated EJM surface, a further contributory factor to surface roughness increases. This new process chain will be of interest to manufacturers seeking to control surface morphology for applications including micro-injection mould/die manufacture. While demonstrated here for steel similar mechanisms are exploitable in other material systems. A new technique has been demonstrated, resulting from the models and processes presented to couple laser and electrolyte jet processing for

Electrochemical jet processing techniques provide an efficient method for large area surface structuring and micro-milling, where the metallurgy of the near-surface is assured and not adversely affected by thermal loading. Here, doped electrolytes are specifically developed for jet techniques to exploit the Gaussian energy distribution as found in energy beam processes. This allows up to 26% reduction in dissolution kerf and enhancements of the defined precision metric of up to 284% when compared to standard electrolytes. This is achieved through the filtering of low energy at discrete points within the energy distribution curve. Two fundamental mechanisms of current filtering and refresh rate are proposed and investigated in order to underpin the performance enhancements found using this methodology. This study aims to demonstrate that a step change in process fidelity and flexibility can be achieved through optimisation of the electrochemistry specific to jet processes.

The increasing demand for optimised component surfaces with enhanced chemical and geometric complexity is a key driver in the manufacturing technology required for advanced surface production. Current methodologies cannot create complex surfaces in an efficient and scalable manner in robust engineering materials. Hence, there is a need for advanced manufacturing technologies which overcome this. Current technologies are limited by resolution, geometric flexibility and mode of energy delivery. By addressing the fundamental limitations of electrochemical jetting techniques through modulation of the current density distribution by mechanical design, significant improvements to the electrochemical jet process methods are presented. A simplified 2D stochastic model was developed with the ability to vary current density distribution to assess the effects of nozzle-tip shape changes. The simulation demonstrated that the resultant profile was found to be variable from that of a standard nozzle. These nozzle-tip modifications were then experimentally tested finding a high degree of variance was possible in the machined profile. Improvements such as an increase in side-wall steepness of 162% are achieved over a standard profile, flat bases to the cut profile and a reduction of profile to surface inter-section radius enable the process to be analogous to traditional milling profiles. Since electrode design can be rapidly modified EJP is shown to be a flexible process capable of varied and complex meso-scale profile creation. Innovations presented here in the modulation of resistance in-jet have enabled electrochemical jet processes to become a viable, top-down, single-step method for applying complex surfaces geometries unachievable by other means.

Traditional methods for achieving hierarchical surface structures include highly specified, deterministic approaches to create features to meet design intention. In this study microstructural alteration was undertaken using laser apparatus and secondary texturing was achieved via succeeding electrochemical processes. Electrochemical jet machining (EJM) was performed on mild steel subjected to laser pre-treatment using power densities of 4167 and 5556 W/cm2 with pulse durations from 0.3 - 1.5 seconds. Results show that in combination, laser pre-treatment and EJM can alter the exposed surface textures and chemistries. Here, machined surface roughness (Sa) was shown to increase from approximately 0.45 µm for untreated surfaces to approximately 18 µm for surfaces subjected to extreme laser pretreatments. After pre-treatments materials were characterised to appraise microstructural changes, shown to be martensite formation, reinforced by complementary simulation data, and significant increases in observable hardness from approximately 261 HV for the asreceived material to over 700 HV after pre-treatment. The greater hardness was retained after EJM. Exposed martensitic lath structures at machined surfaces are shown to be partially responsible for surface roughness increases. The surfaces were explored with energy dispersive X-ray spectroscopy (EDS) and Raman spectroscopy demonstrating changes in apparent surface chemistry. This analysis revealed increasing oxide formation at the surface of the pre-treated EJM surface, a further contributory factor to surface roughness increases. This new process chain will be of interest to manufacturers seeking to control surface morphology for applications including micro-injection mould/die manufacture. While demonstrated here for steel similar mechanisms are exploitable in other material systems. A new technique has been demonstrated, resulting from the models and processes presented to couple laser and electrolyte jet processing for