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L'anàlisi de la viabilitat per implementar la tecnologia de motors híbrids de reluctància variable (HRM) en contactors, feta mitjançant el mètode d'anàlisi d'elements finits magnètics amb FEMM juntament amb MATLAB, va revelar troballes significatives en avaluar els efectes d'introduir un imant permanent i ajustar paràmetres com el gruix de l'imant i les dimensions de l'armadura. La presència de l'imant va generar un augment addicional de la força, i va destacar increments del 117% en condicions específiques. L'optimització del contactor amb imant va conduir a reduccions en el consum elèctric, assolint un 8.84% al primer model i fins a un 17.76% al segon, evidenciant l'eficàcia de la tecnologia en eficiència energètica. En aplicar aquestes troballes en motors HRM, es van aconseguir millores, incloent un augment de 0.75 Nm en el torque estàtic mitjançant ajustaments geomètrics específics. Aquest enfocament no només millora el rendiment del contactor, sinó també augmenta el torc en motors HRM, recolzant l'aplicabilitat de la tecnologia HRM i obrint la porta a futures investigacions on s'emfatitzi l'exploració d'aspectes tèrmics i de mecànica dinàmica per a una comprensió més completa del rendiment amb vista a aplicacions industrials., El análisis de la viabilidad para implementar la tecnología de motores híbridos de reluctancia variable (HRM) en contactores, realizado mediante el método de análisis de elementos finitos magnéticos con FEMM junto con MATLAB, reveló hallazgos significativos al evaluar los efectos de introducir un imán permanente y ajustar parámetros como el espesor del imán y las dimensiones de la armadura. La presencia del imán generó un aumento adicional de la fuerza, destacando incrementos del 117% en condiciones específicas. La optimización del contactor con imán condujo a reducciones en el consumo eléctrico, alcanzando un 8.84% en el primer modelo y hasta un 17.76% en el segundo, evidenciando la eficacia de la tecnología en eficiencia energética. Al aplicar estos hallazgos en motores HRM, se lograron mejoras, incluyendo un aumento de 0.75 Nm en el torque estático mediante ajustes geométricos específicos. Este enfoque no solo mejora el rendimiento del contactor, sino también aumenta el torque en motores HRM, respaldando la aplicabilidad de la tecnología HRM y abriendo la puerta a futuras investigaciones donde se enfatice la exploración de aspectos térmicos y de mecánica dinámica para una comprensión más completa del rendimiento con miras a aplicaciones industriales., The viability analysis for implementing Hybrid Variable Reluctance Motors (HRM) technology in contactors, conducted through the method of magnetic finite element analysis using FEMM along with MATLAB, revealed significant findings when assessing the effects of introducing a permanent magnet and adjusting parameters such as magnet thickness and armature dimensions. The presence of the magnet resulted in an additional force increase, highlighting increments of 117% under specific conditions. Optimizing the contactor with a magnet led to reductions in electrical consumption, reaching 8.84% in the first model and up to 17.76% in the second, demonstrating the effectiveness of the technology in energy efficiency. Applying these findings to HRM motors achieved improvements, including a 0.75 Nm increase in static torque through specific geometric adjustments. This approach not only enhances the contactor's performance but also boosts torque in HRM motors, supporting the applicability of HRM technology and paving the way for future research emphasizing the exploration of thermal and dynamic mechanical aspects for a more comprehensive understanding of performance with a focus on industrial applications.

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

En aquest projecte s’estudiarà la implementació d’un sistema fotovoltaic al Parcmotor Castellolí. El sistema consta de dos màstils ja existents autosuficients amb plaques solars i un futur banc de plaques que s’instal·larà en el circuit. L’objecte d’aquest projecte es basa en l’estudi de la implementació d’aquest banc juntament amb tots els seus elements, la connexió dels elements del sistema entre ells i la xarxa elèctrica, l’estudi de recursos renovables i a posteriori el disseny i control d’un algoritme d’optimització que determini el suministre d’energia per al consum dels màstils, és a dir, quan emmagatzemar energia, quan consumir energia de les bateries, quan consumir de la xarxa elèctrica, quan és necessari carregar bateries consumint de la xarxa, etc., Objectius de Desenvolupament Sostenible::7 - Energia Assequible i No Contaminant::7.2 - Per a 2030, augmentar substancialment el percentatge d’energia renovable en el con­junt de fonts d’energia, Objectius de Desenvolupament Sostenible::9 - Indústria, Innovació i Infraestructura::9.2 - Promoure una industrialització inclusiva i sostenible i, a tot tardar el 2030, augmentar de manera significativa la contribució de la indústria a l’ocupació i al producte interior brut, d’acord amb les circumstàncies nacionals, i duplicar aquesta contribució als països menys avançats

One of the existing problems that the school is facing nowadays is the work immersion program. Work immersion is a critical feature in the senior high school curriculum. The work immersion program is the part of the Grade 12 curriculum that consists of 80 hours of hands-on experience or work simulation. The program is implemented to expose them to the actual work setting and to enrich the competencies they learned in school. As stipulated in the Enhanced Basic Education Act of 2013, this program aims for the enhancement of the skills and knowledge of students, for them to become more equipped in facing future challenges, whether in pursuing higher studies in college or entering the very competitive world of employment. To further explore the phenomenon, the present study conducted a multi-site industry-based participatory action research in five industry-partners across the Municipality of Bagac. This study aimed at improving the work immersion conditions through the active partnership of the school and industry. The study engaged stakeholders and partner industries in the development of a memorandum of agreement that can facilitate the provision of the needs of both parties for the benefit of the students. Using the Narratological research approach, the researchers analyzed and scrutinized the narrative and pictorial report of the work immersion students in the past two years. Findings of narratological research served as the basis for the researchers to proceed to the second phase of the data gathering. The Second Phase employed a Photovoice method; purposively-chosen participants were empowered to express their insights on the work immersion issues using photographs. Interviews followed this and focus group discussions. Data reiterated the continuous problem being experienced by the students in work immersion. By expressing their creativity and with their active use of mobile photography, the participants shared their work immersion experiences. They did this wit

One of the existing problems that the school is facing nowadays is the work immersion program. Work immersion is a critical feature in the senior high school curriculum. The work immersion program is the part of the Grade 12 curriculum that consists of 80 hours of hands-on experience or work simulation. The program is implemented to expose them to the actual work setting and to enrich the competencies they learned in school. As stipulated in the Enhanced Basic Education Act of 2013, this program aims for the enhancement of the skills and knowledge of students, for them to become more equipped in facing future challenges, whether in pursuing higher studies in college or entering the very competitive world of employment. To further explore the phenomenon, the present study conducted a multi-site industry-based participatory action research in five industry-partners across the Municipality of Bagac. This study aimed at improving the work immersion conditions through the active partnership of the school and industry. The study engaged stakeholders and partner industries in the development of a memorandum of agreement that can facilitate the provision of the needs of both parties for the benefit of the students. Using the Narratological research approach, the researchers analyzed and scrutinized the narrative and pictorial report of the work immersion students in the past two years. Findings of narratological research served as the basis for the researchers to proceed to the second phase of the data gathering. The Second Phase employed a Photovoice method; purposively-chosen participants were empowered to express their insights on the work immersion issues using photographs. Interviews followed this and focus group discussions. Data reiterated the continuous problem being experienced by the students in work immersion. By expressing their creativity and with their active use of mobile photography, the participants shared their work immersion experiences. They did this wit

One of the existing problems that the school is facing nowadays is the work immersion program. Work immersion is a critical feature in the senior high school curriculum. The work immersion program is the part of the Grade 12 curriculum that consists of 80 hours of hands-on experience or work simulation. The program is implemented to expose them to the actual work setting and to enrich the competencies they learned in school. As stipulated in the Enhanced Basic Education Act of 2013, this program aims for the enhancement of the skills and knowledge of students, for them to become more equipped in facing future challenges, whether in pursuing higher studies in college or entering the very competitive world of employment. To further explore the phenomenon, the present study conducted a multi-site industry-based participatory action research in five industry-partners across the Municipality of Bagac. This study aimed at improving the work immersion conditions through the active partnership of the school and industry. The study engaged stakeholders and partner industries in the development of a memorandum of agreement that can facilitate the provision of the needs of both parties for the benefit of the students. Using the Narratological research approach, the researchers analyzed and scrutinized the narrative and pictorial report of the work immersion students in the past two years. Findings of narratological research served as the basis for the researchers to proceed to the second phase of the data gathering. The Second Phase employed a Photovoice method; purposively-chosen participants were empowered to express their insights on the work immersion issues using photographs. Interviews followed this and focus group discussions. Data reiterated the continuous problem being experienced by the students in work immersion. By expressing their creativity and with their active use of mobile photography, the participants shared their work immersion experiences. They did this wit

En aquest projecte es presenta l’aplicació d’una tècnica de control anomenada Control per modes lliscants a un equip de laboratori amb una dinàmica semblant a la d’un helicòpter anomenat Twin Rotor MIMO System creat per Feedback Instruments Ldt. A diferència d’un helicòpter en el qual els angles d’atac de les pales influeix en la dinàmica d’aquest, aquest equip es controla regulant la velocitat de les pales amb un angle d’atac fixe. Es regula la velocitat de les pales variant la tensió d’entrada al motor DC acoblat a les dos hèlix respectivament. El sistema resultant és de varies entrades i varies sortides (MIMO), altament no lineal i amb forts acoblaments existents. El projecte es pot dividir en tres fases: la primera fase es tracta de trobar el model matemàtic que dinàmic que governa la dinàmica del TRMS, en aquest cas mitjan¸cant la formulació d’Euler-Lagrange. La segona fase es tracta d’implementar un model de simulació en l’entorn de MATLAB-Simulink que representi la dinàmica de la planta amb les seves entrades i sortides respectivament. Són necessaris experiments per calibrar varis paràmetres del model. Finalment, la tercera part es tracta de dissenyar un controlador mitjan¸cant la tècnica de modes lliscants pel posicionament del TRMS primerament validada en el model de simulació i seguidament experimentalment.

α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore, it is unclear whether activation of GABABR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABABR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABABR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABABR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain.

Background and Purpose: Patients with irritable bowel syndrome suffer from chronic visceral pain (CVP) and limited analgesic therapeutic options are currently available. We have shown that α-conotoxin Vc1.1 induced activation of GABAB receptors on the peripheral endings of colonic afferents and reduced nociceptive signalling from the viscera. However, the analgesic efficacy of more stable, cyclized versions of Vc1.1 on CVP remains to be determined. Experimental Approach: Using ex vivo colonic afferent preparations from mice, we determined the inhibitory actions of cyclized Vc1.1 (cVc1.1) and two cVc1.1 analogues on mouse colonic nociceptors in healthy and chronic visceral hypersensitivity (CVH) states. Using whole-cell patch clamp recordings, we also assessed the inhibitory actions of these peptides on the neuronal excitability of colonic innervating dorsal root ganglion neurons. In vivo, the analgesic efficacy of these analogues was assessed by determining the visceromotor response to colorectal distension in healthy and CVH mice. Key Results: cVc1.1 and the cVc1.1 analogues, [C2H,C8F]cVc1.1 and [N9W] cVc1.1, all caused concentration-dependent inhibition of colonic nociceptors from healthy mice. Inhibition by these peptides was greater than those evoked by linear Vc1.1 and was substantially greater in colonic nociceptors from CVH mice. cVc1.1 also reduced excitability of colonic dorsal root ganglion neurons, with greater effect in CVH neurons. CVH mice treated with cVc1.1 intra-colonically displayed reduced pain responses to noxious colorectal distension compared with vehicle-treated CVH mice. Conclusions and Implications: Cyclic versions of Vc1.1 evoked significant anti-nociceptive actions in CVH states, suggesting that they could be novel candidates for treatment of CVP.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition.

Objective α-Conotoxin Vc1.1 is a small disulfidebonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown. Design We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitativereverse- transcription-PCR, single-cell-reversetranscription- PCR and immunohistochemistry determined ?-aminobutyric acid receptor B (GABABR) and voltagegated calcium channel (CaV2.2, CaV2.3) expression in human and mouse DRG neurons. Results Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABABR did not. Human DRG neurons expressed GABABR and its downstream effector channels CaV2.2 and CaV2.3. Mouse colonic DRG neurons exhibited high GABABR, CaV2.2 and CaV2.3 expression, with upregulation of the CaV2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABABR antagonist prevented Vc1.1-induced inhibition, whereas blocking both CaV2.2 and CaV2.3 caused inhibition comparable with Vc1.1 alone. Conclusions Vc1.1-mediated activation of GABABR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABABR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.

OBJECTIVE: The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. DESIGN: We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. RESULTS: In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. CONCLUSIONS: Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.

Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements. Here, we circumvent this limitation by exploiting cultured intestinal organoids together with single-cell measurements to elucidate intrinsic biophysical, pharmacological, and genetic properties of EC cells. We show that EC cells express specific chemosensory receptors, are electrically excitable, and modulate serotonin-sensitive primary afferent nerve fibers via synaptic connections, enabling them to detect and transduce environmental, metabolic, and homeostatic information from the gut directly to the nervous system.

α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.

Joan Flasch Artists' Book Collection

Cell death is preceded by severe disruption of inorganic ion homeostasis. Seconds to minutes after an injury, calcium, protons, sodium, potassium and chloride are exchanged between the cell and its environment. Simultaneously, ions are shifted between membrane compartments inside the cell, whereby mitochondria and endoplasmic reticulum play a crucial role. Depending of the type and severity of injury, two mutually exclusive metastable states can be reached, which predict the final outcome. Cells characterized by large increases in cytosolic [Ca2+], [Na+]; and [Mg2+] swell and die by necrosis; alternatively, cells characterized by high [H+]and low [K+], with normal [Na+] and normal to moderate [Ca2+] increases die by apoptosis. The levels of these ions represent central determinants in signaling events leading to cell death. Their movements are explained mechanistically by specific modulation of membrane transport proteins including channels, pumps and carriers