A bioelectronic device for electric field treatment of wounds reduces inflammation in an in vivo mouse model.

Electrical signaling plays a crucial role in the cellular response to tissue injury in wound healing and an external electric field (EF) may expedite the healing process. Here, we have developed a standalone, wearable, and programmable electronic device to administer a well-controlled exogenous EF, aiming to accelerate wound healing in an in vivo mouse model to provide pre-clinical evidence. We monitored the healing process by assessing the re-epithelization rate and the ratio of M1/M2 macrophage phenotypes through histology staining. Following three days of treatment, the M1/M2 macrophage ratio decreased by 30.6% and the re-epithelization in the EF-treated wounds trended towards a non-statically significant 24.2% increase compared to the control. These findings provide point towards the effectiveness of the device in shortening the inflammatory phase by promoting reparative macrophages over inflammatory macrophages, and in speeding up re-epithelialization. Our wearable device supports the rationale for the application of programmed EFs for wound management in vivo and provides an exciting basis for further development of our technology based on the modulation of macrophages and inflammation to better wound healing.

Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor.

Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

A pro-reparative bioelectronic device for controlled delivery of ions and biomolecules.

Wound healing is a complex physiological process that requires precise control and modulation of many parameters. Therapeutic ion and biomolecule delivery has the capability to regulate the wound healing process beneficially. However, achieving controlled delivery through a compact device with the ability to deliver multiple therapeutic species can be a challenge. Bioelectronic devices have emerged as a promising approach for therapeutic delivery. Here, we present a pro-reparative bioelectronic device designed to deliver ions and biomolecules for wound healing applications. The device incorporates ion pumps for the targeted delivery of H+ and zolmitriptan to the wound site. In vivo studies using a mouse model further validated the device's potential for modulating the wound environment via H+ delivery that decreased M1/M2 macrophage ratios. Overall, this bioelectronic ion pump demonstrates potential for accelerating wound healing via targeted and controlled delivery of therapeutic agents to wounds. Continued optimization and development of this device could not only lead to significant advancements in tissue repair and wound healing strategies but also reveal new physiological information about the dynamic wound environment.

Delivering biochemicals with precision using bioelectronic devices enhanced with feedback control.

Precision medicine endeavors to personalize treatments, considering individual variations in patient responses based on factors like genetic mutations, age, and diet. Integrating this approach dynamically, bioelectronics equipped with real-time sensing and intelligent actuation present a promising avenue. Devices such as ion pumps hold potential for precise therapeutic drug delivery, a pivotal aspect of effective precision medicine. However, implementing bioelectronic devices in precision medicine encounters formidable challenges. Variability in device performance due to fabrication inconsistencies and operational limitations, including voltage saturation, presents significant hurdles. To address this, closed-loop control with adaptive capabilities and explicit handling of saturation becomes imperative. Our research introduces an enhanced sliding mode controller capable of managing saturation, adept at satisfactory control actions amidst model uncertainties. To evaluate the controller's effectiveness, we conducted in silico experiments using an extended mathematical model of the proton pump. Subsequently, we compared the performance of our developed controller with classical Proportional Integral Derivative (PID) and machine learning (ML)-based controllers. Furthermore, in vitro experiments assessed the controller's efficacy using various reference signals for controlled Fluoxetine delivery. These experiments showcased consistent performance across diverse input signals, maintaining the current value near the reference with a relative error of less than 7% in all trials. Our findings underscore the potential of the developed controller to address challenges in bioelectronic device implementation, offering reliable precision in drug delivery strategies within the realm of precision medicine.

Chronic Diseases and Associated Risk Factors Among Adults in Puerto Rico After Hurricane Maria.

Importance: As public health emergencies become more prevalent, it is crucial to identify adverse physical and mental health conditions that may be triggered by natural disasters. There is a lack of data on whether Hurricane Maria in 2017 influenced the disease burden of adults in Puerto Rico. Objective: To estimate the prevalence of chronic diseases and their associated risk factors among adults living in Puerto Rico before and after Hurricane Maria in 2017. Design, Setting, and Participants: This cross-sectional study used data from 2 previous cross-sectional studies, including the pre-Hurricane Maria Puerto Rico Assessment on Diet, Lifestyles and Disease (PRADLAD) study, conducted in 2015, and the post-Hurricane Maria Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic Disease Trends (PROSPECT), conducted in 2019. Participants included adults aged 30 to 75 years residing in Puerto Rico. Data were analyzed from April to October 2020. Exposures: Self-reported data were obtained on sociodemographic, lifestyle, and psychosocial factors and medically diagnosed conditions using validated questionnaires. Anthropometrics were measured in triplicate. Main Outcomes and Measures: Data were obtained using similar protocols in both studies. Characteristics were contrasted for all participants across studies and for 87 PRADLAD participants who returned to PROSPECT. Results: A total of 825 participants from both cohorts were included, with 380 PRADLAD participants and 532 PROSPECT participants. In the 2019 PROSPECT study, the mean (SD) age was 53.7 (10.8) years, and 363 participants (68.2%) were assigned female at birth and 169 participants (31.8%) were assigned male at birth. In the 2019 cohort, 360 participants (67.7%) had college education or higher, 205 participants (38.5%) reported annual income greater than $20 001, and 263 participants (49.5%) were employed. Most sociodemographic variables were similar between studies, except for higher income and employment after the hurricane. In the main analysis, participants in 2019, compared with participants in 2015, had higher abdominal obesity (389 participants [73.2%] vs 233 participants [61.3%]), sedentarism (236 participants [44.4%] vs 136 participants [35.8%]), binge drinking (95 participants [17.9%] vs 46 participants [12.1%]), and social support (mean [SD] score, 26.9 [7.2] vs 24.7 [7.1]) but lower depressive symptoms (169 participants [31.7%] vs 200 participants [52.6%]) and perceived stress (mean [SD] score, 19.3 [9.5] vs 21.7 [7.7]). In 2019, compared with 2015, there were higher rates of hypertension (252 participants [47.3%] vs 149 participants [39.2%]), arthritis (172 participants [32.3%] vs 97 participants [25.6%]), high cholesterol (194 participants [36.4%] vs 90 participants [23.8%]), high triglycerides (123 participants [23.1%] vs 56 participants [14.7%]), eye disease (94 participants [17.6%] vs 48 participants [12.7%]), fatty liver disease (68 participants [12.8%] vs 29 participants [7.5%]), and osteoporosis (74 participants [13.9%] vs 20 participants [5.2%]). Secondary analysis for the 87 returning participants showed similar results. Conclusions and Relevance: In this cross-sectional study, a higher prevalence of unhealthy behaviors and chronic conditions was noted among adults in Puerto Rico after Hurricane Maria, warranting long-term studies. Psychosocial factors were better, but still need attention. As natural disasters intensify, efforts should focus on continuous surveillance of health outcomes and promoting healthy behaviors, positive emotional health, and disease control, particularly in populations with higher risk for poor health.

Sediment trace metal levels in the Ojo de Liebre Lagoonal Complex (Baja California, Mexico), a marine wildlife protected area.

Surficial sediment quality in the Ojo de Liebre Lagoon (OLL), Mexico, was evaluated via five geochemical indices. Results indicate that concentrations of the elements Ag, As, Cu, Fe, Mn, Mo, Ni, Sb, U, V and Zn do not exert adverse biological effects in this ecosystem. However, minor enrichment was observed for Ba (mean ± SD: 1.09 ± 0.17) and Co (1.57 ± 0.22) and was moderately severe for Cd (9.3 ± 2.0), possibly due to natural processes. The adverse effect index was >1 only for Hg, suggesting that concentrations of this element are sufficiently high (0.40 to 1.13 nmol g-1) to potentially elicit adverse effects on local organisms in contact with sediments. This result is particularly important for grey whales (Eschrichtius robustus), given that they ingest large quantities of benthic organisms during their seasonal stay in the OLL.

Design and Implementation of the Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic Disease Trends (PROSPECT).

The Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic Disease Trends (PROSPECT) is a prospective cohort study in Puerto Rico (PR) aiming to identify trends and longitudinal associations in risk factors for cardiovascular disease (CVD). In 2019, PROSPECT investigators started recruiting a sample of 2,000 adults aged 30-75 years in PR using multistage probabilistic sampling of households and community approaches. Culturally sensitive trained research assistants assess participants, at baseline and at 2-year follow-up, in private rooms at a network of partner clinics. The study collects comprehensive data on demographic factors, socioeconomic and environmental factors, medical history, health conditions, lifestyle behaviors, psychosocial status, and biomarkers of CVD and stress. PROSPECT will estimate the prevalence and incidence of psychosocial, lifestyle, and biological CVD risk factors, describe variations in risk factors by urbanicity (urban areas vs. rural areas) and exposure (before and after) to natural disasters, and determine predictors of longitudinal changes in CVD risk factors. The study has 4 coordinated operational strategies: 1) research productivity (including synergy with existing epidemiologic cohorts of Hispanics/Latinos for comparison); 2) research infrastructure (biorepository, ancillary studies, and clinical research network); 3) capacity-building, education, and training; and 4) community outreach, dissemination, and policy. PROSPECT will inform public health priorities to help reduce CVD in PR.

GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons.

Deficits in fast-spiking inhibitory interneurons (FSINs) within the dorsolateral prefrontal cortex (dlPFC) are hypothesized to underlie cognitive impairment associated with schizophrenia. Though representing a minority of interneurons, this key cell type coordinates broad neural network gamma-frequency oscillations, associated with cognition and cognitive flexibility. Here we report expression of GluN2D mRNA selectively in parvalbumin positive cells of human postmortem dlPFC tissue, but not pyramidal neurons, with little to no GluN2C expression in either cell type. In acute murine mPFC slices the GluN2C/D selective positive allosteric modulator (PAM), CIQ(+), increased the intrinsic excitability as well as enhanced NMDAR-mediated EPSCs onto FSINs. This increase in intrinsic excitability with GluN2C/D PAM was also observed in the Dlx 5/6+/- FSIN developmental deficit model with reported FSIN hypoexcitability. Together these data speak to selective modulation of FSINs by a GluN2D PAM, providing a potential mechanism to counter the FSIN-deficit seen in schizophrenia.

In Vivo Modulation of Hippocampal Excitability by M4 Muscarinic Acetylcholine Receptor Activator: Implications for Treatment of Alzheimer's Disease and Schizophrenic Patients.

Abnormal hippocampal activity has been linked to impaired cognitive performance in Alzheimer's disease and schizophrenia, leading to a hypothesis that normalization of this activity may be therapeutically beneficial. Our work suggests that one approach for hippocampal normalization may be through activation of the M4 muscarinic acetylcholine receptor. We used a brain penetrant M4 muscarinic acetylcholine receptor selective activator, PT-3763, to show dose-dependent attenuation of field potentials in Schaffer collateral (CA3-CA1) and recurrent associational connections (CA3-CA3) ex vivo in hippocampal slices. In vivo, systemic administration of PT-3763 led to attenuation of glutamate release in CA3 as measured by amperometry and to a dose-dependent decrease in population CA1 pyramidal activity as measured by fiber photometry. This decrease in population activity was also evident with a localized administration of the compound to the recorded site. Finally, PT-3763 reversed scopolamine-induced deficit in Morris water maze. Our results suggest that M4 muscarinic acetylcholine receptor activation may be a suitable therapeutic treatment in diseases associated with hyperactive hippocampal activity.

A neural circuit mechanism for regulating vocal variability during song learning in zebra finches.

Motor skill learning is characterized by improved performance and reduced motor variability. The neural mechanisms that couple skill level and variability, however, are not known. The zebra finch, a songbird, presents a unique opportunity to address this question because production of learned song and induction of vocal variability are instantiated in distinct circuits that converge on a motor cortex analogue controlling vocal output. To probe the interplay between learning and variability, we made intracellular recordings from neurons in this area, characterizing how their inputs from the functionally distinct pathways change throughout song development. We found that inputs that drive stereotyped song-patterns are strengthened and pruned, while inputs that induce variability remain unchanged. A simple network model showed that strengthening and pruning of action-specific connections reduces the sensitivity of motor control circuits to variable input and neural 'noise'. This identifies a simple and general mechanism for learning-related regulation of motor variability.

Cumulative activation of voltage-dependent KVS-1 potassium channels.

In this study, we reveal the existence of a novel use-dependent phenomenon in potassium channels, which we refer to as cumulative activation (CA). CA consists of an increase in current amplitude in response to repetitive depolarizing step pulses to the same potential. CA persists for up to 20 s and is similar to a phenomenon called "voltage-dependent facilitation" observed in some calcium channels. The KVS-1 K+ channel, which exhibits CA, is a rapidly activating and inactivating voltage-dependent potassium channel expressed in chemosensory and other neurons of Caenorhabditis elegans. It is unusual in being most closely related to the Shab (Kv2) family of potassium channels, which typically behave like delayed rectifier K+ channels in other species. The magnitude of CA depends on the frequency, voltage, and duration of the depolarizing step pulse. CA also radically changes the activation and inactivation kinetics of the channel, suggesting that the channel may undergo a physical modification in a use-dependent manner; thus, a model that closely simulates the behavior of the channel postulates the existence of two populations of channels, unmodified and modified. Use-dependent changes in the behavior of potassium channels, such as CA observed in KVS-1, could be involved in functional mechanisms of cellular plasticity such as synaptic depression that represent the cellular basis of learning and memory.