Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.

Heterozygous variants in SLC6A1, encoding the GAT-1 GABA transporter, are associated with seizures, developmental delay, and autism. The majority of affected individuals carry missense variants, many of which are recurrent germline de novo mutations, raising the possibility of gain-of-function or dominant-negative effects. To understand the functional consequences, we performed an in vitro GABA uptake assay for 213 unique variants, including 24 control variants. De novo variants consistently resulted in a decrease in GABA uptake, in keeping with haploinsufficiency underlying all neurodevelopmental phenotypes. Where present, ClinVar pathogenicity reports correlated well with GABA uptake data; the functional data can inform future reports for the remaining 72% of unscored variants. Surface localization was assessed for 86 variants; two-thirds of loss-of-function missense variants prevented GAT-1 from being present on the membrane while GAT-1 was on the surface but with reduced activity for the remaining third. Surprisingly, recurrent de novo missense variants showed moderate loss-of-function effects that reduced GABA uptake with no evidence for dominant-negative or gain-of-function effects. Using linear regression across multiple missense severity scores to extrapolate the functional data to all potential SLC6A1 missense variants, we observe an abundance of GAT-1 residues that are sensitive to substitution. The extent of this missense vulnerability accounts for the clinically observed missense enrichment; overlap with hypermutable CpG sites accounts for the recurrent missense variants. Strategies to increase the expression of the wild-type SLC6A1 allele are likely to be beneficial across neurodevelopmental disorders, though the developmental stage and extent of required rescue remain unknown.

Axial Phenoxylation of Aluminum Phthalocyanines for Improved Cannabinoid Sensitivity in OTFT Sensors.

Cannabis producers, consumers, and regulators need fast, accurate, point-of-use sensors to detect Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from both liquid and vapor source samples, and phthalocyanine-based organic thin-film transistors (OTFTs) provide a cost-effective solution. Chloro aluminum phthalocyanine (Cl-AlPc) has emerged as a promising material due to its unique coordinating interactions with cannabinoids, allowing for superior sensitivity. This work explores the molecular engineering of AlPc to tune and enhance these interactions, where a series of novel phenxoylated R-AlPcs are synthesized and integrated into OTFTs, which are then exposed to THC and CBD solution and vapor samples. While the R-AlPc substituted molecules have a comparable baseline device performance to Cl-AlPc, their new crystal structures and weakened intermolecular interactions increase sensitivity to THC. Grazing-incidence wide-angle X-ray scattering (GIWAXS) and atomic force microscopy (AFM) are used to investigate this film restructuring, where a significant shift in the crystal structure, grain size, and film roughness is detected for the R-AlPc molecules that do not occur with Cl-AlPc. This significant crystal reorganization and film restructuring are the driving force behind the improved sensitivity to cannabinoids relative to Cl-AlPc and demonstrate that analyte-semiconductor interactions can be enhanced through chemical modification to create more responsive OTFT sensors.

FMRI correlates of autobiographical memory: Comparing silent retrieval with narrated retrieval.

FMRI studies of autobiographical memory (AM) retrieval typically ask subjects to retrieve memories silently to avoid speech-related motion artifacts. Recently, some fMRI studies have started to use overt (spoken) retrieval to probe moment-to-moment retrieved content. However, the extent to which the overt retrieval method alters fMRI activations during retrieval is unknown. Here we examined this question by eliciting unrehearsed AMs during fMRI scanning either overtly or silently, in the same subjects, in different runs. Differences between retrieval modality (silent vs. narrated) included greater activation for silent retrieval in the anterior hippocampus, left angular gyrus, PCC, and superior PFC, and greater activation for narrated retrieval in speech production regions, posterior hippocampus, and the DLPFC. To probe temporal dynamics, we divided each retrieval period into an initial search phase and a later elaboration phase. The activations during the search and elaboration phases were broadly similar regardless of modality, and these activations were in line with previous fMRI studies of AM temporal dynamics employing silent retrieval. For both retrieval modalities, search activated the hippocampus, mPFC, ACC, and PCC, and elaboration activated the left DLPFC and middle temporal gyri. To examine content-specific reactivation during retrieval, the timecourse of narrated memory content was transcribed and modeled. We observed dynamic activation associated with object content in the lateral occipital complex, and activation associated with scene content in the retrosplenial cortex. The current findings show that both silent and narrated AMs activate a broadly similar memory network, with some key differences, and add to current knowledge regarding the content-specific dynamics of AM retrieval. However, these observed differences between retrieval modality suggest that studies using overt retrieval should carefully consider this method's possible effects on cognitive and neural processing.

Workflow interruptions in an era of instant messaging: A detailed analysis.

INTRODUCTION: The complex practice environment and responsibilities incumbent on diagnostic radiologists creates a workflow susceptible to disruption. While interruptions have been shown to contribute to medical errors in the healthcare delivery environment, the exact impact on highly subspecialized services such as diagnostic radiology is less certain. One potential source of workflow disruption is the use of a departmental instant messaging system (Webex), to facilitate communications between radiology faculty, residents, fellows, and technologists. A retrospective review was conducted to quantify the frequency of interruption experienced by our neuroradiology fellows. MATERIALS AND METHODS: Data logs were gathered comprising all instant messages sent and received within the designated group chats from July 5-December 31, 2021, during weekday shifts staffed by neuroradiology fellows. Interruptions per shift were calculated based on month, week, and day of the week. RESULTS: 14,424 messages were sent across 289 total shifts. The 6 fellows assigned to the main neuroradiology reading room sent 3258 messages and received 10,260 messages from technologists and other staff. There was an average of 50 interruptions per shift when examined by month (range 48-53), and 52 interruptions per shift when examined by day of the week (range 40-60). CONCLUSION: Neuroradiology fellows experience frequent interruptions from the departmental instant messaging system. These disruptions, when considered in conjunction with other non-interpretative tasks, may have negative implications for workflow efficiency, requiring iterative process improvements when incorporating new technology into the practice environment of diagnostic radiology.

Teratognathini Silveira, the priority family-group name for Ancyloscelidini Engel and Michener (Hymenoptera: Apoidea: Apidae: Eucerinae).

The genus Ancyloscelis Latreille, 1829 (Hymenoptera: Apidae), a taxon restricted to the Neotropics and southern Nearctic (Michener 1942, 2000, 2007; Schaller and Roig-Alsina 2021; Melo 2022), has been difficult to place precisely within the higher classification of bees (Roig-Alsina and Michener 1993; Aguiar et al. 2019; Freitas et al. 2020), and even the genus name has a confusing history (see Michener 1942). Michener (1944) placed it together with Exomalopsis Spinola, 1853 within the Exomalopsini Vachal, 1909, and Michener and Moure (1957) later expanded this tribe to include ten additional genera, with Ancyloscelis the sole member of one of the five distinct sections they recognized (reviewed by Silveira 1993). Later, Jesus S. Moure (cited in Roig-Alsina and Michener 1993) suggested that the placement of Ancyloscelis should be within Emphorini Robertson, 1904, a position supported in that work. However, Roig-Alsina and Michener (1993) concluded that it differed enough from other members to recognize two subtribes, proposing Ancyloscelina Roig-Alsina and Michener, 1993 containing only the type genus, with the remaining Emphorini recognized at that time (i.e., Diadasia Patton, 1879, Diadasina Moure, 1950, Melitoma Lepeletier and Serville, 1828, and Ptilothrix Smith, 1853) placed in subtribe Emphorina Robertson, 1904. Michener (2000, 2007) and others (Silveira et al. 2002, Rodrguez and Roig-Alsina 2004) continued to recognize Ancyloscelis within Emphorini, but subtribal classifications were not used in those works.

A review of the Stelidium group of Stelis Panzer, 1806 (Hymenoptera: Megachilidae) with two new species from western North America.

The Stelidium group is readily distinguished from all other members of the subgenus Stelis Panzer, 1806 by the combination of small body size ( 6 mm), pale maculations on the head adjacent to the inner margins of the compound eyes and laterally on the vertex in both sexes, and females with sternum 6 extended beyond tergum 6, the former with the dorsal lip trowel-shaped with the apex broadly rounded or subtruncate to more narrowly pointed. This monophyletic clade, which is endemic to North America, currently consists of members previously placed into two species groups: the permaculata group containing S. anasazi Parker & Griswold, 2013, S. ashmeadiellae Timberlake, 1941, S. permaculata Cockerell, 1898, and S. robertsoni Timberlake, 1941, and the palmarum group containing S. broemelingi Parker & Griswold, 2013, S. elongativentris Parker, 1987, and S. palmarum Timberlake, 1941; two additional species, S. herberti (Cockerell, 1916) from Mexico, and S. nyssonoides (Brues, 1903) from Texas, United States, have not been definitively placed in either species group. Two new species are herein described, one from southcentral British Columbia, Canada, the other from New Mexico, United States. A preliminary molecular phylogeny places both new species in the permaculata species group. In addition, S. herberti is also placed within the permaculata species group based on morphological similarity, sharing the multi-spotted maculation pattern on the terga. Based on molecular affinity, S. broemelingi also belongs to the permaculata species group. Because no type specimen for S. nyssonoides is seemingly available for examination, it is hereby considered nomen dubium until the specimen is found and its taxonomic status clarified in relation to the more recently described species in the permaculata species group. A key to females and diagnoses are provided for all known taxa.

Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.

BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production. METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM ß-hydroxybutyrate (ßOHB). RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high ßOHB or in TAC DAPA hearts, despite ßOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high ßOHB concentrations. Rather, increasing ßOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both ßOHB concentrations by increasing the contribution of glucose oxidation to ATP production. CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.

Multimodality Cardiac Imaging and the Imaging Workforce in the United States: Diversity, Disparities, and Future Directions.

Innovations in cardiac imaging have fundamentally advanced the understanding and treatment of cardiovascular disease. These advances in noninvasive cardiac imaging have also expanded the role of the cardiac imager and dramatically increased the demand for imagers who are cross-trained in multiple modalities. However, we hypothesize that there is significant variation in the availability of cardiac imaging expertise and a disparity in the adoption of advanced imaging technologies across the United States. To evaluate this, we have brought together the leaders of cardiovascular imaging societies, imaging trainees, as well as collaborated with national imaging accreditation commissions and imaging certification boards to assess the state of cardiac imaging and the diversity of the imaging workforce in the United States. Aggregate data confirm the presence of critical gaps, such as limited access to imaging and imaging expertise in rural communities, as well as disparities in the imaging workforce, notably among women and underrepresented minorities. Based on these results, we have proposed solutions to promote and maintain a robust and diverse community of cardiac imagers and improve equity and accessibility for cardiac imaging technologies.

Habitat selection and refuge-use by a color polymorphic salamander reveal behavioral niche differences.

Color polymorphic species provide an excellent opportunity to investigate the ecology and evolution of intraspecific niche differences. The red-backed salamander, Plethodon cinereus, is a fully terrestrial lungless salamander with two common color forms, striped and unstriped. Previous research suggests the morphs may be differentially adapted to surface and subsurface microhabitats, with the unstriped morph being more fossorial. This hypothesis predicts that the unstriped morph should be more sensitive to the risks of surface activity (e.g., thermal stress, dehydration, predation), and therefore be more selective than striped morphs when choosing soil surface microhabitats. To test this hypothesis, we experimentally manipulated leaf litter mass in small forest patches (~0.45 m2). Leaf litter addition reduced soil temperatures, buffered against changes in air temperature, and likely provided physical protection from predators. Over 3 years, we found that unstriped adults responded positively to leaf litter addition, but striped adults did not. In addition, unstriped morphs spent significantly more time in protective refuges (opaque, moistened tubes) than striped morphs in laboratory assays. Taken together, the field and laboratory results support the hypothesis that the unstriped morph is more sensitive to the risks of surface activity, and therefore is more likely to be fossorial. This difference in microhabitat use, combined with spatiotemporal variation in leaf litter accumulation on the forest floor, may play an important role in the maintenance of the polymorphism.

Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation ß-blocker and a biased agonist that exhibits agonist-like effects through ß arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac ß arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

Single-pulse electrical stimulation artifact removal using the novel matching pursuit-based artifact reconstruction and removal method (MPARRM).

Objective.Single-pulse electrical stimulation (SPES) has been widely used to probe effective connectivity. However, analysis of the neural response is often confounded by stimulation artifacts. We developed a novel matching pursuit-based artifact reconstruction and removal method (MPARRM) capable of removing artifacts from stimulation-artifact-affected electrophysiological signals.Approach.To validate MPARRM across a wide range of potential stimulation artifact types, we performed a bench-top experiment in which we suspended electrodes in a saline solution to generate 110 types of real-world stimulation artifacts. We then added the generated stimulation artifacts to ground truth signals (stereoelectroencephalography signals from nine human subjects recorded during a receptive speech task), applied MPARRM to the combined signal, and compared the resultant denoised signal with the ground truth signal. We further applied MPARRM to artifact-affected neural signals recorded from the hippocampus while performing SPES on the ipsilateral basolateral amygdala in nine human subjects.Main results.MPARRM could remove stimulation artifacts without introducing spectral leakage or temporal spread. It accommodated variable stimulation parameters and recovered the early response to SPES within a wide range of frequency bands. Specifically, in the early response period (5-10 ms following stimulation onset), we found that the broadband gamma power (70-170 Hz) of the denoised signal was highly correlated with the ground truth signal (R=0.98±0.02, Pearson), and the broadband gamma activity of the denoised signal faithfully revealed the responses to the auditory stimuli within the ground truth signal with94%±1.47%sensitivity and99%±1.01%specificity. We further found that MPARRM could reveal the expected temporal progression of broadband gamma activity along the anterior-posterior axis of the hippocampus in response to the ipsilateral amygdala stimulation.Significance.MPARRM could faithfully remove SPES artifacts without confounding the electrophysiological signal components, especially during the early-response period. This method can facilitate the understanding of the neural response mechanisms of SPES.

Discovering how the amygdala shapes human behavior: From lesion studies to neuromodulation.

Case studies of patients with amygdala damage or those receiving direct amygdala stimulation have informed our understanding of the amygdala's role in emotion and cognition. These foundational studies illustrate how the human amygdala influences our present behavior and prioritizes memories of our past in service of future experiences. This broad influence makes the amygdala a novel target for clinical neuromodulation.

An ERP measure of non-conscious memory reveals dissociable implicit processes in human recognition using an open-source automated analytic pipeline.

Non-conscious processing of human memory has traditionally been difficult to objectively measure and thus understand. A prior study on a group of hippocampal amnesia (N = 3) patients and healthy controls (N = 6) used a novel procedure for capturing neural correlates of implicit memory using event-related potentials (ERPs): old and new items were equated for varying levels of memory awareness, with ERP differences observed from 400 to 800 ms in bilateral parietal regions that were hippocampal-dependent. The current investigation sought to address the limitations of that study by increasing the sample of healthy subjects (N = 54), applying new controls for construct validity, and developing an improved, open-source tool for automated analysis of the procedure used for equating levels of memory awareness. Results faithfully reproduced prior ERP findings of parietal effects that a series of systematic control analyses validated were not contributed to nor contaminated by explicit memory. Implicit memory effects extended from 600 to 1000 ms, localized to right parietal sites. These ERP effects were found to be behaviorally relevant and specific in predicting implicit memory response times, and were topographically dissociable from other traditional ERP measures of implicit memory (miss vs. correct rejections) that instead occurred in left parietal regions. Results suggest first that equating for reported awareness of memory strength is a valid, powerful new method for revealing neural correlates of non-conscious human memory, and second, behavioral correlations suggest that these implicit effects reflect a pure form of priming, whereas misses represent fluency leading to the subjective experience of familiarity.

A pilot study of closed-loop neuromodulation for treatment-resistant post-traumatic stress disorder.

The neurophysiological mechanisms in the human amygdala that underlie post-traumatic stress disorder (PTSD) remain poorly understood. In a first-of-its-kind pilot study, we recorded intracranial electroencephalographic data longitudinally (over one year) in two male individuals with amygdala electrodes implanted for the management of treatment-resistant PTSD (TR-PTSD) under clinical trial NCT04152993. To determine electrophysiological signatures related to emotionally aversive and clinically relevant states (trial primary endpoint), we characterized neural activity during unpleasant portions of three separate paradigms (negative emotional image viewing, listening to recordings of participant-specific trauma-related memories, and at-home-periods of symptom exacerbation). We found selective increases in amygdala theta (5-9 Hz) bandpower across all three negative experiences. Subsequent use of elevations in low-frequency amygdala bandpower as a trigger for closed-loop neuromodulation led to significant reductions in TR-PTSD symptoms (trial secondary endpoint) following one year of treatment as well as reductions in aversive-related amygdala theta activity. Altogether, our findings provide early evidence that elevated amygdala theta activity across a range of negative-related behavioral states may be a promising target for future closed-loop neuromodulation therapies in PTSD.

Subsets of cortico-cortical evoked potentials propagate as traveling waves.

Emerging evidence suggests that the temporal dynamics of cortico-cortical evoked potentials (CCEPs) may be used to characterize the patterns of information flow between and within brain networks. At present, however, the spatiotemporal dynamics of CCEP propagation cortically and subcortically are incompletely understood. We hypothesized that CCEPs propagate as an evoked traveling wave emanating from the site of stimulation. To elicit CCEPs, we applied single-pulse stimulation to stereoelectroencephalography (SEEG) electrodes implanted in 21 adult patients with intractable epilepsy. For each robust CCEP, we measured the timing of the maximal descent in evoked local field potentials and broadband high-gamma power (70-150 Hz) envelopes relative to the distance between the recording and stimulation contacts using three different metrics (i.e., Euclidean distance, path length, geodesic distance), representing direct, subcortical, and transcortical propagation, respectively. Many evoked responses to single-pulse electrical stimulation appear to propagate as traveling waves (~17-30%), even in the sparsely sampled, three-dimensional SEEG space. These results provide new insights into the spatiotemporal dynamics of CCEP propagation.

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.

BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min-1 g dry wt-1 in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.

A wearable platform for closed-loop stimulation and recording of single-neuron and local field potential activity in freely moving humans.

Advances in technologies that can record and stimulate deep brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and restricted full-duplex bidirectional capability. In this study, we developed a wearable bidirectional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans and, consequently, bridge decades of neuroscientific findings across species.