Assessing experts' perspectives on challenges in substance misuse prevention, harm reduction, and treatment to shape funding priorities in New York State.

BACKGROUND: Drug overdose is a leading cause of death and opioid-related deaths increased by more than 300% from 2010 to 2020 in New York State. Experts holding a range of senior leadership positions from across New York State were asked to identify the greatest challenges in substance misuse prevention, harm reduction, and treatment continuum of care. Expert input was used to shape funding priorities. METHOD: Individual semi-structured interviews of sixteen experts were conducted in April and May 2023. Experts included academics, medical directors, leaders of substance misuse service agencies, administrators of a state agency, a county mental health commissioner, the president of a pharmacy chain, and a senior vice president of an addiction-related national non-profit. Zoom interviews were conducted individually by an experienced qualitative interviewer and were recorded, transcribed, and coded for content. An initial report, with the results of the interviews organized by thematic content, was reviewed by the research team and emailed to the expert interviewees for feedback. RESULTS: The research team identified five major themes: 1. Siloed and fragmented care delivery systems; 2. Need for a skilled workforce; 3. Attitudes towards addiction (stigma); 4. Limitations in treatment access; and 5. Social and drug related environmental factors. Most experts identified challenges in each major theme; over three-quarters identified issues related to siloed and fragmented systems and the need for a skilled workforce. Each expert mentioned more than one theme, three experts mentioned all five themes and six experts mentioned four themes. CONCLUSIONS: Research, educational, and programmatic agendas should focus on identified topics as a means of improving the lives of patients at risk for or suffering from substance use-related disorders. The results of this project informed funding of pilot interventions designed to address the identified care challenges.

Liraglutide increases islet Ca2+ oscillation frequency and insulin secretion by activating hyperpolarization-activated cyclic nucleotide-gated channels.

AIM: To determine whether hyperpolarization-activated cyclic nucleotide-gated (HCN) channels impact glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) modulation of islet Ca2+ handling and insulin secretion. METHODS: The impact of liraglutide (GLP-1 analogue) on islet Ca2+ handling, HCN currents and insulin secretion was monitored with fluorescence microscopy, electrophysiology and enzyme immunoassays, respectively. Furthermore, liraglutide-mediated ß-to-δ-cell cross-communication was assessed following selective ablation of either mouse islet δ or ß cells. RESULTS: Liraglutide increased ß-cell Ca2+ oscillation frequency in mouse and human islets under stimulatory glucose conditions. This was dependent in part on liraglutide activation of HCN channels, which also enhanced insulin secretion. Similarly, liraglutide activation of HCN channels also increased ß-cell Ca2+ oscillation frequency in islets from rodents exposed to a diabetogenic diet. Interestingly, liraglutide accelerated Ca2+ oscillations in a majority of islet δ cells, which showed synchronized Ca2+ oscillations equivalent to ß cells; therefore, we assessed if either cell type was driving this liraglutide-mediated islet Ca2+ response. Although δ-cell loss did not impact liraglutide-mediated increase in ß-cell Ca2+ oscillation frequency, ß-cell ablation attenuated liraglutide-facilitated acceleration of δ-cell Ca2+ oscillations. CONCLUSION: The data presented here show that liraglutide-induced stimulation of islet HCN channels augments Ca2+ oscillation frequency. As insulin secretion oscillates with ß-cell Ca2+ , these findings have important implications for pulsatile insulin secretion that is probably enhanced by liraglutide activation of HCN channels and therapeutics that target GLP-1Rs for treating diabetes. Furthermore, these studies suggest that liraglutide as well as GLP-1-based therapies enhance δ-cell Ca2+ oscillation frequency and somatostatin secretion kinetics in a ß-cell-dependent manner.

Real-Time Fatigue Mitigation with Air-Medical Personnel: The SleepTrackTXT2 Randomized Trial.

Objective: The aims of this study were: 1) to determine the short-term impact of the SleepTrackTXT2 intervention on air-medical clinician fatigue during work shifts and 2) determine the longer-term impact on sleep quality over 120 days. Methods: We used a multi-site randomized controlled trial study design with a targeted enrollment of 100 (ClinicalTrials.gov NCT02783027). The intervention was behavioral (non-pharmacological) and participation was scheduled for 120 days. Participation was voluntary. All consented participants answered baseline as well as follow-up surveys. All participants answered text message queries, which assessed self-rated fatigue, sleepiness, concentration, recovery, and hours of sleep. Intervention participants received additional text messages with recommendations for behaviors that can mitigate fatigue. Intervention participants received weekly text messages that promoted sleep. Our analysis was guided by the intent-to-treat principle. For the long-term outcome of interest (sleep quality at 120 days), we used a two-sample t-test on the change in sleep quality to determine the intervention effect. Results: Eighty-three individuals were randomized and 2,828 shifts documented (median shifts per participant =37, IQR 23-49). Seventy-one percent of individuals randomized (n = 59) participated up to the 120-day study period and 52% (n = 43) completed the follow-up survey. Of the 69,530 text messages distributed, participants responded to 61,571 (88.6%). Mean sleep quality at 120 days did not differ from baseline for intervention (p > 0.05) or control group participants (p > 0.05), and did not differ between groups (p > 0.05). There was no change from baseline to 120 days in the proportion with poor sleep quality in either group. Intra-shift fatigue increased (worsened) over the course of 12-hour shifts for participants in both study arms. Fatigue at the end of 12-hour shifts was higher among control group participants than participants in the intervention group (p < 0.05). Pre-shift hours of sleep were often less than 7 hours and did not differ between the groups over time. Conclusions: The SleepTrackTXT2 behavioral intervention showed a positive short-term impact on self-rated fatigue during 12-hour shifts, but did not impact longer duration shifts or have a longer-term impact on sleep quality among air-medical EMS clinicians.

Impact of shift duration on alertness among air-medical emergency care clinician shift workers.

BACKGROUND: Greater than half of Emergency Medical Services (EMS) shift workers report fatigue at work and most work long duration shifts. We sought to compare the alertness level of EMS shift workers by shift duration. METHODS: We used a multi-site, 14-day prospective observational cohort study design of EMS clinician shift workers at four air-medical EMS organizations. The primary outcome was behavioral alertness as measured by psychomotor vigilance tests (PVT) at the start and end of shifts. We stratified shifts by duration (< 24 h and 24 h), night versus day, and examined the impact of intra-shift napping on PVT performance. RESULTS: One hundred and twelve individuals participated. The distribution of shifts <24 h and 24 h with complete data were 54% and 46%, respectively. We detected no differences in PVT performance measures stratified by shift duration (P > 0.05). Performance for selected PVT measures (lapses and false starts) was worse on night shifts compared to day shifts (P < 0.05). Performance also worsened with decreasing time between waking from a nap and the end of shift PVT assessment. CONCLUSIONS: Deficits in performance in the air-medical setting may be greatest during night shifts and proximal to waking from an intra-shift nap. Future research should examine alertness and performance throughout air-medical shifts, as well as investigate the timing and duration of intra-shift naps on outcomes.

Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.

miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.

Variation in Rural African Gut Microbiota Is Strongly Correlated with Colonization by Entamoeba and Subsistence.

The human gut microbiota is impacted by host nutrition and health status and therefore represents a potentially adaptive phenotype influenced by metabolic and immune constraints. Previous studies contrasting rural populations in developing countries to urban industrialized ones have shown that industrialization is strongly correlated with patterns in human gut microbiota; however, we know little about the relative contribution of factors such as climate, diet, medicine, hygiene practices, host genetics, and parasitism. Here, we focus on fine-scale comparisons of African rural populations in order to (i) contrast the gut microbiota of populations inhabiting similar environments but having different traditional subsistence modes and either shared or distinct genetic ancestry, and (ii) examine the relationship between gut parasites and bacterial communities. Characterizing the fecal microbiota of Pygmy hunter-gatherers as well as Bantu individuals from both farming and fishing populations in Southwest Cameroon, we found that the gut parasite Entamoeba is significantly correlated with microbiome composition and diversity. We show that across populations, colonization by this protozoa can be predicted with 79% accuracy based on the composition of an individual's gut microbiota, and that several of the taxa most important for distinguishing Entamoeba absence or presence are signature taxa for autoimmune disorders. We also found gut communities to vary significantly with subsistence mode, notably with some taxa previously shown to be enriched in other hunter-gatherers groups (in Tanzania and Peru) also discriminating hunter-gatherers from neighboring farming or fishing populations in Cameroon.

Restriction Site-Associated DNA Sequencing (RAD-seq) Reveals an Extraordinary Number of Transitions among Gecko Sex-Determining Systems.

Sex chromosomes have evolved many times in animals and studying these replicate evolutionary "experiments" can help broaden our understanding of the general forces driving the origin and evolution of sex chromosomes. However this plan of study has been hindered by the inability to identify the sex chromosome systems in the large number of species with cryptic, homomorphic sex chromosomes. Restriction site-associated DNA sequencing (RAD-seq) is a critical enabling technology that can identify the sex chromosome systems in many species where traditional cytogenetic methods have failed. Using newly generated RAD-seq data from 12 gecko species, along with data from the literature, we reinterpret the evolution of sex-determining systems in lizards and snakes and test the hypothesis that sex chromosomes can routinely act as evolutionary traps. We uncovered between 17 and 25 transitions among gecko sex-determining systems. This is approximately one-half to two-thirds of the total number of transitions observed among all lizards and snakes. We find support for the hypothesis that sex chromosome systems can readily become trap-like and show that adding even a small number of species from understudied clades can greatly enhance hypothesis testing in a model-based phylogenetic framework. RAD-seq will undoubtedly prove useful in evaluating other species for male or female heterogamety, particularly the majority of fish, amphibian, and reptile species that lack visibly heteromorphic sex chromosomes, and will significantly accelerate the pace of biological discovery.

Inhibition of miR-15 protects against cardiac ischemic injury.

RATIONALE: Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI. OBJECTIVE: This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury. METHODS AND RESULTS: Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI. CONCLUSIONS: Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.

Characteristics of Patients Presenting at an Emergency Department for a Heroin Overdose vs Detoxification.

Purpose: This study compares substance use, treatment histories, and sociodemographic characteristics of patients presenting to an emergency department (ED) following a heroin overdose or seeking detoxification services for heroin and examines risk factors for a subsequent return to the ED for a substance-related problem. Methods: A convenience sample of patients presenting for an overdose or detoxification at an urban teaching ED was recruited for this study. During their ED visit, patients were interviewed regarding demographics, substance use experiences, and treatment history. Subsequently, a review of patient records for past and subsequent ED use was performed. Results: Patients requesting detox and those with an overdose were similar in terms of prior treatment. Both groups had similar extensive polysubstance histories. As a group, however, patients presenting for detox were more likely to report use of each of three substances (benzodiazepines, opioid pain medications, and heroin) more than three times per week, compared to those presenting for overdose. Detox patients had higher scores on the 3-item Alcohol Use Disorder Identification Test-C and the drug problems scale compared to overdose patients. Overall, 28% of the patients returned to the ED within 90 days for a drug-related issue, including 8% that returned for an overdose. Factors predictive of a return ED visit included ED visits for substance use in the previous year and recent frequent heroin use. Conclusion: Patients requesting detox were similar in most domains to those presenting following an overdose. Notably, overdose patients were less likely to use heroin more than three times per week compared to detox patients. Both groups were equally likely to return for an SUD reason within 3-months, however for both groups, previous ED visits and recent frequent heroin use predicted a return visit.

Comparison of 30-day retention in treatment among patients referred to opioid use disorder treatment from emergency department and telemedicine settings.

INTRODUCTION: Telemedicine is a feasible alternative to in-person evaluations for people with opioid use disorder (OUD). The literature on medications for opioid use disorder (MOUD) telemedicine has focused on ongoing OUD treatment. Emergency department (ED) visits are an opportunity to initiate MOUD; however, little is known regarding the outcomes of patients following telemedicine referrals for MOUD from emergency settings. The current study describes rates of initial outpatient clinic appointment attendance and 30-day retention in care among patients referred by telemedicine compared to ED referrals. METHODS: This paper reports a retrospective review of data for patients referred from EDs or telemedicine through the Medication for Addiction Treatment and Electronic Referrals (MATTERS) Network. The MATTERS online platform collects data on patient demographic information (e.g., age, gender, race/ethnicity, and insurance type), reason for visit, prior medical and mental health history, prior OUD treatment history, and past 30-day substance use behaviors. Analyses compared initial visit attendance and 30-day retention among the patients for whom follow-up data were received from clinics by demographic and initial treatment factors. RESULTS: Between October 2020 and September 2022, the MATTERS Network made 1349 referrals; 39.7 % originated from an ED and 47.8 % originated from telemedicine. For patients with available data, those referred from telemedicine were 1.64 times more likely to attend their initial clinic appointment and 2.59 times more likely be engaged in treatment at 30 days compared to those referred from an ED. More than two-thirds of patients referred from the emergency telemedicine environment followed up at their first clinic visit and more than half of these patients were still retained in treatment 30 days after referral. CONCLUSIONS: The rates of initial clinic visit and 30-day retention when referred following a telemedicine evaluation are encouraging. Further development of telemedicine programs that offer evaluations, access to medications, and referrals to treatment should be considered.

COVID-19-Induced Phlegmasia Cerulea Dolens.

A 44-year-old male with a history of deep venous thrombosis (DVT) and pulmonary embolism (PE) with the inferior vena cava (IVC) filter in place and peripheral vascular disease (PVD) status post lower extremity vascular stenting presented from a COVID-19 rehabilitation center with bilateral phlegmasia cerulea dolens and no palpable popliteal or dorsalis pedis pulses, at risk for venous gangrene and loss of limbs. The patient was anticoagulated and taken emergently to the operating room for vascular surgery where thrombolysis with alteplase and mechanical thrombectomy were performed. Bilateral thrombolysis infusion catheters were placed for two days. The patient had a return of arterial signals in the feet and decreasing clot burden. The patient is expected to make a full recovery.

Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure.

BACKGROUND: Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options. MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to diastolic dysfunction or other forms of heart disease is currently unknown. METHODS AND RESULTS: Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates significant changes in circulating levels of miRNAs on antimiR-208a treatment. CONCLUSIONS: These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart disease progression.

Expression of key retinoic acid modulating genes suggests active regulation during development and regeneration of the amphibian limb.

We have previously shown differential regulation of components of the Retinoic acid (RA) pathway in Xenopus tadpole hindlimb regeneration. RA is thought to act as a morphogen, providing positional information during development and regeneration. We have investigated the regulation of genes involved in RA synthesis, catabolism, and binding in developing and regenerating Xenopus limbs. Our data indicate that RA is synthesised by Raldh2 in proximal cells during limb bud outgrowth. Furthermore, Cyp26b is expressed transiently in the progress zone of developing limbs and the blastema of regenerating limbs suggesting degradation of RA occurs in both processes. The RA-binding protein Crabp2 is also upregulated during regeneration. We summarise this data to predict the presence of evolving gradients of RA in the developing amphibian limb. Thus, RA from the stump cells could be responsible for the establishment of proximal-distal pattern during limb regeneration, as predicted by classical studies.

Implementing a Novel Statewide Network to Support Emergency Department-initiated Buprenorphine Treatment.

INTRODUCTION: Medications for opioid use disorder (MOUD), including buprenorphine, represent an evidence-based treatment that supports long-term recovery and reduces risk of overdose death. Patients in crisis from opioid use disorder (OUD) often seek care from emergency departments (ED). The New York Medication for Addiction Treatment and Electronic Referrals (MATTERS) network is designed to support ED-initiated buprenorphine and urgent referrals to long-term care for patients suffering from OUD. METHODS: Using the PRECEDE-PROCEED implementation science framework, we provide an overview of the creation of the MATTERS network in Western New York. We also include an explanation of how the network was designed and launched as a response to the opioid epidemic. Finally, we analyzed the program's outputs and outcomes, thus far, as it continues to grow across the state. RESULTS: The New York MATTERS network was created and implemented in 2019 with a single hospital referring patients with OUD to three local clinics. In the social assessment and situational analysis phase, we describe the opioid epidemic and available resources in the region at the outset of the program. In the epidemiological assessment phase, we quantify the epidemic on the state and regional levels. In the educational and ecological assessment, we review local ED practices and resources. In the administrative and policy assessment and intervention alignment phase, the program's unique framework is reviewed. In the piloting phase, we describe the initial deployment of New York MATTERS. Finally, in the process evaluation phase, we depict the early lessons we learned. By the beginning of 2021, the New York MATTERS network included 35 hospitals that refer to 47 clinics throughout New York State. CONCLUSION: The New York MATTERS network provides a structured approach to reduce barriers to ED-initiated buprenorphine and urgent referral to long-term care. An implementation framework provides a structured means of evaluating this best practice model.

Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation.

Gi/o-coupled somatostatin or α2-adrenergic receptor activation stimulated ß-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of ß-cell Gi/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. ß-cell membrane potential hyperpolarization resulting from Gi/o-GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, ß-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated ß-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.

PKC-permitted elevation of sarcolemmal KATP concentration may explain female-specific resistance to myocardial infarction.

The female myocardium, relative to that of the male, exhibits sustained resistance to ischaemic tissue injury, a phenomenon termed sex-specific cardioprotection (SSC). SSC is dependent upon the sarcolemmal K(ATP) channel (sarcK(ATP)), and protein kinase C (PKC). Here we investigate whether PKC-mediated regulation of sarcK(ATP) concentration can explain this endogenous form of protection. Hearts from male (M) and female (F) rats were Langendorff-perfused for 30 min prior to either regional ischaemia-reperfusion (I/R), or global ischaemia (GISC). For both protocols, pre-ischaemic blockade of PKC was achieved by chelerythrine (Chel) in male (M + C) and female (F + C) hearts. Additional female hearts underwent sarcK(ATP) antagonism during I/R by HMR-1098 (HMR), either alone or in combination with Chel (HMR + Chel). GISC hearts were fractionated to assess cellular distribution of PKC and sarcK(ATP). Sex-specific infarct resistance was apparent under control I/R (F, 23 +/- 3% vs. M, 36 +/- 4%, P < 0.05) and abolished by Chel (F + C, 36 +/- 3%). Female infarct resistance was susceptible to sarcK(ATP) blockade (Control, 16 +/- 2% vs. HMR, 27 +/- 3%), and PKC blockade had no additional effect (HMR + Chel, 26 +/- 2%). The prevalence of Kir6.2 and SUR2 was higher in the sarcolemmal fractions of females (Kir6.2: F, 1.24 +/- 0.07 vs. M, 1.02 +/- 0.06; SUR2: F, 3.16 +/- 0.22 vs. M, 2.45 +/- 0.09; ratio units), but normalized by Chel (Kir6.2: F, 1.06 +/- 0.07 vs. M, 0.99 +/- 0.06; SUR2: F, 2.99 +/- 0.09 vs. M, 2.82 +/- 0.22, M; ratio units). Phosphorylation of sarcolemmal PKC was reduced by Chel (p-PKC/PKC: control, 0.43 +/- 0.02; Chel, 0.29 +/- 0.01; P < 0.01). We conclude that PKC-mediated regulation of sarcK(ATP) may account for the physiologically sustainable dependence of SSC upon both PKC and sarcK(ATP), and that this regulation involves PKC-permitted enrichment of the female sarcolemma with sarcK(ATP). As such, the PKC-sarcK(ATP) axis may represent a target for sustainable prophylactic induction of cardioprotection.

Neural mechanisms of movement speed and tau as revealed by magnetoencephalography.

A fundamental aspect of goal-directed behavior concerns the closure of motion-gaps in a timely fashion. In this context, the critical variable is the time-to-closure, called tau (Lee in Perception 5:437-459, 1976), and is defined as the ratio of the current distance-to-goal gap over the current instantaneous speed towards the goal. In this study, we investigated the neural mechanisms of speed and tau in pointing hand movements by recording MEG activity from the whole brain of 20 right-handed healthy human subjects operating a joystick with their right hand. The relations between neural signals and speed and tau were analyzed using an autoregressive multiple regression model, where the time-varying MEG signal was the dependent variable and the corresponding value of speed and tau were the independent variables. With respect to speed, we found that 81% of sensors showed significant relations over the left frontal-parietal, left parieto-temporal, and, less prominently, the right temporo-occipital sensor space. These results document the widespread involvement of brain areas with movement speed, especially in the left hemisphere (i.e., contralateral to the moving limb), in accord with previous studies. With respect to tau, 22% of sensors showed significant relations over the parietal (bilaterally), right parietal-temporal, and, less prominently, the left temporo-occipital sensor space. The tau effects often occurred concurrently with speed effects and spatially overlapped in the left fronto-parietal sensors. These findings document for the first time the time-varying, dynamic processing of information regarding tau in specific brain areas, including the right parietal cortex. This is of special interest, for that area has been found to be involved in processing information concerning the duration of time intervals in perceptual tasks (Harrington et al. in J Neurosci 18:1085-1095, 1998; Rao et al. in Nat Neurosci 4:317-323, 2001). Since tau is itself a time interval, we hypothesize that the right parietal focus of tau processing observed in this study reflects the ongoing processing of tau as an interval for a timely arrival of the hand to the target.