A Differential-Geometric Approach to Quantum Ignorance Consistent with Entropic Properties of Statistical Mechanics.

In this paper, we construct the metric tensor and volume for the manifold of purifications associated with an arbitrary reduced density operator ρS. We also define a quantum coarse-graining (CG) to study the volume where macrostates are the manifolds of purifications, which we call surfaces of ignorance (SOI), and microstates are the purifications of ρS. In this context, the volume functions as a multiplicity of the macrostates that quantifies the amount of information missing from ρS. Using examples where the SOI are generated using representations of SU(2), SO(3), and SO(N), we show two features of the CG: (1) A system beginning in an atypical macrostate of smaller volume evolves to macrostates of greater volume until it reaches the equilibrium macrostate in a process in which the system and environment become strictly more entangled, and (2) the equilibrium macrostate takes up the vast majority of the coarse-grained space especially as the dimension of the total system becomes large. Here, the equilibrium macrostate corresponds to a maximum entanglement between the system and the environment. To demonstrate feature (1) for the examples considered, we show that the volume behaves like the von Neumann entropy in that it is zero for pure states, maximal for maximally mixed states, and is a concave function with respect to the purity of ρS. These two features are essential to typicality arguments regarding thermalization and Boltzmann's original CG.

Complexity and efficiency of minimum entropy production probability paths from quantum dynamical evolutions.

We present an information geometric characterization of quantum driving schemes specified by su(2;C) time-dependent Hamiltonians in terms of both complexity and efficiency concepts. Specifically, starting from pure output quantum states describing the evolution of a spin-1/2 particle in an external time-dependent magnetic field, we consider the probability paths emerging from the parametrized squared probability amplitudes of quantum origin. The information manifold of such paths is equipped with a Riemannian metrization specified by the Fisher information evaluated along the parametrized squared probability amplitudes. By employing a minimum action principle, the optimum path connecting initial and final states on the manifold in finite time is the geodesic path between the two states. In particular, the total entropy production that occurs during the transfer is minimized along these optimum paths. For each optimum path that emerges from the given quantum driving scheme, we evaluate the so-called information geometric complexity (IGC) and our newly proposed measure of entropic efficiency constructed in terms of the constant entropy production rates that specify the entropy minimizing paths being compared. From our analytical estimates of complexity and efficiency, we provide a relative ranking among the driving schemes being investigated. Moreover, we determine that the efficiency and the temporal rate of change of the IGC are monotonic decreasing and increasing functions, respectively, of the constant entropic speed along these optimum paths. Then, after discussing the connection between thermodynamic length and IGC in the physical scenarios being analyzed, we briefly examine the link between IGC and entropy production rate. Finally, we conclude by commenting on the fact that an higher entropic speed in quantum transfer processes seems to necessarily go along with a lower entropic efficiency together with a higher information geometric complexity.

Confronting COVID, racism, and addiction: The association of multidisciplinary education and research in substance use and addiction (AMERSA).

The COVID-19 pandemic, the ongoing opioid epidemic, rise in substance use, and social and political unrest in the US and globally has impacted how substance use-related health needs are addressed. These issues were driving forces in planning AMERSA's 44th annual conference. True to the multidisciplinary spirit, and with diversity goals and advocacy at the forefront of mind, "together we rise" became the beacon for the AMERSA 2020 conference. This commentary provides an overview of the conference proceedings, topics that were highly relevant for clinicians, educators, researchers, and advocates for change.

Co-occurring Substance Use Disorders in Youth With Chronic Medical Conditions: The Need for Integration of Addiction Treatment into Mainstream Medical Facilities.

: Approximately 5% of adolescents in the US meet criteria for a substance use disorder (SUD), and many of them benefit from residential treatment programs at points in the course of the disorder to achieve early sobriety and stabilization. Youth with chronic medical conditions use alcohol, marijuana, and other substances at levels similar to peers, but are at greater risk of progression to heavy or problem use of alcohol, marijuana, and tobacco by young adulthood and often encounter unique treatment barriers that limit access to an appropriate level of care. We describe 2 such adolescents; a 15-year-old boy with type 1 diabetes who experienced interruptions in substance use treatment because of concerns regarding routine glycemic management and a 17-year-old boy with inflammatory bowel disease, who experienced treatment delays in the context of increasing alcohol and marijuana use because of digestive symptoms. For both of these adolescents, lack of access to professionals who could manage chronic medical conditions prevented delivery of substance use treatment and resulted in an increase in substance use behaviors. These cases illustrate the need for integrated substance use care within medical specialty settings. We propose opportunities for improvement, such as providing cross-training for medical and addiction treatment teams and integration of substance use treatment within traditional medical facilities.

Challenges and new horizons in substance use and addictions: Overview of the 2019 conference of the Association of Multidisciplinary Education and Research in Substance use and Addiction (AMERSA).

The morbidity and mortality associated with opioids, alcohol and other substances challenges clinicians, educators, researchers and policy makers to address these preventable health problems. Interventions are needed to address the many and complex factors that are needed for access to and receipt of life-saving treatment and resources for those who are at risk because of substance use and those with substance use disorders. This article provides an overview of the 43rd annual conference of the Association of Multidisciplinary Education and Research in Substance use and Addiction (AMERSA) held in Boston, MA on November 7-9, 2019. With more than 500 attendees from the nursing, social work, behavioral health, psychiatry, medicine, pharmacy, research and policy among others, the conference provided a platform to address challenges and new horizons in substance and addiction prevention, treatment and research, as well as opportunities for collegial discussion and networking.

A novel approach to treating adolescents with opioid use disorder in pediatric primary care.

BACKGROUND: Medication treatment for opioid use disorder is effective, and recommended for adolescents, though very few adolescents with opioid use disorder ever receive medications. Reasons include lack of trained medication prescribers for this age group and difficulty in identifying adolescents with substance use disorders. This manuscript examines a novel implementation model of identifying and providing treatment for substance use disorders, including opioid use disorder, in a pediatric primary care practice. METHODS: Patients presenting to a selected primary care pediatrics practice for any reason between March 9, 2017 and July 24, 2017 that were identified by screening, self-report or other clinical information to have a substance use problem were referred to an integrated clinical social worker for treatment. We recorded the number of patients that were referred, number of visits completed and SUD and mental health diagnoses. RESULTS: In the first 4 months of this program, 683 patients aged 12-22 completed a health maintenance appointment; 20 were referred for substance use disorder treatment and 13 completed at least one substance use disorder treatment visit with the integrated clinical social worker. The mean number of visits completed was 5.3. Three patients with opioid use disorders were identified and 2 were induced on buprenorphine. CONCLUSIONS: Our model for treatment of substance use disorders, including opioid use disorders, was feasible and acceptable in a pediatric primary care practice. Broadly implemented, such a model could substantially increase access to substance use disorder treatment for adolescents and young adults.

Redox-active Cu(II)-Aß causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner.

BACKGROUND: The beta-amyloid (Aß) peptide comprises the amyloid plaques that characterise Alzheimer's disease (AD), and is thought to significantly contribute towards disease pathogenesis. Oxidative stress is elevated in the AD brain, and there is substantial evidence that the interaction between Aß and redox-active copper is a major contributing factor towards oxidative stress in AD. RESULTS: The major findings of this study are that redox-active Cu(II)-Aß causes pronounced axonal pathology in long-term neuronal cultures, including axonal fragmentation and the formation of hyperphosphorylated tau-immunoreactive axonal swellings. Notably, MAP-2 expressing dendritic processes remain largely un-affected by Cu(II)-Aß treatment. These dystrophic axonal manifestations resemble some of the characteristic neuritic pathology of the AD brain. We show that Cu(II)-Aß directly causes formation of intra-axonal swellings via the generation of free radicals and subsequent efflux of K+ out of neurons. CONCLUSION: In summary, we report that redox-active Cu(II)-Aß can induce substantial neurodegenerative changes in mature neurons, and may have an important role to play in the slowly progressing pathogenesis of AD.

Tg2576 cortical neurons that express human Ab are susceptible to extracellular Aß-induced, K+ efflux dependent neurodegeneration.

BACKGROUND: One of the key pathological features of AD is the formation of insoluble amyloid plaques. The major constituent of these extracellular plaques is the beta-amyloid peptide (Aß), although Aß is also found to accumulate intraneuronally in AD. Due to the slowly progressive nature of the disease, it is likely that neurons are exposed to sublethal concentrations of both intracellular and extracellular Aß for extended periods of time. RESULTS: In this study, we report that daily exposure to a sublethal concentration of Aß(1-40) (1 µM) for six days induces substantial apoptosis of cortical neurons cultured from Tg2576 mice (which express substantial but sublethal levels of intracellular Aß). Notably, untreated Tg2576 neurons of similar age did not display any signs of apoptosis, indicating that the level of intracellular Aß present in these neurons was not the cause of toxicity. Furthermore, wildtype neurons did not become apoptotic under the same chronic Aß(1-40) treatment. We found that this apoptosis was linked to Tg2576 neurons being unable to maintain K(+) homeostasis following Aß treatment. Furthermore, blocking K(+) efflux protected Tg2576 neurons from Aß-induced neurotoxicity. Interestingly, chronic exposure to 1 µM Aß(1-40) caused the generation of axonal swellings in Tg2576 neurons that contained dense concentrations of hyperphosphorylated tau. These were not observed in wildtype neurons under the same treatment conditions. CONCLUSIONS: Our data suggest that when neurons are chronically exposed to sublethal levels of both intra- and extra-cellular Aß, this causes a K(+)-dependent neurodegeneration that has pathological characteristics similar to AD.

Olfactory ensheathing cells moderate nuclear factor kappaB translocation in astrocytes.

Nuclear factor kappaB (NFκB) is a key transcriptional regulator of inflammatory genes. We investigated the modulatory effects of olfactory ensheathing cells (OECs), microglia and meningeal fibroblasts on translocation of NFκB to astrocyte nuclei. The percentage of activated astrocytes in co-cultures with OECs was significantly less than for co-cultures with microglia (p<0.001) and fibroblasts (p<0.05). Phorbol myristate acetate (PMA) and calcium ionophore stimulation of p65 NFκB translocation to nuclei provided an in vitro model of astrocyte inflammatory activation. Soluble factors released by OECs significantly moderated the astrocytic NFκB translocation induced by either PMA/calcium ionophore or microglia-derived factors (p<0.001). Insulin-like growth factor-1 may contribute to these effects, since it is expressed by OECs and also significantly moderated the astrocytic NFκB translocation (p<0.05), albeit insufficiently to fully account for the OEC-induced moderation (p<0.01). Olfactory ensheathing cells significantly moderated the increased transcription of the pro-inflammatory cytokine, granulocyte macrophage-colony stimulating factor in the activated astrocytes (p<0.01). These results suggest that transplanted OECs could improve neural repair after CNS injury by moderating astrocyte activation.

The native copper- and zinc-binding protein metallothionein blocks copper-mediated Abeta aggregation and toxicity in rat cortical neurons.

BACKGROUND: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (Abeta) plaques. There are compelling data suggesting that Abeta aggregation is catalysed by reaction with the metals zinc and copper. METHODOLOGY/PRINCIPAL FINDINGS: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Abeta1-40 and Abeta1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Abeta, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Abeta aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Abeta induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. CONCLUSIONS/SIGNIFICANCE: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Abeta aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Abeta leaving a metal-free Abeta that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Abeta leaves the Abeta in a Zn-bound, relatively inert form.

Transcriptional and epigenetic regulation of the GM-CSF promoter by RUNX1.

The RUNX1 gene, which is essential for normal hematopoiesis, is frequently rearranged by the t(8;21) chromosomal translocation in acute myeloid leukemia. The resulting RUNX1-ETO fusion protein contributes to leukemic progression by directing aberrant association of transcriptional cofactors and epigenetic modifiers to RUNX1 target genes. For example, the GM-CSF gene is activated by RUNX1, but is repressed by RUNX1-ETO. Here we show that RUNX1 normally cooperates with the histone acetyltransferase, CBP, to regulate GM-CSF expression at two levels. Firstly, it directs the establishment of a competent chromatin environment at the GM-CSF promoter prior to gene activation. It then participates in the transcriptional activation of the promoter in response to immune stimuli. In contrast, RUNX1-ETO, which cannot associate with CBP, is unable to transactivate the GM-CSF promoter and is associated with the generation of a repressive chromatin environment at the promoter.