Transcriptional Profile of Exercise-Induced Protection Against Relapse to Cocaine Seeking in a Rat Model.

Background: Exercise has shown promise as a treatment for cocaine use disorder; however, the mechanism underlying its efficacy has remained elusive. Methods: We used a rat model of relapse (cue-induced reinstatement) and exercise (wheel running, 2 hours/day) coupled with RNA sequencing to establish transcriptional profiles associated with the protective effects of exercise (during early withdrawal [days 1-7] or throughout withdrawal [days 1-14]) versus noneffective exercise (during late withdrawal [days 8-14]) against cocaine-seeking and sedentary conditions. Results: As expected, cue-induced cocaine seeking was highest in the sedentary and late-withdrawal exercise groups; both groups also showed upregulation of a Grin1-associated transcript and enrichment of Drd1-Nmdar1 complex and glutamate receptor complex terms. Surprisingly, these glutamate markers were also enriched in the early- and throughout-withdrawal exercise groups, despite lower levels of cocaine seeking. However, a closer examination of the Grin1-associated transcript revealed a robust loss of transcripts spanning exons 9 and 10 in the sedentary condition relative to saline controls that was normalized by early- and throughout-withdrawal exercise, but not late-withdrawal exercise, indicating that these exercise conditions may normalize RNA mis-splicing induced by cocaine seeking. Our findings also revealed novel mechanisms by which exercise initiated during early withdrawal may modulate glutamatergic signaling in dorsomedial prefrontal cortex (e.g., via transcripts associated with non-NMDA glutamate receptors or those affecting signaling downstream of NMDA receptors), along with mechanisms outside of glutamatergic signaling such as circadian rhythm regulation and neuronal survival. Conclusions: These findings provide a rich resource for future studies aimed at manipulating these molecular networks to better understand how exercise decreases cocaine seeking.

Spray fabrication of additive-free electrodes for advanced Lithium-Ion storage technologies.

Polymer binders and carbon conductivity enhancers are inevitably required to make improvements in structural durability and electrochemical performance of lithium-ion battery (LIB) electrodes, although these additive constituents incur weight and volume penalties on the overall battery capacity. Here, additive-free electrode architectures were successfully fabricated over 20 × 20 cm2 electrode areas using a layer-by-layer spray coating approach, with the ultimate goal to boost gravimetric/volumetric electrode capacity and to reduce the total cost of LIB cells. Initially, the binder fraction of spray-coated Li4Ti5O12 (LTO) electrodes was reduced progressively, from 40 to 0 wt%. The electrochemical behavior of electrodes was then re-optimized as a proportion of conductivity enhancers within the binder-free electrode decreased to zero. Further, the otherwise identical spray coating process was applied to manufacture LiFePO4 (LFP) positive electrodes, leading to all-additive-free full-cell LIB configurations with attractive energy density of âˆ¼310 Wh/kg and power performance of âˆ¼1500 W/kg.

Globally elevated levels of histone H3 lysine 9 trimethylation in early infancy are associated with poor growth trajectory in Bangladeshi children.

BACKGROUND: Stunting is a global health problem affecting hundreds of millions of children worldwide and contributing to 45% of deaths in children under the age of five. Current therapeutic interventions have limited efficacy. Understanding the epigenetic changes underlying stunting will elucidate molecular mechanisms and likely lead to new therapies. RESULTS: We profiled the repressive mark histone H3 lysine 9 trimethylation (H3K9me3) genome-wide in peripheral blood mononuclear cells (PBMCs) from 18-week-old infants (n = 15) and mothers (n = 14) enrolled in the PROVIDE study established in an urban slum in Bangladesh. We associated H3K9me3 levels within individual loci as well as genome-wide with anthropometric measurements and other biomarkers of stunting and performed functional annotation of differentially affected regions. Despite the relatively small number of samples from this vulnerable population, we observed globally elevated H3K9me3 levels were associated with poor linear growth between birth and one year of age. A large proportion of the differentially methylated genes code for proteins targeting viral mRNA and highly significant regions were enriched in transposon elements with potential regulatory roles in immune system activation and cytokine production. Maternal data show a similar trend with child's anthropometry; however, these trends lack statistical significance to infer an intergenerational relationship. CONCLUSIONS: We speculate that high H3K9me3 levels may result in poor linear growth by repressing genes involved in immune system activation. Importantly, changes to H3K9me3 were detectable before the overt manifestation of stunting and therefore may be valuable as new biomarkers of stunting.

Clinical Guidelines for Working with Clients Involved in Kink.

People involved in kink (BDSM or fetish) subcultures often encounter stigma and bias in healthcare settings or when seeking psychotherapy. Such individuals typically encounter well-meaning clinicians who are not prepared to provide culturally competent care or who have not recognized their own biases. Over a two-year period, a team of 20 experienced clinicians and researchers created clinical practice guidelines for working with people involved with kink, incorporating an extensive literature review and documentation of clinical expertise. This article summarizes the guidelines and discusses relevant issues facing clinicians and their clients, as well as implications for clinical practice, research and training.

Dendrite initiation and propagation in lithium metal solid-state batteries.

All-solid-state batteries with a Li anode and ceramic electrolyte have the potential to deliver a step change in performance compared with today's Li-ion batteries1,2. However, Li dendrites (filaments) form on charging at practical rates and penetrate the ceramic electrolyte, leading to short circuit and cell failure3,4. Previous models of dendrite penetration have generally focused on a single process for dendrite initiation and propagation, with Li driving the crack at its tip5-9. Here we show that initiation and propagation are separate processes. Initiation arises from Li deposition into subsurface pores, by means of microcracks that connect the pores to the surface. Once filled, further charging builds pressure in the pores owing to the slow extrusion of Li (viscoplastic flow) back to the surface, leading to cracking. By contrast, dendrite propagation occurs by wedge opening, with Li driving the dry crack from the rear, not the tip. Whereas initiation is determined by the local (microscopic) fracture strength at the grain boundaries, the pore size, pore population density and current density, propagation depends on the (macroscopic) fracture toughness of the ceramic, the length of the Li dendrite (filament) that partially occupies the dry crack, current density, stack pressure and the charge capacity accessed during each cycle. Lower stack pressures suppress propagation, markedly extending the number of cycles before short circuit in cells in which dendrites have initiated.

Numerical Design of Microporous Carbon Binder Domains Phase in Composite Cathodes for Lithium-Ion Batteries.

Lithium-ion battery (LIB) performance can be significantly affected by the nature of the complex electrode microstructure. The carbon binder domain (CBD) present in almost all LIB electrodes is used to enhance mechanical stability and facilitate electronic conduction, and understanding the CBD phase microstructure and how it affects the complex coupled transport processes is crucial to LIB performance optimization. In this work, the influence of microporosity in the CBD phase has been studied in detail for the first time, enabling insight into the relationships between the CBD microstructure and the battery performance. To investigate the effect of the CBD pore size distributions, a random field method is used to generate in silico a multiple-phase electrode structure, including bimodal pore size distributions seen in practice and microporous CBD with a tunable pore size and variable transport properties. The distribution of macropores and the microporous CBD phase substantially affected simulated battery performance, where battery specific capacity improved as the microporosity of the CBD phase increased.

Sequential Deposition of Integrated Cathode-Inorganic Separator-Anode Multilayers for High Performance Li-Ion Batteries.

A porous, spray-deposited Al2O3-based separator was developed to enable the direct deposition of an electrode/separator/electrode Li-ion battery full cell assembly in a single operation. The optimized sprayed separator consisted of 50 nm Al2O3 particles, 1 wt % poly(acrylic acid), and 5 wt % styrene-butadiene rubber, deposited from an 80:20 vol % suspension of water and isopropanol. Separators between 5 and 22 µm thick had consistent and similar porosity of ∼58%, excellent wettability, thermal stability to at least 180 °C, adequate electrochemical stability and high effective ionic conductivity of ∼1 mS cm-1 at room temperature in an EC/DMC electrolyte, roughly double that of a conventional polypropylene separator. A sequentially deposited three-layer LiFePO4/Al2O3/Li4Ti5O12 full cell, the first of its kind, showed similar rate performance to an identical cell with a conventional polypropylene separator, with a capacity of ∼50 mAh g-1 at 30 C. However, after cycling at 2 C for 400 cycles, Al2O3 separator full cells retained 96.3% capacity, significantly more than conventional full cells with a capacity of 79.2% remaining.

Choosing optimal trigger points for ex situ, in toto conservation of single population threatened species.

Many endangered species exist in only a single population, and almost all species that go extinct will do so from their last remaining population. Understanding how to best conserve these single population threatened species (SPTS) is therefore a distinct and important task for threatened species conservation science. As a last resort, managers of SPTS may consider taking the entire population into captivity-ex situ, in toto conservation. In the past, this choice has been taken to the great benefit of the SPTS, but it has also lead to catastrophe. Here, we develop a decision-support tool for planning when to trigger this difficult action. Our method considers the uncertain and ongoing decline of the SPTS, the possibility that drastic ex situ action will fail, and the opportunities offered by delaying the decision. Specifically, these benefits are additional time for ongoing in situ actions to succeed, and opportunities for the managers to learn about the system. To illustrate its utility, we apply the decision tool to four retrospective case-studies of declining SPTS. As well as offering support to this particular decision, our tool illustrates why trigger points for difficult conservation decisions should be formulated in advance, but must also be adaptive. A trigger-point for the ex situ, in toto conservation of a SPTS, for example, will not take the form of a simple threshold abundance.

X-ray Imaging of Alloy Solidification: Crystal Formation, Growth, Instability and Defects.

Synchrotron and laboratory-based X-ray imaging techniques have been increasingly used for in situ investigations of alloy solidification and other metal processes. Several reviews have been published in recent years that have focused on the development of in situ X-ray imaging techniques for metal solidification studies. Instead, this work provides a comprehensive review of knowledge provided by in situ X-ray imaging for improved understanding of solidification theories and emerging metal processing technologies. We first review insights related to crystal nucleation and growth mechanisms gained by in situ X-ray imaging, including solute suppressed nucleation theory of α-Al and intermetallic compound crystals, dendritic growth of α-Al and the twin plane re-entrant growth mechanism of faceted Fe-rich intermetallics. Second, we discuss the contribution of in situ X-ray studies in understanding microstructural instability, including dendrite fragmentation induced by solute-driven, dendrite root re-melting, instability of a planar solid/liquid interface, the cellular-to-dendritic transition and the columnar-to-equiaxed transition. Third, we review investigations of defect formation mechanisms during near-equilibrium solidification, including porosity and hot tear formation, and the associated liquid metal flow. Then, we discuss how X-ray imaging is being applied to the understanding and development of emerging metal processes that operate further from equilibrium, such as additive manufacturing. Finally, the outlook for future research opportunities and challenges is presented.

Design of Scalable, Next-Generation Thick Electrodes: Opportunities and Challenges.

Lithium-ion battery electrodes are on course to benefit from current research in structure re-engineering to allow for the implementation of thicker electrodes. Increasing the thickness of a battery electrode enables significant improvements in gravimetric energy density while simultaneously reducing manufacturing costs. Both metrics are critical if the transition to sustainable transport systems is to be fully realized commercially. However, significant barriers exist that prevent the use of such microstructures: performance issues, manufacturing challenges, and scalability all remain open areas of research. In this Perspective, we discuss the challenges in adapting current manufacturing processes for thick electrodes and the opportunities that pore engineering presents in order to design thicker and better electrodes while simultaneously considering long-term performance and scalability.

High Energy Density Single-Crystal NMC/Li6PS5Cl Cathodes for All-Solid-State Lithium-Metal Batteries.

To match the high capacity of metallic anodes, all-solid-state batteries require high energy density, long-lasting composite cathodes such as Ni-Mn-Co (NMC)-based lithium oxides mixed with a solid-state electrolyte (SSE). However in practice, cathode capacity typically fades due to NMC cracking and increasing NMC/SSE interface debonding because of NMC pulverization, which is only partially mitigated by the application of a high cell pressure during cycling. Using smart processing protocols, we report a single-crystal particulate LiNi0.83Mn0.06Co0.11O2 and Li6PS5Cl SSE composite cathode with outstanding discharge capacity of 210 mA h g-1 at 30 °C. A first cycle coulombic efficiency of >85, and >99% thereafter, was achieved despite a 5.5% volume change during cycling. A near-practical discharge capacity at a high areal capacity of 8.7 mA h cm-2 was obtained using an asymmetric anode/cathode cycling pressure of only 2.5 MPa/0.2 MPa.

Amorphization in extreme deformation of the CrMnFeCoNi high-entropy alloy.

Ever-harsher service conditions in the future will call for materials with increasing ability to undergo deformation without sustaining damage while retaining high strength. Prime candidates for these conditions are certain high-entropy alloys (HEAs), which have extraordinary work-hardening ability and toughness. By subjecting the equiatomic CrMnFeCoNi HEA to severe plastic deformation through swaging followed by either quasi-static compression or dynamic deformation in shear, we observe a dense structure comprising stacking faults, twins, transformation from the face-centered cubic to the hexagonal close-packed structure, and, of particular note, amorphization. The coordinated propagation of stacking faults and twins along {111} planes generates high-deformation regions, which can reorganize into hexagonal packets; when the defect density in these regions reaches a critical level, they generate islands of amorphous material. These regions can have outstanding mechanical properties, which provide additional strengthening and/or toughening mechanisms to enhance the capability of these alloys to withstand extreme loading conditions.

The biochemical and genetic discovery of the SAGA complex.

One of the major advances in our understanding of gene regulation in eukaryotes was the discovery of factors that regulate transcription by controlling chromatin structure. Prominent among these discoveries was the demonstration that Gcn5 is a histone acetyltransferase, establishing a direct connection between transcriptional activation and histone acetylation. This breakthrough was soon followed by the purification of a protein complex that contains Gcn5, the SAGA complex. In this article, we review the early genetic and biochemical experiments that led to the discovery of SAGA and the elucidation of its multiple activities.

Active Metamaterials with Negative Static Electric Susceptibility.

Although well-established textbook arguments suggest that static electric susceptibility χ(0) must be positive in "all bodies," it has been pointed out that materials that are not in thermodynamic equilibrium are not necessarily subject to this restriction. Media with inverted populations of atomic and molecular energy levels have been predicted theoretically to exhibit a χ(0) < 0 state, however the systems envisioned require reduced temperature, reduced pressure, and an external pump laser to maintain the population inversion. Further, the existence of χ(0) < 0 has never been confirmed experimentally. Here, a completely different approach is taken to the question of χ(0) < 0 and a design concept to achieve "true" χ(0) < 0 is proposed based on active metamaterials with internal power sources. Two active metamaterial structures are fabricated that, despite still having their power sources implemented externally for reasons of practical convenience, provide evidence in support of the general concept. Effective values are readily achieved at room temperature and pressure and are tunable throughout the range of stability -1 < χ(0) < 0, resulting in experimentally-determined magnitudes that are over one thousand times greater than those predicted previously. Since χ(0) < 0 is the missing electric analog of diamagnetism, this work opens the door to new technological capabilities such as stable electrostatic levitation.

Ant-icipating Change: An Epigenetic Switch in Reprogramming the Social Lives of Ants.

Glastad et al. (2019) describe a role for the neuronal CoREST corepressor and changes in juvenile hormone (JH) and ecdysone signaling during the reprogramming of social behavioral phenotypes in ants that are reflective of a natural mechanism differentiating "Major" and "Minor" worker ants.

Comparison of intraoperative tranexamic acid and epsilon-aminocaproic acid in cardiopulmonary bypass patients.

Objective: To compare tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Over a consecutive 2-year period, 824 adult cardiac surgery patients who received TXA during an EACA shortage were compared with 778 patients who received EACA postshortage. Patient characteristics and process and outcome variables were collected through chart review and database queries. This retrospective analysis used inverse probability of treatment weighting to control for confounding by indication, and propensity scores were calculated using a logistic regression model. Results: In adjusted models, overall transfusion rates for the TXA cohort (odds ratio [OR], 0.94; 95% confidence interval [95% CI], 0.81-1.10) and administration of platelets (OR, 1.04; 95% CI, 0.85-1.27), red blood cells (OR, 0.93; 95% CI, 0.80-1.09), fresh frozen plasma (OR, 1.00; 95% CI, 0.79-1.25), and cryoprecipitate (OR, 1.08; 95% CI, 0.71-1.64) were equivalent to the EACA cohort. In addition, there was no statistical difference with respect to stroke, seizure, mortality, reoperation for bleeding, chest tube drainage, and acute kidney injury. Patients who received TXA had shorter ventilator times (difference in medians -1.33 hours [95% CI, -1.86 to -0.80]) and lower postsurgical charges (difference of medians -$2913 [95% CI, -5147 to -679]). Conclusions: Substituting TXA for EACA during cardiac surgery with cardiopulmonary bypass did not change transfusion rate or amount, nor was there a significant difference in chest tube drainage. Patients who received TXA had a statistically significant but not clinically significant lower postoperative ventilator times and charges without an increase in mortality, stroke, reoperation for bleeding, acute kidney injury, or seizures.

4D Bragg Edge Tomography of Directional Ice Templated Graphite Electrodes.

Bragg edge tomography was carried out on novel, ultra-thick, directional ice templated graphite electrodes for Li-ion battery cells to visualise the distribution of graphite and stable lithiation phases, namely LiC12 and LiC6. The four-dimensional Bragg edge, wavelength-resolved neutron tomography technique allowed the investigation of the crystallographic lithiation states and comparison with the electrode state of charge. The tomographic imaging technique provided insight into the crystallographic changes during de-/lithiation over the electrode thickness by mapping the attenuation curves and Bragg edge parameters with a spatial resolution of approximately 300 µm. This feasibility study was performed on the IMAT beamline at the ISIS pulsed neutron spallation source, UK, and was the first time the 4D Bragg edge tomography method was applied to Li-ion battery electrodes. The utility of the technique was further enhanced by correlation with corresponding X-ray tomography data obtained at the Diamond Light Source, UK.

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

Scalable, Large-Area Printing of Pore-Array Electrodes for Ultrahigh Power Electrochemical Energy Storage.

Through-electrode thickness honeycomb architectures were layer-by-layer self-assembled directly through a scalable printing process for ultrapower hybrid lithium-ion capacitor applications. Initially, the electrochemical performance of the pore-array electrodes was investigated as a function of the active material type (graphene plates, carbon nanofibers, and activated carbon). Inactive components (conductive carbon and polymer binder) were then minimized to 5 wt %. Finally, an optimized activated carbon-based cathode was paired with a spray-printed Li4Ti5O12-based anode and a range of anode-to-cathode mass ratios in a lithium-ion capacitor arrangement were investigated. A 1:5 anode/cathode mass ratio provided an attractive energy density comparable with a Li4Ti5O12/LiFePO4 lithium-ion battery but with outstanding power capability that was an order of magnitude greater than typical for lithium-ion batteries. The pore-array electrode was reproduced over areas of 20 cm × 15 cm in a double-sided coated configuration, and the option for selectively patterning electrodes was also demonstrated.

Mechanisms underlying the efficacy of exercise as an intervention for cocaine relapse: a focus on mGlu5 in the dorsal medial prefrontal cortex.

RATIONALE: Exercise shows promise as a treatment option for addiction; but in order to prevent relapse, it may need to be introduced early in the course of treatment. OBJECTIVE: We propose that exercise, by upregulating dorsal medial prefrontal cortex (dmPFC)-nucleus accumbens (NAc) transmission, offsets deficits in pathways targeting glutamate, BDNF, and dopamine during early abstinence, and in doing so, normalizes neuroadaptations that underlie relapse. METHODS: We compared the effects of exercise (wheel running, 2-h/day) during early (days 1-7), late (days 8-14), and throughout abstinence (days 1-14) to sedentary conditions on cocaine-seeking and gene expression in the dmPFC and NAc core of male rats tested following 24-h/day extended-access cocaine (up to 96 infusions/day) or saline self-administration and protracted abstinence (15 days). Based on these data, we then used site-specific manipulation to determine whether dmPFC metabotropic glutamate receptor5 (mGlu5) underlies the efficacy of exercise. RESULTS: Exercise initiated during early, but not late abstinence, reduced cocaine-seeking; this effect was strongly associated with dmPFC Grm5 expression (gene encoding mGlu5), and modestly associated with dmPFC Grin1 and Bdnf-IV expression. Activation of mGlu5 in the dmPFC during early abstinence mimicked the efficacy of early-initiated exercise; however, inhibition of these receptors prior to the exercise sessions did not block its efficacy indicating that there may be redundancy in the mechanisms through which exercise reduces cocaine-seeking. CONCLUSION: These findings indicate that addiction treatments, including exercise, should be tailored for early versus late phases of abstinence since their effectiveness will vary over abstinence due to the dynamic nature of the underlying neuroadaptations.