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Hybrid ionic-electronic conductors have the potential to generate memory effects and neuronal behavior. The functionality of these mixed materials depends on ion motion through thin polarizable channels. Here, we explore different polarization models to show that the current and conductivity of electrolytes is higher when confined by conductors than by dielectrics. We find nonlinear currents in both dielectrics and conductors, and we recover the known linear (Ohmic) result only in the two-dimensional limit between conductors. We show that the polarization charge location impacts electrolyte structure and transport properties. This work suggests a mechanism to induce memristor hysteresis loops using conductor-dielectric switchable materials.

Abstract Background GHB (gammahydroxybutyrate) and its precursors are popular recreational drugs due to their sedative, anxiolytic and sexually stimulating effects. Their use has been steadily increasing in recent years. The detoxification process is complex and prone to high rates of complications while little is known about the pathophysiology. This study aims to elucidate the characteristics of GHB-addicted patients and to evaluate the risks and complications of GHB withdrawal treatment. Methods This observational study describes prospectively the socioeconomic status, clinical history and course of inpatient detoxification treatment of a group of 39 patients suffering from GHB substance use disorder. Detoxification treatment took place in a highly specialized psychiatric inpatient unit for substance use disorders. Results GHB patients were characterised by being young, well-educated and by living alone. More than 50% of the patients had no regular income. The patients were male and female in equal numbers. Detoxification treatment was complicated, with high rates of delirium (30.8%) and high need for intensive care (20.5%). Conclusions In our sample, GHB users were young, well-educated people and male and female in equal number. Detoxification proved to be dangerous for GHB-addicted patients. The presence of delirium and the need for transfer to an intensive care unit during detoxification treatment was extraordinarily high, even with appropriate clinical treatment. The reasons for this remain unknown. Therefore an intensive care unit should be available for GHB detoxification treatment. Further studies are needed to evaluate the options for prophylactic treatment of delirium during detoxification.

Dielectric interfaces are crucial to the behavior of charged membranes, from graphene to synthetic and biological lipid bilayers. Understanding electrolyte behavior near these interfaces remains a challenge, especially in the case of rough dielectric surfaces. A lack of analytical solutions consigns this problem to numerical treatments. We report an analytic method for determining electrostatic potentials near curved dielectric membranes in a two-dimensional periodic "slab" geometry using a periodic summation of Green's functions. This method is amenable to simulating arbitrary groups of charges near surfaces with two-dimensional deformations. We concentrate on one-dimensional undulations. We show that increasing membrane undulation increases the asymmetry of interfacial charge distributions due to preferential ionic repulsion from troughs. In the limit of thick membranes, we recover results mimicking those for electrolytes near a single interface. Our work demonstrates that rough surfaces generate charge patterns in electrolytes of charged molecules or mixed-valence ions. [ABSTRACT FROM AUTHOR]

Abstract Embodied cognition theories posit direct interactions between sensorimotor and mental processing. Various clinical observations have been interpreted in this controversial framework, amongst others, low verb generation in word production tasks performed by persons with Parkinson’s disease (PD). If this were the consequence of reduced motor simulation of prevalent action semantics in this word class, reduced PD pathophysiology should result in increased verb production and a general shift of lexical contents towards particular movement-related meanings. 17 persons with PD and bilateral deep brain stimulation (DBS) of the subhtalamic nucleus (STN) and 17 healthy control persons engaged in a semantically unconstrained, phonemic verbal fluency task, the former in both DBS-off and DBS-on states. The analysis referred to the number of words produced, verb use, and the occurrence of different dimensions of movement-related semantics in the lexical output. Persons with PD produced fewer words than controls. In the DBS-off, but not in the DBS-on condition, the proportion of verbs within this reduced output was lower than in controls. Lowered verb production went in parallel with a semantic shift: in persons with PD in the DBS-off, but not the DBS-on condition, the relatedness of produced words to own body-movement was lower than in controls. In persons with PD, DBS induced-changes of the motor condition appear to go along with formal and semantic shifts in word production. The results are compatible with the idea of some impact of motor system states on lexical processing.

This paper extends the use of the Monopoly® board game as an economic simulation exercise designed to reinforce an understanding of how the accounting cycle impacts the financial statements used to evaluate management performance. This extension adds elements of debt not previously utilized to allow for an introduction of the fundamentals of ratio analysis at a foundation level in financial accounting instruction. This extended approach uses the rules and strategies of a familiar board game to create a simulation of business and economic realities, which then becomes an effective, interactive, in-class financial accounting practice set. The unique combination of each player's skill and luck provides for unlimited outcome possibilities, delivering an interpretive result that students can neither predict nor easily manipulate. This pedagogical approach serves to provide students with a sense of proprietorship in the activities of the instruction and fosters a competitive spirit to succeed in class activities that will ultimately be presented to the entire class. While the instructor surrenders a significant level of control in the class exercise, the uniqueness of each Monopoly® team's game results requires active engagement in-class and additional individual effort on the follow-up assignments outside the classroom. In the previous use of the Monopoly® board game, the class activity provided a valuable parallel for reality in practicing the financial accounting cycle and emphasizing its use by external parties. Because of the dynamic sense of capturing the "real-time" aspect of the game into finished financial statements for analysis, students start to sense a greater appreciation for the role that accounting cycle activities play in business reporting and the assessment of operating results. Using the Monopoly® board game in the first course in financial accounting tends to generate a higher level of competitive energy in the classroom experience, with more actively engaged students grasping the nature and purpose of the financial accounting system more quickly and actively than with other pedagogical approaches previously used. More recently, using Microsoft Excel to reflect the game results and present the financial statements has added to the robust learning experience achieved by incorporating the Monopoly® board game.

Abstract Motor signs such as dyspraxia and abnormal gait are characteristic features of autism spectrum disorder (ASD). However, motor behavior in adults with ASD has scarcely been quantitatively characterized. In this pilot study, we aim to quantitatively examine motor signature of adults with ASD without intellectual impairment using marker-less visual-perceptive motion capture. 82 individuals (37 ASD and 45 healthy controls, HC) with an IQ > 85 and aged 18 to 65 years performed nine movement tasks and were filmed by a 3D-infrared camera. Anatomical models were quantified via custom-made software and resulting kinematic parameters were compared between individuals with ASD and HCs. Furthermore, the association between specific motor behaviour and severity of autistic symptoms (Autism Diagnostic Observation Schedule 2, Autism Spectrum Quotient) was explored. Adults with ASD showed a greater mediolateral deviation while walking, greater sway during normal, tandem and single leg stance, a reduced walking speed and cadence, a greater arrhythmicity during jumping jack tasks and an impaired manual dexterity during finger tapping tasks (p 0.48) compared to HC. Furthermore, in the ASD group, some of these parameters correlated moderately to severity of ASD symptoms. Adults with ASD seem to display a specific motor signature in this disorder affecting movement timing and aspects of balance. The data appear to reinforce knowledge about motor signs reported in children and adolescents with ASD. Also, quantitative motor assessment via visual-perceptive computing may be a feasible instrument to detect subtle motor signs in ASD and perhaps suitable in the diagnosis of ASD in the future.

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA. [ABSTRACT FROM AUTHOR]

Non‐union during healing of bone fractures affects up to ~5% of patients worldwide. Given the success of recombinant human platelet‐derived growth factor‐B chain homodimer (rhPDGF‐BB) in promoting angiogenesis and bone fusion in the hindfoot and ankle, rhPDGF‐BB combined with bovine type I collagen/β‐TCP matrix (AIBG) could serve as a viable alternative to autografts in the treatment of non‐unions. Defects (~2 mm gaps) were surgically induced in tibiae of skeletally mature New Zealand white rabbits. Animals were allocated to one of four groups—(1) negative control (empty defect, healing for 8 weeks), (2 and 3) acute treatment with AIBG (healing for 4 or 8 weeks), and (4) chronic treatment with AIBG (injection 4 weeks post defect creation and then healing for 8 weeks). Bone formation was analyzed qualitatively and semi‐quantitatively through histology. Samples were imaged using dual‐energy X‐ray absorptiometry and computed tomography for defect visualization and volumetric reconstruction, respectively. Delayed healing or non‐healing was observed in the negative control group, whereas defects treated with AIBG in an acute setting yielded bone formation as early as 4 weeks with bone growth appearing discontinuous. At 8 weeks (acute setting), substantial remodeling was observed with higher degrees of bone organization characterized by appositional bone growth. The chronic healing, experimental, group yielded bone formation and remodeling, with no indication of non‐union after treatment with AIBG. Furthermore, bone growth in the chronic healing group was accompanied by an increased presence of osteons, osteonal canals, and interstitial lamellae. Qualitatively and semiquantitatively, chronic application of AI facilitated complete bridging of the induced non‐union defects, while untreated defects or defects treated acutely with AIBG demonstrated a lack of complete bridging at 8 weeks. [ABSTRACT FROM AUTHOR]

Individuals with Autism Spectrum Disorder (ASD) experience a variety of symptoms sometimes including atypicalities in language use. The study explored differences in semantic network organisation of adults with ASD without intellectual impairment. We assessed clusters and switches in verbal fluency tasks ('animals', 'human feature', 'verbs', 'r-words') via curve fitting in combination with corpus-driven analysis of semantic relatedness and evaluated socio-emotional and motor action related content. Compared to participants without ASD (n = 39), participants with ASD (n = 32) tended to produce smaller clusters, longer switches, and fewer words in semantic conditions (no "p" values survived Bonferroni-correction), whereas relatedness and content were similar. In ASD, semantic networks underlying cluster formation appeared comparably small without affecting strength of associations or content.

We investigate the electronic and vibrational properties of bottom-up synthesized aligned armchair graphene nanoribbons of N = 7 carbon atoms width periodically doped by substitutional boron atoms (B-7AGNRs). Using angle-resolved photoemission spectroscopy and density functional theory calculations, we find that the dopant-derived valence and conduction band states are notably hybridized with electronic states of Au substrate and spread in energy. The interaction with the substrate leaves the bands with pure carbon character rather unperturbed. This results in an identical effective mass of ≈0.2 m0 for the next-highest valence band compared with pristine 7AGNRs. We probe the phonons of B-7AGNRs by ultrahigh-vacuum (UHV) Raman spectroscopy and reveal the existence of characteristic splitting and red shifts in Raman modes due to the presence of substitutional boron atoms. Comparing the Raman spectra for three visible lasers (red, green, and blue), we find that interaction with gold suppresses the Raman signal from B-7AGNRs and the energy of the green laser (2.33 eV) is closer to the resonant E22 transition. The hybridized electronic structure of the B-7AGNR-Au interface is expected to improve electrical characteristics of contacts between graphene nanoribbon and Au. The Raman fingerprint allows the easy identification of B-7AGNRs, which is particularly useful for device fabrication.

Misforecasting the adoption of customer-owned distributed photovoltaics (DPV) can have operational and financial implications for utilities; forecasting capabilities can be improved, but generally at a cost. This paper informs this decision-space by using a suite of models to explore the capacity expansion and operation of the Western Interconnection over a 15-year period across a wide range of DPV growth rates and misforecast severities. The system costs under a misforecast are compared against the costs under a perfect forecast, to quantify the costs of misforecasting. Using a simplified probabilistic method applied to these modeling results, an analyst can make a first-order estimate of the financial benefit of improving a utility’s forecasting capabilities, and thus be better informed about whether to make such an investment. For example, under our base assumptions, a utility with 10 TWh per year of retail electric sales who initially estimates that DPV growth could range from 2% to 7.5% of total generation over the next 15 years could expect total present-value savings of approximately $4 million if they could reduce the severity of misforecasting to within ±25%. Utility resource planners can compare those savings against the costs needed to achieve that level of precision, to guide their decision on whether to make an investment in tools or resources.

To understand the optical and transport properties of graphene nanoribbons, an unambiguous determination of their electronic band structure is needed. In this work we demonstrate that the photoemission intensity of each valence sub-band, formed due to the quantum confinement in quasi-one-dimensional (1D) graphene nanoribbons, is a peaked function of the two-dimensional (2D) momentum. We resolve the long-standing discrepancy regarding the valence band effective mass (m∗VB) of armchair graphene nanoribbons with a width of N = 7 carbon atoms (7-AGNRs). In particular, angle-resolved photoemission spectroscopy (ARPES) and scanning tunneling spectroscopy report m∗VB .0.2 and .0.4 of the free electron mass (me), respectively. ARPES mapping in the full 2D momentum space identifies the experimental conditions for obtaining a large intensity for each of the three highest valence 1D sub-bands. Our detail map reveals that previous ARPES experiments have incorrectly assigned the second sub-band as the frontier one. The correct frontier valence sub-band for 7-AGNRs is only visible in a narrow range of emission angles. For this band we obtain an ARPES derived effective mass of 0.4 me, a charge carrier velocity in the linear part of the band of 0.63 106 m s.1 and an energy separation of only .60 meV to the second sub-band. Our results are of importance not only for the growing research field of graphene nanoribbons but also for the community, which studies quantum confined systems.

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience—demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that plays a determinative role in promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

Claudins regulate paracellular permeability, contribute to epithelial polarization and are dysregulated during inflammation and carcinogenesis. Variants of the claudin-binding domain of Clostridium perfringens enterotoxin (cCPE) are highly sensitive protein ligands for generic detection of a broad spectrum of claudins. Here, we investigated the preferential binding of YFP- or GST-cCPE fusion proteins to non-junctional claudin molecules. Plate reader assays, flow cytometry and microscopy were used to assess the binding of YFP- or GST-cCPE to non-junctional claudins in multiple in vitro and ex vivo models of human and rat gastrointestinal epithelia and to monitor formation of a tight junction barrier. Furthermore, YFP-cCPE was used to probe expression, polar localization and dysregulation of claudins in patient-derived organoids generated from gastric dysplasia and gastric cancer. Live-cell imaging and immunocytochemistry revealed cell polarity and presence of tight junctions in glandular organoids (originating from intestinal-type gastric cancer and gastric dysplasia) and, in contrast, a disrupted diffusion barrier for granular organoids (originating from discohesive tumor areas). In sum, we report the use of cCPE fusion proteins as molecular probes to specifically and efficiently detect claudin expression, localization and tight junction dysregulation in cell lines, tissue explants and patient-derived organoids of the gastrointestinal tract.

We investigate the N = 9 atoms wide armchair-type graphene nanoribbons (9-AGNRs) by performing a comprehensive spectroscopic and microscopic characterization of this novel material. In particular, we use X-ray photoelectron, near edge X-ray absorption fine structure, scanning tunneling, polarized Raman and angle-resolved photoemission (ARPES) spectroscopies. The ARPES measurements are aided by calculations of the photoemission matrix elements which yield the position in k space having the strongest photoemission cross section. Comparison with well-studied narrow N = 7 AGNRs shows that the effective electron mass in 9-AGNRs is reduced by two times and the valence band maximum is shifted to lower binding energy by ∼0.6 eV. In polarized Raman measurements of the aligned 9-AGNR, we reveal anisotropic signal depending upon the phonon symmetry. Our results indicate the 9-AGNRs are a novel 1D semiconductor with a high potential in nanoelectronic applications.

Sleep loss can severely impair the ability to perform, yet the ability to recover from sleep loss is not well understood. Sleep regulatory processes are assumed to lie exclusively within the brain mainly due to the strong behavioral manifestations of sleep. Whole-body knockout of the circadian clock gene Bmal1 in mice affects several aspects of sleep, however, the cells/tissues responsible are unknown. We found that restoring Bmal1 expression in the brains of Bmal1-knockout mice did not rescue Bmal1-dependent sleep phenotypes. Surprisingly, most sleep-amount, but not sleep-timing, phenotypes could be reproduced or rescued by knocking out or restoring BMAL1 exclusively in skeletal muscle, respectively. We also found that overexpression of skeletal-muscle Bmal1 reduced the recovery response to sleep loss. Together, these findings demonstrate that Bmal1 expression in skeletal muscle is both necessary and sufficient to regulate total sleep amount and reveal that critical components of normal sleep regulation occur in muscle.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.

The use of renewable energy (RE) sources, primarily wind and solar generation, is poised to grow significantly within the Indian power system. The Government of India has established a target of 175 gigawatts (GW) of installed RE capacity by 2022, including 60 GW of wind and 100 GW of solar, up from 29 GW wind and 9 GW solar at the beginning of 2017. Using advanced weather and power system modeling made for this project, the study team is able to explore operational impacts of meeting India’s RE targets and identify actions that may be favorable for integration. Our primary tool is a detailed production cost model, which simulates optimal scheduling and dispatch of available generation in a future year (2022) by minimizing total production costs subject to physical, operational, and market constraints. Our team comprises a core group from the Power System Operation Corporation, Ltd. (POSOCO), which is the national grid operator (with representation from the National, Southern, and Western Regional Load Dispatch Centers) under Ministry of Power, National Renewable Energy Laboratory (NREL), and Lawrence Berkeley National Laboratory (Berkeley Lab), and a broader modeling team that includes Central Electricity Authority (CEA), POWERGRID (the central transmission utility, CTU), and State Load Dispatch Centers in Maharashtra, Gujarat, Tamil Nadu, Karnataka, Rajasthan, and Andhra Pradesh. Our model includes high-resolution wind and solar data (forecasts and actuals), unique properties for each generator, CEA/CTU’s anticipated buildout of the power system, and enforced state-to-state transmission flows. Assuming the fulfillment of current efforts to provide better access to the physical flexibility of the power system, we find that power system balancing with 100 GW of solar and 60 GW of wind is achievable at 15-minute operational timescales with minimal RE curtailment. This RE capacity meets 22% of total projected 2022 electricity consumption in India with annual RE curtailment of 1.4%, in line with experiences in other countries with significant RE penetrations (Bird et al. 2016). Changes to operational practice can further reduce the cost of operating the power system and reduce RE curtailment. Coordinating scheduling and dispatch over a broader area is the largest driver to reduce costs, saving INR 6300 crore (USD 980 million) annually when optimized regionally. Lowering minimum operating levels of coal plants (from 70% to 40%) is the biggest driver to reduce RE curtailment—from 3.5% down to 0.76%. In fact, this operating property is more influential than faster thermal generation ramp rates in lowering the projected levels of curtailment. While this study does not answer every question relevant to planning for India’s 2022 RE targets, it is an important step toward analyzing operational challenges and cost saving opportunities using state-of-the-art power system planning tools. Further analysis can build upon this basis to explore optimal renewable resource and intrastate transmission siting, system stability during contingencies, and the influence of total power system investment costs on customer tariffs.

The use of renewable energy (RE) sources, primarily wind and solar generation, is poised to grow significantly within the Indian power system. The Government of India has established an installed capacity target of 175 gigawatts (GW) RE by 2022 that includes 60 GW of wind and 100 GW of solar, up from current capacities of 29 GW wind and 9 GW solar. India’s contribution to global efforts on climate mitigation extends this ambition to 40% non-fossil-based generation capacity by 2030. Global experience demonstrates that power systems can integrate wind and solar at this scale; however, evidence-based planning is important to achieve wind and solar integration at least cost. The purpose of this analysis is to evaluate the operation of India’s power grid with 175 GW of RE in order to identify potential cost and operational concerns and actions needed to efficiently integrate this level of wind and solar generation.

Brain and muscle-ARNT-like factor (Bmal1/BMAL1) is an essential transcriptional/translational factor of circadian clocks. Loss of function of Bmal1/BMAL1 is highly disruptive to physiological and behavioral processes. In light of these previous findings, we examined if transgenic overexpression of Bmal1/BMAL1 in skeletal muscle could alter metabolic processes. First, we characterized in vivo and ex vivo metabolic phenotypes of muscle overexpressed mice (male and female) compared to wild-type littermates (WT). Second, we examined in vivo and ex vivo metabolic processes in the presence of positive and negative homeostatic challenges: high-intensity treadmill running (positive) and acute sleep deprivation (negative). In vivo measures of metabolic processes included body composition, respiratory exchange ratio (RER; VCO2/VO2), energy expenditure, total activity counts, and food intake collected from small animal indirect calorimetry. Ex vivo measure of insulin sensitivity in skeletal muscle was determined from radioassays. RER was lower for muscle overexpressed females compared to female WTs. There were no genotype-dependent differences in metabolic phenotypes for males. With homeostatic challenges, muscle overexpressed mice had lower energy expenditure after high-intensity treadmill running. Acute sleep deprivation reduced insulin sensitivity in skeletal muscle in overexpressed male mice, but not male WTs. The present study contributes to a body of evidence showing pleiotropic, non-circadian, and homeostatic effects of altered Bmal1/BMAL1 expression on metabolic processes, demonstrating a critical need to further investigate the broad and complex actions of Bmal1/BMAL1 on physiology and behavior.

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used SIAH2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of SIAH2-deficiency on the regulation of rhythmically expressed genes in the liver. The absence of SIAH2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic transcriptome in the liver by increasing the number of day-time expressed genes, and flipping the rhythmic expression from nighttime expressed genes to the daytime. These effects are not readily explained by effects on known sexually dimorphic pathways in females. Moreover, loss of SIAH2 in females, not males, preferentially altered the expression of transcription factors and genes involved in regulating lipid and lipoprotein metabolism. Consequently, SIAH2-deficient females, but not males, displayed disrupted daily lipid and lipoprotein patterns, increased adiposity and impaired metabolic homeostasis. Overall, these data suggest that SIAH2 may be a key component of a female-specific circadian transcriptional output circuit that directs the circadian timing of gene expression to regulate physiological rhythms, at least in the liver. In turn, our findings imply that sex-specific transcriptional mechanisms may closely interact with the circadian clock to tailor overt rhythms for sex-specific needs.

Not all our intentions translate into actions, as our capacity to act may be influenced by a variety of mental and biochemical factors. In this article, we present a comprehensive account of how neuro-immunological processes affect our intentional abilities and our capacity to act. We do so by extending the theory of thought-shapers (TTS) through the notion of action-shapers and combining this theory with the essential embodiment thesis (EE). This thesis about the mind-body relation says that human minds are necessarily and completely embodied. Action-shapers dynamically constitute the action-space of individuals, affecting their capacity to take action or to select one course of action over another. We highlight the effects and interactions of neuro-immunological effective processes in the body to demonstrate how they shape the action-space. In this article, we consider neuro-immunological effective processes that influence the gut-brain axis, chronic stress, high levels of sugar intake, the amygdala and the effects of prolonged stress. We investigate the effects of these processes on the perception and on the capacity to form intentions and act on them. We conclude the paper by providing a concise account of action-shapers, in which we attempt to summarize the line of argumentation and provide suggestions for further research.

Abstract Background Despite the intensive efforts to improve the diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock. Methods This prospective pilot study was performed at the university hospital Charité–Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 h over a 24-h period to isolate CD14-positive monocytes and to measure the expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. A rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic), and expression data were compared to data of a healthy study population additionally. Results 77% of the measured clock genes showed inconclusive rhythms, i.e., neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. Overall, the rhythmicity scores for septic shock patients were significantly (p

In this paper, we use a regularized theta lifting to construct harmonic Maass forms corresponding to binary theta functions of weight k ≥ 2 under the 휉-operator. As a result, we show that their holomorphic parts have algebraic Fourier coefficients, with compatible Galois action. As an application, we prove rationality properties of coefficients of harmonic Maass forms corresponding to CM newforms, answering a question of Bruinier, Ono and Rhoades. [ABSTRACT FROM AUTHOR]

Since three-dimensional (3D) bioprinting has emerged, it has continuously to evolved as a revolutionary technology in surgery, offering new paradigms for reconstructive and regenerative medical applications. This review highlights the integration of 3D printing, specifically bioprinting, across several surgical disciplines over the last five years. The methods employed encompass a review of recent literature focusing on innovations and applications of 3D-bioprinted tissues and/or organs. The findings reveal significant advances in the creation of complex, customized, multi-tissue constructs that mimic natural tissue characteristics, which are crucial for surgical interventions and patient-specific treatments. Despite the technological advances, the paper introduces and discusses several challenges that remain, such as the vascularization of bioprinted tissues, integration with the host tissue, and the long-term viability of bioprinted organs. The review concludes that while 3D bioprinting holds substantial promise for transforming surgical practices and enhancing patient outcomes, ongoing research, development, and a clear regulatory framework are essential to fully realize potential future clinical applications. [ABSTRACT FROM AUTHOR]

Since conflict is a ubiquitous phenomenon in inter-but also intraorganizational work, conflict management behavior (CMB) is a preconditioning factor for successful cooperations. Prior research shows that CMB can be individualistic or collectivistic in orientation and highlights the episodic nature of CMB. However, in focusing on analyzing specific conflicts and conflict dynamics in collaborative contexts, research paid less attention to how conflict and CMB are influenced by structural patterns and thus might overstate the role of individual agency compared to the role of the general structure of the cooperation. We address this issue by investigating the inter-organizational cooperation of IT-freelancers and their client organizations. Based on 18 semi-structured problem-centered and expert interviews with IT-freelancers, representatives of client organizations and agencies, we show that the CMB orientation depends on the institutionalized sequential stages of the cooperation. While individualistic CMBs dominate the pre-contract sequence, in which recruitment processes and negotiations take place, the parties switch to collectivistic CMB in the contract sequence, in which the actual cooperation is carried out. The postcontract sequence serves for reflections on the cooperation and thus influences the willingness to engage in future cooperations and, in turn, affects future pre-contract sequences. With a focus on the IT industry, the paper addresses research gaps related to the specific temporality and temporal structuring of contingent work. It introduces a sequence-oriented framework and analysis of conflict and conflict management in interorganizational projects, complementing related episodic perspectives on conflict, and psychological contracts with a more chronological and structural perspective. [ABSTRACT FROM AUTHOR]

Bone regeneration remains a significant clinical challenge, often necessitating surgical approaches when healing bone defects and fracture nonunions. Within this context, the modulation of adenosine signaling pathways has emerged as a promising therapeutic option, encouraging osteoblast activation and tempering osteoclast differentiation. A literature review of the PubMed database with relevant keywords was conducted. The search criteria involved in vitro or in vivo models, with clear methodological descriptions. Only studies that included the use of indirect adenosine agonists, looking at the effects of bone regeneration, were considered relevant according to the eligibility criteria. A total of 29 articles were identified which met the inclusion and exclusion criteria, and they were reviewed to highlight the preclinical translation of adenosine agonists. While preclinical studies demonstrate the therapeutic potential of adenosine signaling in bone regeneration, its clinical application remains unrealized, underscoring the need for further clinical trials. To date, only large, preclinical animal models using indirect adenosine agonists have been successful in stimulating bone regeneration. The adenosine receptors (A1, A2A, A2B, and A3) stimulate various pathways, inducing different cellular responses. Specifically, indirect adenosine agonists act to increase the extracellular concentration of adenosine, subsequently agonizing the respective adenosine receptors. The agonism of each receptor is dependent on its expression on the cell surface, the extracellular concentration of adenosine, and its affinity for adenosine. This comprehensive review analyzed the multitude of indirect agonists currently being studied preclinically for bone regeneration, discussing the mechanisms of each agonist, their cellular responses in vitro, and their effects on bone formation in vivo. [ABSTRACT FROM AUTHOR]

Impaired performance in verbal fluency (VF) tasks is a frequent observation in Parkinson’s disease (PD). As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication (ON) as well as after drug withdrawal (i.e., OFF), and in a sample of age-matched healthy volunteers (both groups n = 26). Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates.

Study objectivesEpisodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia.MethodsEEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities (Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings.ResultsTwo days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia.ConclusionsThese results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome.

Abstract Background Pancreatic cancer remains a fatal disease. Experimental systems are needed for personalized treatment strategies, drug testing and to further understand tumor biology. Cell cultures can serve as an excellent preclinical platform, but their generation remains challenging. Methods Tumor cells from surgically removed pancreatic ductal adenocarcinoma (PDAC) specimens were cultured under novel protocols. Cellular growth and composition were analyzed and culture conditions were continuously optimized. Characterization of cell cultures and primary tumors was performed via hematoxylin and eosin (HE) and immunofluorescence (IF) staining. Results Protocols for two- and three-dimensional PDAC primary cell cultures could successfully be established. Primary cell culture depended on dissociation techniques, growth factor supplementation and extracellular matrix components containing Matrigel being crucial for the transformation to three-dimensional PDAC organoids. The generated cultures showed to be highly resemblant to established PDAC primary cell cultures. HE and IF staining for cell culture and corresponding primary tumor characterization could successfully be performed. Conclusions The work presented herein shows novel and effective methods to successfully establish primary PDAC cell cultures in a distinct time frame. Factors contributing to cell growth and differentiation could be identified with important implications for further primary cell culture protocols. The established protocols might serve as novel tools in personalized tumor therapy.

Cesium atoms that are grown on intercalated bilayer graphene can create an ordered epitaxial film. Here, the authors report that such a strained film can host quantum well states with high electronic quality as characterized through angle-resolved photoemission spectroscopy.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Several investigations have shown language impairments following electrode implantation surgery for Deep Brain Stimulation (DBS) in movement disorders. The impact of the actual stimulation, however, differs between DBS targets with further deterioration in formal language tests induced by thalamic DBS in contrast to subtle improvement observed in subthalamic DBS. Here, we studied speech samples from interviews with participants treated with DBS of the thalamic ventral intermediate nucleus (VIM) for essential tremor (ET), or the subthalamic nucleus (STN) for Parkinson’s disease (PD), and healthy volunteers (each n = 13). We analyzed word frequency and the use of open and closed class words. Active DBS increased word frequency in case of VIM, but not STN stimulation. Further, relative to controls, both DBS groups produced fewer open class words. Whereas VIM DBS further decreased the proportion of open class words, it was increased by STN DBS. Thus, VIM DBS favors the use of relatively common words in spontaneous language, compatible with the idea of lexical simplification under thalamic stimulation. The absence or even partial reversal of these effects in patients receiving STN DBS is of interest with respect to biolinguistic concepts suggesting dichotomous thalamic vs. basal ganglia roles in language processing.