Search

Adolescence is a period of increased risk taking, including increased alcohol and drug use. Multiple clinical studies report a positive relationship between adolescent alcohol consumption and risk of developing an alcohol use disorder (AUD) in adulthood. However, few preclinical studies have attempted to tease apart the biological contributions of adolescent alcohol exposure, independent of other social, environmental, and stress factors, and studies that have been conducted show mixed results. Here we use several adolescent voluntary consumption of alcohol models, conducted across four labs in three institutes and with two rodent species, to investigate the ramifications of adolescent alcohol consumption on adulthood alcohol consumption in controlled, pre-clinical environments. We consistently demonstrate a lack of robust increases in adulthood alcohol consumption. This work highlights that risks seen in both human datasets and other murine drinking models may be due to unique social and environmental factors – some of which may be unique to humans.

Intestinal helminth infection triggers a type 2 immune response that promotes a 'weep-and sweep' response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether altered intestinal motility driven by the murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility, an observation that extended to another rodent nematode, Heligmosomoides polygyrus. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (

Quantum cascade lasers (QCLs) have emerged as promising candidate sources for free-space communications. High optical power densities, short photon lifetimes, and low internal capacitance are important factors influencing the transmission bandwidth. We report the design and fabrication of 4.7 μm emitting, 1.5 mm cavity length, single-mode distributed-feedback QCLs, with a CW front-facet output power of 165 mW and a calculated photon lifetime of 11.6 ps, resulting in an electrically limited CW modulation with a 3 dB cutoff at 850 MHz.

By employing a graded-interfaces model based on a generalized formalism for interface-roughness (IFR) scattering that was modified for mid-infrared emitting quantum cascade lasers (QCLs), we have accurately reproduced the electro-optical characteristics of published record-performance 4.9 µm- and 8.3 µm-emitting QCLs. The IFR-scattering parameters at various interfaces were obtained from measured values and trends found via atom-probe tomography analysis of one of our 4.6 μm-emitting QCL structures with variable barrier heights. Those values and trends, when used for designing a graded-interface, 4.6 μm-emitting QCL, led to experimental device characteristics in very good agreement with calculated ones. We find that the published record-high performance values are mainly due to both injection from a prior-stage low-energy (active-region) state directly into the upper-laser (ul) level, thus at low field-strength values, as well as to strong photon-induced carrier transport. However, the normalized leakage-current density J leak/J is found to be quite high: 26–28 % and 23.3 %, respectively, mainly because of IFR-triggered shunt-type leakage through high-energy active-region states, in the presence of high average electron temperatures in the ul laser level and an energy state adjacent to it: 1060 K and 466 K for 4.9 µm- and 8.3 µm-emitting QCLs, respectively. Then, modeling with graded interfaces becomes a tool for designing devices of performances superior to the best reported to date, thus closing in on fundamental limits. The model is employed to design a graded-interface 8.1 µm-emitting QCL with suppressed carrier leakage via conduction-band engineering, which reaches a maximum front-facet wall-plug efficiency value of 22.2 %, significantly higher than the current record (17 %); thus, a value close to the fundamental front-facet, upper limit (i.e., 25 %) for ∼8 µm-emitting QCLs.

Abstract Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults. Temozolomide (TMZ) is the standard systemic therapy in GBM but has limited and restricted efficacy. Better treatments are urgently needed. The role of endoplasmic reticulum stress (ER stress) is increasingly described in GBM pathophysiology. A key molecular mediator of ER stress, the spliced form of the transcription factor x‐box binding protein 1 (XBP1s) may constitute a novel therapeutic target; here we report XBP1s expression and biological activity in GBM. Tumor samples from patients with GBM (n = 85) and low‐grade glioma (n = 20) were analyzed by immunohistochemistry for XBP1s with digital quantification. XBP1s expression was significantly increased in GBM compared to low‐grade gliomas. XBP1s mRNA showed upregulation by qPCR analysis in a panel of patient‐derived GBM cell lines. Inhibition of XBP1 splicing using the small molecular inhibitor MKC‐3946 significantly reduced GBM cell viability and potentiated the effect of TMZ in GBM cells, particularly in those with methylated O6‐methylguanine‐DNA methyl transferase gene promoter. GBM cells resistant to TMZ were also responsive to MKC‐3946 and the long‐term inhibitory effect of MKC‐3946 was confirmed by colony formation assay. In conclusion, this data reveals that XBP1s is overexpressed in GBM and contributes to cancer cell growth. XBP1s warrants further investigation as a clinical biomarker and therapeutic target in GBM.

Introduction Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes encephalitis and other morbidity in Southeast Asia. Since February 2022, geographically dispersed JEV human, animal and vector detections occurred on the Australian mainland for the first time. This study will determine the prevalence of JEV-specific antibodies in human blood with a focus on populations at high risk of JEV exposure and determine risk factors associated with JEV seropositivity by location, age, occupation and other factors.Method Samples are collected using two approaches: from routine blood donors (4153 samples), and active collections targeting high-risk populations (convenience sampling). Consent-based sampling for the latter includes a participant questionnaire on demographic, vaccination and exposure data. Samples are tested for JEV-specific total antibody using a defined epitope-blocking ELISA, and total antibody to Australian endemic flaviviruses Murray Valley encephalitis and Kunjin viruses.Analysis Two analytic approaches will occur: descriptive estimates of seroprevalence and multivariable logistic regression using Bayesian hierarchical models. Descriptive analyses will include unadjusted analysis of raw data with exclusions for JEV-endemic country of birth, travel to JEV-endemic countries, prior JEV-vaccination, and sex-standardised and age-standardised analyses. Multivariable logistic regression will determine which risk factors are associated with JEV seropositivity likely due to recent transmission within Australia and the relative contribution of each factor when accounting for effects within the model.Ethics National Mutual Acceptance ethical approval was obtained from the Sydney Children’s Hospitals Network Human Research Ethics Committee (HREC). Local approvals were planned to be sought in each jurisdiction, as per local ethics processes. Ethical approval was also obtained from the Australian Red Cross Lifeblood HREC.Dissemination Findings will be communicated to participants and their communities, and human and animal health stakeholders and policy-makers iteratively and after final analyses. Understanding human infection rates will inform procurement and targeted allocation of limited JEV vaccine, and public health strategies and communication campaigns, to at-risk populations.

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats.

Neural networks, trained with the ADAM algorithm followed by a globally convergent modification to Newton’s method, are developed to predict the threshold gain of the fundamental and first higher-order modes as functions of the refractive-index profile in a quantum cascade laser cavity. The networks are used to optimize the design of a refractive-index profile that provides essentially single-spatial-mode performance in a nominally multi-moded cavity by maximizing the threshold-gain differential between the modes. The use of neural networks allows the optimization to be performed in seconds, instead of days or weeks which would be required if Maxwell’s equations were repeatedly solved to obtain the threshold gains.

Introduction Physical activity (PA) has beneficial effects on brain health and cardiovascular disease (CVD) risk. Yet, we know little about whether PA-induced changes to physiological mediators of CVD risk influence brain health and whether benefits to brain health may also explain PA-induced improvements to CVD risk. This study combines neurobiological and peripheral physiological methods in the context of a randomised clinical trial to better understand the links between exercise, brain health and CVD risk.Methods and analysis In this 12-month trial, 130 healthy individuals between the ages of 26 and 58 will be randomly assigned to either: (1) moderate-intensity aerobic PA for 150 min/week or (2) a health information control group. Cardiovascular, neuroimaging and PA measurements will occur for both groups before and after the intervention. Primary outcomes include changes in (1) brain structural areas (ie, hippocampal volume); (2) systolic blood pressure (SBP) responses to functional MRI cognitive stressor tasks and (3) heart rate variability. The main secondary outcomes include changes in (1) brain activity, resting state connectivity, cortical thickness and cortical volume; (2) daily life SBP stress reactivity; (3) negative and positive affect; (4) baroreflex sensitivity; (5) pulse wave velocity; (6) endothelial function and (7) daily life positive and negative affect. Our results are expected to have both mechanistic and public health implications regarding brain–body interactions in the context of cardiovascular health.Ethics and dissemination Ethical approval has been obtained from the University of Pittsburgh Institutional Review Board (IRB ID: 19020218). This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule.Trial registration number NCT03841669.

To predict long term device aging under use bias, models extracted from voltage accelerated tests must be extrapolated into the future. The traditional model uses a power law, to linearly fit the test data on a log-log plot, and then extrapolates aging kinetics. The challenge is that the measured data do not always follow a straight line on the log-log plot, calling the accuracy of such prediction into question. Although there are models that can fit test data well in this case, their prediction capability for future aging is typically not verified. The key advance of this work is the development of a methodology for extracting models that can verifiably predict future aging over a wide (Vg, Vd) bias space, when aging kinetics do not follow a simple power law. This is achieved by experimentally separating aging into four types of traps and modelling each of them by a straight line individually. The applicability of this methodology is verified on 3 different CMOS processes where it can predict aging at least 3 orders of magnitude into the future. The contributions of each type of traps across the (Vg, Vd) space are mapped. It is also shown that good fitting with test data does not warrant good prediction, so that good fitting should not be used as the only criterion for validating a model.

This paper studies the application of neural networks to Viterbi detection of FTN signals in an intersymbol interference (ISI) channel. The main contribution of this paper is to propose a receiver structure for detecting FTN signals in unknown static ISI channel. In particular, we propose a novel low-complexity neural network structure for calculating the branch metrics, and we explore its suitability for FTN signalling with channel uncertainty. We compare the proposed network, which we call the Metric Net (MetNet), to a benchmark neural network-based technique for metric calculation, the ViterbiNet, which was originally designed for ISI channels. The simulation results confirm that the MetNet outperforms the ViterbiNet, with two orders of magnitude lower complexity, and is much more resilient to channel uncertainty than the traditional Viterbi detector, which uses Euclidean distance for metric calculations. We further show that the MetNet exhibits robustness to being trained at mismatched SNR values and FTN pulse acceleration factors, meaning that the number of trained models required can be significantly reduced. Additionally, the results show that the proposed MetNet remains a favorable alternative at much higher levels of channel uncertainties. The results also reflect that we can generalize the MetNet to work with different channel models defined by different decaying factors. Finally, we show that we succeed in achieving a bandwidth efficiency gain of 33% due to FTN by using the MetNet in the presence of channel uncertainty.

Physical activity (PA) in the form of aerobic exercise (AE) preserves and improves neurocognitive function across the lifespan. However, a mechanistic understanding of the pathways by which aerobic exercise impacts brain health is still lacking, particularly with respect to stress-related pathways. One mechanistic hypothesis is that AE improves neurocognitive health in part by modifying circulating levels of stress-related hormones and signaling factors associated with the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), as commonly measured by the biomarkers cortisol (CORT) and salivary α-amylase (sAA). Thus, this hypothesis predicts that changes in stress biomarkers, such as CORT and sAA, are possible explanatory pathways mediating the positive effects of AE on neurocognitive health. In the present review article, we provide a summary of available studies examining the possibility that exercise-induced changes to stress biomarkers could partly account for exercise-related improvements in neurocognitive health. Our review indicates that despite the intuitive appeal of this hypothesis, there is insufficient evidence available to conclude that chronic and habitual AE affects neurocognitive health by altering stress biomarker pathways. The cross-sectional nature of the majority of reviewed studies highlights the need for well-controlled studies to adequately test this hypothesis.

Abstract Introduction The integrated care pathways for atopic dermatitis (AD‐ICPs) aim to bridge the gap between existing AD treatment evidence‐based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co‐ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. Methods The GA2LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD‐ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2EN ADCARE centres. Results The AD‐ICPs outline the diagnostic procedures, possible co‐morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. Conclusion The AD‐ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD.