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Although previously restricted to a limited number of medical conditions, there is a growing appreciation that 'autoimmune' (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell 'autoimmune'-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many 'autoimmune'/'immune-mediated' disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies. [ABSTRACT FROM AUTHOR]

The objectives of the study were: (1) to examine the overall distribution of baseline platelet serotonin (5-hydroxytryptamine, 5-HT) values in patients seeking treatment for depression and to define subgroups based on the apparent presence or absence of drug exposure; (2) to assess the bioeffect of 5-HT reuptake inhibitors (SRIs) at the platelet 5-HT transporter; and (3) to examine the relationships of demographic variables including population (ancestry), sex, age, and season of sampling to platelet 5-HT concentration. Platelet 5-HT levels were measured in a cross-sectional study of 1433 Veterans Administration (VA) patients participating in a pragmatic multi-site pharmacogenomic treatment study of depression. Patients were characterized medically and demographically using VA health records and self-report. A clearly bimodal distribution was observed for platelet 5-HT levels with the lower mode associated with patients exposed to SRIs at baseline. Median transporter blockade bioeffects were similar across the various selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/norepinephrine reuptake inhibitors (SNRIs). In a subset of patients apparently not exposed to an SRI, significant effects of population and sex were observed with group mean platelet 5-HT levels being 25 % greater (p < 0.001) in African-American (AA) individuals compared to European-Americans (EAs). The female group mean was 14 % (p < 0.001) greater than male group mean. An effect of age was observed (r = −0.11, p < 0.001) and no effect of season or month of sampling was seen. Further research is warranted to understand the bases and clinical implications of the population and sex differences. The apparent similarity in bioeffect at the 5-HT transporter across SSRIs and when comparing SSRIs and SNRIs informs discussions about initiating, dose adjustment and switching of 5-HT reuptake inhibitors. • Serotonin reuptake inhibitors (SRIs) markedly lowered platelet serotonin (5-HT). • SSRIs and SNRIs had similar inhibitory bioeffect at the platelet 5-HT transporter. • African-Americans had 25 % higher baseline platelet 5-HT than European-Americans. • No effect of season or month of sampling was observed on baseline 5-HT values. • The ancestry difference and the SRI similarities may be important clinically. [ABSTRACT FROM AUTHOR]

The author highlights the role of the melatonergic pathway, providing a more integrated dementia pathophysiology including alterations in gut microbiome/permeability. Topics discussed include evidence of the melatonergic pathway in all mitochondria-containing cells, link between melatonergic pathway induction and optimized mitochondrial function, and gut microbiome and gut permeability in modulation of the melatonergic pathway.

Type 1 diabetes mellitus (T1DM) arises from the failure of pancreatic β-cells to produce adequate insulin, usually as a consequence of extensive pancreatic β-cell destruction. T1DM is classed as an immune-mediated condition. However, the processes that drive pancreatic β-cell apoptosis remain to be determined, resulting in a failure to prevent ongoing cellular destruction. Alteration in mitochondrial function is clearly the major pathophysiological process underpinning pancreatic β-cell loss in T1DM. As with many medical conditions, there is a growing interest in T1DM as to the role of the gut microbiome, including the interactions of gut bacteria with Candida albicans fungal infection. Gut dysbiosis and gut permeability are intimately associated with raised levels of circulating lipopolysaccharide and suppressed butyrate levels, which can act to dysregulate immune responses and systemic mitochondrial function. This manuscript reviews broad bodies of data on T1DM pathophysiology, highlighting the importance of alterations in the mitochondrial melatonergic pathway of pancreatic β-cells in driving mitochondrial dysfunction. The suppression of mitochondrial melatonin makes pancreatic β-cells susceptible to oxidative stress and dysfunctional mitophagy, partly mediated by the loss of melatonin's induction of PTEN-induced kinase 1 (PINK1), thereby suppressing mitophagy and increasing autoimmune associated major histocompatibility complex (MHC)-1. The immediate precursor to melatonin, N-acetylserotonin (NAS), is a brain-derived neurotrophic factor (BDNF) mimic, via the activation of the BDNF receptor, TrkB. As both the full-length and truncated TrkB play powerful roles in pancreatic β-cell function and survival, NAS is another important aspect of the melatonergic pathway relevant to pancreatic β-cell destruction in T1DM. The incorporation of the mitochondrial melatonergic pathway in T1DM pathophysiology integrates wide bodies of previously disparate data on pancreatic intercellular processes. The suppression of Akkermansia muciniphila, Lactobacillus johnsonii, butyrate, and the shikimate pathway—including by bacteriophages—contributes to not only pancreatic β-cell apoptosis, but also to the bystander activation of CD8+ T cells, which increases their effector function and prevents their deselection in the thymus. The gut microbiome is therefore a significant determinant of the mitochondrial dysfunction driving pancreatic β-cell loss as well as 'autoimmune' effects derived from cytotoxic CD8+ T cells. This has significant future research and treatment implications. [ABSTRACT FROM AUTHOR]

Surgical robots were first proposed in the 1960s with subsequent development and clinical implementation in the 1980s and 1990s. Recent advances in technology have led to widespread utilization of robots in many surgical subspecialties. In spine surgery, robots are primarily utilized for pedicle screw placement, with several studies highlighting the potential benefits of improved accuracy and reduction in radiation exposure. Once streamlined, robotic spine surgery (RSS) can provide financial renumeration through potential cost savings and marketing benefits, and in the future will likely aid in more complex surgeries. In Rhode Island, this technology has been implemented and has the potential to deliver optimized outcomes for patients. Robotic spine surgery is not a substitute for a skilled spine surgeon however, and careful diagnosis, care planning, and surgical execution are still mandatory to deliver the best possible patient outcomes. In this review, we chronicle the history of RSS, outline currently available RSS platforms, describe the efficacy, risks, and complications of RSS procedures, and explain the current and future utilization of RSS in Rhode Island. [ABSTRACT FROM AUTHOR]

The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integration of the wide array of biological underpinnings of MDD, including gut dysbiosis and permeability, as well as developmental and social stressors, which can act to suppress the capacity of mitochondria to upregulate the melatonergic pathway, with consequences for oxidant-induced changes in patterned microRNAs and subsequent patterned gene responses. This is placed within a development context, including how social processes, such as discrimination, can physiologically regulate a susceptibility to MDD. Future research directions and treatment implications are derived from this. [ABSTRACT FROM AUTHOR]

There is a growing interest in the role of alterations in mitochondrial metabolism in the pathoetiology and pathophysiology of cancers, including within the array of diverse cells that can form a given tumor microenvironment. The 'exhaustion' in natural killer cells and CD8+ t cells as well as the tolerogenic nature of dendritic cells in the tumor microenvironment seems determined by variations in mitochondrial function. Recent work has highlighted the important role played by the melatonergic pathway in optimizing mitochondrial function, limiting ROS production, endogenous antioxidants upregulation and consequent impacts of mitochondrial ROS on ROS-dependent microRNAs, thereby impacting on patterned gene expression. Within the tumor microenvironment, the tumor, in a quest for survival, seeks to 'dominate' the dynamic intercellular interactions by limiting the capacity of cells to optimally function, via the regulation of their mitochondrial melatonergic pathway. One aspect of this is the tumor's upregulation of kynurenine and the activation of the aryl hydrocarbon receptor, which acts to metabolize melatonin and increase the N-acetylserotonin/melatonin ratio, with effluxed N-acetylserotonin acting as a brain-derived neurotrophic factor (BDNF) mimic via its activation of the BDNF receptor, TrkB, thereby increasing the survival and proliferation of tumors and cancer stem-like cells. This article highlights how many of the known regulators of cells in the tumor microenvironment can be downstream of the mitochondrial melatonergic pathway regulation. Future research and treatment implications are indicated. [ABSTRACT FROM AUTHOR]

Rationale: Assessment of the bioeffect of serotonin reuptake inhibitors (SRIs, including both selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs)) at the serotonin transporter (SERT) in patients and healthy controls can have important theoretical and clinical implications. Objectives: Bioeffect at SERT has been assessed by neuroimaging of brain SERT occupancy, through in vitro measurements of platelet serotonin (5-HT) uptake, and by measuring platelet 5-HT content pre- and post-initiation of SRI administration. Studies of platelet 5-HT content were reviewed in order to (1) determine the overall apparent bioeffect of SRIs; (2) compare bioeffect across types of SRIs; (3) compare the three approaches to assessing SRI bioeffect; and (4) determine how the findings might inform clinical practice. Methods: We performed a systematic review of the published studies that measured platelet 5-HT content to assess SRI bioeffect at the platelet SERT. Studies using neuroimaging and in vitro platelet 5-HT uptake to assess SRI bioeffect were reviewed for comparison purposes. Results: Clinical doses of SRIs typically resulted in 70–90% reductions in platelet 5-HT content. The observed bioeffect at the platelet SERT appeared similar among different SSRIs and SNRIs. The bioeffect estimations based on platelet 5-HT content were consistent with those obtained using neuroimaging to assess brain SERT occupancy and those based on the in vitro measurement of platelet 5-HT uptake. Conclusions: In general, excellent agreement was seen in the apparent SRI bioeffect (70–90% inhibition) among the platelet 5-HT content studies and across the three bioeffect approaches. Theoretical and practical clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Single domain antibodies (sdAb) are the recombinant variable heavy domains derived from camelid heavy-chain antibodies. While they have binding affinities equivalent to conventional antibodies, sdAb are only one-tenth the size and possess numerous advantages such as excellent thermal stability with the ability to refold following denaturation, and inexpensive production in Escherichia coli or yeast. However, their small size does have drawbacks, one being that they can lose activity upon attachment or adsorption to surfaces, or may fail to adsorb efficiently, as they are highly soluble. This can make the transition from using conventional antibodies to sdAb nontrivial for assay development. Specifically, it is often necessary to re-optimize the protocols and tailor the recombinant sdAb through protein engineering to function efficiently in handheld assays, which currently are utilized for point of care testing and field applications. This work focuses on optimizing the integration of sdAb into rapid vertical flow assays. To achieve this goal, we engineered sdAb-based constructs and developed general protocols for the attachment of the sdAb to both gold nanoparticles and a support membrane. We achieved a limit of detection of 0.11 µg/mL for toxins staphylococcal enterotoxin B and ricin, both potential biothreat agents. Additionally, we demonstrated the ability to detect the nucleocapsid protein of SARS-CoV-2, a common target of antigen tests for COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Phantom limb syndrome is a debilitating complication after extremity amputation that poses significant challenges to recovery. This study aims to examine the relationship between phantom limb syndrome and mental and physical comorbidities, including a comparison between phantom limb pain and phantom limb syndrome without pain in below knee amputees.Methods: This is a retrospective cohort study of patients who underwent below knee amputation of the lower extremity in the PearlDiver database, as identified using CPT codes. Analysis was carried out to evaluate the absence or presence of phantom limb syndrome. Matched bivariate analysis accounting for age, sex, Charlson Comorbidity Index score, and region was used to assess whether the presence of pain in phantom limb syndrome patients was associated with increased comorbidity.Results: In total, 44,028 patients with below knee amputation were examined: 95% (42,493 patients) did not develop phantom limb syndrome while 4.8% (1,535 patients) of patients did develop phantom limb syndrome. Phantom limb syndrome was significantly associated with increased odds of coexistent major depressive disorder (OR = 1.86, p <0.0001), generalized anxiety disorder (OR = 2.14, p = 0.04), posttraumatic stress disorder (OR = 1.7, p <0.0001), suicidal ideation (OR = 1.62, p <0.0001), obesity (OR = 1.28, p = 0.0007), osteoarthritis (OR = 1.53, p <0.0001), osteoporosis (OR = 1.64, p <0.0001), and low back pain (OR = 2.31, p <0.0001). Analysis of patient cohorts of phantom limb syndrome with pain and those without pain did not reveal a statistically significant relationship between the presence of pain and any dependent variable.Conclusions: This investigation of over 44,000 patients with below knee amputation revealed that patients with phantom limb syndrome exhibit significantly higher rate of psychiatric comorbidities compared to those without documented phantom limb pain. Suicidal ideation, major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder were especially common, and consequently a multi-disciplinary approach to management is essential. [ABSTRACT FROM AUTHOR]

Abstract: Surgical robots were invented in the 1980s, and since then, robotic-assisted surgery has become commonplace. In the field of spine surgery, robotic assistance is utilized mainly to place pedicle screws, and multiple studies have demonstrated that robots can increase the accuracy of screw placement and reduce radiation exposure to the patient and the surgeon. However, this may be at the cost of longer operative times, complications, and the risk of errors in mapping the patient's anatomy. [ABSTRACT FROM AUTHOR]

Vertebral compression fractures are the most common complication of osteoporosis, with 700,000 cases reported every year in the United States. Vertebral compression fractures typically present with abrupt-onset low back pain with or without a history of trauma, although more than two-thirds are detected incidentally. Diagnosis is confirmed using plain radiographs, while computed tomography and magnetic resonance imaging may be required to evaluate for a malignant cause or if there are neurological deficits on examination. Magnetic resonance imaging is also the modality of choice to determine if the fracture is acute vs chronic in nature. Patients can be managed with a combination of nonsurgical modalities including medications, bracing, and physical therapy, although when indicated, kyphoplasty or vertebroplasty may be considered to provide symptom relief. [ABSTRACT FROM AUTHOR]

Antibiotic bone cement (ABC) is an effective tool for the prophylaxis and treatment of osteomyelitis due to the controlled, sustained release of local antibiotics. ABC has been proven to be effective in the orthopedic fields of arthroplasty and extremity trauma, but the adoption of ABC in spine surgery is limited. The characteristics of ABC make it an optimal solution for treating vertebral osteomyelitis (VO), a serious complication following spine surgery, typically caused by bacterial and sometimes fungal and parasitic pathogens. VO can be devastating, as infection can result in pathogenic biofilms on instrumentation that is dangerous to remove. New techniques, such as kyphoplasty and novel vertebroplasty methods, could amplify the potential of ABC in spine surgery. However, caution should be exercised when using ABC as there is some evidence of toxicity to patients and surgeons, antibiotic allergies, bone cement structural impairment, and possible development of antibiotic resistance. The purpose of this article is to describe the basic science of antibiotic cement utilization and review its usage in spine surgery. [ABSTRACT FROM AUTHOR]

Soil microbial property is one of the fundamental indicators of soil health and quality, yet it has not been routinely examined in most soil testing protocols most likely due to the inconvenience of the current procedures. This study was initiated to validate a microrespirometry (MicroRes) method on real-time soil microbial respiration rate determinations with an infrared gas analyzer (IRGA) respirometer. The results showed that the two were agreeable (slope = 0.971, r2 = 0.977, n = 24). We then used the MicroRes, in place of an IRGA respirometer, to determine the substrate-induced-maximum-initial-respiration (SIR) microbial biomass carbon (SMBC) on the 63 soil samples collected from 28 states of the US and three provinces of Canada. We also determined the10-day incubation mineralized carbon after rewetting the dried soils on the 63 soil samples. The SIR-SMBC determined correlated well with the 10-day incubation mineralized carbon (slope = 0.688, r2 = 0.816, n = 63). MicroRes is a much simpler and cost-effective alternative to IRGA respirometers in real-time soil respiration rate and SIR-SMBC determinations. Its application makes routine real-time soil microbial property examinations possible under laboratory or filed conditions. [ABSTRACT FROM AUTHOR]

We propose an alternative two-phase stratified ranked set sampling. A comparison of the performances of the proposed estimators made by simulation studies using both real and simulated data sets. It is found that the proposed two-phase stratified regression estimator beats its competitors in literature. [ABSTRACT FROM AUTHOR]

A plethora of factors contribute to the biochemical underpinnings of breast cancer, in the absence of any clear, integrative framework. This article proposes that melatonergic pathway regulation within mitochondria provides an integrative framework for the wide array of data driving breast cancer pathophysiology. As melatonin is toxic to breast cancer cells, its production within mitochondria poses a significant challenge to breast cancer cell survival. Consequently, the diverse plasticity in breast cancer cells may arise from a requirement to decrease mitochondria melatonin synthesis. The aryl hydrocarbon receptor role in breast cancer pathophysiology may be mediated by an increase in cytochrome P450 (CYP)1b1 in mitochondria, leading to the backward conversion of melatonin to N-acetylserotonin (NAS). NAS has distinct effects to melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation significantly contributes to breast cancer cell survival and migration. However, the most important aspect of NAS induction by CYP1b1 in breast cancer cells is the prevention of melatonin effects in mitochondria. Many of the changes occurring in breast cancer cells arise from the need to regulate this pathway in mitochondria, allowing this to provide a framework that integrates a host of previously disparate data, including: microRNAs, estrogen, 14-3-3 proteins, sirtuins, glycolysis, oxidative phosphorylation, indoleamine 2,3-dioxygenase and the kynurenine pathways. It is also proposed that this framework provides a pathoetiological model incorporating the early developmental regulation of the gut microbiome that integrates breast cancer risk factors, including obesity. This has significant treatment, prevention and research implications. [ABSTRACT FROM AUTHOR]

Simulation results are presented for all test cases prescribed in the Second AIAA Sonic Boom Prediction Workshop. An inviscid, embedded-boundary Cartesian-mesh flow solver is used to compute "boom carpets"--pressure signatures at a range of specified distances and off-track angles. To accelerate the process, each boom carpet is automatically decomposed into several independent meshes, computed in parallel. Each mesh uses output-based mesh adaptation to affordably obtain credible results. This paper discusses improved Cartesian meshing strategies for boom prediction, including Mach alignment, azimuthal alignment, high-aspect-ratio cells, and adaptation functional weighting. The resulting nearfield signatures generally exhibit good convergence with mesh refinement. For an independent evaluation of our results, this study introduces a local error estimation procedure that highlights regions of the signatures most sensitive to mesh refinement. Results are also presented for the two atmospheric propagation test cases, which investigate the effects of atmospheric profiles on ground noise. Propagation is handled with an augmented Burgers' equation method (NASA's sBOOM), and ground noise metrics are compared. [ABSTRACT FROM AUTHOR]

Endometriosis is a common, often painful, condition that has significant implications for a woman’s fertility. Classically, endometriosis has been conceptualized as a local estrogen-mediated uterine condition driven by retrograde menstruation. However, recent work suggests that endometriosis may be a systemic condition modulated, if not driven, by prenatal processes. Although a diverse array of factors have been associated with endometriosis pathophysiology, recent data indicate that the low body mass index and decreased adipogenesis may be indicative of an early developmental etiology with alterations in metabolic function crucial to endometriosis pathoetiology. The present article reviews the data on the pathoetiology and pathophysiology of endometriosis, suggesting key roles for alterations in mitochondria functioning across a number of cell types and body systems, including the immune system and gut microbiome. These changes are importantly regulated by decreases in vitamin A and its retinoic acid metabolites as well as increases in mitochondria estrogen receptorbeta and the N-acetylserotonin/melatonin ratio across development. This has treatment and future research implications for this still poorly managed condition, as well as for the association of endometriosis with a number of cancers. [ABSTRACT FROM AUTHOR]

Bipolar disorders (BDs) are severe and common psychiatric disorders. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. In addition, infradian fluctuations of mood, social activity, weight and sleep patterns are very frequent in BD. Disease course with a seasonal pattern (SP) occurs in approximately 25% of depressive and 15% of manic episodes, which is coupled to a more severe disease symptomatology. The pathophysiological mechanisms of seasonal effects in BD await clarification, with likely important clinical consequences. This review aims at synthesizing available data regarding the underlying pathophysiological mechanisms of seasonality in BD patients, with implications for future research directions in the study of seasonality in BD. Three factors are suggested to play significant roles in BD with SP, namely the suprachiasmatic nuclei, as well as the melatonergic and photoperiodism systems. It is proposed that BD with SP may be considered as a complex disorder resulting from the interaction of clock gene vulnerabilities and biological clock neuroplasticity, with environmental factors, such as the response to light. Light seems to play a key role in BD with SP, mainly due to two seasonal signaling pathways: a light to cortex serotonin transporter pathway, as well as a pathway connecting light to melatonin synthesis. This provides a theoretical framework for BD with SP, including for future research and clinical management. The review proposes that future research should explore markers of seasonality in BD, such as plasma melatonin, sleep-wake rhythms (with actigraphy) and genetic or epigenetic variants within the melatonin synthesis pathway. The role of light in driving BD with SP is an active area of research. Seasonality may also be intimately linked to wider aspects of BD, including via interactions with the gut microbiome, the gut-liver axis, cholesterol regulation, aspects of metabolic syndrome, vitamin D, decreased longevity, suicide risk and medication treatment targets. Further research on the role of seasonality in BD is likely to clarify the etiology, course and treatment of BD more widely. [ABSTRACT FROM AUTHOR]

Annals Graphic Medicine brings together original graphic narratives, comics, animation/video, and other creative forms by those who provide or receive health care. They address medically relevant topics—whether they be poignant, thought-provoking, or just plain entertaining. [ABSTRACT FROM AUTHOR]

Annals Graphic Medicine brings together original graphic narratives, comics, animation/video, and other creative forms by those who provide or receive health care. They address medically relevant topics—whether they be poignant, thought-provoking, or just plain entertaining. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is still a devastating diagnosis. As with most cancer, the local microenvironments, both within and surrounding GBM/GSC, are important drivers of GBM/GSC gene expressions, including determining the proposed "go or grow" GBM phenotypes. As the activation of TrkB increases the survival and proliferation of GBM/GSC [3], factors acting to regulate the NAS/melatonin ratio in GBM/GSC will be important to determine. [Extracted from the article]

Methoxyindoles have been of continued interest due to their biological effects. Recent studies using enzyme-linked immunosorbent assays (ELISAs) have reported micromolar levels of 5-methoxytryptophan (MeOTRP) in human plasma. This prompted our development of a method for the determination of MeOTRP in human plasma that involved solid phase extraction (SPE) followed by HPLC. The identity of a putative MeOTRP peak was confirmed through chromatographic, voltammometric and fluorometric characterization. Using a standard addition approach, actual mean human plasma MeOTRP levels were found to be approximately 2 ng/mL, 20 to 100 times lower than previously reported. Prior studies on the physiological and possible biomarker roles of MeOTRP need to be reconsidered and future studies of MeOTRP need to take the present findings into consideration. [ABSTRACT FROM AUTHOR]

The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and melatonergic pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective phenomenology. [ABSTRACT FROM AUTHOR]

The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions. [ABSTRACT FROM AUTHOR]

There is an unmet need for snake antivenoms that can be stored ready to use near the point of care. To address that need we have taken two anti-α-cobratoxin single domain antibodies and increased their thermal stability to improve their ambient temperature shelf-life. The anti-α-cobratoxin single domain antibodies C2 and C20 were first isolated, and demonstrated to be toxin neutralizing by Richard et al., 2013 (Richard, G., Meyers, A.J., McLean, M.D., Arbabi-Ghahroudi, M., MacKenzie, R., Hall, J.C., 2013. In vivo neutralization of alpha-cobratoxin with high-affinity llama single-domain antibodies (VHHs) and a VHH-Fc antibody. PLoS One 8, e69495). To thermal stabilize C2 and C20, we first made changes to their frame work 1 region that we had previously identified to be stabilizing, as well as reverted to the hallmark amino acids highly conserved in VHH domains; these changes improved their melting temperature (Tm) by 2 and 6 °C respectively. The further addition of a non-canonical disulfide bond raised the Tm an additional 13 and 9 °C respectively; giving final Tm values of 86 and 75 °C. Testing these mutants at 1 mg/mL at a range of elevated temperatures for an hour; we found that at 65 °C the wild type C2 and C20 had lost 35 and 95% of their binding activity respectively, while the mutants with the added disulfide bond retained nearly 100% of their initial binding activity. While significant work remains to formulate and field a shelf-stable antivenom, our results indicate such a product should be attainable in the near future. [ABSTRACT FROM AUTHOR]

Development of antimicrobial peptide (AMP)-functionalized materials has renewed interest in using poly(ethylene glycol) (PEG)-mediated linking to minimize unwanted interactions while engendering the peptides with sufficient flexibility and freedom of movement to interact with the targeted cell types. While PEG-based linkers have been used in many AMP-based materials, the role of the tether length has been minimally explored. Here, we assess the impact of varying the length of PEG-based linkers on the binding of bacterial cells by surface-immobilized AMPs. While higher surface densities of immobilized AMPs were observed using shorter PEG linkers, the increased density was insufficient to fully account for the increased binding activity of peptides. Furthermore, effects were specific to both the peptide and cell type tested. These results suggest that simple alterations in linking strategies—such as changing tether length—may result in large differences in the surface properties of the immobilized AMPs that are not easily predictable. [ABSTRACT FROM AUTHOR]

Immunoassay formats, in which antibodies provide sensitivity and specificity, are often utilized to provide rapid and simple diagnostic tests. Surface plasmon resonance is frequently used to evaluate the suitability of antibodies by determining binding kinetics to agents or surrogate antigens. We used SPR to evaluate a number of commercial monoclonal antibodies as well as single domain antibodies produced in-house. All the antibodies targeted the Ebola virus viral protein 40 (VP40). We determined the ability of each antibody to bind to immobilized VP40, and ensured they did not bind Ebola glycoprotein or the nucleoprotein. A subset of the monoclonal antibodies was immobilized to characterize antigen capture in solution. It can be advantageous to utilize antibodies that recognize distinct epitopes when choosing reagents for detection and diagnostic assays. We determined the uniqueness of the epitope recognized by the anti-VP40 antibodies using a checkerboard format that exploits the 6 × 6 array of interactions monitored by the Bio-Rad ProteOn XPR36 SPR instrument. The results demonstrate the utility of surface plasmon resonance to characterize monoclonal and recombinant antibodies. Additionally, the analysis presented here enabled the identification of pairs of anti-VP40 antibodies which could potentially be utilized in sandwich type immunoassays for the detection of Ebola virus. [ABSTRACT FROM AUTHOR]

Recent work indicates an intimate interaction of the tryptophan catabolite (TRYCAT) pathways with the melatonergic pathways, primarily via TRYCAT pathway induction taking tryptophan away from the production of serotonin, which is a necessary precursor for the melatonergic pathways. The alpha 7 nicotinic receptor may be significantly modulated by this interaction, given its inactivation by the TRYCAT, kynurenic acid, and its induction by melatonin. Similarly, the aryl hydrocarbon receptor is activated by both kynurenic acid and kynurenine, leading to CYP1A2 and melatonin metabolism, whereas melatonin may act to inhibit the aryl hydrocarbon receptor. These 2 receptors and pathways may therefore be intimately linked, with relevance to a host of intracellular processes of clinical relevance. In this article, these interactions are reviewed. Interestingly, mitochondria may be a site for direct interactions of these pathways and receptors, suggesting that their differential induction may not only be modulating neuronal, glia, and immune cell processes and activity but also be directly acting to regulate mitochondrial functioning. This is likely to have significant consequences as to how an array of diverse central nervous system and psychiatric conditions are conceptualized and treated. [ABSTRACT FROM AUTHOR]

Single-domain antibodies derived from the unique New Antigen Receptor found in sharks have numerous potential applications, ranging from diagnostic reagents to therapeutics. Shark-derived single-domain antibodies possess the same characteristic ability to refold after heat denaturation found in single-domain antibodies derived from camelid heavy-chain-only antibodies. Recently, two shark derived single-domain antibodies specific for the nucleoprotein of Ebola virus were described. Our evaluation confirmed their high affinity for the nucleoprotein, but found their melting temperatures to be low relative to most single-domain antibodies. Our first approach towards improving their stability was grafting antigen-binding regions (complementarity determining regions) of one of these single-domain antibodies onto a high melting temperature shark single-domain antibody. This resulted in two variants: one that displayed excellent affinity with a low melting temperature, while the other had poor affinity but a higher melting temperature. These new proteins, however, differed in only 3 amino acids within the complementarity determining region 2 sequence. In shark single-domain antibodies, the complementarity determining region 2 is often referred to as hypervariable region 2, as this segment of the antibody domain is truncated compared to the sequence in camelid single-domain antibodies and conventional heavy chain variable domains. To elucidate which of the three amino acids or combinations thereof were responsible for the affinity and stability we made the 6 double and single point mutants that covered the intermediates between these two clones. We found a single amino acid change that achieved a 10°C higher melting temperature while maintaining sub nM affinity. This research gives insights into the impact of the shark sdAb hypervariable 2 region on both stability and affinity. [ABSTRACT FROM AUTHOR]

Biosensor development has been a highly dynamic field of research and has progressed rapidly over the past two decades. The advances have accompanied the breakthroughs in molecular biology, nanomaterial sciences, and most importantly computers and electronics. The subfield of evanescent wave fluorescence biosensors has also matured dramatically during this time. Fundamentally, this review builds on our earlier 2005 review. While a brief mention of seminal early work will be included, this current review will focus on new technological developments as well as technology commercialized in just the last decade. Evanescent wave biosensors have found a wide array applications ranging from clinical diagnostics to biodefense to food testing; advances in those applications and more are described herein. [ABSTRACT FROM AUTHOR]

A network conceptualization might contribute to understanding the occurrence and interacting nature of behavioral traits in the autism realm. Networks were constructed based on correlations of item scores of the Autism Diagnostic Observation Schedule for Modules 1, 2 and 3 obtained for a group of 477 Dutch individuals with developmental disorders. After combining Modules, networks were obtained and compared for male versus female, high- versus low-functioning, seizure versus non-seizure, autism spectrum disorder versus intellectual disability, and younger versus older subjects. The network visualizations and calculated network parameters provide new perspectives that generate new hypothesis and suggest follow-up studies. The approach should be useful in characterizing individuals and groups, in elucidating mechanisms of trait generation and routes to outcome phenotypes, and in suggesting points of intervention. [ABSTRACT FROM AUTHOR]

Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker 'tests' for autism/ASD will do more harm than good. Finally, the serotonin-melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation. [ABSTRACT FROM AUTHOR]

Summary Background Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism. Methods The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day1, 1600 h, 0800 h-Day2 for 46 individuals with autism and 27 controls, and 0800 h-Day1, 1100 h, 1600 h, 2400 h, 0800 h-Day2 for 13 individuals with autism and 20 controls). Overnight (2000 h–0800 h) urinary cortisol excretion was also measured. Results The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day2 compared to Day1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups. Conclusion Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day2 versus 0800 h-Day1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety. [ABSTRACT FROM AUTHOR]

Issue addressed This paper explored the first-time use of Twitter by the Australian Health Promotion Association (AHPA) at its 2013 National Health Promotion Conference. Methods The @AHPA_AU Twitter account and #AHPA2013 hashtag were established and included in the conference program. Attendees were encouraged throughout the conference to use it. A total of 748 tweets were captured under the hashtag #AHPA2013 in chronological order from 16-19 June 2013. Tweets with photos and more than one hashtag were recorded. A thematic analysis of tweets was conducted. Results Thirteen broad themes were identified, with each of the 748 tweets allocated to one of the themes. Tweets about keynote sessions made up 38% of all tweets, followed by 14% for concurrent sessions. A photo was included in 11% of tweets, and 25% were sent to more than one hashtag. There were 96 tweeters; 75% of them posted five or less tweets and 9%, including a professional blogger, posted greater than 20 tweets. At the Aboriginal and Torres Strait Islander pre-conference workshop there was a relatively high level of Twitter engagement. Conclusion Twitter could potentially be useful for promoting conference content and activities, but what it adds in value to a health promotion conference cannot be determined by this study. So what? This paper highlights the engagement of tweeters with conference content and activities and suggests that tweeting benefited from the engagement of a professional health blogger. [ABSTRACT FROM AUTHOR]

Issue addressed: This paper explored the first-time use of Twitter by the Australian Health Promotion Association (AHPA) at its 2013 National Health Promotion Conference. Methods: The @AHPA_AU Twitter account and #AHPA2013 hashtag were established and included in the conference program. Attendees were encouraged throughout the conference to use it. A total of 748 tweets were captured under the hashtag #AHPA2013 in chronological order from 16-19 June 2013. Tweets with photos and more than one hashtag were recorded. A thematic analysis of tweets was conducted. Results: Thirteen broad themes were identified, with each of the 748 tweets allocated to one of the themes. Tweets about keynote sessions made up 38% of all tweets, followed by 14% for concurrent sessions. A photo was included in 11% of tweets, and 25% were sent to more than one hashtag. There were 96 tweeters; 75% of them posted five or less tweets and ~9%, including a professional blogger, posted greater than 20 tweets. At the Aboriginal and Torres Strait Islander pre-conference workshop there was a relatively high level of Twitter engagement. Conclusion: Twitter could potentially be useful for promoting conference content and activities, but what it adds in value to a health promotion conference cannot be determined by this study. [ABSTRACT FROM AUTHOR]

2 Fehsel K, Schwanke K, Kappel BA, et al. (2022) Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction. Fehsel et al., show clozapine to activate the aryl hydrocarbon receptor (AhR), thereby increasing preadipocyte differentiation and impairing vasodilatory responses in endothelial cells ([2]). As such, AhR activation by clozapine may be mediating important clinical and side-effects via the regulation of the melatonergic pathway in different cells and tissues. [Extracted from the article]

Accumulating data have led to a re-conceptualization of depression that emphasizes the role of immune-inflammatory processes, coupled to oxidative and nitrosative stress (O&NS). These in turn drive the production of neuroregulatory tryptophan catabolites (TRYCATs), driving tryptophan away from serotonin, melatonin, and N-acetylserotonin production, and contributing to central dysregulation. This revised perspective better encompasses the diverse range of biological changes occurring in depression and in doing so provides novel and readily attainable treatment targets, as well as potential screening investigations prior to treatment initiation. We briefly review the role that immune-inflammatory, O&NS, and TRYCAT pathways play in the etiology, course, and treatment of depression. We then discuss the pharmacological treatment implications arising from this, including the potentiation of currently available antidepressants by the adjunctive use of immune- and O&NS-targeted therapies. The use of such a frame of reference and the treatment benefits attained are likely to have wider implications and utility for depression-associated conditions, including the neuroinflammatory and (neuro)degenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized. Methods: Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. Results: The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Conclusions: Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism. [ABSTRACT FROM AUTHOR]

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/ symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/ CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions. [ABSTRACT FROM AUTHOR]

• Values reported for indolic metabolites of tryptophan were compiled and compared. • Consistencies and discrepancies in reported values were discussed. • The progress in analytical and chromatographic methodologies used was reviewed. • Areas in need of greater attention were noted. Concentrations reported for indolic microbial metabolites of tryptophan in human and rodent brain, cerebrospinal fluid, plasma, saliva and feces were compiled and discussed. A systematic review of the literature was accomplished by key word searches of Pubmed, Google Scholar and the Human Metabolome Data Base (HMDB), and by searching bibliographies of identified publications including prior reviews. The review was prompted by the increasing appreciation of the physiological importance of the indolic compounds in human health and disease. The compounds included were indoleacetic acid (IAA), indole propionic acid (IPA), indoleacrylic acid (IACR), indolelactic acid (ILA) indolepyruvic acid (IPY), indoleacetaldehyde (IAALD), indolealdehyde (IALD), tryptamine (TAM), indole (IND) and skatole (SKT). The undertaking aimed to vet and compare existing reports, to resolve apparent discrepancies, to draw biological inferences from the consideration of multiple analytes across sample types, to survey the analytical methodologies used, and to point out areas in need of greater attention. [ABSTRACT FROM AUTHOR]

This article discusses the importance of ethical and inclusive engagement between non-Indigenous researchers and Indigenous communities in Arctic research. It acknowledges the historical mistreatment of Indigenous peoples by researchers and emphasizes the need to build respectful relationships. The article provides ten rules for researchers to follow, including researching the culture and history of the research site, understanding different approaches to knowledge production, and establishing reciprocal community relationships. It highlights the value of Indigenous knowledge and the need for collaboration with Indigenous communities for high-quality research outcomes. The document offers guidelines and best practices for researchers seeking to collaborate with Arctic Indigenous communities, emphasizing the importance of recognizing shared humanity, respectful contact methods, aligning research questions with community objectives, compensating Indigenous participants, and planning for the continuation of research and scientific engagement. The paper underscores the need for ethical collaboration that centers Indigenous sovereignty, empowerment, and self-determination, while respecting Indigenous communities and their land and resources. [Extracted from the article]

Highlights: [•] Anti-ricin single domain antibodies (sdAb) were self-assembled on quantum dots (QDs). [•] Conjugates were prepared using dihydrolipoic acid-capped CdSe–ZnS core–shell QDs. [•] The sdAb–QD conjugates functioned in fluoroimmunoassays for ricin detection. [•] The conjugates provided signal amplification in surface plasmon resonance assays. [•] Conjugates provided sensitive detection compared to unconjugated sdAb reporters. [ABSTRACT FROM AUTHOR]

Abstract: Life forms populating the Earth must face environmental challenges to assure individual and species survival. The strategies predisposed to maintain organismal homeostasis and grant selective advantage rely on anticipatory phenomena facing periodic modifications, and compensatory phenomena facing unpredictable changes. Biological processes bringing about these responses are respectively driven by the circadian timing system, a complex of biological oscillators entrained to the environmental light/dark cycle, and by regulatory and metabolic networks that precisely direct the body's adjustments to variations of external conditions and internal milieu. A critical role in organismal homeostatic functions is played by the aryl hydrocarbon receptor (AHR) complex, which senses environmental and endogenous compounds, influences metabolic responses controlling phase I/II gene expression, and modulates vital phenomena such as development, inflammation and adaptive immunity. A physiological cross-talk between circadian and AHR signaling pathways has been evidenced. The alteration of AHR signaling pathway deriving from genetic damage with polymorphisms or mutations, or produced by exogenous or endogenous AHR activation, and chronodisruption caused by mismatch between the body's internal clock and geophysical time/social schedules, are capable of triggering pathological mechanisms involved in metabolic, immune-related and neoplastic diseases. On the other hand, the molecular components of the circadian clock circuitry and AHR signaling pathway may represent useful tools for preventive interventions and valuable targets of therapeutic approaches. [Copyright &y& Elsevier]

Abstract: Schizophrenia and depression are two common and debilitating psychiatric conditions. Up to 61% of schizophrenic patients have comorbid clinical depression, often undiagnosed. Both share significant overlaps in underlying biological processes, which are relevant to the course and treatment of both conditions. Shared processes include changes in cell‐mediated immune and inflammatory pathways, e.g. increased levels of pro-inflammatory cytokines and a Th1 response; activation of oxidative and nitrosative stress (O&NS) pathways, e.g. increased lipid peroxidation, damage to proteins and DNA; decreased antioxidant levels, e.g. lowered coenzyme Q10, vitamin E, glutathione and melatonin levels; autoimmune responses; and activation of the tryptophan catabolite (TRYCAT) pathway through induction of indoleamine-2,3-dioxygenase. Both show cognitive and neurostructural evidence of a neuroprogressive process. Here we review the interlinked nature of these biological processes, suggesting that schizophrenia is immunologically primed for an increased expression of depression. Such a conceptualization explains, and incorporates, many of the current perspectives on the nature of schizophrenia and depression, and has implications for the nature of classification and treatment of both disorders. An early developmental etiology to schizophrenia, driven by maternal infection, with subsequent impact on offspring immuno-inflammatory responses, creates alterations in the immune pathways, which although priming for depression, also differentiates the two disorders. [Copyright &y& Elsevier]

Abstract: In 1995, the macrophage–T lymphocyte theory of schizophrenia (Smith and Maes, 1995) considered that activated immuno‐inflammatory pathways may account for the higher neurodevelopmental pathology linked with gestational infections through the detrimental effects of activated microglia, oxidative and nitrosative stress (O&NS), cytokine‐induced activation of the tryptophan catabolite (TRYCAT) pathway and consequent modulation of the N‐methyl d‐aspartate receptor (NMDAr) and glutamate production. The aim of the present paper is to review the current state‐of‐the art regarding the role of the above pathways in schizophrenia. Accumulating data suggest a powerful role for prenatal infection, both viral and microbial, in driving an early developmental etiology to schizophrenia. Models of prenatal rodent infection show maintained activation of immuno‐inflammatory pathways coupled to increased microglia activation. The ensuing activation of immuno‐inflammatory pathways in schizophrenia may activate the TRYCAT pathway, including increased kynurenic acid (KA) and neurotoxic TRYCATs. Increased KA, via the inhibition of the α7 nicotinic acetylcholine receptor, lowers gamma‐amino‐butyric‐acid (GABA)ergic post‐synaptic current, contributing to dysregulated glutamatergic activity. Hypofunctioning of the NMDAr on GABAergic interneurons will contribute to glutamatergic dysregulation. Many susceptibility genes for schizophrenia are predominantly expressed in early development and will interact with these early developmental driven changes in the immuno‐inflammatory and TRYCAT pathways. Maternal infection and subsequent immuno‐inflammatory responses are additionally associated with O&NS, including lowered antioxidants such as glutathione. This will contribute to alterations in neurogenesis and myelination. In such a scenario a) a genetic or epigenetic potentiation of immuno‐inflammatory pathways may constitute a double hit on their own, stimulating wider immuno‐inflammatory responses and thus potentiating the TRYCAT pathway and subsequent NMDAr dysfunction and neuroprogression; and b) antipsychotic‐induced changes in immuno‐inflammatory, TRYCAT and O&NS pathways would modulate the CNS glia‐neuronal interactions that determine synaptic plasticity as well as myelin generation and maintenance. [Copyright &y& Elsevier]