Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry. The objectives of the current review are to ...comprehensively evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD. Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology. Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD. Orexin antagonists have been shown to treat insomnia effectively without disrupting normal sleep architecture in both preclinical (e.g., animal models) and clinical studies. Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence. Orexin antagonists have also been shown to possess antidepressant-like properties in some animal models of MDD. Extant evidence indicates that orexin-modulating treatments exert pleiotropic effects on multiple neural systems implicated in the phenomenology of mood disorders and suggests orexins as a promising target for investigation and intervention in mood disorders. To date, no human clinical trials evaluating the antidepressant effects of orexin antagonists in MDD have been completed. Given the promising results from preclinical studies, clinical trials are merited to evaluate the antidepressant effects of orexin antagonists in MDD.
•Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry•Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology•Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD•Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence and has shown to possess antidepressant properties•The objectives are to evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD
Brainstem gliomas are a heterogeneous group of tumors that encompass both benign tumors cured with surgical resection and highly lethal cancers with no efficacious therapies. We perform a ...comprehensive study incorporating epigenetic and genomic analyses on a large cohort of brainstem gliomas, including Diffuse Intrinsic Pontine Gliomas. Here we report, from DNA methylation data, distinct clusters termed H3-Pons, H3-Medulla, IDH, and PA-like, each associated with unique genomic and clinical profiles. The majority of tumors within H3-Pons and-H3-Medulla harbors H3F3A mutations but shows distinct methylation patterns that correlate with anatomical localization within the pons or medulla, respectively. Clinical data show significantly different overall survival between these clusters, and pathway analysis demonstrates different oncogenic mechanisms in these samples. Our findings indicate that the integration of genetic and epigenetic data can facilitate better understanding of brainstem gliomagenesis and classification, and guide future studies for the development of novel treatments for this disease.
Cognitive dysfunction is a principal determinant of functional impairment in major depressive disorder (MDD) and often persists during periods of euthymia. Abnormalities in the glutamate system, ...particularly in N-methyl-d-aspartate receptors (NMDARs) activity, have been shown to contribute to both mood and cognitive symptoms in MDD. The current narrative review aims to evaluate the potential pro-cognitive effects of targeting the glycine site of NMDARs in the treatment of psychiatric disorders, with a special focus on how these results may apply to MDD. Literature databases were searched from inception to May 2018 for relevant pre-clinical and clinical studies evaluating antidepressant and pro-cognitive effects of NMDAR glycine site modulators in both MDD and non-MDD samples. Six glycine site modulators with pro-cognitive and antidepressant properties were identified: d-serine (co-agonist), d-cycloserine (partial agonist), d-alanine (co-agonist), glycine (agonist), sarcosine (co-agonist) and rapastinel (partial agonist). Preclinical animal studies demonstrated improved neuroplasticity and pro-cognitive effects with these agents. Numerous proof-of-concept clinical trials demonstrated pro-cognitive and antidepressant effects trans-diagnostically (e.g., in healthy participants, MDD, schizophrenia, anxiety disorders, major neurocognitive disorders). The generalizability of these clinical studies was limited by the small sample sizes and the paucity of studies directly evaluating cognitive effects in MDD samples, as most clinical trials were in non-MDD samples. Taken together, preliminary results suggest that the glycine site of NMDARs is a promising target to ameliorate symptoms of depression and cognitive dysfunction. Additional rigorously designed clinical studies are required to determine the cognitive effects of these agents in MDD.
•The NMDAR has been previously implicated in cognitive dysfunction in MDD•Pro-cognitive effects of targeting the glycine site of NMDARs was evaluated•Preclinical studies demonstrated improved neuroplasticity and pro-cognitive effects•Preliminary clinical trials demonstrated pro-cognitive and antidepressant effects•Preliminary results suggest that the glycine site of NMDARs is a promising target
Magnetic insulators (MIs) attract tremendous interest for spintronic applications due to low Gilbert damping and the absence of Ohmic loss. Spin-orbit torques (SOTs) on MIs are more intriguing than ...magnetic metals since SOTs cannot be transferred to MIs through direct injection of electron spins. Understanding of SOTs on MIs remains elusive, especially how SOTs scale with the MI film thickness. Here, we observe the critical role of dimensionality on the SOT efficiency by studying the MI layer thickness-dependent SOT efficiency in tungsten/thulium iron garnet (W/TmIG) bilayers. We show that the TmIG thin film evolves from two-dimensional to three-dimensional magnetic phase transitions as the thickness increases. We report the significant enhancement of the measured SOT efficiency as the TmIG thickness increases, which is attributed to the increase of the magnetic moment density. We demonstrate the current-induced SOT switching in the W/TmIG bilayers with a TmIG thickness up to 15 nm.
•Numerous studies indicate that probiotics have anti-inflammatory effects.•Immune-inflammatory modulation may mediate the antidepressant effects of probiotics.•Probiotics may be more effective in ...depressed subgroups with elevated inflammation.•Future studies should parse out the heterogeneous effects of different probiotics.
During the past decade, there has been renewed interest in the relationship between brain-based disorders, the gut microbiota, and the possible beneficial effects of probiotics. Emerging evidence suggests that modifying the composition of the gut microbiota via probiotic supplementation may be a viable adjuvant treatment option for individuals with major depressive disorder (MDD). Convergent evidence indicates that persistent low-grade inflammatory activation is associated with the diagnosis of MDD as well as the severity of depressive symptoms and probability of treatment response. The objectives of this review are to (1) evaluate the evidence supporting an anti-inflammatory effect of probiotics and (2) describe immune system modulation as a potential mechanism for the therapeutic effects of probiotics in populations with MDD. A narrative review of studies investigating the effects of probiotics on systemic inflammation was conducted. Studies were identified using PubMed/Medline, Google Scholar, and clinicaltrials.gov (from inception to November 2017) using the following search terms (and/or variants): probiotic, inflammation, gut microbiota, and depression. The available evidence suggests that probiotics should be considered a promising adjuvant treatment to reduce the inflammatory activation commonly found in MDD. Several controversial points remain to be addressed including the role of leaky gut, the role of stress exposure, and the role of blood-brain-barrier permeability. Taken together, the results of this review suggest that probiotics may be a potentially beneficial, but insufficiently studied, antidepressant treatment intervention.
•Forty-two eligible papers with 4,217 participants were included in the analysis.•Lower TRP levels and higher circulating KYN/TRP ratios existed in subjects with SCZ.•Lower KYN levels were associated ...with medication-free persons with SCZ.•The KYN levels were higher in subjects with SCZ after antipsychotic treatments when compared with baseline.•The current evidence provides valuable insight of the potential roles of KYN pathway in the pathogenesis of SCZ.
The kynurenine (KYN) pathway is postulated to play various roles in immune system dysregulation of schizophrenia (SCZ). We conducted a meta-analysis to explore the association between six key metabolites of KYN pathway (i.e., tryptophan (TRP), KYN, quinolinic acid (QUIN), and kynurenic acid (KYNA)) and SCZ. Priori Bonferroni adjustments were conducted for multiple comparisons. In total, 42 studies that examined the relationship between the metabolites in KYN pathway mentioned above and SCZ in 4217 participants and nine studies that examined alterations of these metabolites after antipsychotic treatments were included. The results demonstrate that (1) subjects with prescribed medication had significantly higher KYN levels when compared to controls; (2) higher KYN levels in cerebrospinal fluid (CSF), lower plasma KYN levels and higher CSF KYNA levels were associated with SCZ; (3) the KYN levels were higher in subjects with SCZ after antipsychotic treatments when compared with baseline. The evidence provides valuable insight of the potential underlying involvement of the KYN pathway in the pathogenesis of SCZ.
This study (registered with PROSPERO, CRD42018085967) compares the efficacy (i.e. pro‐cognitive effects) and acceptability of antidiabetic agents for Alzheimer's disease (AD) and mild cognitive ...impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials comparing antidiabetic agents with placebo and/or another active antidiabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4855) evaluating the effects of 6 different antidiabetic drugs (i.e. intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo. Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta‐analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro‐cognitive class effect of antidiabetic agents in AD/MCI. Other antidiabetic agents should also be investigated in future studies.
Major Depressive Disorder (MDD) is a prevalent, chronic, disabling, and multidimensional mental disorder. Cognitive dysfunction represents a core diagnostic and symptomatic criterion of MDD, and is a ...principal determinant of functional non-recovery. Cognitive impairment has been observed to persist despite remission of mood symptoms, suggesting dissociability of mood and cognitive symptoms in MDD. Recurrent impairments in several domains including, but not limited to, executive function, learning and memory, processing speed, and attention and concentration, are associated with poor psychosocial and occupational outcomes. Attempts to restore premorbid functioning in individuals with MDD requires regular screenings and assessment of objective and subjective measures of cognition by clinicians. Easily accessible and cost-effective tools such as the THINC-integrated tool (THINC-it) are suitable for use in a busy clinical environment and appear to be promising for routine usage in clinical settings. However, antidepressant treatments targeting specific cognitive domains in MDD have been insufficiently studied. While select antidepressants, e.g., vortioxetine, have been demonstrated to have direct and independent pro-cognitive effects in adults with MDD, research on additional agents remains nascent. A comprehensive clinical approach to cognitive impairments in MDD is required. The current narrative review aims to delineate the importance and relevance of cognitive dysfunction as a symptomatic target for prevention and treatment in the phenomenology of MDD.
Geometric Hall effect is induced by the emergent gauge field experienced by the carriers adiabatically passing through certain real-space topological spin textures, which is a probe to non-trivial ...spin textures, such as magnetic skyrmions. We report experimental indications of spin-texture topological charges induced in heterostructures of a topological insulator (Bi,Sb)
Te
coupled to an antiferromagnet MnTe. Through a seeding effect, the pinned spins at the interface leads to a tunable modification of the averaged real-space topological charge. This effect experimentally manifests as a modification of the field-dependent geometric Hall effect when the system is field-cooled along different directions. This heterostructure represents a platform for manipulating magnetic topological transitions using antiferromagnetic order.
Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we ...explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.
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