Stress Axis Research Articles

Direct modulation of CRH nerve terminal function by noradrenaline and corticosterone.

Nerve terminals are the final point of regulation before neurosecretion. As such, neuromodulators acting on nerve terminals can exert significant influence on neural signalling. Hypothalamic corticotropin-releasing hormone (CRH) neurons send axonal projections to the median eminence where CRH is secreted to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. Noradrenaline and corticosterone are two of the most important neuromodulators of HPA axis function; noradrenaline excites CRH neurons and corticosterone inhibits CRH neurons by negative feedback. Here, we used GCaMP6f Ca2+ imaging and measurement of nerve terminal CRH secretion using sniffer cells to determine whether these neuromodulators act directly on CRH nerve terminals in male mice. Contrary to expectations, noradrenaline inhibited action potential-dependent Ca2+ elevations in CRH nerve terminals and suppressed evoked CRH secretion. This inhibitory effect was blocked by α2-adrenoreceptor antagonism. Corticosterone also suppressed evoked CRH peptide secretion from nerve terminals, independent of action potential-dependent Ca2+ levels. This inhibition was prevented by the glucocorticoid receptor antagonist, RU486, and indicates that CRH nerve terminals may be a site of fast glucocorticoid negative feedback. Together these findings establish median eminence nerve terminals as a key site for regulation of the HPA axis.Significance Statement Corticotropin-releasing hormone (CRH) neurons control the stress axis. Noradrenaline and corticosterone are two signalling molecules that control CRH neuron cell body excitability. However, their effect on CRH nerve terminal function is unknown. To examine this, we performed live Ca2+ imaging and measured CRH secretion. We found that noradrenaline suppressed nerve terminal Ca2+ levels and inhibited nerve terminal CRH secretion. Corticosterone had no effect on nerve terminal Ca2+, but inhibited nerve terminal CRH secretion. This suggests that CRH nerve terminals may be a site of fast corticosteroid negative feedback. Together, these data demonstrate that CRH nerve terminals are a critical point of regulation in the control of the stress axis.

Impact of stress-induced precipitate variant selection on anisotropic electrical properties of piezoceramics

Precipitation hardening has been recently validated as a new mechanism for domain wall pinning and mechanical loss reduction in piezoelectrics. While anisometric precipitates have high pinning strengths, there is limited knowledge about the electrical anisotropy of the precipitation-hardened piezoceramics. In the present work, we successfully orient the precipitates in Li0.18Na0.82NbO3 piezoceramics by applying a uniaxial stress during the aging and studied its electrical anisotropy. Predicted by mechanical simulation and verified by transmission electron microscopy, it is demonstrated that the precipitate variant with its long axis perpendicular to the applied stress is energetically favored. The electrical anisotropy of the stress-assisted aged Li0.18Na0.82NbO3 is studied by applying electrical fields parallel or perpendicular to the stress axis. The domain wall contribution to permittivity is found to vary by more than a factor of two depending on orientation. In addition, the domain walls are more difficult to be activated by increasing the temperature when the electric field is perpendicular to the stress axis. Our work highlights the precipitate variant selection induced by stress-assisted aging and the related electrical anisotropy in piezoceramics. This technique enables the precipitate orientation in piezoceramics and the utilization of its anisotropy, providing fundamental insight into precipitate-domain-wall interactions and setting the ground for leveraging precipitation hardening effect in piezoceramics.

Inhibition of IRE1α/XBP1 axis alleviates LPS-induced acute lung injury by suppressing TXNIP/NLRP3 inflammasome activation and ERK/p65 signaling pathway

BackgroundAcute lung injury or acute respiratory distress syndrome (ALI/ARDS) is a devastating clinical syndrome with high incidence and mortality rates. IRE1α-XBP1 pathway is one of the three major signaling axes of endoplasmic reticulum stress that is involved in inflammation, metabolism, and immunity. The role and potential mechanisms of IRE1α-XBP1 axis in ALI/ARDS has not well understood.MethodsThe ALI murine model was established by intratracheal administration of lipopolysaccharide (LPS). Hematoxylin and eosin (H&E) staining and analysis of bronchoalveolar lavage fluid (BALF) were used to evaluate degree of lung injury. Inflammatory responses were assessed by ELISA and RT-PCR. Apoptosis was evaluated using TUNEL staining and western blot. Moreover, western blot, immunohistochemistry, and immunofluorescence were applied to test expression of IRE1α, XBP1, NLRP3, TXNIP, IL-1β, ERK1/2 and NF-κB p65.ResultsThe expression of IRE1α significantly increased after 24 h of LPS treatment. Inhibition of the IRE1α-XBP1 axis with 4µ8C notably improved LPS-induced lung injury and inflammatory infiltration, reduced the levels of IL-6, IL-1β, and TNF-α, and decreased cell apoptosis as well as the activation of the NLRP3 inflammasome. Besides, in LPS-stimulated Beas-2B cells, both 4µ8C and knockdown of XBP1 diminished the mRNA levels of IL-6 and IL-1B, inhibited cell apoptosis and reduced the protein levels of TXNIP, NLRP3 and secreted IL-1β. Mechanically, the phosphorylation and nuclear translocation of ERK1/2 and p65 were significantly suppressed by 4µ8C and XBP1 knockdown.ConclusionsIn summary, our findings suggest that IRE1α-XBP1 axis is crucial in the pathogenesis of ALI/ARDS, whose suppression could mitigate the pulmonary inflammatory response and cell apoptosis in ALI through the TXNIP/NLRP3 inflammasome and ERK/p65 signaling pathway. Our study may provide new evidence that IRE1α-XBP1 may be a promising therapeutic target for ALI/ARDS.

Laboratory evaluation of calcareous sand specimens with inclined sedimentary surfaces

Sedimentary processes often produce natural and blown calcareous sands that are deposited in inclined and layered formations. These calcareous sands frequently exist in a complex stress state with rotating principal stress axes that result in intricate mechanical properties. To investigate the mechanical behaviors of calcareous sands with inclined sedimentary surfaces, we developed a device to prepare hollow cylindrical specimens from artificially crushed calcareous sands. By combining this device with a hollow cylindrical torsional shear apparatus, undrained monotonic loading and pure principal stress rotation tests were conducted to investigate the static and dynamic properties of the inherently anisotropic calcareous sands. The results indicate that the shear dilatancy property is related to the principal stress direction; the shear dilatancy of calcareous sand decreases as the direction of the principal stress increases, and the peak stress ratio decreases with increasing principal stress direction and increases with increasing deposition direction. In the precyclic loading period, increases in the deposition direction led to increases in the stabilities of the specimens and decreases in excess pore pressure accumulation, which further affect the dynamic shear modulus and damping ratio of the calcareous sand. In the late stage of cyclic loading, the inherent anisotropies of the specimens are destroyed, so that the excess pressure and hysteresis loop characteristics start to converge.

Chronic stress and hair cortisol concentration in mothers: A two-study investigation.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one mechanism through which chronic stress during pregnancy and parenthood may affect parental, child, and family health. Hair cortisol concentration (HCC) may be well-suited to elucidate associations between chronic stress and HPA axis regulation because HCC reflects cortisol output over several months. However, most previous studies that examine chronic stress in conjunction with cortisol in pregnant individuals or mothers use measures that reflect HPA axis output over a relatively limited time. We report findings from two longitudinal studies that tested associations between chronic stress and HCC in women during the perinatal period (Study 1; n=144) and mothers of young children (Study 2; n=102). Both studies measured chronic stress with a measure developed to comprehensively assess chronic stressors in community samples. Hair samples were collected three times in Study 1 (mid-pregnancy, one month postpartum, and 12months postpartum) and twice in Study 2, approximately one year apart. Chronic stress was associated with higher HCC in both studies. Exploratory analyses indicated that the strength of associations between chronic stress and HCC differed as a function of the life domain of chronic stress. Chronic work and family demands were associated with higher postpartum HCC in Study 1 whereas neighbourhood/housing and discrimination chronic stress were associated with higher HCC in Study 2. These findings provide evidence of a biological pathway through which chronic stress may influence health in mothers and support the utility of hair cortisol as a neuroendocrine measure of chronic stress during pregnancy and parenthood.

Negative Mechanical Characteristics of Self‐Similar Star‐Like Hinged Grilles

Ferroelastic textures called star patterns are transformable into grilles whose rigid bars replace domain boundaries and are connected with hinges at their junctions. The grilles show several levels of self‐similarity. Exact formulae for the scaling factors as functions of the shape and number N of the arms are provided. The minimal dynamic model of such systems involves force constants at only one level (generation) of self‐similarity. The minimal set of force constants ensures stability of the stars with N = 2 and N = 3. At N = 4 the minimal model exhibits exactly one mode of zero frequency. The reaction of the four‐arm star to a tensile stress applied at the level of the force constants depends on the self‐similarity scaling factor and on the separation between the applied stress and the generation where the observation is made. In some regions of these parameters the reaction is analogous to auxetics but it also shows negative tensile characteristics, that is, a shrinking in the direction of the stress axis. With increasing distance from the external perturbation toward outer generations of self‐similarity the system shows a surprisingly fast restoration of the symmetry broken by the stress.

Relocation and Stress Analysis of the 2018 Mandali-Sumar Earthquake Sequence, Iraq-Iran Border

The 2018 Mandali-Sumar earthquake sequence started in January 2018 at the Iraq – Iran border within the Low Folded Zone of the Zagros Fold-Thrust Belt. To study the fault that is responsible for this earthquake sequence, the relocation of 32 earthquakes was conducted. In addition, moment tensor solutions of 9 large earthquakes were collected to know the fault motion and stress regime in the study area. The Computer Programs in Seismology (CPS) was used to analyze waveform data taken from 33 seismic stations located in Iraq and Iran to relocate earthquakes. The location of the earthquake sequence based on the IRSC bulletin shows a scattered spatial distribution, but the results of the relocations show that the earthquakes of the sequences are aligned in a longitudinal feature parallel to an anticline limb located in Ilam and Kermanshah provinces near the Iraqi border. The moment tensor solutions indicate that the sequence is related to a thrust fault with a 342º strike direction, 35º NE dip angle, and 76º rake angle. The TENSOR program was used to perform formal stress inversion of moment stress axes, which revealed that the azimuth of the maximum horizontal stress axis is 63º. The epicenters of the sequence are located between the Mountain Front Fault to the NE and the Zagros Foredeep Fault to the Southeast. We believe that the 2018 Mandali-Sumar earthquake sequence is related to displacement on the surface of the Zagros Foredeep Fault within the uppermost basement and the lowermost Phanerozoic cover.

Asymmetric deformation and failure behavior of roadway subjected to different principal stress based on biaxial tests

The magnitude and direction of stress will affect the failure of roadway. The impact of stress magnitude and direction on roadway failure was investigated using a rock failure system equipped with true triaxial loading, acoustic emission (AE), and digital image correlation (DIC) technologies. The system allowed for the simulation of rock sample failures under various three-dimensional stress conditions, while real-time monitoring was conducted using a high-precision microseismic system. By prefabricating rectangular holes at different angles in sandstone specimens, roadways under different stress effects in engineering can be simulated. Biaxial loading tests were then performed on these prefabricated sandstone cube specimens to observe external fracture characteristics and internal fracture information using acoustic emission equipment. The peak strength of samples with holes is approximately 38–56% of that of intact samples. In the early and middle loading stages, the strain on the surface is on the order of 10-3. In the later loading stage, the strain on the surface is on the order of 10-2. The findings indicate that roadway failure primarily involves local particle ejection, fragment spalling, large-scale particle ejection, plate crack buckling, and eventual failure. The ultimate failure mode varies based on stress deflection angles: with no included angle, the roadway exhibits a ’V’ shaped failure zone on both sides, predominantly experiencing tensile failure. At included angles of 30°, 45°, and 60° between stress and roadway axis, the roadway displays a “—” failure pattern along the diagonal, characterized by a combination of tension and shear failure. The extension angle of the“—” failure zone varies depending on the stress deflection angle. At a 90° included angle, the roadway shows a ’V’ shaped failure in the roof and floor, primarily undergoing tensile failure. Real-time monitoring of the strain field evolution around the roadway during failure using DIC method revealed valuable insights. AE events at different deflection angles reflect the progression of micro cracks in the specimen, showing a strong correlation with macro failure. The research outcomes elucidate the mechanisms behind various forms of roadway failure induced by stress deflection and shed light on the failure mechanism at different stress deflection angles.

Obtusin ameliorates diabetic retinopathy by inhibiting oxidative stress and inflammation.

Diabetic retinopathy (DR) is linked to an increased risk of psychiatric and neurological conditions, largely due to chronic inflammation, oxidative stress, and microvascular damage associated with the disease. Emerging evidence suggests that Cassia seed extract has significant anti-inflammatory and antioxidant properties. However, the therapeutic potential of obtusin, a major compound in Cassia seed, and its underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic efficacy of obtusin in the treatment of DR. Db/db mice were treated with obtusin (5 and 10mg/kg/day) for 12 weeks. Throughout the study, body weight, blood glucose levels, and lipid profiles were monitored. Retinal histopathology and transmission electron microscopy were used to assess the pharmacological effects of obtusin in vivo. Additionally, in vitro assays were conducted on human retinal microvascular endothelial cells cultured under high glucose conditions to explore obtusin's potential role in mitigating DR. Obtusin treatment in diabetic mice significantly reduced blood glucose levels, improved dyslipidemia, thickened retinal layers, reduced retinal oxidative stress, and inhibited the upregulation of inflammatory cytokines. It also lessened fundus microangiopathy and preserved the retina's normal barrier function. Mechanistic in vitro analysis suggested that obtusin targets the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway, both of which are implicated in DR. Our findings suggest that the Poldip2-Nox4 oxidative stress axis and the NF-κB-MAPK-VEGFA inflammatory pathway could be therapeutic targets for obtusin in the treatment of DR and its associated psychiatric and neurological conditions.

Stress Axis: Molecular and Cellular Regulation of the HPI/HPA Axis

Stress Axis: Molecular and Cellular Regulation of the HPI/HPA Axis

Neuronutrition and Its Impact on Post-Stroke Neurorehabilitation: Modulating Plasticity Through Diet.

The recovery of neurological deficits after ischemic stroke largely depends on the brain's ability to reorganize its undamaged neuronal circuits and neuronal plasticity phenomena. The consolidated evidence highlights the involvement of the patient's impaired nutritional conditions in post-stroke recovery and unsatisfying rehabilitative outcomes. Standardized nutritional protocols usually applied in hospitalized patients in a rehabilitation setting aim mainly to improve the general health conditions of patients, do not consider the high inter-individual variability in neurorehabilitation outcomes, and are not sufficiently modifiable to provide neuroprotective and restorative dietary patterns that could promote neuronal plasticity and functional recovery during neurorehabilitation. Neuronutrition, an emergent scientific field of neuroscience, represents a valid model of a personalized nutritional approach, assuring, for each patient, nutrients having antioxidant and anti-inflammatory properties, ensuring a balanced microbiota composition, and providing adequate neurotrophic support, essential for improving neuronal plasticity, brain functional recovery, and rehabilitative outcomes. In the present narrative review, we provide an overview of the current knowledge on neuronutrition as an adjuvant strategy of a personalized nutritional approach potentially effective in improving post-stroke neuroplasticity and neurorehabilitation by counteracting or at least limiting post-stroke oxidative/nitrosative stress, neuroinflammation, and gut-brain axis disturbance.

PACAP regulates neuroendocrine and behavioral stress responses via CRF-containing neurons of the rat hypothalamic paraventricular nucleus

AbstractPituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the brain including the hypothalamic paraventricular nucleus (PVN) implying a regulatory role in stress function. Recent evidence indicates that one of the main targets of PACAP within the PVN are corticotropin-releasing factor (CRF) neurons, which are key regulators of the hypothalamic-pituitary-adrenal (HPA) axis. However, the neural correlates that mediate PACAP effects on stress function are not fully understood. In the present study, we characterized the neuronal mechanism by which PACAP regulates neuroendocrine and behavioral stress responses in rats. We found that intracerebroventricular administration of PACAP increased the swim stress-induced c-Fos expression in distinct brain areas of the stress and anxiety circuitry including the parvocellular part of the PVN and changed behavioral stress coping during forced swimming to a more passive coping style (i.e., indicated by increased floating and reduced struggling behavior). Subsequently, PACAP administration directly into the PVN mimicked these behavioral effects and potentiated the plasma ACTH response to forced swim stress suggesting an excitatory role of PACAP on HPA stress axis reactivity. In addition, immunohistochemical analysis revealed a considerable portion of stress-activated CRF neurons in the medial parvocellular part of the PVN that co-localized PAC1 receptors suggesting that PACAP-induced effects on stress function are likely mediated directly by activation of CRF neurons in the PVN. Thus, these findings suggest that the PVN may represent one of the key areas where PACAP regulates the neuroendocrine and behavioral stress response.

Cemented sand under hollow cylinder multiaxial loading

Improvement of granular soils’ mechanical properties can be achieved by the addition of bonding agents. In this research, low amount of Portland cement was added to a sand, and its beneficial shear strengthening effects were evaluated under a range of multiaxial stress paths. The influence of the orientation of the principal axes of stress and strain on the stress–strain response and failure of cemented sand has only been scarcely investigated. Therefore, this experimental investigation reports the results of a series of consolidated drained hollow cylinder torsional tests with constant principal stress path direction, ασ, varying from 0° to 90°. Results were compared with the shear behaviour of the uncemented sand tested under similar loading conditions. Results show that the addition of cement to the sand matrix increases the soil strength for all multiaxial stress path directions. The suitability of two multiaxial strength criteria for reproducing the shape of the failure envelope as a function of the orientation of principal stress axis ασ has also been analysed.

Influence of tunnel excavation on the magnitude and rotation angle of principal stress in surrounding rock

The stress disturbances induced by deep tunnel excavation are a key factor leading to the instability and failure of surrounding rock. To investigate the stress evolution in surrounding rock, this study utilizes a physical simulation system for deep caverns to replicate the actual excavation process of tunnels. The study quantitatively analyzes changes in the magnitude and orientation of surrounding rock stresses, and validates the experimental results through numerical analysis. The study revealed that: (1) In elasto-plastic tests, the trajectories of the principal stress axes at the vault and bottom are symmetrical about the XZ plane, whereas in elastic tests, they exhibit symmetry about the origin. (2) The experimental and numerical simulation results of the principal stress axis evolution at four key monitoring points (vault, shoulder, waist, and bottom) are consistent. Using FLAC3D, the regions between these points were further divided, identifying seven distinct regions of surrounding rock, each characterized primarily by one of the four representative patterns, with the shoulder region acting as a transitional zone. (3) Regardless of whether the surrounding rock is in an elastic or elasto-plastic state, the evolution of the principal stress magnitudes and their angles with the coordinate axes remained entirely consistent.

The Association Between Obesity, Chronic Inflammation, Metabolic Disorders and Mood Disorders Among Patients up to 12 Months After Hospitalization for SARS-CoV-2.

The relationship between BMI, inflammation, and mental health is complex. A high BMI, especially obesity, is associated with chronic inflammation, which can lead to mental disorders such as depression. Inflammatory cytokines affect neurotransmitters and the stress axis, worsening mental health. Obesity and mental disorders can mutually reinforce each other. New findings show that inflammation can lead to neurobiological changes, and the gut microbiota may play a key role. Obesity has been implicated as a factor in the high mortality and duration of influenza-like illnesses, even in people who do not have other chronic diseases that may increase the risk of complications. The aim of this study was to determine the associations between BMI and chronic inflammation, metabolic disorders, depression, and anxiety in patients hospitalized with COVID-19 up to 12 months after hospitalization. The study included 248 participants previously hospitalized for SARS-CoV-2 infection up to 12 months after hospitalization. The study was conducted in a multistage design using a diagnostic survey, anthropometric measurements, and laboratory methods. A statistically significantly higher BDI-II score was observed among women. Statistical analysis showed a statistically significant higher GAD-7 score among women and those over 75 years of age. Higher BMI among subjects is often associated with elevated values of inflammatory markers and immune cells, such as WBC, neutrophils, monocytes, and CRP, as well as higher blood glucose levels. These associations may be related to the chronic inflammation and metabolic disorders that often accompany obesity. Lymphocytes and eosinophils may show more varied relationships depending on individual factors and specific health conditions. It is therefore important to continue research in this area.

Freshwater habitat invaders: Impacts on artificial flow refuge use by native fish under pulsed flows

Flow regulation and the spread of invasive species are significant threats to freshwater biodiversity, including native fish communities in rivers across the globe. The bleak (Alburnus alburnus), an invasive fish currently widespread throughout the main rivers of the Iberian Peninsula, threatens native fish biodiversity, mostly via trophic competition and hybridisation. In this study, we assessed the impacts of bleak presence and rapid flow fluctuations (both main and interactive effects) on the use of artificial habitats (a flow refuge) and the stress physiology of barbels. We examined how bleak's presence influenced the selection of flow refuges by the native Iberian barbel (Luciobarbus bocagei) under base (continuous 7 L s−1 flow stimulus) and pulsed (7 L s−1 to a 60 L s−1 pulse) flows in an indoor flume. We quantified habitat use within three specific regions of two installed flow refuges and two physiological responses (glucose and lactate) associated with the stress axis. The results indicated that the presence of bleak significantly reduced flow refuge use by barbels and this effect was more prominent during pulsed flows. Additionally, barbels exhibited higher levels of glucose and lactate in the presence of bleaks. These results show that bleaks compete with barbels for habitat under fluctuating flows and induce physiological adjustments that may reduce the ability of barbels to find low-velocity areas to shelter. Overall, the bleaks had a competitive advantage under high flow variability. This underscores the need for further studies and effective management strategies to protect native freshwater fish communities in the context of biological invasions and anthropogenic flow variability.

Long-term, Dynamic Remodelling of the Corticotroph Transcriptome and Excitability After a Period of Chronic Stress.

Chronic stress results in long-term dynamic changes at multiple levels of the hypothalamic-pituitary-adrenal (HPA) axis resulting in stress axis dysregulation with long-term impacts on human and animal health. However, the underlying mechanisms and dynamics of altered of HPA axis function, in particular at the level of pituitary corticotrophs, during a period of chronic stress and in the weeks after its cessation (defined as "recovery") are very poorly understood. Here, we address the fundamental question of how a period of chronic stress results in altered anterior pituitary corticotroph function and whether this persists in recovery, as well as the transcriptomic changes underlying this. We demonstrate that, in mice, spontaneous and corticotrophin-releasing hormone-stimulated electrical excitability of corticotrophs, essential for ACTH secretion, is suppressed for weeks to months of recovery following a period of chronic stress. Surprisingly, there are only modest changes in the corticotroph transcriptome during the period of stress, but major alterations occur in recovery. Importantly, although transcriptional changes for a large proportion of mRNAs follow the time course suppression of corticotroph excitability, many other genes display highly dynamic transcriptional changes with distinct time courses throughout recovery. Taken together, this suggests that chronic stress results in complex dynamic transcriptional and functional changes in corticotroph physiology, which are highly dynamic for weeks following cessation of chronic stress. These insights provide a fundamental new framework to further understand underlying molecular mechanisms as well approaches to both diagnosis and treatment of stress-related dysfunction of the HPA axis.

Crustal stress near the Yakutat microplate collision from probabilistic earthquake focal mechanisms

Earthquake source characteristics provide a valuable constraint on crustal stress and regional plate tectonics. Earthquake source studies in Yukon and northern British Columbia have been limited by sparse seismic network coverage. In this work, we leverage recent seismic network improvements to estimate focal mechanisms for small and moderate-magnitude (M>2.0) earthquakes from P-wave first-motion polarity data. We invert these data within a probabilistic framework to rigorously quantify mechanism uncertainties. Subsequently, probabilistic earthquake focal mechanisms are used as input for inversions for the orientation of principal stress axes, and stress shape ratio, for spatial windows throughout the region. We implement a novel, data-driven approach to propagate focal mechanism uncertainty in stress inversion. Our results improve the spatial coverage of existing earthquake focal mechanisms and enable an orogenic-scale study of crustal stress near the Yakutat-North America collision. Overall, the region is characterized by a transpressive stress regime. Maximum horizontal compressive stress orientations exhibit a pattern orthogonal to the Yakutat collision syntaxis. Stress inversion results also reveal an abrupt change in orientation east-to-west, which we interpret as a change in stress regime across the Fairweather-Connector-Totschunda fault system that is likely related to coupling between the subducting Yakutat slab and North America. This work improves our understanding of potential earthquake hazards in southwestern Yukon and the surrounding region.

Comparative targeted lipidomics between serum and cerebrospinal fluid of multiple sclerosis patients shows sex and age-specific differences of endocannabinoids and glucocorticoids

Multiple sclerosis (MS) is a complex chronic neuroinflammatory disease characterized by demyelination leading to neuronal dysfunction and neurodegeneration manifested by various neurological impairments. The endocannabinoid system (ECS) is a lipid signalling network, which plays multiple roles in the central nervous system and the periphery, including synaptic signal transmission and modulation of inflammation. The ECS has been identified as a potential target for the development of novel therapeutic interventions in MS patients. It remains unclear whether ECS-associated metabolites are changed in MS and could serve as biomarkers in blood or cerebrospinal fluid (CSF). In this retrospective study we applied targeted lipidomics to matching CSF and serum samples of 74 MS and 80 non-neuroinflammatory control patients. We found that MS-associated lipidomic changes overall did not coincide between CSF and serum. While glucocorticoids correlated positively, only the endocannabinoid (eCB) 2-arachidonoyl glycerol (2-AG) showed a weak positive correlation (r = 0.3, p < 0.05) between CSF and serum. Peptide endocannabinoids could be quantified for the first time in CSF but did not differ between MS and controls. MS patients showed elevated levels of prostaglandin E2 and steaorylethanolamide in serum, and 2-oleoylglycerol and cortisol in CSF. Sex-specific differences were found in CSF of MS patients showing increased levels of 2-AG and glucocorticoids in males only. Overall, arachidonic acid was elevated in CSF of males. Interestingly, CSF eCBs correlated positively with age only in the control patients due to the increased levels of eCBs in young relapsing-remitting MS patients. Our findings reveal significant discrepancies between CSF and serum, underscoring that measuring eCBs in blood matrices is not optimal for detecting MS-associated changes in the central nervous system. The identified sex and age-specific changes of analytes of the stress axis and ECS specifically in the CSF of MS patients supports the role of the ECS in MS and may be relevant for drug development strategies.

Cell structure development during cyclic deformation of near-[001] and near-[011] copper single crystals

Dislocation cell structures significantly influence the fatigue failure process. Research on the cell structures in multiple-slip-oriented copper single crystals has focused primarily on the [1‾11] orientation, whereas formation mechanisms and development processes of cell structures in [001] and [011] copper single crystals remain unclear. Therefore, this study examines the dislocation structures of near-[001] and near-[011] copper single crystals under cyclic deformation at high strain amplitudes. The cyclic stress–strain curve of the [011] crystals showed a distinct plateau at plastic shear strain amplitudes ≤7.5 × 10−3. In the plateau region, the dislocation structures consisted of cell structures along the (111) primary slip plane and matrix wall structures. Furthermore, (111) cell structures were formed in the single-slip deformation bands (DBs). After the plateau region, several types of new DBs could be observed due to the activation of multiple-slip systems. Multiple-slip DBs have a higher degree of plastic strain concentration than single-slip DBs, leading to the preferential formation of cell structures. For the near-[001] crystals, (111) cell structures were uniformly formed throughout the matrix, without the formation of DBs. The formation mechanism of the (111) cell boundary was independent of the stress axis and resulted from the interaction between the primary and coplanar slip systems.