Inhibition Of Function Research Articles

Suppressive effect of resveratrol, catechin and their conformationally constrained analogs on neutrophil extracellular trap formation by HL-60-derived neutrophils.

Neutrophil extracellular trap (NET) formation is a unique self-defense mechanism of neutrophils; however, it is also involved in many diseases, including atherosclerosis. Resveratrol and catechin are antioxidants with anti-atherosclerotic properties. Here, we examined the effects of resveratrol, catechin, and other related compounds on NET formation. HL-60-derived neutrophils were pretreated with resveratrol and other compounds before stimulation with phorbol-myristate acetate (PMA). DNA and myeloperoxidase released from neutrophils were determined. Resveratrol suppressed the DNA release from neutrophils in a dose-dependent manner. NET formation was enhanced by 1-palmitoyl-2-oxovaleroyl phosphatidylcholine (POVPC), a truncated form of oxidized phospholipid, and resveratrol suppressed NET formation induced by POVPC and PMA. Furthermore, we designed several analogs of resveratrol or catechin whose conformation was restricted by the inhibition of the free rotation of aromatic rings. The conformationally constrained analogs were more effective at inhibiting NET formation; however, their inhibitory function decreased when compound was a large, hydrophobic analog. The most potent compounds, planar catechin and resveratrol, suppressed myeloperoxidase release from activated neutrophils. In addition, these compounds suppressed DNA release from neutrophils stimulated with calcium ionophore. These results suggest that resveratrol, catechin and their analogs exert anti-NET effects, and that constraining the geometry of these compounds enhanced their inhibitory effects.

Examining short interval intracortical inhibition with different transcranial magnetic stimulation-induced current directions in ALS

ObjectiveTo establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker. MethodsThreshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex. ResultsAt group level, SICI3ms-PA (AUROC = 0.7), SICI3ms-AP (AUROC = 0.8) and SICI1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICIPA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI3ms-AP alone. SICI3ms-AP and SICI3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI1ms-PA and SICI3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI3ms-PA were not those with the lowest SICI3ms-AP. ICF was similar between groups (AUROC = 0.50). ConclusionsSICIPA and SICIAP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS. SignificanceExamining both SICIPA and SICIAP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS.

Investigation of the relationship between neuroplasticity and grapheme-color synesthesia.

Grapheme-color synesthesia is a normal and healthy variation of human perception. It is characterized by the association of letters or numbers with color perceptions. The etiology of synesthesia is not yet fully understood. Theories include hyperconnectivity in the brain, cross-activation of adjacent or functionally proximate sensory areas of the brain, or various models of lack of inhibitory function in the brain. The growth factor brain-derived neurotrophic (BDNF) plays an important role in the development of neurons, neuronal pathways, and synapses, as well as in the protection of existing neurons in both the central and peripheral nervous systems. ELISA methods were used to compare BDNF serum concentrations between healthy test subjects with and without grapheme-color synesthesia to establish a connection between concentration and the occurrence of synesthesia. The results showed that grapheme-color synesthetes had an increased BDNF serum level compared to the matched control group. Increased levels of BDNF can enhance the brain's ability to adapt to changing environmental conditions, injuries, or experiences, resulting in positive effects. It is discussed whether the integration of sensory information is associated with or results from increased neuroplasticity. The parallels between neurodegeneration and brain regeneration lead to the conclusion that synesthesia, in the sense of an advanced state of consciousness, is in some cases a more differentiated development of the brain rather than a relic of early childhood.

Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess.

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

Characteristics of Visual Cognition in Patients with Anoxic Encephalopathy: An Eye-tracking Study.

: Despite the frequent occurrence of visual cognitive impairment after anoxic encephalopathy, only a few studies have analyzed gaze movements following encephalopathy. This study determined the visual cognitive characteristics of patients with anoxic encephalopathy using an eye-tracking system. : This study included ten patients with anoxic encephalopathy and ten age/sex-matched controls. Factors for anoxic encephalopathy onset and brain imaging findings were extracted from medical records. An eye-tracking system was used to track eye movements during three visual search tasks (pop-out, serial search, and saliency) in patient and healthy control groups. The average target search time, number of saccades, and number of fixations to salient stimuli were compared. : Stagnant blood flow, observed in six of ten patients, was the most common cause of disease onset, four of whom exhibited hypoperfusion in bilateral occipital or parietal lobes on single-photon emission computed tomography. The patient group required longer search times during all visual search tasks and a higher number of saccades during pop-out and serial search tasks. However, no significant difference was observed between the two groups for the number of fixations to salient stimuli during the saliency task. : Following anoxic encephalopathy, bottom-up (pop-out task) and top-down (serial search task) gaze control were considered impaired because of extensive parieto-occipital lobe damage after blood flow stagnation. Patients exhibited reduced top-down function for finding targets (serial search task) but relatively retain inhibitory function for salient stimuli (saliency task). Gaze analysis can be used to reveal the clinical characteristics of anoxic encephalopathy.

Effect of home-based transcranial direct current stimulation combined with nutritional counseling therapy on binge eating disorder symptoms: A randomized pilot trial.

To examine the effect of nutritional counseling therapy (NCT) combined with transcranial direct current stimulation (tDCS) on Binge Eating Disorder (BED) symptoms. 40 women with BED were randomly (ratio of 2:2:2) allocated to one of the groups: active tDCS (a-tDCS), NCT, sham tDCS (s-tDCS) with NCT, and a-tDCS with NCT. Home-based tDCS was applied to the dorsolateral prefrontal cortex for 28 sessions. A mixed analysis of variance showed no main effect between groups or a time × group interaction. However, a significant main effect was found for time on the primary outcome: Binge Eating Scale (p = 0.001; eta2p= 0.325), which tended to decrease during treatment and follow-up. A significant main effect was found on the secondary outcome: short-interval intracortical inhibition (SICI) (p = 0.02; eta2p= 0.112), a measure of inhibitory function, which increased from baseline to the final period in the a-tDCS group, without significant differences between groups. These findings reveal that the combined therapy did not have a synergic effect on BED symptoms. Since this is a pilot study and this is a promising area, we provide data to plan future larger-scale studies investigating the effects of tDCS and behavioral interventions in BED treatment.

Controlling corrosion protection of mild steel in acidic environment via environmentally benign organic inhibitor

The current research employed electrochemical techniques to evaluate a green corrosion inhibitor Subphthalocyanine chloride (SubPc) to control the corrosion mitigation of mild steel in acidic environments. The corrosion rates and hydrogen evolution rates were measured by weight loss. The inhibitor was found to be highly effective with a corrosion-inhibiting efficiency up to 97.6% at a concentration of 150 ppm in 1 M HCl solution loaded with synthesized (SubPc) through variable concentrations. According to the obtained information from the polarization technique, the corrosion current density, icorr, decreases with increasing the concentration levels of (SubPcs) inhibitors in 1 M HCl medium. The inhibition mechanism of mild steel has been suggested as well as its excess surface charge was determined employing electrochemical impedance spectroscopy (EIS). The results suggest that the inhibitory functions by forming a protective barrier on the steel surface, hindering the corrosion process. The present study provides a new insight into developing eco-friendly and cost-effective corrosion inhibitor to protect mild steel from acidic corrosion.

Kinetic and thermodynamic parameters of curcumin in edible oils with different degrees of unsaturation

The antioxidant activity of curcumin (0.02-0.1%) was evaluated in olive, sesame, and safflower oils at 373, 383, and 393 K. The results were examined in contrast to the effects of tocopherol (0.1%) and BHT (0.02%), so that the inhibitory function of curcumin was evaluated comparatively. The activation energy of oxidation was determined for olive (82.94 kJ·mol-1), sesame (77.39 kJ·mol-1) and safflower oils (74.42 kJ·mol-1). Adding curcumin (0.1%) enhanced the activation energy by 26.26, 26.64, and 38.81% in the case of olive, safflower, and sesame oils, respectively. Based on Gibbs free energy, curcumin functioned more effectively in olive oil at 373 K (growth coefficient: 1.52%), compared to the action of the other two antioxidants, namely tocopherol (1.43%) and BHT (1.39%). The efficiency of curcumin was lower in oils which had a higher degree of polyunsaturation due to the disproportionation of the hydrogen-donating mechanism and the rate of free-radical formation in these oils.

CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions.

CD4 and LAG-3 are related molecules that are receptors for MHC class II molecules. Their major functional differences are situated in their cytoplasmic tails, in which CD4 has an activation motif and LAG-3 an inhibitory motif. Here, we identify shark LAG-3 and show that a previously identified shark CD4-like gene has a genomic location, expression pattern, and motifs similar to CD4 in other vertebrates. In nurse shark (Ginglymostoma cirratum) and cloudy catshark (Scyliorhinus torazame), the highest CD4 expression was consistently found in the thymus whereas such was not the case for LAG-3. Throughout jawed vertebrates, the CD4 cytoplasmic tail possesses a Cx(C/H) motif for binding kinase LCK, and the LAG-3 cytoplasmic tail possesses (F/Y)xxL(D/E) including the previously determined FxxL inhibitory motif resembling an immunoreceptor tyrosine-based inhibition motif (ITIM). On the other hand, the acidic end of the mammalian LAG-3 cytoplasmic tail, which is believed to have an inhibitory function as well, was acquired later in evolution. The present study also identified CD4-1, CD4-2, and LAG-3 in the primitive ray-finned fishes bichirs, sturgeons, and gars, and experimentally determined these sequences for sterlet sturgeon (Acipenser ruthenus). Therefore, with CD4-1 and CD4-2 already known in teleosts (modern ray-finned fish), these two CD4 lineages have now been found within all major clades of ray-finned fish. Although different from each other, the cytoplasmic tails of ray-finned fish CD4-1 and chondrichthyan CD4 not only contain the Cx(C/H) motif but also an additional highly conserved motif which we expect to confer a function. Thus, although restricted to some species and gene copies, in evolution both CD4 and LAG-3 molecules appear to have acquired functional motifs besides their canonical Cx(C/H) and ITIM-like motifs, respectively. The presence of CD4 and LAG-3 molecules with seemingly opposing functions from the level of sharks, the oldest living vertebrates with a human-like adaptive immune system, underlines their importance for the jawed vertebrate immune system. It also emphasizes the general need of the immune system to always find a balance, leading to trade-offs, between activating and inhibiting processes.

Nanobodies as negative allosteric modulators for human calcium sensing receptor

Human calcium sensing receptor (CaSR) senses calcium ion concentrations in vivo and is an important class of drug targets. Mutations in the receptor can lead to disorders of calcium homeostasis, including hypercalcemia and hypocalcemia. Here, 127 CaSR-targeted nanobodies were generated from camels, and four nanobodies with inhibitory function were further identified. Among these nanobodies, NB32 can effectively inhibit the mobilization of intracellular calcium ions (Ca2+i) and suppress the G12/13 and ERK1/2 signaling pathways downstream of CaSR. Moreover, it enhanced the inhibitory effect of the calcilytics as a negative allosteric modulator (NAM). We determined the structure of complex and found NB32 bound to LB2 (Ligand-binding 2) domain of CaSR to prevent the interaction of LB2 domains of two protomers to stabilize the inactive state of CaSR.

Eupatilin ameliorates postmenopausal osteoporosis via elevating microRNA-211-5p and repressing JAK2/STAT3 pathway.

Postmenopausal osteoporosis (PMOP) poses a significant threat to women's health worldwide. Eupatilin is a key bioactive component of the Chinese herbal medicine Artemisia asiatica Nakai. Recent research reports have proved the inhibitory function of Eupatilin in many diseases. MicroRNAs (miRNAs) are 21-23 nucleotide-long, single-stranded, noncoding RNA molecules generated endogenously, and many studies have indicated that miRNAs are involved in the development of osteoporosis. This study explored the role and potential mechanism of Eupatilin underlying PMOP. First, rats were given intragastric administration of Eupatilin every day and subcutaneous injections of oligonucleotides or plasmids that interfered with miR-211-5p or janus kinase 2 (JAK2) once a week. After 4 weeks, the PMOP rat model was established. Then, serum alkaline phosphatase, calcium, and phosphorus levels, as well as femur bone mineral density and biomechanical parameters, were detected. Hematoxylin-eosin staining and Masson staining were applied for detecting the pathological condition of femur, and immunohistochemical staining was for detecting osteocalcin. MC3T3-E1 cells were transfected with plasmid vectors interfering with miR-211-5p or JAK2; and cell viability, lactate dehydrogenase cytotoxicity, and cell mineralization were subsequently examined. The relationship between miR-211-5p and JAK2/signal transducer and activator of transcription 3 (STAT3) pathway was analyzed. The targeting relation between miR-211-5p and JAK2 was also verified. The experimental results revealed that Eupatilin improved the pathological conditions of PMOP rats by promoting the proliferation and mineralization of osteoblasts. MiR-211-5p was down-regulated and JAK2/STAT3 was upregulated in PMOP rats. Upregulation of miR-211-5p further improved the pathological conditions of PMOP rats based on Eupatilin treatment. MiR-211-5p inhibited the JAK2/STAT3 pathway. JAK2 offset the effects of elevated miR-211-5p on PMOP rats. Overall, Eupatilin attenuates PMOP through elevating miR-211-5p and repressing JAK2/STAT3 pathway, which suggests the utility of Eupatilin as a potential drug for POMP treatment.

Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation

Cyclic GMP–AMP synthase (cGAS), initially identified as a cytosolic DNA sensor, detects DNA fragments to trigger an innate immune response. Recently, accumulating evidence reveals the presence of cGAS within the nucleus. However, the biological functions of nuclear cGAS are not fully understood. Here, we demonstrate that nuclear cGAS represses LINE-1 (L1) retrotransposition to preserve genome integrity in human cells. Mechanistically, the E3 ligase TRIM41 interacts with and ubiquitinates ORF2p to influence its stability, and cGAS enhances the association of ORF2p with TRIM41, thereby promoting TRIM41-mediated ORF2p degradation and the suppression of L1 retrotransposition. In response to DNA damage, cGAS is phosphorylated at serine residues 120 and 305 by CHK2, which promotes cGAS-TRIM41 association, facilitating TRIM41-mediated ORF2p degradation. Moreover, we show that nuclear cGAS mediates the repression of L1 retrotransposition in senescent cells induced by DNA damage agents. We also identify several cancer-associated cGAS mutations that abolish the suppressive effect on L1 retrotransposition by disrupting the CHK2-cGAS-TRIM41-ORF2p regulatory axis. Together, these findings indicate that nuclear cGAS exhibits an inhibitory function in L1 retrotransposition which could provide avenues for future interventions in both aging and tumorigenesis.

Circular RNA circXPO1 Promotes Multiple Myeloma Progression by Regulating miR-495-3p/DNA Damage-Induced Transcription 4 Axis.

Multiple myeloma (MM) is a hematologic malignancy that results from uncontrolled plasma cell proliferation. Circular RNAs are versatile regulators that influence cancer aggression. The pathogenic mechanism of circXPO1 in MM is still unknown. In this study, the expression of circXPO1, miR-495-3p, and DNA damage-induced transcription 4 (DDIT4) was detected. Knockdown and overexpression assays were used to evaluate the effect of circXPO1 on MM. Specifically, 5-ethynyl-2'-deoxyuridine and cell counting kit-8 assay were used to investigate cell proliferation. Meanwhile, flow cytometry was adopted to detect cell apoptosis and cell cycle. Apoptosis-associated and cell cycle-related proteins were detected by Western blot. Mechanistically, biotin RNA pull-down assay and dual-luciferase assay were implemented to verify the combination among miR495-3p and circXPO1 or DDIT4. The function of circXPO1 in vivo was explored in xenograft experiments. The results showed that circXPO1 was up-regulated in both MM samples and MM cell lines and miR-495-3p was down-regulated in MM patients. Silencing circXPO1 inhibited cell proliferation, increased apoptosis rates, and caused the G1 phase arrest. Overexpression of circXPO1 yielded opposite results. In addition, RNA pull-down experiment demonstrated the interaction between circXPO1 and miR-495-3p. Silencing miR-495-3p rescued the inhibitory function caused by the knockdown of circXPO1. DDIT4 was the target of miR-495-3p. Finally, silencing circXPO1 inhibited the growth of subcutaneous tumors in vivo. In conclusion, our findings showed that circXPO1 could promote MM progression via the miR-495-3p/DDIT4 axis.

Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury.

The inhibitory function of GABA at the spinal level and its central modulation in the brain are essential for pain perception. However, in post-surgical pain, the exact mechanism and modes of action of GABAergic transmission have been poorly studied. This work aimed to investigate GABA synthesis and uptake in the incisional pain model in a time-dependent manner. Here, we combined assays for mechanical and heat stimuli-induced withdrawal reflexes with video-based assessments and assays for non-evoked (NEP, guarding of affected hind paw) and movement-evoked (MEP, gait pattern) pain-related behaviors in a plantar incision model in male rats to phenotype the effects of the inhibition of the GABA transporter (GAT-1), using a specific antagonist (NO711). Further, we determined the expression profile of spinal dorsal horn GAT-1 and glutamate decarboxylase 65/67 (GAD65/67) by protein expression analyses at four time points post-incision. Four hours after incision, we detected an evoked pain phenotype (mechanical, heat and movement), which transiently ameliorated dose-dependently following spinal inhibition of GAT-1. However, the NEP-phenotype was not affected. Four hours after incision, GAT-1 expression was significantly increased, whereas GAD67 expression was significantly reduced. Our data suggest that GAT-1 plays a role in balancing spinal GABAergic signaling in the spinal dorsal horn shortly after incision, resulting in the evoked pain phenotype. Increased GAT-1 expression leads to increased GABA uptake from the synaptic cleft and reduces tonic GABAergic inhibition at the post-synapse. Inhibition of GAT-1 transiently reversed this imbalance and ameliorated the evoked pain phenotype.

Synergistic effects of immune checkpoints and checkpoint inhibitors in inflammatory neuropathies: Implications and mechanisms.

Immune checkpoint molecules play pivotal roles in the regulation of immune homeostasis. Disruption of the immune checkpoints causes autoimmune/inflammatory as well as malignant disorders. Over the past few years, the immune checkpoint molecules with inhibitory function emerged as potential therapeutic targets in oncological conditions. The inhibition of the function of these molecules by using immune checkpoint inhibitors (ICIs) has brought paradigmatic changes in cancer therapy due to their remarkable clinical benefits, not only in improving the quality of life but also in prolonging the survival time of cancer patients. Unfortunately, the ICIs soon turned out to be a "double-edged sword" as the use of ICIs caused multiple immune-related adverse effects (irAEs). The development of inflammatory neuropathies such as Guillain-Barré syndrome (GBS) and Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) as the secondary effects of immunotherapy appeared very challenging as these conditions result in significant and often permanent disability. The underlying mechanism(s) through which ICIs trigger inflammatory neuropathies are currently not known. Compelling evidence suggests autoimmune reaction and/or inflammation as the independent risk mechanism of inflammatory neuropathies. There is a lack of understanding as to whether prior exposure to the risk factors of inflammatory neuropathies, the presence of germline genetic variants in immune function-related genes, genetic variations within immune checkpoint molecules, the existence of autoantibodies, and activated/memory T cells act as determining factors for ICI-induced inflammatory neuropathies. Herein, we highlight the available pieces of evidence, discuss the mechanistic basis, and propose a few testable hypotheses on inflammatory neuropathies as irAEs of immunotherapy.

Characterization of a R493X progranulin haploinsufficient knockin mouse model of frontotemporal dementia

AbstractBackgroundFrontotemporal dementia (FTD) is the second most common form of dementia in young individuals, characterized by impairments in social cognition, language processing and executive function. Heterozygous loss‐of‐function mutations in the progranulin gene (GRN) are well known as a major genetic cause of a TDP‐43‐positive subtype of FTD (FTD‐GRN). The role of progranulin in the pathogenesis of FTD is not fully understood but has been shown to be associated with lysosomal dysfunction, impaired neuronal survival, and neuroinflammation. Rodent models of FTD‐GRN have been extensively used to model disease pathophysiology, but most studies utilize mice null for GRN. Our lab recently published a comprehensive neuropathological and behavioural assessment of a GRN R493X homozygous mouse model, confirming several phenotypes relevant to human FTD.To our knowledge, haploinsufficient R493X mice have not previously been studied. Here we assessed whether haploinsufficient GRN 493X mice would demonstrate relevant phenotypes for FTD pathophysiologic studies and drug screening.MethodWe characterized behavioural and neuropathological phenotypes of aged GRN R493X+/‐, GRN R493X‐/‐ and age‐matched C57BL/6J wildtype mice. The open‐field test was used to assess anxiety phenotype. Brain lysosomal dysfunction was assessed by western blot, and neuroinflammation, including astrogliosis and microgliosis, as well as hippocampal and thalamic synaptic dysfunction were analyzed by immunohistochemistry.ResultAs expected, our preliminary data show a higher progranulin level in GRN R493X+/‐ mice in comparison with the homozygous GRN R493X mice. Behavioural data, as well as analysis of neuroinflammation, lysosomal dysfunction and brain excitatory and inhibitory synaptic function, are being analyzed and will be presented.ConclusionHeterozygous GRN R493X mice more closely resemble the human genetic condition. Our characterization and comparison of neuropathologic phenotypes in aged GRN R493X+/‐ and GRN R493X‐/‐ mice provide insights into the molecular mechanisms underlying the effects of GRN haploinsufficiency and the suitability of this model for drug screening studies in FTD‐GRN.

Neuronal hyperexcitability in AD

AbstractBackgroundBecause neuronal and network deficits are the imperative immediate consequences of pathological changes of disease mechanisms, neurophysiological manifestations associated with Aβ and tau are uniquely positioned to demonstrate the abnormal homeostatic and maladaptive circuit alterations and the dynamic integrated effects of underlying genetics and neuropathological changes in Alzheimer’s disease (AD). Importantly, network dysfunction manifesting as abnormal hyper‐ as well as hypo‐active oscillatory brain rhythms is detectable even during the prodromal phase of disease. Here we leveraged the higher spatial and precise temporal resolution of Magnetoencephalography (MEG) to define frequency‐specific and region‐dependent patterns of oscillatory deficits in AD patients, and to demonstrate the earliest neurophysiological abnormalities associated with AD neuropathology and their mechanistic relationships to network hyperexcitability.MethodWe studied the resting brain oscillations in individuals with AD‐spectrum (n = 88) and age‐matched controls (n = 70) using MEG. In addition, subsets of participants were evaluated with positron emission tomography (PET) with Aβ and tau specific tracers and fluid biomarker including plasma P‐tau181 and Neuro‐Filament‐Light (NFL). We used statistical mixed models to investigate the associations between neural oscillations and pathology. We used a linear Neural‐Mass‐Model (NMM) in combination with empirical MEG spectra to derive the excitatory‐to‐inhibitory activity within neuronal subpopulations in AD patients. Based on standard neurophysiological monitoring we determined clinical evidence of hyperexcitability as AD with and without epileptiform activity (AD‐EPI+; AD‐EPI‐).ResultWhile increase and decrease of oscillatory activity are distinctly associated Aβ and tau, respectively, the characteristic frequency‐specific manifestation in AD was increased spectral signature within delta‐theta (2‐7Hz) and reduced spectral signature within alpha (8‐12Hz). Earliest spectral changes were detected in Aβ+ cognitively unimpaired and the increased spectral signature associated with Aβ was replicated in identical associations with plasma p‐tau181. The presence of APO‐E4 allele strengthened these associations. NMM demonstrated greater excitatory‐inhibitory‐activity in AD‐EPI+ vs. AD‐EPI‐ while these were specifically correlated with the reduced alpha spectrum which was more profound in AD‐EPI+ as well as uniquely associated with increased tau depositions.ConclusionOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aβ, in patients with AD.

Early life adversity shapes social subordination and cell type-specific transcriptomic patterning in the ventral hippocampus.

Adverse events in early life can modulate the response to additional stressors later in life and increase the risk of developing psychiatric disorders. The underlying molecular mechanisms responsible for these effects remain unclear. Here, we uncover that early life adversity (ELA) in mice leads to social subordination. Using single-cell RNA sequencing (scRNA-seq), we identified cell type-specific changes in the transcriptional state of glutamatergic and GABAergic neurons in the ventral hippocampus of ELA mice after exposure to acute social stress in adulthood. These findings were reflected by an alteration in excitatory and inhibitory synaptic transmission induced by ELA in response to acute social stress. Finally, enhancing the inhibitory network function through transient diazepam treatment during an early developmental sensitive period reversed the ELA-induced social subordination. Collectively, this study significantly advances our understanding of the molecular, physiological, and behavioral alterations induced by ELA, uncovering a previously unknown cell type-specific vulnerability to ELA.

SPATIAL WORKING MEMORY IN PRODROMAL STAGE: AN EYE TRACKING STUDY

AbstractBackgroundIndividuals at ultra‐high risk for psychosis and bipolar disorder (UHR‐P and UHR‐BD) have shown cognitive abnormalities and sub‐threshold clinical features (de Paula et al., 2015; Metzler et al., 2014). Assessing saccadic eye movements is one of the useful methods for investigating high cognitive functions like spatial working memory and inhibition (Pierrot‐Deseilligny et al., 2005; Winograd‐Gurvich et al., 2008). Memory‐guided saccade (MGS) may be described as short‐term maintenance of attention both when a peripheral target is presented, and a delay screen. The purpose of this study was to examine the differences between clinical risk groups and healthy controls (HCs) based on the memory‐guided saccade.MethodThe study was included 33 UHR‐P (age: 21.61 ± 3.24), 28 UHR‐BD (age: 21.64 ± 4.02), and 28 HCs (age: 22.11 ± 4.03). Participants were selected from cases of clinical‐high‐risk criteria in interviews made with The Structured Interview of Psychosis Risk Syndromes and Bipolar Prodrome Symptom Interview and Scale. The memory‐guided saccade was measured with the number of the correct, incorrect, anticipatory and express saccades, also latency, peak velocity and amplitude for the correct saccades. Eye movement data were recorded from the right eye using an EyeLink 1000 Plus eye‐tracker. All results were analyzed with SPSS software.ResultThe anticipatory and express saccades in the cue screen, the anticipatory saccade in the delay screen and the total error response were significant between groups (p<0.05). There was a significant increase in UHR‐BD compared to controls in the error responses (p = 0.018). The anticipatory saccades in UHR‐BD were higher than in both UHR‐P and HC on the cue screen (p = 0.005 and p = 0.014), and controls on the delay screen (p = 0.027). In addition, the express saccades in the cue screen showed statistical differences between the risk groups (p = 0.032). ConclusionMemory‐guided saccades are used to assess the top‐down mechanism, including perceptual organization and goal‐directed behaviors, and are related to frontal lobe functions like spatial working memory and inhibitory control (Ostendorf et al., 2004). The elevation of incorrect saccades and predictive parameters like anticipatory saccades have indicated that individuals at the prodromal stage may appear spatial problems in inhibitory and exhibitory functions.

Antimicrobial effects of Arctium lappa against infectious bacteria: Experimental in vitro analysis

Arctium lappa (A. lappa) is one of the most significant edible medicinal plants with high antibacterial effects, in which it could be supposed to grow with more beneficial effects under administration by salicylic acid and chitosan based biofertilizers. Accordingly, the effects of salicylic acid, chitosan, and 50% moisture discharge were investigated in this work to see the antimicrobial treatments of some foodborne pathogens effects by A. lappa. To this aim, plants were cultivated based on different concentrations of salicylic acid and chitosan with/without drought stress, in which their extracted essential oils were examined for showing the antimicrobial effect against different bacterial agents. The results indicated that the salicylic acid and chitosan administrated A. lappa could work with improved inhibitory functions. Comparing with referenced antibiotics showed even higher antimicrobial effects of A. lappa against the targeted bacterial agents, in which the species with 14 mmol of salicylic acid and 2 g/l of chitosan was a distinguished one for approaching the purpose. Consequently, the achievements of this work could be further investigated for producing novel antibiotic drug agents.