Search

Brief beta bursts, rather than sustained oscillations, support cognition by providing transient, functional inhibition. Analyzing the timing of beta bursts helps establish neural correlates of cognitive behavior on a single trial level. The intermittent and nonlinear nature of beta bursts provides novel insights into interareal interactions. Diversity of beta burst types may reflect differences in circuit-level origins and may yield insights into the underlying activity motifs and function. We suggest that spatiotemporal patterns of beta bursting implement cognitive control operations underlying goal-directed behavior. Beta oscillations are linked to the control of goal-directed processing of sensory information and the timing of motor output. Recent evidence demonstrates they are not sustained but organized into intermittent high-power bursts mediating timely functional inhibition. This implies there is a considerable moment-to-moment variation in the neural dynamics supporting cognition. Beta bursts thus offer new opportunities for studying how sensory inputs are selectively processed, reshaped by inhibitory cognitive operations and ultimately result in motor actions. Recent method advances reveal diversity in beta bursts that provide deeper insights into their function and the underlying neural circuit activity motifs. We propose that brain-wide, spatiotemporal patterns of beta bursting reflect various cognitive operations and that their dynamics reveal nonlinear aspects of cortical processing. [ABSTRACT FROM AUTHOR]

Working memory (WM) enables the temporary storage of limited information and is a central component of higher order cognitive function. Irrelevant and/or distracting information can have a negative impact on WM processing and suppressing such incoming stimuli is critical to maintaining adequate performance. However, the neural mechanisms and dynamics underlying such distractor inhibition remain poorly understood. In the current study, we enrolled 46 healthy adults (Mage: 27.92, Nfemale: 28) who completed a Sternberg type WM task with high- and low-distractor conditions during magnetoencephalography (MEG). MEG data were transformed into the time-frequency domain and significant task-related oscillatory responses were imaged to identify the underlying anatomical areas. Whole-brain paired t-tests, with cluster-based permutation testing for multiple comparisons correction, were performed to assess differences between the low- and high-distractor conditions for each oscillatory response. Across conditions, we found strong alpha and beta oscillations (i.e., decreases relative to baseline) and increases in theta power throughout the encoding and maintenance periods. Whole-brain contrasts revealed significantly stronger alpha and beta oscillations in bilateral prefrontal regions during maintenance in high- compared to low-distractor trials, with the stronger beta oscillations being centered on the left dorsolateral prefrontal cortex and right inferior frontal gyrus, while those for alpha being within the right anterior prefrontal cortices and the right middle frontal gyrus. These findings suggest that alpha and beta oscillations in the bilateral prefrontal cortices play a major role in the inhibition of distracting information during WM maintenance. Our results also contribute to prior research on cognitive control and functional inhibition, in which prefrontal regions have been widely implicated.

Startle disease (SD) is characterized by enhanced startle responses, generalized muscle stiffness, unexpected falling, and fatal apnea episodes due to disturbed feedback inhibition in the spinal cord and brainstem of affected individuals. Mutations within the glycine receptor (GlyR) subunit and glycine transporter 2 (GlyT2) genes have been identified in individuals with SD. Impaired inhibitory neurotransmission in SD is due to pre- and/or postsynaptic GlyR or presynaptic GlyT2 dysfunctions. Previous research has focused on mutated GlyRs and GlyT2 that impair ion channel/transporter function or trafficking. With insights provided by recently solved cryo–electron microscopy and X-ray structures of GlyRs, a detailed picture of structural transitions important for receptor gating has emerged, allowing a deeper understanding of SD at the molecular level. Moreover, studies on novel SD mutations have demonstrated a higher complexity of SD, with identification of additional clinical signs and symptoms and interaction partners representing key players for fine-tuning synaptic processes. Although our knowledge has steadily improved during the last years, changes in synaptic localization and GlyR or GlyT2 homeostasis under disease conditions are not yet completely understood. Combined proteomics, interactomics, and high-resolution microscopy techniques are required to reveal alterations in receptor dynamics at the synaptic level under disease conditions. [ABSTRACT FROM AUTHOR]

• How distractors affect the oscillations serving working memory remains unclear. • We used MEG to examine neural responses during distractor inhibition in 46 adults. • Participants performed a working memory task with high/low distractor conditions. • Stronger prefrontal alpha/beta oscillations were observed during high distractors. • Alpha/beta oscillations in bilateral prefrontal cortices aid distractor inhibition. Working memory (WM) enables the temporary storage of limited information and is a central component of higher order cognitive function. Irrelevant and/or distracting information can have a negative impact on WM processing and suppressing such incoming stimuli is critical to maintaining adequate performance. However, the neural mechanisms and dynamics underlying such distractor inhibition remain poorly understood. In the current study, we enrolled 46 healthy adults (M age : 27.92, N female: 28) who completed a Sternberg type WM task with high- and low-distractor conditions during magnetoencephalography (MEG). MEG data were transformed into the time-frequency domain and significant task-related oscillatory responses were imaged to identify the underlying anatomical areas. Whole-brain paired t -tests, with cluster-based permutation testing for multiple comparisons correction, were performed to assess differences between the low- and high-distractor conditions for each oscillatory response. Across conditions, we found strong alpha and beta oscillations (i.e., decreases relative to baseline) and increases in theta power throughout the encoding and maintenance periods. Whole-brain contrasts revealed significantly stronger alpha and beta oscillations in bilateral prefrontal regions during maintenance in high- compared to low-distractor trials, with the stronger beta oscillations being centered on the left dorsolateral prefrontal cortex and right inferior frontal gyrus, while those for alpha being within the right anterior prefrontal cortices and the right middle frontal gyrus. These findings suggest that alpha and beta oscillations in the bilateral prefrontal cortices play a major role in the inhibition of distracting information during WM maintenance. Our results also contribute to prior research on cognitive control and functional inhibition, in which prefrontal regions have been widely implicated. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are one of the most successful and versatile protein-based pharmaceutical products used to treat multiple pathological conditions. The remarkable specificity of mAbs and their affinity for biological targets has led to the implementation of mAbs in the therapeutic regime of oncogenic, chronic inflammatory, cardiovascular, and infectious diseases. Thus, the discovery of novel mAbs with defined functional activities is of crucial importance to expand our ability to address current and future clinical challenges. In vitro, antigen-driven affinity selection employing phage display biopanning is a commonly used technique to isolate mAbs. The success of biopanning is dependent on the quality and the presentation format of the antigen, which is critical when isolating mAbs against membrane protein targets. Here, we provide a comprehensive investigation of two established panning strategies, surface-tethering of a recombinant extracellular domain and cell-based biopanning, to examine the impact of antigen presentation on selection outcomes with regards to the isolation of positive mAbs with functional potential against a proof-of-concept type I cell surface receptor. Based on the higher sequence diversity of the resulting antibody repertoire, presentation of a type I membrane protein in soluble form was more advantageous over presentation in cell-based format. Our results will contribute to inform and guide future antibody discovery campaigns against cell surface proteins. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit‐containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit‐containing receptor subtypes. Experimental Approach Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5‐subunits. Based on a chlorpromazine binding site observed in a GABA‐gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes. [ABSTRACT FROM AUTHOR]

To make sense of ambiguous and, at times, fragmentary sensory input, the brain must rely on a process of active interpretation. At any given moment, only one of several possible perceptual representations prevails in our conscious experience. Our hypothesis is that the competition between alternative representations induces a pattern of neural activation resembling cognitive conflict, eventually leading to fluctuations between different perceptual outcomes in the case of steep competition. To test this hypothesis, we probed changes in perceptual awareness between competing images using binocular rivalry. We drew our predictions from the conflict monitoring theory, which holds that cognitive control is invoked by the detection of conflict during information processing. Our results show that fronto‐medial theta oscillations (5–7 Hz), an established electroencephalography (EEG) marker of conflict, increases right before perceptual alternations and decreases thereafter, suggesting that conflict monitoring occurs during perceptual competition. Furthermore, to investigate conflict resolution via attentional engagement, we looked for a neural marker of perceptual switches as by parieto‐occipital alpha oscillations (8–12 Hz). The power of parieto‐occipital alpha displayed an inverse pattern to that of fronto‐medial theta, reflecting periods of high interocular inhibition during stable perception, and low inhibition around moments of perceptual change. Our findings aim to elucidate the relationship between conflict monitoring mechanisms and perceptual awareness. [ABSTRACT FROM AUTHOR]

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70-150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7-14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function. [ABSTRACT FROM AUTHOR]

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasia characterized by the presence of the Philadelphia (Ph) chromosome in hematopoietic cells (HCs). As one of the most important components of the bone marrow microenvironment (BMM), bone mesenchymal stromal cells (BMSCs) are critical in the development of leukemia and essential in the regulation of hematopoiesis. However, little is known regarding the alterations of BMSCs in CML. The current study performed Cell Counting Kit-8 and colony-forming unit fibroblast assays to evaluate the proliferative ability of BMSCs. The percentage of senescent BMSCs was evaluated by a senescence-associated β-galactosidase staining assay. Subsequently, a long-term culture-initiating cell assay was designed to explore the HC-supporting capacity of the BMSCs. Furthermore, cytogenetics were detected by conventional cytogenetic analysis and fluorescence in situ hybridization analysis. The current results revealed that CML-BMSCs exhibited decreased cell proliferation and impaired HC-support capacity, as well as increased susceptibility to senescence. No chromosomal aberrations, including the absence of the Ph chromosome, were noted in all CML-BMSCs. In conclusion, the current study demonstrated functional inhibition of CML-BMSCs; however, no signs of chromosomal aberrations were observed, thereby providing insight into the changes occurring in the CML-BMM. [ABSTRACT FROM AUTHOR]

As a frequently used neonicotinoid insecticide, imidacloprid can impair the chemoreceptive behavior of honey bees even at sublethal doses, while the physiochemical mechanism has not been further revealed. Here, multiple fluorescence spectra, thermodynamic method, and molecular docking were used to study the interaction and the functional inhibition of imidacloprid to the recombinant CSP1 protein in Asian honey bee, Apis cerana . The results showed that the fluorescence intensity (λ em = 332 nm) of CSP1 could be significantly quenched by imidacloprid in a dynamic mode. During the quenching process, Δ H > 0, Δ S > 0, indicating that the acting forces of imidacloprid with CSP1 are mainly hydrophobic interactions. Synchronous fluorescence showed that the fluorescence of CSP1 was mainly derived from tryptophan, and the hydrophobicity of tryptophan decreased with the increase of imidacloprid concentration. Molecular docking predicted the optimal pose and the amino acid composition of the binding process. Circular dichroism (CD) spectra showed that imidacloprid reduced the α-helix of CSP1 and caused the extension of the CSP1 peptide chain. In addition, the binding of CSP1 to floral scent β-ionone was inhibited by nearly 50% of the apparent association constant ( K A ) in the presence of 0.28–2.53 ng/bee of imidacloprid, and the inhibition rate of nearly 95% at 3.75 ng/bee of imidacloprid at sublethal dose level. This study initially revealed the molecular physiochemical mechanism that sublethal doses of neonicotinoid still interact and inhibit the physiological function of the honey bees' chemoreceptive system. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of basal ganglia has become a frequently performed surgery in patients with advanced Parkinson's disease. Throughout the years, this technique has reached advances in imaging techniques, neurophysiological recording possibilities, and in hardware and software technology. Nevertheless, to reach optimal results of DBS therapy, a number of aspects must be carefully considered. In current paper, overview of DBS procedure is provided with special focus on complications of this, an even so ever more promising therapeutic approach. [ABSTRACT FROM AUTHOR]

Although chemical inhibition of the DNA damage response (DDR) in cancer cells triggers cell death, it is not clear if the fork blockade achieved with inhibitors that neutralise proteins of the replisome is sufficient on its own to overcome the DDR. Monoclonal antibodies to PCNA, which block the DNA elongation process in vitro , have been developed. When these antibodies were transduced into cancer cells, they are able to inhibit the incorporation of nucleoside analogues. When co-delivered with anti-PCNA siRNA, the cells were flattened and the size of their nuclei increased by up to 3-fold, prior to cell death. Analysis of these nuclei by super-resolution microscopy revealed the presence of large numbers of phosphorylated histone H2AX foci. A senescence-like phenotype of the transduced cells was also observed upon delivery of the corresponding Fab molecules or following PCNA gene disruption or when the Fab fragment of an antibody that neutralises DNA polymerase alpha was used. Primary melanoma cells and leukaemia cells that are resistant to chemical inhibitors were similarly affected by these antibody treatments. These results demonstrate that transduced antibodies can trigger a lethal DNA replication stress, which kills cancer cells by abolishing the biological activity of several constituents of the replisome. [ABSTRACT FROM AUTHOR]

Background: Poor prognosis in gallbladder cancer is due to late presentation of the disease, lack of reliable biomarkers for early diagnosis and limited targeted therapies. Early diagnostic markers and novel therapeutic targets can significantly improve clinical management of gallbladder cancer.Methods: Proteomic analysis of four gallbladder cancer cell lines based on the invasive property (non-invasive to highly invasive) was carried out using the isobaric tags for relative and absolute quantitation labeling-based quantitative proteomic approach. The expression of macrophage migration inhibitory factor was analysed in gallbladder adenocarcinoma tissues using immunohistochemistry. In vitro cellular assays were carried out in a panel of gallbladder cancer cell lines using MIF inhibitors, ISO-1 and 4-IPP or its specific siRNA.Results: The quantitative proteomic experiment led to the identification of 3,653 proteins, among which 654 were found to be overexpressed and 387 were downregulated in the invasive cell lines (OCUG-1, NOZ and GB-d1) compared to the non-invasive cell line, TGBC24TKB. Among these, macrophage migration inhibitory factor (MIF) was observed to be highly overexpressed in two of the invasive cell lines. MIF is a pleiotropic proinflammatory cytokine that plays a causative role in multiple diseases, including cancer. MIF has been reported to play a central role in tumor cell proliferation and invasion in several cancers. Immunohistochemical labeling of tumor tissue microarrays for MIF expression revealed that it was overexpressed in 21 of 29 gallbladder adenocarcinoma cases. Silencing/inhibition of MIF using siRNA and/or MIF antagonists resulted in a significant decrease in cell viability, colony forming ability and invasive property of the gallbladder cancer cells.Conclusions: Our findings support the role of MIF in tumor aggressiveness and suggest its potential application as a therapeutic target for gallbladder cancer. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA A receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit-containing GABA A receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit-containing receptor subtypes., Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA A receptor subtypes by two-electrode voltage-clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings., Key Results: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABA A receptor subtypes, including those containing α5-subunits. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABA A receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands., Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA A receptor subtypes., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Abstract: We used functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) to study the negative blood oxygenation level dependent (BOLD) signal and its underlying blood flow changes in healthy human subjects. This was combined with psychophysiological measurements to test that the negative BOLD signal is associated with functional inhibition. Electrical stimulation of the median nerve at 7Hz evoked robust negative BOLD signals in the primary somatosensory cortex (SI) ipsilateral to stimulation, and positive BOLD signals in contralateral SI. The negative BOLD signal in ipsilateral SI was accompanied by commensurate decreases in relative regional cerebral blood flow (rCBF). Conjunction analysis of the fMRI and PET data revealed a region in the ipsilateral postcentral gyrus showing overlap of negative BOLD signals and relative rCBF decreases. The current perception threshold (CPT) at the ipsilateral finger during concomitant stimulation of the contralateral median nerve increased significantly, suggesting augmented functional inhibition. Since the CPT in the ipsilateral hallux did not significantly change in response to median nerve stimulation, it is more likely that the CPT-increase for the finger is due to functional inhibition (Kastrup et al., 2008) than to changes in selective attention. In conclusion, our data provide evidence that stimulus-induced reductions in relative rCBF may underlie the negative BOLD signal, which in turn may reflect increments in functional inhibition. [Copyright &y& Elsevier]

Xenobiotic transporters of the ATP-binding cassette (ABC) protein superfamily play important roles in maintaining the biochemical barrier of various tissues, but their precise functions in the skin are not yet known. Screening of the expressions of the known xenobiotic transporter genes in two in vitro keratinocyte differentiation models revealed that the ABCC4 and ABCG2 transporters are highly expressed in proliferating keratinocytes, their expressions decreasing along with differentiation. Abrogation of the ABCC4 and ABCG2 protein functions by siRNA-mediated silencing and chemical inhibition did not affect the proliferation of HaCaT cells. In contrast, disruption of the ABCG2 function had no effect on normal human epidermal keratinocyte proliferation, while the inhibition of ABCC-type transporters by probenecid resulted in a striking decrease in the proliferation of the cells. These results indicate that, besides their possible therapy-modulating effects, xenobiotic transporters may contribute significantly to other keratinocyte functions, such as cell proliferation. [ABSTRACT FROM AUTHOR]

P2X family receptors form ATP-gated ion channels by assembling homo/hetero-trimers from seven receptor subunits. The homomeric P2X7 receptor is extraordinary in that in addition to distinctive localization and biological functions it exhibits several hallmark properties, for example, the receptor is potently inhibited by divalent cations such as calcium, magnesium, zinc and copper. Despite the fact that this distinct feature was first described almost three decades ago, our understanding is still contentious. Recent site-directed mutagenesis studies have provided direct evidence showing that functional inhibition by zinc and copper primarily results from direct interaction with the receptor. In this short review, I will give a concise description of the major localization, biological functions, and unique properties of the P2X7 receptor, and particularly discuss the evolving understanding of how divalent cations inhibit the P2X7 receptor and the potential implication of such inhibition to the physiological and pathophysiological role of the P2X7 receptor. [ABSTRACT FROM AUTHOR]

One of the very first observations made regarding α oscillations (8-14 Hz), is that they increase in power over posterior areas when awake participants close their eyes. Recent work, especially in the context of (spatial) attention, suggests that α activity reflects a mechanism of functional inhibition. However, it remains unclear how eye closure impacts anticipatory α modulation observed in attention paradigms, and how this affects subsequent behavioral performance. Here, we recorded magnetoencephalography (MEG) in 33 human participants performing a tactile discrimination task with their eyes open versus closed. We replicated the hallmarks of previous somatosensory spatial attention studies: α lateralization across the somatosensory cortices as well as α increase over posterior (visual) regions. Furthermore, we found that eye closure leads to (1) reduced task performance; (2) widespread increase in α power; and (3) reduced anticipatory visual α modulation (4) with no effect on somatosensory α lateralization. Regardless of whether participants had their eyes open or closed, increased visual α power and somatosensory α lateralization improved their performance. Thus, we provide evidence that eye closure does not alter the impact of anticipatory α modulations on behavioral performance. We propose there is an optimal visual α level for somatosensory task performance, which can be achieved through a combination of eye closure and top-down anticipatory attention., (Copyright © 2022 ElShafei et al.)

Noncoding RNAs have essential biochemical functions in different areas of cellular metabolism, including protein synthesis, RNA splicing, protein secretion, and DNA replication. We have successfully used Morpholino antisense oligonucleotides for the functional inactivation of small noncoding RNAs required for DNA replication (Y RNAs in vertebrates and stem-bulge RNAs in nematodes). Here we discuss specific issues of targeting functional noncoding RNAs for inactivation by Morpholino antisense oligonucleotides. We present protocols for the design, preparation, and efficacy controls of Morpholino antisense oligonucleotides, as well as brief descriptions for their delivery into vertebrate and nematode embryos.