Inhibition Of Function Research Articles

Propagation Effect of Epileptic Seizures in a Coupled Thalamocortical Network

Epileptic seizures have spatial features related to the propagation of seizure waves. As the main characteristic of absence seizures, 2–4[Formula: see text]Hz spike-wave discharges (SWDs) originate from the cortices and are maintained by the thalamus. In this study, we explore the onset and propagation effect of absence seizures based on a thalamocortical model. First, we develop a two-compartment model and consider the autapse of the thalamic reticular nucleus as a crucial parameter to investigate transition behaviors. Moreover, we present dynamical mechanisms through bifurcation analysis. Simulation results show that the absence seizures can be induced and advanced as the coupling strength increases. Second, we investigate excitatory and inhibitory coupling functions in a three-compartment model. Our research indicates that the excitatory coupling function can lead to SWDs when all the compartments are initially saturated. In the process of propagation, excitatory coupling also gives rise to SWDs in normal compartments, whereas inhibitory coupling plays a limited role. Finally, we reproduce the above results in a 10-compartment model and verify the robustness against the variation of the number of modules. This work may shed new light on the field of seizure propagation and provide potential dynamical mechanisms.

Kinetic study on the production of biodegradable lubricant by enzymatic transesterification of high oleic palm oil

Kinetic studies are necessary to identify inhibitors of lipase enzyme deactivation in reaction systems because varying substrate concentrations can affect the enzyme's catalytic activity. The present study aimed to analyze the reaction kinetics of palm-based polyol ester production catalyzed by commercial lipase Novozyme 435 (N435). The enzymatic transesterification reaction was performed in a solvent-free medium. The effect of substrates concentration, specifically high oleic palm methyl ester (HO-PME) and trimethylolpropane (TMP), on the kinetic constant was studied at the initial reaction rate. The study was conducted based on the Ping-pong Bi-bi model, assuming that both substrates could inhibit the reaction. The reaction was carried out at 70 °C and 15.25 mbar with a 3 % (w/w) N435 enzyme load to investigate the effect of various HO-PME and TMP concentrations. The kinetic constants obtained are as follows: Km(HOPME) = 61.112 mol/L, Km(TMP) = 0.336 mol/L, Ki(HOPME)= 0.002 mol/L, Ki(TMP) = 2.415 mol/L and Vmax = 17.24 mol/L.hr. The results implied that N435 has higher affinity towards TMP than HO-PME. Inhibition constant indicated a lower inhibitory function of the TMP than HO-PME (Ki(TMP) >Ki(HOPME)). The reaction kinetics obtained in this study agreed well with the model used with TMP and HO-PME as competitive inhibitor during enzymatic transesterification.

Investigation of the Inhibition Mechanism of Xanthine Oxidoreductase by Oxipurinol: A Computational Study.

Xanthine oxidoreductase (XOR) is an enzyme found in various organisms. It converts hypoxanthine to xanthine and urate, which are crucial steps in purine elimination in humans. Elevated uric acid levels can lead to conditions like gout and hyperuricemia. Therefore, there is significant interest in developing drugs that target XOR for treating these conditions and other diseases. Oxipurinol, an analogue of xanthine, is a well-known inhibitor of XOR. Crystallographic studies have revealed that oxipurinol directly binds to the molybdenum cofactor (MoCo) in XOR. However, the precise details of the inhibition mechanism are still unclear, which would be valuable for designing more effective drugs with similar inhibitory functions. In this study, molecular dynamics and quantum mechanics/molecular mechanics calculations are employed to investigate the inhibition mechanism of XOR by oxipurinol. The study examines the structural and dynamic effects of oxipurinol on the pre-catalytic structure of the metabolite-bound system. Our results provide insights on the reaction mechanism catalyzed by the MoCo center in the active site, which aligns well with experimental findings. Furthermore, the results provide insights into the residues surrounding the active site and propose an alternative mechanism for developing alternative covalent inhibitors.

Antiproliferative assay of suma or Brazilian ginseng (Hebanthe eriantha) methanolic extract on HCT116 and 4T1 cancer cell lines, in vitro toxicity on Artemia salina larvae, and antibacterial activity

Hebanthe eriantha is a medicinal plant used in folk medicine and a subject of commercial interest. The cytotoxicity effects from H. eriantha root extracts on cancerous and normal cells were assessed by the MTT method, and in vitro toxicity was evaluated on Artemia salina. The inhibition of the proliferation of bacteria and MIC values were examined by the disc diffusion and the broth microdilution method, respectively. Human colon cancer HCT116 and mouse breast tumour model 4T1 cells treated with methanolic extract showed a significant decrease in viability of cells with IC50: 272.6 and 88.5 µg/mL at 72h, respectively. The methanolic extract of H. eriantha showed moderate toxicity against A. salina (LC50: 589.4 µg/mL). In antimicrobial activity, the methanolic extract showed the highest inhibitory function against S. aureus and P. vulgaris (17.5 and 16 mm) with MICs of 500 µg/mL. The results confirmed the potential of plant roots as cytotoxic agents.

MicroRNA-211 Regulates Proliferation, Expansion, and Immune Inhibitory Function of Myeloid-Derived Suppressor Cells via Mediation of CHOP Expression

ABSTRACT Background Myeloid-derived suppressor cells (MDSCs) are capable of effectively repressing immune responses against tumors and orchestrating the tumor microenvironment, which can promote tumor angiogenesis and metastasis. The pathway networks used to modulate tumor-expanded MDSC accumulation and function remain unclear. This study identified microRNA-211 (miR-211), whose expression was significantly decreased by factors derived from tumors. Methods miR-211 was assumed to be critical in modulating the accumulation and activity of MDSCs isolated from ovarian cancer (OC)-bearing mice by targeting C/EBP homologous protein (CHOP). Results The upregulation of miR-211 repressed MDSC proliferation, inhibited MDSC immunosuppressive functions, and increased the number of co-incubated CD4+ and CD8+ cells. Furthermore, overexpression of miR-211 led to decreased activities of the NF-κB, PI3K/Akt, and STAT3 pathways and the subsequent downregulation of matrix metalloproteinases to promote tumor cell invasion and metastasis. CHOP overexpression counteracted the effects of miR-211 elevation on these phenotypic changes. Upregulation of miR-211 also dramatically impaired the activity of MDSCs and suppressed OC tumor growth in vivo. Conclusion These results indicated that the miR-211-CHOP axis in MDSCs plays an essential role in the metastasis and proliferation of tumor-expanded MDSCs and might represent a promising cancer treatment target.

Human phytanoyl-CoA dioxygenase domain-containing 1 (PHYHD1) is a putative oxygen sensor associated with RNA and carbohydrate metabolism.

Human phytanoyl-CoA dioxygenase domain-containing 1 (PHYHD1) is a 2-oxoglutarate (2OG)-dependent dioxygenase implicated in Alzheimer's disease, some cancers, and immune cell functions. The substrate, kinetic and inhibitory properties, function and subcellular localization of PHYHD1 are unknown. We used recombinant expression and enzymatic, biochemical, biophysical, cellular and microscopic assays for their determination. The apparent Km values of PHYHD1 for 2OG, Fe2+ and O2 were 27, 6 and > 200 μm, respectively. PHYHD1 activity was tested in the presence of 2OG analogues, and it was found to be inhibited by succinate and fumarate but not R-2-hydroxyglutarate, whereas citrate acted as an allosteric activator. PHYHD1 bound mRNA, but its catalytic activity was inhibited upon interaction. PHYHD1 was found both in the nucleus and cytoplasm. Interactome analyses linked PHYHD1 to cell division and RNA metabolism, while phenotype analyses linked it to carbohydrate metabolism. Thus, PHYHD1 is a potential novel oxygen sensor regulated by mRNA and citrate.

Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition

α5 subunit-containing GABA type-A receptors (α5 GABAARs) are enriched in the hippocampus and play critical roles in neurodevelopment, synaptic plasticity, and cognition. α5 GABAAR preferring negative allosteric modulators (α5 NAMs) show promise mitigating cognitive impairment in preclinical studies of conditions characterized by excess GABAergic inhibition, including Down syndrome and memory deficits post-anesthesia. However, previous studies have primarily focused on acute application or single-dose α5 NAM treatment. Here, we measured the effects of chronic (7-day) in vitro treatment with L-655,708 (L6), a highly selective α5 NAM, on glutamatergic and GABAergic synapses in rat hippocampal neurons. We previously showed that 2-day in vitro treatment with L6 enhanced synaptic levels of the glutamate NMDA receptor (NMDAR) GluN2A subunit without modifying surface α5 GABAAR expression, inhibitory synapse function, or L6 sensitivity. We hypothesized that chronic L6 treatment would further increase synaptic GluN2A subunit levels while maintaining GABAergic inhibition and L6 efficacy, thus increasing neuronal excitation and glutamate-evoked intracellular calcium responses. Immunofluorescence experiments revealed that 7-day L6 treatment slightly increased the synaptic levels of gephyrin and surface α5 GABAARs. Functional studies showed that chronic α5 NAM treatment did not alter inhibition or α5 NAM sensitivity. Surprisingly, chronic L6 exposure decreased surface levels of GluN2A and GluN2B subunits, concurrent with reduced NMDAR-mediated neuronal excitation as seen by faster synaptic decay rates and reduced glutamate-evoked calcium responses. Together, these results show that chronic in vitro treatment with an α5 NAM leads to subtle homeostatic changes in inhibitory and excitatory synapses that suggest an overall dampening of excitability.

The Importance of Low-frequency Alpha (8-10 Hz) Waves and Default Mode Network in Behavioral Inhibition.

: Alpha wave of electroencephalography (EEG) is known to be related to behavioral inhibition. Both the alpha wave and default mode network (DMN) are predominantly activated during resting-state. To study the mechanisms of the trait inhibition, this research investigating the relations among alpha wave, DMN and behavioral inhibition in resting-state. : We explored the relationship among behavioral inhibition, resting-state alpha power, and DMN. Resting-state EEG, behavioral inhibition/behavioral activation scale (BIS/BAS), Barratt impulsivity scale, and no-go accuracy were assessed in 104 healthy individuals. Three groups (i.e., participants with low/middle/high band power) were formed based on the relative power of each total-alpha, low-alpha (LA), and high-alpha band. Source-reconstructed EEG and functional network measures of 25 DMN regions were calculated. : Significant differences and correlations were found based on LA band power alone. The high LA group had significantly greater BIS, clustering coefficient, efficiency, and strength, and significantly lower path length than low/middle LA group. BIS score showed a significant correlation with functional network measures of DMN. : Our study revealed that LA power is related to behavioral inhibition and functional network measures of DMN of LA band appear to represent significant inhibitory function.

Anti-angiogenic drug aggravates the degree of anti-resorptive drug-based medication-related osteonecrosis of the jaw by impairing the proliferation and migration function of gingival fibroblasts

BackgroundLong-term use of anti-resorptive or anti-angiogenic drugs in cancer patients with odontogenic infections may lead to medication-related osteonecrosis of the jaw (MRONJ). This study investigated whether anti-angiogenic agents aggravate MRONJ occurrence in anti-resorptive-treated patients.MethodsThe clinical stage and jawbone exposure of MRONJ patients caused by different drug regimens were analyzed to ascertain the aggravation effect of anti-angiogenic drugs on anti-resorptive drug-based MRONJ. Next, a periodontitis mice model was established, and tooth extraction was performed after administering anti-resorptive and/or anti-angiogenic drugs; the imaging and histological change of the extraction socket were observed. Moreover, the cell function of gingival fibroblasts was analyzed after the treatment with anti-resorptive and/or anti-angiogenic drugs in order to evaluate their effect on the gingival tissue healing of the extraction socket.ResultsPatients treated with anti-angiogenic and anti-resorptive drugs had an advanced clinical stage and a bigger proportion of necrotic jawbone exposure compared to patients treated with anti-resorptive drugs alone. In vivo study further indicated a greater loss of mucosa tissue coverage above the tooth extraction in mice treated with sunitinib (Suti) + zoledronate (Zole) group (7/10) vs. Zole group (3/10) and Suti group (1/10). Micro-computed tomography (CT) and histological data showed that the new bone formation in the extraction socket was lower in Suti + Zole and Zole groups vs. Suti and control groups. In vitro data showed that the anti-angiogenic drugs had a stronger inhibitory ability on the proliferation and migration function of gingival fibroblasts than anti-resorptive drugs, and the inhibitory effect was obviously enhanced after combining zoledronate and sunitinib.ConclusionOur findings provided support for a synergistic contribution of anti-angiogenic drugs to anti-resorptive drugs-based MRONJ. Importantly, the present study revealed that anti-angiogenic drugs alone do not induce severe MRONJ but aggravate the degree of MRONJ via the enhanced inhibitory function of gingival fibroblasts based on anti-resorptive drugs.

Dysfunction of inhibitory interneurons contributes to synaptic plasticity via GABABR-pNR2B signaling in a chronic migraine rat model.

According to our previous study, the loss of inhibitory interneuron function contributes to central sensitization in chronic migraine (CM). Synaptic plasticity is a vital basis for the occurrence of central sensitization. However, whether the decline in interneuron-mediated inhibition promotes central sensitization by regulating synaptic plasticity in CM remains unclear. Therefore, this study aims to explore the role of interneuron-mediated inhibition in the development of synaptic plasticity in CM. A CM model was established in rats by repeated dural infusion of inflammatory soup (IS) for 7 days, and the function of inhibitory interneurons was then evaluated. After intraventricular injection of baclofen [a gamma-aminobutyric acid type B receptor (GABABR) agonist] or H89 [a protein kinase A (PKA) inhibitor), behavioral tests were performed. The changes in synaptic plasticity were investigated by determining the levels of the synapse-associated proteins postsynaptic density protein 95 (PSD95), synaptophysin (Syp) and synaptophysin-1(Syt-1)]; evaluating the synaptic ultrastructure by transmission electron microscopy (TEM); and determining the density of synaptic spines via Golgi-Cox staining. Central sensitization was evaluated by measuring calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), c-Fos and substance P (SP) levels. Finally, the PKA/Fyn kinase (Fyn)/tyrosine-phosphorylated NR2B (pNR2B) pathway and downstream calcium-calmodulin-dependent kinase II (CaMKII)/c-AMP-responsive element binding protein (pCREB) signaling were assessed. We observed dysfunction of inhibitory interneurons, and found that activation of GABABR ameliorated CM-induced hyperalgesia, repressed the CM-evoked elevation of synapse-associated protein levels and enhancement of synaptic transmission, alleviated the CM-triggered increases in the levels of central sensitization-related proteins, and inhibited CaMKII/pCREB signaling via the PKA/Fyn/pNR2B pathway. The inhibition of PKA suppressed the CM-induced activation of Fyn/pNR2B signaling. These data reveal that the dysfunction of inhibitory interneurons contributes to central sensitization by regulating synaptic plasticity through the GABABR/PKA/Fyn/pNR2B pathway in the periaqueductal gray (PAG) of CM rats. Blockade of GABABR-pNR2B signaling might have a positive influence on the effects of CM therapy by modulating synaptic plasticity in central sensitization.

Proteins released into the plant apoplast by the obligate parasitic protist Albugo selectively repress phyllosphere-associated bacteria.

Biotic and abiotic interactions shape natural microbial communities. The mechanisms behind microbe-microbe interactions, particularly those protein based, are not well understood. We hypothesize that released proteins with antimicrobial activity are a powerful and highly specific toolset to shape and defend plant niches. We have studied Albugo candida, an obligate plant parasite from the protist Oomycota phylum, for its potential to modulate the growth of bacteria through release of antimicrobial proteins into the apoplast. Amplicon sequencing and network analysis of Albugo-infected and uninfected wild Arabidopsis thaliana samples revealed an abundance of negative correlations between Albugo and other phyllosphere microbes. Analysis of the apoplastic proteome of Albugo-colonized leaves combined with machine learning predictors enabled the selection of antimicrobial candidates for heterologous expression and study of their inhibitory function. We found for three candidate proteins selective antimicrobial activity against Gram-positive bacteria isolated from A. thaliana and demonstrate that these inhibited bacteria are precisely important for the stability of the community structure. We could ascribe the antibacterial activity of the candidates to intrinsically disordered regions and positively correlate it with their net charge. This is the first report of protist proteins with antimicrobial activity under apoplastic conditions that therefore are potential biocontrol tools for targeted manipulation of the microbiome.

Acute effects of different exercise forms on executive function and the mechanism of cerebral hemodynamics in hospitalized T2DM patients: a within-subject study.

This study aimed to investigate the acute effects of aerobic exercise (AE), resistance exercise (RE), and integrated concurrent exercise (ICE; i.e., AE plus RE) on executive function among hospitalized type 2 diabetes mellitus (T2DM) inpatients, and the mechanism of cerebral hemodynamics. A within-subject design was applied in 30 hospitalized patients with T2DM aged between 45 and 70 years in the Jiangsu Geriatric Hospital, China. The participants were asked to take AE, RE, and ICE for 3 days at 48-h intervals. Three executive function (EF) tests, namely, Stroop, More-odd shifting, and 2-back tests, were applied at baseline and after each exercise. The functional near-infrared spectroscopy brain function imaging system was used to collect cerebral hemodynamic data. The one-way repeated measurement ANOVA was used to explore training effects on each test indicator. Compared with the baseline data, the EF indicators have been improved after both ICE and RE (p < 0.05). Compared with the AE group, the ICE and RE groups have demonstrated significant improvements in inhibition (ICE: MD = - 162.92 ms; RE: MD = -106.86 ms) and conversion functions (ICE: MD = -111.79 ms; RE: MD = -86.95 ms). Based on the cerebral hemodynamic data, the beta values of brain activation in executive function related brain regions increased after three kinds of exercise, the EF improvements after the ICE showed synchronous activation of blood flow in the dorsolateral prefrontal cortex (DLPFC), the frontal polar (FPA) and orbitofrontal cortex (OFC), the improvement of inhibitory function after RE displayed synchronous activation of DLPFC and FPA, and AE mainly activates DLPFC. The HbO2 concentration in the pars triangularis Broca's area increased significantly after AE, but the EF did not improve significantly. The ICE is preferred for the improvements of executive function in T2DM patients, while AE is more conducive to the improvements of refresh function. Moreover, a synergistic mechanism exists between cognitive function and blood flow activation in specific brain regions.

Increased pyramidal and VIP neuronal excitability in rat primary auditory cortex directly correlates with tinnitus behaviour.

Tinnitus affects roughly 15%-20% of the population while severely impacting 10% of those afflicted. Tinnitus pathology is multifactorial, generally initiated by damage to the auditory periphery, resulting in a cascade of maladaptive plastic changes at multiple levels of the central auditory neuraxis as well as limbic and non-auditory cortical centres. Using a well-established condition-suppression model of tinnitus, we measured tinnitus-related changes in the microcircuits of excitatory/inhibitory neurons onto layer 5 pyramidal neurons (PNs), as well as changes in the excitability of vasoactive intestinal peptide (VIP) neurons in primary auditory cortex (A1). Patch-clamp recordings from PNs in A1 slices showed tinnitus-related increases in spontaneous excitatory postsynaptic currents (sEPSCs) and decreases in spontaneous inhibitory postsynaptic currents (sIPSCs). Both measures could be correlated to the rat's behavioural evidence of tinnitus. Tinnitus-related changes in PN excitability were independent of changes in A1 excitatory or inhibitory cell numbers. VIP neurons, part of an A1 local circuit that can control the excitation of layer 5 PNs via disinhibitory mechanisms, showed significant tinnitus-related increases in excitability that directly correlated with the rat's behavioural tinnitus score. That PN and VIP changes directly correlated to tinnitus behaviour suggests an important role in A1 tinnitus pathology. Tinnitus-related A1 changes were similar to findings in studies of neuropathic pain in somatosensory cortex suggesting a common pathology of these troublesome perceptual impairments. Improved understanding between excitatory, inhibitory and disinhibitory sensory cortical circuits can serve as a model for testing therapeutic approaches to the treatment of tinnitus and chronic pain. KEY POINTS: We identified tinnitus-related changes in synaptic function of specific neuronal subtypes in a reliable animal model of tinnitus. The findings show direct and indirect tinnitus-related losses of normal inhibitory function at A1 layer 5 pyramidal cells, and increased VIP excitability. The findings are similar to what has been shown for neuropathic pain suggesting that restoring normal inhibitory function at synaptic inputs onto A1 pyramidal neurons (PNs) could conceptually reduce tinnitus discomfort.

In-silico lead identification of the pan-mutant IDH1 and IDH2 inhibitors to target glioblastoma

Glioblastoma (GBM) is an aggressive malignant type of brain tumor. Targeting one single intracellular pathway might not alleviate the disease, rather it activates the other molecular pathways that lead to the worsening of the disease condition. Therefore, in this study, we attempted to target both isocitrate dehydrogenase 1 (IDH1) and IDH2, which are one of the most commonly mutated proteins in GBM and other cancer types. Here, standard precision and extra precision docking, IFD, MM-GBSA, QikProp, and molecular dynamics (MD) simulation were performed to identify the potential dual inhibitor for IDH1 and IDH2 from the enamine database containing 59,161 ligands. Upon docking the ligands with IDH1 (PDB: 6VEI) and IDH2 (PDB: 6VFZ), the top eight ligands were selected, based on the XP Glide score. These ligands produced favourable MMGBSA scores and ADME characteristics. Finally, the top four ligands 12953, 44825, 51295, and 53210 were subjected to MD analysis. Interestingly, 53210 showed maximum interaction with Gln 277 for 99% in IDH1 and Gln 316 for 100% in IDH2, which are the crucial amino acids for the inhibitory function of IDH1 and IDH2 to target GBM. Therefore, the present study attempts to identify the novel molecules which could possess a pan-inhibitory action on both IDH1 and IDH that could be crucial in the management of GBM. Yet further evaluation involving in vitro and in vivo studies is warranted to support the data in our current study. Communicated by Ramaswamy H. Sarma

Short-Term TERT Inhibition Impairs Cellular Proliferation via a Telomere Length-Independent Mechanism and Can Be Exploited as a Potential Anticancer Approach.

Telomerase reverse transcriptase (TERT), the catalytic component of telomerase, may also contribute to carcinogenesis via telomere-length independent mechanisms. Our previous in vitro and in vivo studies demonstrated that short-term telomerase inhibition by BIBR1532 impairs cell proliferation without affecting telomere length. Here, we show that the impaired cell cycle progression following short-term TERT inhibition by BIBR1532 in in vitro models of B-cell lymphoproliferative disorders, i.e., Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines (LCLs), and B-cell malignancies, i.e., Burkitt's lymphoma (BL) cell lines, is characterized by a significant reduction in NF-κB p65 nuclear levels leading to the downregulation of its target gene MYC. MYC downregulation was associated with increased expression and nuclear localization of P21, thus promoting its cell cycle inhibitory function. Consistently, treatment with BIBR1532 in wild-type zebrafish embryos significantly decreased Myc and increased p21 expression. The combination of BIBR1532 with antineoplastic drugs (cyclophosphamide or fludarabine) significantly reduced xenografted cells' proliferation rate compared to monotherapy in the zebrafish xenograft model. Overall, these findings indicate that short-term inhibition of TERT impairs cell growth through the downregulation of MYC via NF-κB signalling and supports the use of TERT inhibitors in combination with antineoplastic drugs as an efficient anticancer strategy.

MiR-145-3p Inhibits MuSCs Proliferation and Mitochondria Mass via Targeting MYBL1 in Jianzhou Big-Eared Goats

Muscle growth and injury-induced regeneration are controlled by skeletal muscle satellite cells (MuSCs) through myogenesis in postnatal animals. Meanwhile, myogenesis is accompanied by mitochondrial function and enzyme activity. Nevertheless, the underlying molecular mechanisms involving non-coding RNAs including circular RNAs (circRNAs) and microRNAs (miRNAs) remain largely unsolved. Here, we explored the myogenic roles of miR-145-3p and MYBL1 on muscle development and mitochondrial mass. We noticed that overexpression of miR-145-3p inhibited MuSCs proliferation and reduced the number of viable cells. Meanwhile, deficiency of miR-145-3p caused by LNAantimiR-145-3p or an inhibitor retarded the differentiation of MuSCs. miR-145-3p altered the mitochondrial mass in MuSCs. Moreover, miR-145-3p targeted and negatively regulated the expression of CDR1as and MYBL1. The knockdown of the MYBL1 using ASO-2'MOE modification simulated the inhibitory function of miR-145-3p on cell proliferation. Additionally, MYBL1 mediated the regulation of miR-145-3p on Vexin, VCPIP1, COX1, COX2, and Pax7. These imply that CDR1as/miR-145-3p/MYBL1/COX1, COX2, VCPIP1/Vexin expression at least partly results in a reduction in mitochondrial mass and MuSCs proliferation. These novel findings confirm the importance of mitochondrial mass during myogenesis and the boosting of muscle/meat development in mammals.

Sex Differences in Excitatory and Inhibitory Function in the Primary Somatosensory Cortex during the Early Follicular Phase: A Preliminary Study.

We examined sex differences in the excitatory and inhibitory functions of the primary somatosensory cortex (S1) between males and females during the early follicular phase, when estradiol hormones are unaffected. Fifty participants (25 males and 25 females) underwent measurement of somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) in the S1; SEPs and PPI were elicited by constant current square-wave pulses (0.2 ms duration) delivered to the right median nerve by electrical stimulation. Paired-pulse stimulation occurred at 30- and 100-ms interstimulus intervals. Participants were randomly presented with 1500 (500 stimuli each) single- and paired-pulse stimuli at 2 Hz. The N20 amplitude was significantly larger in female subjects than in male subjects, and the PPI-30 ms was significantly potentiated in female subjects compared to that in male subjects. The excitatory and inhibitory functions in S1 differ between male and female subjects, at least during the early follicular phase.

Computational Modeling to Determine the Effect of Phenotypic Heterogeneity in Tumors on the Collective Tumor–Immune Interactions

Tumor immunotherapy aims to maintain or enhance the killing capability of CD8+ T cells to clear tumor cells. The tumor-immune interactions affect the function of CD8+ T cells. However, the effect of phenotype heterogeneity of a tumor mass on the collective tumor-immune interactions is insufficiently investigated. We developed the cellular-level computational model based on the principle of cellular Potts model to solve the case mentioned above. We considered how asymmetric division and glucose distribution jointly regulated the transient changes in the proportion of proliferating/quiescent tumor cells in a solid tumor mass. The evolution of a tumor mass in contact with T cells was explored and validated by comparing it with previous studies. Our modeling exhibited that proliferating/quiescent tumor cells, exhibiting distinct anti-apoptotic and suppressive behaviors, redistributed within the domain accompanied by the evolution of a tumor mass. Collectively, a tumor mass prone to a quiescent state weakened the collective suppressive functions of a tumor mass on cytotoxic T cells and triggered a decline of apoptosis of tumor cells. Although quiescent tumor cells did not sufficiently do their inhibitory functions, the possibility of long-term survival was improved due to their interior location within a mass. Overall, the proposed model provides a useful framework to investigate collective-targeted strategies for improving the efficiency of immunotherapy.

Abstract #1394329: An Association Between Stiff Person Syndrome and Type 1 Diabetes

Stiff-person syndrome (SPS) is a rare neuromuscular disorder characterized by progressive muscular spasms and rigidity. Anti-glutamic acid decarboxylase (anti-GAD) antibodies are found in type 1 diabetes mellitus (T1DM). Thirty percent of patients diagnosed with SPS have T1DM. This relationship infers that SPS and T1DM share pathogenetic features. We describe a case of a 66-year-old female with a history of SPS who developed T1DM soon after the diagnosis was made. A 66-year-old female with a history of SPS, T1DM, and discoid lupus was referred to our university endocrinology clinic for diabetes management. She had ataxia, loss of balance, and muscle stiffness since 2012. The patient was diagnosed with spinal cerebellar ataxia. She was not treated with any specific agents and continued to have left-sided muscle stiffness with preserved strength. She denied weakness, pain, paresthesia, or muscle atrophy but had difficulty ambulating due to rigidity. The diagnosis of SPS was made based on positive anti-GAD antibodies (normal < 0.02) and positive N-channel antibodies in April 2016. She required hospital admission one month later and received solumedrol and IVIG. Her HbA1c was 6.5% (normal < 5.7% of total Hgb), and glucose levels were between 200-300 mg/dL, which were treated with basal and bolus insulin. She was discharged home in May 2016 with no diabetic medications. The patient developed polyuria and polydipsia with 11 Ibs unintentional weight loss 20 days after hospital discharge. She was referred to the endocrine clinic in June 2016 for further workup. Her HbA1c was 11% with C-peptide less than 0.01 (normal 0.78-5.20 ng/mL). Basal and bolus insulin were initiated, and she remains on an insulin regimen. SPS affects an estimated one person per million per year. Decreased level of gamma amino butyric acid (GABA) in the central nervous system (CNS) in SPS has been implicated, which causes a loss of neural inhibition. Glutamic acid decarboxylase (GAD) is the main enzyme required for the GABA inhibitory pathway. Anti-GAD antibodies decrease inhibitory function within the CNS and cause increased muscle activities and subsequent muscle spasms. While most patients with T1DM do not develop SPS, most with anti-GAD-positive SPS will have or develop T1DM. Either SPS or T1DM may be diagnosed first. Awareness of these associations is essential for early diagnosis and treatment of these disorders.

Hsa_circ_0093741 competes with FRS2 for miR-562 binding sites to promote nephroblastoma progression.

Circular RNA (circRNA) has been shown to play an essential role in cancer progression, including nephroblastoma. Hsa_circ_0093741 was discovered to be highly expressed in nephroblastoma. However, its function and mechanism in nephroblastoma development are still vague. The expression levels of hsa_circ_0093741, miR-562 and FRS2 (Fibroblast Growth Factor Receptor Substrate 2) were detected using western blotting and quantitative real-time polymerase chain reaction. Functional experiments were performed by using cell counting kit-8, colony formation, 5-ethynyl-2'-deoxyuridine (EdU), transwell, scratch assays in vitro and animal experiments in vivo. The interaction analysis was conducted using dual-luciferase reporter assay and RIP assay. Hsa_circ_0093741 was highly expressed in nephroblastoma tissues and cells. Functionally, hsa_circ_0093741 silencing significantly suppressed the growth, invasion, and migration of nephroblastoma cells in vitro. MiR-562 was decreased in nephroblastoma, and was validated to be a target of hsa_circ_0093741. Inhibition of miR-562 reversed the anticancer functions of hsa_circ_0093741 silencing on nephroblastoma cells. FRS2 expression was increased in nephroblastoma and served as a target of miR-562, moreover, FRS2 overexpression attenuated the inhibitory functions of miR-562 on the nephroblastoma cell malignant phenotypes mentioned above. Pre-clinically, lentivirus-mediated hsa_circ_0093741 silencing also impeded nephroblastoma tumor growth and metastasis in vivo. Knockdown of hsa_circ_0093741 suppresses nephroblastoma cell growth, migration and invasion by regulating the miR-562/FRS2 axis, suggesting the potential involvement of hsa_circ_0093741 in nephroblastoma progression.