Imaging Study of Electroconvulsive Modulation of Brain Markers of Emotional Processing and Activation of Various Brain Regions in Schizophrenic Patients.

Aims: An imaging study to investigate electroconvulsive modulation of brain markers of emotional processing and activity of various brain regions in patients with schizophrenia. Materials and Methods: One hundred and twenty patients with schizophrenia admitted to The Brain Hospital of Hunan Province from January 2020 to July 2022 were divided into a comparison group and a study group of 60 patients each according to the order of admission. The comparison group received conventional pharmacological interventions and the study group implemented conventional pharmacological and electroconvulsive modulation therapy to compare the neurotransmitter power, neuropsychological assessment, and efficacy evaluation between the two groups. Results: Before treatment, there was no statistically significant difference in neurotransmitter power between the two groups (P > .05); 30 min after treatment, GABA, Glu, 5-HT, Ach, NE, and DA were elevated in both groups and were higher in the study group than in the comparison group, and the difference was statistically significant (P < .05). Before treatment, there was no statistically significant difference in the neuropsychological measurements between the two groups (P > .05). Clinical efficacy evaluation after treatment revealed that the clinical efficacy rate of patients in the study group was 95.00% significantly higher than that of the comparison group, which was 83.33%, and the comparative difference was statistically significant (P < .05). Conclusion: Electroconvulsive therapy was found to significantly improve neuropsychological assessment and clinical outcomes in patients with psychiatric disorders.

A hybrid event-triggered stabilization approach for switched systems under asynchronous switching and its application.

This paper investigates the stabilization problem of switched systems with mismatched modes by an event-triggered control approach. A hybrid event-triggered scheme (HETS) with a dynamically adjustable threshold is newly proposed, which combines periodic sampling, continuous event-trigger and slow switching. It is assumed that the modes and states of the controller are updated only at each triggering instant, so the situation of asynchronous switching could arise. Compared with the control strategy under static HETS, the proposed hybrid event-triggered control strategy has the advantage of potentially speeding up the stabilization while reducing the communication burden. To ease the analysis, the closed-loop system is accordingly represented as a combination of the switched system with a periodically sampled control input and the one with a continuously event-triggered control input. By considering input delay information in the construction of multiple Lyapunov-Krasovskii functional (LKF), a discontinuous and non-positive definite LKF is developed to establish sufficient conditions on the exponential stability for the closed-loop switched system. The design method of the desired controller and HETS is then provided. Finally, the result obtained in this paper is applied to a networked continuous stirred tank reactors system.

Adaptive fixed-time output synchronization for complex dynamical networks with multi-weights.

This paper addresses fixed-time output synchronization problems for two types of complex dynamical networks with multi-weights (CDNMWs) by using two types of adaptive control methods. Firstly, complex dynamical networks with multiple state and output couplings are respectively presented. Secondly, several fixed-time output synchronization criteria for these two networks are formulated based on Lyapunov functional and inequality techniques. Thirdly, by employing two types of adaptive control methods, fixed-time output synchronization issues of these two networks are dealt with. At last, the analytical results are verified by two numerical simulations.

Extended analysis on the global Mittag-Leffler synchronization problem for fractional-order octonion-valued BAM neural networks.

In this paper, a new case of neural networks called fractional-order octonion-valued bidirectional associative memory neural networks (FOOVBAMNNs) is established. First, the higher dimensional models are formulated for FOOVBAMNNs with general activation functions and the special linear threshold ones, respectively. On one hand, employing Cayley-Dichson construction in octonion multiplication which is essentially neither commutative nor associative, the system of FOOVBAMNNs is divided into four fractional-order complex-valued ones. On the other hand, Caputo fractional derivative's character and BAM's interactive feature are also properly dealt with. Second, the general criteria are obtained by the new design of LKFs, the application of the related inequalities and the construction of the linear feedback controllers for the global Mittag-Leffler synchronization problem of FOOVBAMNNs. Finally, we present two numerical examples to show the realizability and progress of the derived results.

Unified Analysis on the Global Dissipativity and Stability of Fractional-Order Multidimension-Valued Memristive Neural Networks With Time Delay.

The unified criteria are analyzed on the global dissipativity and stability for the delayed fractional-order systems of multidimension-valued memristive neural networks (FSMVMNNs) in this article. First, based on the comprehensive knowledge about multidimensional algebra, fractional derivatives, and nonsmooth analysis, we establish the unified model for the studied FSMVMNNs in order to propose a more uniform method to analyze the dynamic behaviors of multidimensional neural networks. Then, by mainly applying the Lyapunov method, employing several new lemmas, and solving some mathematical difficulties, without any separation, we acquire the unified and concise criteria. The derived criteria have many advantages in a smaller calculation, lower conservatism, more diversity, and higher flexibility. Finally, we provide two numerical examples to express the availability and improvements of the theoretical results.

Vaccine Hyporesponse Induced by Individual Antibiotic Treatment in Mice and Non-Human Primates Is Diminished upon Recovery of the Gut Microbiome.

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in the disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.

Improved approach to the problem of the global Mittag-Leffler synchronization for fractional-order multidimension-valued BAM neural networks based on new inequalities.

This paper studies the problem of the global Mittag-Leffler synchronization for fractional-order multidimension-valued BAM neural networks (FOMVBAMNNs) with general activation functions (AFs). First, the unified model is established for the researched systems of FOMVBAMNNs which can be turned into the corresponding multidimension-valued systems as long as the state variables, the connection weights and the AFs of the neural networks are valued to be real, complex, or quaternion. Then, without any decomposition, the criteria in unified form are derived by constructing the new Lyapunov-Krasovskii functionals (LKFs) in vector form, combining two new inequalities and considering the easy controllers. It is worth mentioning that the obtained criteria have many advantages in higher flexibility, more diversity, smaller computation, and lower conservatism. Finally, a simulation example is provided to illustrate the availability and improvements of the acquired results.

Novel Inequalities to Global Mittag-Leffler Synchronization and Stability Analysis of Fractional-Order Quaternion-Valued Neural Networks.

This article is concerned with the problem of the global Mittag-Leffler synchronization and stability for fractional-order quaternion-valued neural networks (FOQVNNs). The systems of FOQVNNs, which contain either general activation functions or linear threshold ones, are successfully established. Meanwhile, two distinct methods, such as separation and nonseparation, have been employed to solve the transformation of the studied systems of FOQVNNs, which dissatisfy the commutativity of quaternion multiplication. Moreover, two novel inequalities are deduced based on the general parameters. Compared with the existing inequalities, the new inequalities have their unique superiorities because they can make full use of the additional parameters. Due to the Lyapunov theory, two novel Lyapunov-Krasovskii functionals (LKFs) can be easily constructed. The novelty of LKFs comes from a wider range of parameters, which can be involved in the construction of LKFs. Furthermore, mainly based on the new inequalities and LKFs, more multiple and more flexible criteria are efficiently obtained for the discussed problem. Finally, four numerical examples are given to demonstrate the related effectiveness and availability of the derived criteria.

New approach to global Mittag-Leffler synchronization problem of fractional-order quaternion-valued BAM neural networks based on a new inequality.

In this paper, a novel kind of neural networks named fractional-order quaternion-valued bidirectional associative memory neural networks (FQVBAMNNs) is formulated. On one hand, applying Hamilton rules in quaternion multiplication which is essentially non-commutative, the system of FQVBAMNNs is separated into eight fractional-order real-valued systems. Meanwhile, the activation functions are considered to be quaternion-valued linear threshold ones which help to reduce the unnecessary computational complexity. On the other hand, based on fractional-order Lyapunov technology, a new fractional-order derivative inequality is established. Mainly by employing the new inequality technique, constructing three novel Lyapunov-Krasovskii functionals (LKFs) and designing simple linear controllers, the global Mittag-Leffler synchronization problems are investigated and the corresponding criteria are acquired for the system of FQVBAMNNs and its special cases such as fractional-order complex-valued BAM neural networks (FCVBAMNNs) and fractional-order real-valued BAM neural networks (FRVBAMNNs), respectively. Finally, two numerical examples are given to show the effectiveness and availability of the proposed results.

Effects of MCRS1 on proliferation, migration, invasion, and epithelial mesenchymal transition of gastric cancer cells by interacting with Pkmyt1 protein kinase.

Microspherule protein 1(MCRS1) is known to be an oncogene in several tumors. However, recent studies have shown that MCRS1 inhibits lymphatic metastasis in gastric cancer (GC) patients by inhibiting telomerase activity. Protein kinase, membrane associated tyrosine/threonine 1(Pkmyt1), a member of the WEE1 family, has been found to interact with MCRS1 by yeast two-hybrid assay; however, how these two proteins interact in GC is still unclear. Hence, this study aimed to investigate the effect of MCRS1 interaction with Pkmyt1 on GC cell proliferation, migration, and invasion. Initially, we observed increased expression of MCRS1 in GC SGC-7901 cells and decreased expression in GC BGC-823 cells. Hence, we down-regulated MCRS1 expression in SGC-7901 cells and up-regulated it in BGC-823 cells. Our results showed that overexpression of MCRS1 inhibits the growth, invasion and migration of GC cells, while downregulation of MCRS1 promotes the growth, invasion and migration of GC cells. When MK1775, an inhibitor of WEE1 kinase, was added after downregulation of MCRS1, phenotypic recovery effects were observed. Overexpression of MCRS1 also inhibited the expression of Pkmyt1 and vice versa. This indicated that there might be a possible interaction between MCRS1 and Pkmyt1. Furthermore, immunoprecipitation assay revealed the interaction between MCRS1 and Pkmyt1 in virto, and immunofluorescence experiments showed that the two proteins were co-localized in the cytoplasm. In conclusion, our study confirmed the specific tumor suppressive activity of MCRS1 in GC proliferation, invasion and migration and suggested that it might inhibit the progression of GC through its interaction with Pkmyt1.

Accelerating the discovery of DGAT1 inhibitors through the application of parallel medicinal chemistry (PMC).

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.

Benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety.

Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.

Use of Translational Pharmacokinetic/Pharmacodynamic Infection Models To Understand the Impact of Neutropenia on the Efficacy of Tedizolid Phosphate.

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated that tedizolid has improved potency and pharmacokinetics/pharmacodynamics (PK/PD) compared with those of linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immunocompetent (IC) mice compared with neutropenic (immunosuppressed [IS]) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about its use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1 to 150 mg/kg of body weight tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 h after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis against MRSA ATCC 33591 and MSSA ATCC 29213 at 72 h at a human clinical dose of 200 mg, severalfold lower than that in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that, with time, both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with an MRSA or MSSA thigh infection.

Autophagy is involved in the protective effect of endophilin A2 on H2O2-induced apoptosis in H9C2 cardiomyocytes.

Apoptosis plays a critical role in normal embryonic development and tissue homeostasis regulation. EndophilinA2 (EndoA2) is widely reported to regulate endocytosis. Additionally, EndoA2 has been demonstrated to be involved in tumor metastasis, neuroregulation and vascular function. In this study, we used siRNA and Ad-EndoA2 transfection strategy to investigate whether EndoA2 provides a protective effect against apoptosis induced by H2O2 in H9C2 cardiomyocytes and the underlying mechanisms. We found that EndoA2 siRNA knockdown promoted H2O2-induced apoptosis in H9C2 cardiomyocytes, evidenced by decreased cell number, increased apoptotic cells, and activation of caspase-3. In contrast, EndoA2 overexpression showed the opposite effects and inhibited H2O2-induced apoptosis in H9C2 cardiomyocytes. Further studies revealed that EndoA2 overexpression strengthened autophagy, evidenced by the increased LC3 II/I ratio and P62 degradation, whereas EndoA2 siRNA knockdown produced the opposite effects. Furthermore, we revealed that there was an interaction between Bif-1 and Beclin-1. Upon H2O2 treatment, the association of Bif-1 and Beclin-1 remarkably increased. EndoA2 overexpression further promoted the binding of Bif-1 with Beclin-1, whereas EndoA2 siRNA knockdown reduced this association. These data strongly suggested that EndoA2 inhibited H2O2-induced apoptosis in H9C2 cardiomyocytes, possibly by promoting Bif-1 to form a complex with Beclin-1 and strengthening autophagy. This study provides a novel target for heart diseases.

The interaction between RACK1 and WEE1 regulates the growth of gastric cancer cell line HGC27.

Receptor of activated C Kinase 1 (RACK1) is an essential scaffold and anchoring protein, which serves an important role in multiple tumorigenesis signaling pathways. The present study aimed to investigate the expression of RACK1 in gastric cancer (GC), and its association with the occurrence and development of GC. In addition, the effect and mechanism of RACK1 overexpression on the growth, and proliferation of GC cells was examined. Firstly, the protein expression of RACK1 was detected in 70 cases of GC tissues and 30 cases of noncancerous tissues using immunohistochemical staining, and the association between clinical and pathological features of GC was analyzed. Secondly, the mRNA and protein expression of RACK1 was determined in the poorly-differentiated human gastric cancer cell line HGC27 and gastric epithelial cell line GES-1. The growth of HGC27 cells following the upregulation of RACK1 was detected using MTT method. Subsequently, the interaction and co-location between RACK1, and WEE1 homolog (S. pombe) (WEE1) in HGC27 cells was confirmed using co-immunoprecipitation and indirect immunofluorescence. The expression level of RACK1 in GC was significantly lower compared with that in pericarcinous tissues (P<0.05). The protein level of RACK1 expression correlated with tumor node metastasis stage, tumor differentiation and lymph node metastasis. The mRNA and protein levels of RACK1 in HGC27 cells were significantly reduced, and overexpressed RACK1 downregulated WEE1 protein expression, thus inhibiting the growth of HGC27 cells. Co-immunoprecipitation and immunofluorescence confirmed that RACK1, and WEE1 interacted and co-located in the cytoplasm of HGC27 cells. Therefore, the abnormal expression of RACK1 in GC tissues was identified to be involved in the occurrence and development of GC. Overexpression of RACK1 was able to inhibit the growth of HGC27 cells. The current study suggests that low expression of RACK1 is an important indicator of poor prognosis of GC. RACK1 and WEE1 interact to regulate the growth of HGC27 cells.

[Knock-down of KHDRBS3 gene inhibits proliferation of human ovarian cancer CAOV-3 cells].

Objective To investigate the effect of KH RNA binding domain-containing, signal transduction-associated 3 (KHDRBS3) gene on the proliferation of human ovarian cancer CAOV-3 cells in vitro. Methods The logarithmic growth phase cells were divided into non-transfection group, unrelated small interfering RNA (siRNA) sequence transfection group and KHDRBS3-siRNA transfection group. Reverse transcription PCR and Western blotting were used to verify the result of KHDRBS3 gene silencing. The proliferation of CAOV-3 cells in different groups was compared by MTT assay. The cell cycle distribution of CAOV-3 cells in different treatment groups was detected by flow cytometry. Results KHDRBS3-siRNA transfection significantly decreased the mRNA and protein levels of KHDRBS3 gene in CAOV-3 cells. After the knock-down of KHDRBS3 gene in CAOV-3 cells, the proliferation of the cells markedly decreased, the percentage of G0/G1 phase cells increased, and the percentage of S phase cells decreased, while the percentage of G2/M phase cells did not change significantly. Conclusion Down-regulating the KHDRBS3 gene can cause G0/G1 phase arrest and inhibit cell proliferation in CAOV-3 cells.

PAK4 regulates G6PD activity by p53 degradation involving colon cancer cell growth.

The p21-activated kinase 4 (PAK4) is overexpressed in different cancers and promotes proliferation of cancer cells. Reprogramming of glucose metabolism is found in most cancer cells which in turn supports rapid proliferation. However, the relationship between PAK4 and glucose metabolism in cancer cells has not been explored. In this study, we reported that PAK4 promoted glucose intake, NADPH production and lipid biosynthesis, leading to an increased proliferation of colon cancer cells. Mechanistically, PAK4 interacted with glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway and increased G6PD activity via enhancing Mdm2-mediated p53 ubiquitination degradation. In addition, we demonstrated a close positive correlation between PAK4 and G6PD expression in colon cancer specimens. Furthermore, expression of PAK4 or G6PD was positively correlated with an aggressive phenotype of clinical colon cancer. These findings revealed a novel glucose metabolism-related mechanism of PAK4 in promoting colon cancer cell growth, suggesting that PAK4 and/or G6PD blockage might be a potential therapeutic strategy for colon cancer.

Quantitation of wall teichoic acid in Staphylococcus aureus by direct measurement of monomeric units using LC-MS/MS.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created an urgent need for new therapeutic agents capable of combating this threat. We have previously reported on the discovery of novel inhibitors targeting enzymes involved in the biosynthesis of wall teichoic acid (WTA) and demonstrated that these agents can restore ß-lactam efficacy against MRSA. In those previous reports pathway engagement of inhibitors was demonstrated by reduction in WTA levels measured by polyacrylamide gel electrophoresis. To enable a more rigorous analysis of these inhibitors we sought to develop a quantitative method for measuring whole-cell reductions in WTA. Herein we describe a robust methodology for hydrolyzing polymeric WTA to the monomeric component ribitol-N-acetylglucosamine coupled with measurement by LC-MS/MS. Critical elements of the protocol were found to include the time and temperature of hydrofluoric acid-mediated hydrolysis of polymeric WTA and optimization of these parameters is fully described. Most significantly, the assay enabled accurate and reproducible measurement of depletion EC50s for tunicamycin and representatives from the novel class of TarO inhibitors, the tarocins. The method described can readily be adapted to quantifying levels of WTA in tissue homogenates from a murine model of infection, highlighting the applicability for both in vitro and in vivo characterizations.

The Renal Outer Medullary Potassium Channel Inhibitor, MK-7145, Lowers Blood Pressure, and Manifests Features of Bartter's Syndrome Type II Phenotype.

The renal outer medullary potassium (ROMK) channel, located at the apical surface of epithelial cells in the thick ascending loop of Henle and cortical collecting duct, contributes to salt reabsorption and potassium secretion, and represents a target for the development of new mechanism of action diuretics. This idea is supported by the phenotype of antenatal Bartter's syndrome type II associated with loss-of-function mutations in the human ROMK channel, as well as, by cardiovascular studies of heterozygous carriers of channel mutations associated with type II Bartter's syndrome. Although the pharmacology of ROMK channels is still being developed, channel inhibitors have been identified and shown to cause natriuresis and diuresis, in the absence of any significant kaliuresis, on acute oral dosing to rats or dogs. Improvements in potency and selectivity have led to the discovery of MK-7145 [5,5'-((1R,1'R)-piperazine-1,4-diylbis(1-hydroxyethane-2,1-diyl))bis(4-methylisobenzofuran-1(3H)-one)], a potential clinical development candidate. In spontaneously hypertensive rats, oral dosing of MK-7145 causes dose-dependent lowering of blood pressure that is maintained during the entire treatment period, and that displays additive/synergistic effects when administered in combination with hydrochlorothiazide or candesartan, respectively. Acute or chronic oral administration of MK-7145 to normotensive dogs led to dose-dependent diuresis and natriuresis, without any significant urinary potassium losses or changes in plasma electrolyte levels. Elevations in bicarbonate and aldosterone were found after 6 days of dosing. These data indicate that pharmacological inhibition of ROMK has potential as a new mechanism for the treatment of hypertension and/or congestive heart failure. In addition, Bartter's syndrome type II features are manifested on exposure to ROMK inhibitors.

Extended dissipative state estimation for memristive neural networks with time-varying delay.

This paper investigates the problem of extended dissipative state estimation for memristor-based neural networks (MNNs) with time-varying delay. Based on both nonsmooth analysis and the construction of a new Lyapunov-Krasovskii functional, the extended dissipative state estimation criteria are obtained by mainly applying differential inclusions, set-valued maps and many new integral inequalities. The extended dissipative state estimation can be adopted to deal with l2-l∞ state estimation, H∞ state estimation, passive state estimation and dissipative state estimation by valuing the corresponding weighting matrices. Finally, two numerical examples are given to show the effectiveness and less conservatism of the proposed criteria.