Factors influencing passage of time judgment in individuals' daily lives: evidence from the experience sampling and diary methods.

People often express feeling that time passes quickly or slowly in their daily lives, which is termed passage of time judgment (PoTJ). Past studies have shown that PoTJ is affected by emotional valence and arousal; however, few studies have verified the effects of alertness, attention to time, and time expectation on PoTJ and whether the effects are stable over different time periods. Using the experience sampling method (ESM) and diary method, the present study collected data from 105 participants and examined for the first time whether alertness, attention to time, and time expectation affect PoTJ based on daily life data, as well as whether above factors, emotional valence, and arousal are stable over different time periods. All participants answered a questionnaire five times a day on their in-the-day PoTJ and related factors regarding the last 30 min, and answered the same questionnaire once a day at 23:00 regarding the of-the-day PoTJ. The results showed that alertness and time expectation, as well as emotional valence and arousal, predicted an individual's in-the-day PoTJ over a shorter period (i.e., the last 30 min); in contrast, only time expectation and emotional arousal predicted of-the-day PoTJ over a longer period (i.e., the past day). These results suggest that, alertness and time expectation are important factors influencing PoTJ, in addition to emotional state. Of-the-day PoTJ correlates most strongly with the mean and latest in-the-day PoTJ, implying that overall perception of time passage is influenced by both cumulative temporal experience and recent temporal experience.

Effect of cortical extracellular GABA on motor response.

To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory cortical network ([Formula: see text]) and a motor cortical network ([Formula: see text]) are reciprocally connected, and the [Formula: see text] projects to spinal motoneurons (Mns). The [Formula: see text] was presented with a feature stimulus and the reaction time of Mns was measured. The flattening of sensory tuning in [Formula: see text] caused by decreasing the concentration of gamma-aminobutyric acid (GABA) in extracellular space resulted in a decrease in the stimulus-sensitive [Formula: see text] pyramidal cell activity while increasing the stimulus-insensitive [Formula: see text] pyramidal cell activity, thereby prolonging the reaction time of Mns to the applied feature stimulus. We suggest that a reduction in extracellular GABA concentration in sensory cortex may interfere with selective activation in motor cortex, leading to slowing the activation of spinal motoneurons and therefore to slowing motor responses.

Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma.

BACKGROUND: Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME. METHODS: Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor). RESULTS: We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC. CONCLUSIONS: Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

Perceptual judgments via sensory-motor interaction assisted by cortical GABA.

Recurrent input to sensory cortex, via long-range reciprocal projections between motor and sensory cortices, is essential for accurate perceptual judgments. GABA levels in sensory cortices correlate with perceptual performance. We simulated a neuron-astrocyte network model to investigate how top-down, feedback signaling from a motor network (Nmot) to a sensory network (Nsen) affects perceptual judgments in association with ambient (extracellular) GABA levels. In the Nsen, astrocytic transporters modulated ambient GABA levels around pyramidal cells. A simple perceptual task was implemented: detection of a feature stimulus presented to the Nsen. The Nmot showed distinct perceptual behaviors: hit, fault, and miss. A hit is a correct response to the stimulus, a fault is a wrong response to the stimulus, and a miss is no response to the stimulus. In hits, the feedback signaling increased the gain of Nsen pyramidal cells and accelerated the reaction speed of Nmot pyramidal cells to the stimulus. Without feedback signaling, the Nsen but not Nmot responded to the stimulus, resulting in a miss. With too strong feedback signaling, the Nmot resulted in a fault, namely, stimulus-insensitive but not stimulus-sensitive pyramidal cells wrongly responded. Balancing the feedforward and feedback signaling formed a coherent, ongoing-spontaneous neuronal state, by which the highest hit rate was achieved. A transient reduction in local ambient GABA levels, triggered by the stimulus, contributed to accelerating the reaction speed under noisy environmental conditions. Adjusting the basal ambient GABA level ensured high hit rates. We suggest that motor cortex feedback may accelerate reaction speed to sensory stimulation by promoting coherency in ongoing-spontaneous neuronal activity between sensory and motor cortices, thereby achieving prompt perceptual judgments. Spatiotemporal modulation of ambient GABA levels, possibly by astrocytic transporters, assists in making reliable perceptual judgments.

Improved Perceptual Learning by Control of Extracellular GABA Concentration by Astrocytic Gap Junctions.

Learning of sensory cues is believed to rely on synchronous pre- and postsynaptic neuronal firing. Evidence is mounting that such synchronicity is not merely caused by properties of the underlying neuronal network but could also depend on the integrity of gap junctions that connect neurons and astrocytes in networks too. In this perspective, we set out to investigate the effect of astrocytic gap junctions on perceptual learning, introducing a model for coupled neuron-astrocyte networks. In particular, we focus on the fact that astrocytes are rich of GABA transporters (GATs) which can either uptake or release GABA depending on the astrocyte membrane potential, which is a function of local neural activity. We show that GABAergic signaling is a crucial component of intracolumnar neuronal synchronization, thereby promoting learning by neurons in the same cell assembly that are activated by a shared sensory cue. At the same time, we show that this effect can critically depend on astrocytic gap junctions insofar as these latter could synchronize extracellular GABA levels around many neurons and throughout entire cell assemblies. These results are supported by extensive computational arguments and predict that astrocytic gap junctions could improve perceptual learning by controlling extracellular GABA.

Reduction of Trial-to-Trial Perceptual Variability by Intracortical Tonic Inhibition.

Variability is a prominent characteristic of cognitive brain function. For instance, different trials of presentation of the same stimulus yield higher variability in its perception: subjects sometimes fail in perceiving the same stimulus. Perceptual variability could be attributable to ongoing-spontaneous fluctuation in neuronal activity prior to sensory stimulation. Simulating a cortical neural network model, we investigated the underlying neuronal mechanism of perceptual variability in relation to variability in ongoing-spontaneous neuronal activity. In the network model, populations of principal cells (cell assemblies) encode information about sensory features. Each cell assembly is sensitive to one particular feature stimulus. Transporters on GABAergic interneurons regulate ambient GABA concentration in a neuronal activity-dependent manner. Ambient GABA molecules activate extrasynaptic GABAa receptors on principal cells and interneurons, and provide them with tonic inhibitory currents. We controlled the variability of ongoing-spontaneous neuronal activity by manipulating the basal level of ambient GABA and assessed the perceptual performance of the network: detection of a feature stimulus. In an erroneous response, stimulus-irrelevant but not stimulus-relevant principal cells were activated, generating trains of action potentials. Perceptual variability, reflected in error rate in detecting the same stimulus that was presented repeatedly to the network, was increased as the variability in ongoing-spontaneous membrane potential among cell assemblies increased. Frequent, transient membrane depolarization below firing threshold was the major cause of the increased neuronal variability, for which a decrease in basal ambient GABA concentration was responsible. We suggest that ambient GABA in the brain may have a role in reducing the variability in ongoing-spontaneous neuronal activity, leading to a decrease in perceptual variability and therefore to reliable sensory perception.

GABA diffusion across neuronal columns for efficient sensory tuning.

Synaptic (phasic) lateral inhibition between neuronal columns mediated by GABAergic interneurons is, in general, essential for primary sensory cortices to respond selectively to elemental features. We propose here a neural network model with a nonsynaptic (tonic) lateral inhibitory mechanism. While firing, intrasynaptic GABA molecules spill over into extracellular space and accumulate in neuronal columns. Through accumulation in and diffusion across these columns, a level of ambient (extracellular) GABA changes in a neuronal activity-dependent manner. Ambient GABA molecules act on extrasynaptic receptors and provide neurons with tonic inhibitory currents. We examined whether and how the diffusion of GABA molecules across neuronal columns affects tuning performance of the network to a feature stimulus: selective responsiveness. The GABA diffusion led to reducing ambient GABA in the stimulus-relevant column while augmenting ambient GABA in stimulus-irrelevant columns, thereby improving the tuning performance. The GABA diffusion was effective especially when provided with a broader sensory input. Interestingly, this diffusion-based, nonsynaptic (tonic) lateral inhibitory scheme worked well together with the conventional, synaptic (phasic) lateral inhibitory scheme, enhancing the sensory tuning. We suggest that the nonsynaptic lateral inhibition, mediated through GABA diffusion across neuronal columns, may be beneficial for the cortex to tune to sensory features.

Facilitation of neuronal responses by intrinsic default mode network activity.

Default mode network (DMN) shows intrinsic, high-level activity at rest. We tested a hypothesis proposed for its role in sensory information processing: Intrinsic DMN activity facilitates neural responses to sensory input. A neural network model, consisting of a sensory network (Nsen) and a DMN, was simulated. The Nsen contained cell assemblies. Each cell assembly comprised principal cells, GABAergic interneurons (Ia, Ib), and glial cells. We let the Nsen carry out a perceptual task: detection of sensory stimuli. During DMN activation, glial cells were hyperpolarized by Ia-to-glia circuitry, by which glial membrane transporters imported GABA molecules from the extracellular space and decreased ambient GABA concentration. Acting on extrasynaptic GABA receptors, the decrease in ambient GABA concentration reduced inhibitory current in a tonic manner. This depolarized principal cells below their firing threshold during the ongoing spontaneous time period and accelerated their reaction speed to a sensory stimulus. During the stimulus presentation period, the Nsen inhibited the DMN and caused DMN deactivation. The DMN deactivation made Nsen Ia cells cease firing, thereby stopping the glial membrane hyperpolarization, quitting the GABA import, returning to the basal ambient GABA level, and thus enhancing global inhibition. Notably, the stimulus-relevant P cell firing could be maintained when GABAergic gliotransmission via Ia-glia signaling worked, decreasing ambient GABA concentration around the stimulus-relevant P cells. This enabled the Nsen to reliably detect the stimulus. We suggest that intrinsic default model network activity may accelerate the reaction speed of the sensory network by modulating its ongoing-spontaneous activity in a subthreshold manner. Ambient GABA contributes to achieve an optimal ongoing spontaneous subthreshold neuronal state, in which GABAergic gliotransmission triggered by the intrinsic default model network activity may play an important role.

Tonically balancing intracortical excitation and inhibition by GABAergic gliotransmission.

For sensory cortices to respond reliably to feature stimuli, the balancing of neuronal excitation and inhibition is crucial. A typical example might be the balancing of phasic excitation within cell assemblies and phasic inhibition between cell assemblies. The former controls the gain of and the latter the tuning of neuronal responses. A change in ambient GABA concentration might affect the dynamic behavior of neurons in a tonic manner. For instance, an increase in ambient GABA concentration enhances the activation of extrasynaptic receptors, augments an inhibitory current, and thus inhibits neurons. When a decrease in ambient GABA concentration occurs, the tonic inhibitory current is reduced, and thus the neurons are relatively excited. We simulated a neural network model in order to examine whether and how such a tonic excitatory-inhibitory mechanism could work for sensory information processing. The network consists of cell assemblies. Each cell assembly, comprising principal cells (P), GABAergic interneurons (Ia, Ib), and glial cells (glia), responds to one particular feature stimulus. GABA transporters, embedded in glial plasma membranes, regulate ambient GABA levels. Hypothetical neuron-glia signaling via inhibitory (Ia-to-glia) and excitatory (P-to-glia) synaptic contacts was assumed. The former let transporters import (remove) GABA from the extracellular space and excited stimulus-relevant P cells. The latter let them export GABA into the extracellular space and inhibited stimulus-irrelevant P cells. The main finding was that the glial membrane transporter gave a combinatorial excitatory-inhibitory effect on P cells in a tonic manner, thereby improving the gain and tuning of neuronal responses. Interestingly, it worked cooperatively with the conventional, phasic excitatory-inhibitory mechanism. We suggest that the GABAergic gliotransmission mechanism may provide balanced intracortical excitation and inhibition so that the best perceptual performance of the cortex can be achieved.

Combined inhibition of HER2 and VEGFR synergistically improves therapeutic efficacy via PI3K-AKT pathway in advanced ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC. METHODS: OC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM. RESULTS: Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells. CONCLUSIONS: These findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.

Impaired proactive control in individuals with methamphetamine use disorder: Evidence from ERPs.

BACKGROUND: Research suggests that methamphetamine use is associated with impaired cognitive control, which may contribute to impulsive drug use. Cognitive control is dynamically mediated by proactive and reactive control (reflecting various processing stages of cognitive control with different properties), and it is crucial to determine whether methamphetamine use impairs proactive and/or reactive control. To address this issue, we conducted an event-related potential (ERP) study to examine proactive and reactive control in individuals with methamphetamine use disorder (MUD). METHODS: Abstinent individuals with MUD (n = 25) and healthy controls (HC, n = 27) completed a cued task-switching task while brain electrical activity was recorded. Cue- and target-locked ERP components modulated by task switching were linked to proactive and reactive control, respectively. RESULTS: No behavioral differences between the groups were found. However, the HC group showed cue-locked switch-positivity (i.e., more positive amplitudes for switch than repeat trials) in both the early and late time windows, although the MUD group only showed late switch-positivity, which was smaller than the HC group. Independent of switch or congruent condition, the MUD group had smaller target-locked positivity than the HC group. CONCLUSIONS: These findings suggest that individuals with MUD exhibit reduced proactive control and mobilize extra reactive control efforts to compensate. Our study contributes to a better understanding of cognitive control impairment in individuals with MUD and has implications for potential interventions.

Diffusive feedback influences on hierarchical information processing.

In visual information processing, feedforward projection from primary to secondary visual cortex (V1-to-V2) is essential for integrating combinations of oriented bars in order to extract angular information embedded within contours that represent the shape of objects. For feedback (V2-to-V1) projection, two distinct types of pathways have been observed: clustered projection and diffused projection. The former innervates V1 domains with a preferred orientation similar to that of V2 cells of origin. In contrast, the latter innervates without such orientation specificity. V2 cells send their axons to V1 domains with both similar and dissimilar orientation preferences. It is speculated that the clustered feedback projection has a role in contour integration. The role of the diffused feedback projection, however, remains to be seen. We simulated a minimal, functional V1-V2 neural network model. The diffused feedback projection contributed to achieving ongoing-spontaneous subthreshold membrane oscillations in V1 cells, thereby reducing the reaction time of V1 cells to a pair of bars that represents specific angular information. Interestingly, the feedback influence took place even before V2 responses, which might stem largely from ongoing-spontaneous signaling from V2. We suggest that the diffusive feedback influence from V2 could act early in V1 responses and accelerate their reaction speed to sensory stimulation in order to rapidly extract angular information.

Plasma Metabolites Forecast Occurrence and Prognosis for Patients With Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma with considerable heterogeneity and different clinical prognosis. However, plasma metabomics used to forecast occurrence and prognosis of DLBCL are rarely addressed. Method: A total of 65 volunteers including 22 healthy controls (Ctrl), 25 DLBCL patients newly diagnosed (ND), and 18 DLBCL patients achieving complete remission (CR) were enrolled. A gas chromatography mass spectrometry-based untargeted plasma metabolomics analysis was performed. Results: Multivariate statistical analysis displayed distinct metabolic features among Crtl, ND, and CR groups. Surprisingly, metabolic profiles of newly diagnosed DLBCL patients undergoing different prognosis showed clear and distinctive clustering. Based on the candidate metabolic biomarkers (glucose and aspartate) and clinical indicators (lymphocyte, red blood count, and hemoglobin), a distinct diagnostic equation was established showing improved diagnostic performance with an area under curve of 0.936. The enrichment of citric acid cycle, deficiency of branched chain amino acid, methionine, and cysteine in newly diagnosed DLBCL patients was closely associated with poor prognosis. In addition, we found that malate and 2-hydroxy-2-methylbutyric acid were positively correlated with the baseline tumor metabolic parameters (metabolically active tumor volume and total lesion glycolysis), and the higher abundance of plasma malate, the poorer survival. Conclusion: Our preliminary data suggested plasma metabolomics study was informative to characterize the metabolic phenotypes and forecast occurrence and prognosis of DLBCL. Malate was identified as an unfavorable metabolic biomarker for prognosis-prediction of DLBCL, which provided a new insight on risk-stratification and therapeutic targets of DLBCL. More studies to confirm these associations and investigate potential mechanisms are in the process.

Water-soluble chlorin e6-hydroxypropyl chitosan as a high-efficiency photoantimicrobial agent against Staphylococcus aureus.

The development of new antimicrobial agents is important to combat infections caused by pathogenic bacteria. Herein, Hydroxypropyl chitosan (HPCS), a hydrophilic modified product of chitosan (CS), was employed as a carrier of the photosensitizer chlorin e6 (Ce6) through an amide bond to obtain the products (HPCS-Ce6 conjugates) with a degree of substitution (DS) ranging from 2.95% to 5.25%. The UV-vis absorption spectra and 1H NMR spectra confirmed the successful synthesis of the products. The products have a better and more stable reactive oxygen species (ROS) generation capacity and higher bacterial affinity than Ce6. At a very low dose (1.8 µg/mL), the highest DS product (HPCS-Ce6-3) can effectively kill Staphylococcus aureus (S. aureus) under 660 nm irradiation. In addition, the HPCS-Ce6 conjugates showed high biocompatibility in the CCK-8 test. The HPCS-Ce6 conjugates could be a photodynamic antibacterial agent with good water solubility, high biocompatibility, and antibacterial activity.

ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation.

Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.

Insufficient augmentation of ambient GABA responsible for age-related cognitive deficit.

Age-related degeneration of intracortical inhibition could underlie declines in cognitive function during senescence. Based on a hypothesis that a decrease in basal concentration of ambient (extrasynaptic) GABA with aging leads to depressing intracortical inhibition, we investigated how the basal concentration affects stimulus-evoked activity (as signal), ongoing-spontaneous activity (as noise) of neurons and their (signal-to-noise) ratio S/N. We simulated a neural network model equipped with a GABA transport system that regulates ambient GABA concentration in a neuronal activity-dependent manner. An increase in basal concentration augmented ambient GABA, increased GABA-mediated inhibitory current, and depressed ongoing-spontaneous activity while still keeping stimulus-evoked activity. This led to S/N improvement, for which it was necessary for the reversal potential of GABA transporter to be close to the resting potential of neurons. Above the resting potential, ongoing-spontaneous activity was predominantly enhanced due to excessive GABA-uptake from the extracellular space by transporters. Below the resting potential, stimulus-evoked activity was predominantly depressed, caused by excessive GABA-release. We suggest that the insufficient augmentation of ambient GABA due to a decrease in its basal concentration may be one of the possible causes of cognitive deficit with aging, increasing ongoing-spontaneous neuronal activity as noise. GABA transporter may contribute to improving S/N, provided that its reversal potential is close to the resting potential.

Chlorin e6 conjugated chitosan as an efficient photoantimicrobial agent.

The development of antibacterial agents with high bacteria-binding capability and antibacterial efficiency is highly desirable. Herein, cationic polysaccharide chitosan (CS) was combined with photosensitizer Chlorin e6 (Ce6) to construct a novel photodynamic antibacterial agent (CS-Ce6 conjugates) for combating gram-positive bacteria Staphylococcus aureus (S. aureus) and gram-negative bacteria Escherichia coli (E. coli). CS-Ce6 conjugates with different degrees of substitution (DS) were synthesized and characterized by a spectroscopic method and organic elemental analysis to understand the relationship between structure and antibacterial effect. CS-Ce6 conjugates revealed good reactive oxygen species (ROS) generation ability and photodynamic antibacterial effect. Meanwhile, they both were positively correlated with DS in the range of 4.81% ~ 11.56% resulting in stronger photodynamic antibacterial ability. These findings highlight that CS-Ce6 conjugates have the potential as an effective photodynamic bactericidal agent in the antibacterial field.

Metabolomic approach to characterize the metabolic phenotypes and varied response to ouabain of diffuse large B-cell lymphoma cells.

Germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtype diffuse large B-cell lymphoma (DLBCL) showed differential prognosis. Our results suggested that ouabain induced stronger inhibition of growth in Su-DHL4 (GCB), and it triggered obvious apoptosis in Su-DHL4 rather than in OCI-Ly3 (ABC). Two subtype cell lines also showed distinct metabolic phenotypes involving remarkable enrichment of Ribulose-5-Phosphate, hypoxanthine, and guanine in Su-DHL4 cells. Ouabain disturbed metabolic patterns of both cell lines dose-dependently manifested inhibition of free fatty acids and amino acids metabolism, among which ornithine was further identified as potential quantitative marker. Up-regulated Ribulose-5-Phosphate and NADPH/NADP+ level, SOD1, and CAT expression by ouabain enabled OCI-Ly3 cells to resist ROS, while enhanced hypoxanthine and guanine oxidation promoting ROS generation by ouabain, and lowered capacity of scavenging ROS indicated by lowered SOD1 and CAT expression and NADPH/NADP+ levels in Su-DHL4 cells made it more vulnerable to apoptosis through caspase 7 pathway.

Metabolic markers for diagnosis and risk-prediction of multiple myeloma.

AIMS: To discriminate metabolic biomarkers for diagnosis and risk prediction of multiple myeloma (MM) on a basis of metabolic characteristics in systemic circulation and local pathogenic niche. MAIN METHODS: A gas chromatography mass spectrometry-based untargeted metabolomics analysis was performed within the bone marrow (BM) supernatants and peripheral plasma from healthy donors and patients with MM. KEY FINDINGS: Distinct metabolic features between MM patients and healthy volunteers were profiled in both BM and plasma. Metabolic profiles of subgroups in which MM patients undergo high/medium/low risk displayed risk-dependent metabolic shift especially in BM. In MM patients, up-regulated glutamate level and down-regulated glutamine level in BM indicated enhanced glutamate metabolism which provided NH4+ for ammonia utilization. This resulted in increased level of urea and creatinine produced from urea cycle, arginine and proline metabolism in both BM and plasma collected from MM patients. The disorders of tricarboxylic acid cycle and carnitine synthesis were unique in BM of MM patients. Receiver operating characteristic curve analysis indicated that aspartate was a candidate plasma biomarker for diagnosis with the highest sensitivity and specificity in both BM and plasma. Threonine was identified as a preferential plasma biomarker for risk prediction due to significant relation with various risk indexes of MM in both BM and plasma. SIGNIFICANCE: The perturbed glutamate metabolism and carnitine synthesis in BM of MM patients provided a new sight on pathogenesis of MM. The plasma level of aspartate and threonine may become a preferential metabolic marker for diagnosis and risk prediction of MM, respectively.

A general strategy to synthesis chitosan oligosaccharide-O-Terpenol derivatives with antibacterial properties.

The objectives of the present study are to synthesize a series of chitosan oligosaccharide-O-Terpenol (COS-O-Ter) derivatives and their implication to evaluate in vitro antibacterial activity. Herein, a general strategy is described for preparing COS-O-Ter derivatives, including substitution and deprotection reactions. The structures of COS-O-Ter derivatives were characterized by FT-IR, 1H NMR, XRD, TGA, and elemental analysis. COS-O-Ter derivatives revealed the excellent solubility and in vitro antibacterial activity. Moreover, their antibacterial activities were more sensitive to Staphylococcus aureus (S. aureus) than Escherichia coli (E. coli) indicating the effective potential application of COS-O-Ter derivatives as natural antibacterial agents. The aforementioned study opens a pave to expand the application scope of COS and its derivatives in the food and pharmaceutical industries.