Gestational supplementation of Bifidobacterium, Lactobacillus, and Streptococcus thermophilus attenuates hepatic steatosis in offspring mice through promoting fatty acid ß-oxidation.

Currently, Bifidobacterium, Lactobacillus, and Streptococcus thermophilus (BLS) are widely recognized as the crucially beneficial bacteria in the gut. Many preclinical and clinical studies have shown their protective effects against non-alcoholic fatty liver disease (NAFLD). However, whether gestational BLS supplementation could alleviate NAFLD in the offspring is still unknown. Kunming mice were given a high-fat diet (HFD) for 4 weeks before mating. They received BLS supplementation by gavage during pregnancy. After weaning, offspring mice were fed with a regular diet up to 5 weeks old. Gestational BLS supplementation significantly increased the abundance of Actinobacteriota, Bifidobacterium, and Faecalibaculum in the gut of dams exposed to HFD. In offspring mice exposed to maternal HFD, maternal BLS intake significantly decreased the ratio of Firmicutes to Bacteroidetes as well as the relative abundance of Prevotella and Streptococcus, but increased the relative abundance of Parabacteroides. In offspring mice, maternal BLS supplementation significantly decreased the hepatic triglyceride content and mitigated hepatic steatosis. Furthermore, maternal BLS supplementation increased the glutathione content and reduced malondialdehyde content in the liver. In addition, mRNA and protein expression levels of key rate-limiting enzymes in mitochondrial ß-oxidation (CPT1α, PPARα, and PGC1α) in the livers of offspring mice were significantly increased after gestational BLS supplementation. Thus, gestational BLS supplementation may ameliorate maternal HFD-induced steatosis and oxidative stress in the livers of offspring mice by modulating fatty acid ß-oxidation.

Lipid accumulation product is a valid predictor of hepatic steatosis and nonalcoholic fatty liver disease.

Aims: To evaluate and compare lipid accumulation product (LAP) with alanine aminotransferase (ALT), aspartate aminotransferase (AST), visceral adiposity index (VAI) and triglyceride-glucose index (TyG) as biomarkers for hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Methods: LAP, ALT, AST, VAI and TyG were measured in 52 biopsy-proven NAFLD patients and 21 control subjects. Additionally, LAP was also measured in 448 ultrasound-proven NAFLD patients and 1009 control subjects. Results: LAP was positively associated with hepatic steatosis and inflammation in biopsy-proven NAFLD. The risk of NAFLD was positively related to LAP and TyG, but LAP showed a better area under the receiver operating characteristic curve for hepatic steatosis and NAFLD. LAP also performed well in recognizing ultrasound-proven NAFLD. Conclusion: LAP is an ideal biomarker of hepatic steatosis and NAFLD.

"Leader-Follower" Dynamic Perturbation Manipulates Multi-Item Working Memory in Humans.

Manipulating working memory (WM) is a central yet challenging notion. Previous studies suggest that WM items with varied memory strengths reactivate at different latencies, supporting a time-based mechanism. Motivated by this view, here we developed a purely bottom-up "Leader-Follower" behavioral approach to manipulate WM in humans. Specifically, task-irrelevant flickering color disks that are bound to each of the memorized items are presented during the delay period, and the ongoing luminance sequences of the color disks follow a Leader-Follower relationship, that is, a hundreds of milliseconds temporal lag. We show that this dynamic behavioral approach leads to better memory performance for the item associated with the temporally advanced luminance sequence (Leader) than the item with the temporally lagged luminance sequence (Follower), yet with limited effectiveness. Together, our findings constitute evidence for the essential role of temporal dynamics in WM operation and offer a promising, noninvasive WM manipulation approach.

Maternal Betaine Supplementation Mitigates Maternal High Fat Diet-Induced NAFLD in Offspring Mice through Gut Microbiota.

Maternal betaine supplementation has been proven to alleviate non-alcoholic fatty liver disease (NAFLD) in offspring caused by maternal high-fat diet (MHFD). The gut-liver axis plays an important role in NAFLD pathogenesis. However, whether maternal betaine supplementation can alleviate NAFLD in offspring by the gut-liver axis is unknown. C57BL/6J mice were fed with high-fat diet for 4 weeks before mating, and supplemented with 1% betaine during pregnancy and lactation. After weaning, offspring mice were fed with standard diet to 10 weeks. Maternal betaine supplementation reduced hepatic triglyceride content and alleviated hepatic steatosis in offspring mice exposed to MHFD. Furthermore, the mRNA expression of PPARα, CPT1α and FATP2 was increased and TNFα was reduced by maternal betaine supplementation. Maternal betaine intake decreased the relative abundances of Proteobateria, Desulfovibrio and Ruminococcus, but increased the relative abundances of Bacteroides and Parabacteroides. Moreover, maternal betaine intake increased the concentrations of short-chain fatty acids (SCFAs), including acetic acid, butyric acid and valeric acid, in the feces. Gut microbiota and SCFAs were significantly correlated with hepatic triglyceride content and expression of the above genes. Maternal betaine intake had no effect on other gut microbiota-related metabolites (bile acid and trimethylamine-n-oxide). Altogether, maternal betaine supplementation ameliorated MHFD-induced NAFLD possibly through regulating gut microbiota and SCFAs in offspring mice.

Sequence structure organizes items in varied latent states of working memory neural network.

In memory experiences, events do not exist independently but are linked with each other via structure-based organization. Structure context largely influences memory behavior, but how it is implemented in the brain remains unknown. Here, we combined magnetoencephalogram (MEG) recordings, computational modeling, and impulse-response approaches to probe the latent states when subjects held a list of items in working memory (WM). We demonstrate that sequence context reorganizes WM items into distinct latent states, that is, being reactivated at different latencies during WM retention, and the reactivation profiles further correlate with recency behavior. In contrast, memorizing the same list of items without sequence task requirements weakens the recency effect and elicits comparable neural reactivations. Computational modeling further reveals a dominant function of sequence context, instead of passive memory decaying, in characterizing recency effect. Taken together, sequence structure context shapes the way WM items are stored in the human brain and essentially influences memory behavior.

Temporally coherent perturbation of neural dynamics during retention alters human multi-item working memory.

Temporarily storing a list of items in working memory (WM), a fundamental ability in cognition, has been posited to rely on the temporal dynamics of multi-item neural representations during retention. However, the causal evidence, particularly in human subjects, is still lacking, let alone WM manipulation. Here, we develop a novel "dynamic perturbation" approach to manipulate the relative memory strength of WM items held in human brain, by presenting temporally correlated luminance sequences during retention to interfere with the multi-item neural dynamics. Six experiments on more than 150 subjects confirm the effectiveness of this WM manipulation approach. A computational model combining continuous attractor neural network (CANN) and short-term synaptic plasticity (STP) principles further reproduces all the empirical findings. The model reveals that the "dynamic perturbation" modifies the synaptic efficacies of WM items through STP principles, eventually leading to changes in their relative memory strengths. Our results support the causal role of temporal dynamics of neural network in mediating multi-item WM, and offer a promising, purely bottom-up approach to manipulate WM.

Saliency-based Rhythmic Coordination of Perceptual Predictions.

Objects, shown explicitly or held in mind internally, compete for limited processing resources. Recent studies have demonstrated that attention samples locations and objects rhythmically. Interestingly, periodic sampling not only operates over objects in the same scene but also occurs for multiple perceptual predictions that are held in attention for incoming inputs. However, how the brain coordinates perceptual predictions that are endowed with different levels of bottom-up saliency information remains unclear. To address the issue, we used a fine-grained behavioral measurement to investigate the temporal dynamics of processing of high- and low-salient visual stimuli, which have equal possibility to occur within experimental blocks. We demonstrate that perceptual predictions associated with different levels of saliency are organized via a theta-band rhythmic course and are optimally processed in different phases within each theta-band cycle. Meanwhile, when the high- and low-salient stimuli are presented in separate blocks and thus not competing with each other, the periodic behavioral profile is no longer present. In summary, our findings suggest that attention samples and coordinates multiple perceptual predictions through a theta-band rhythm according to their relative saliency. Our results, in combination with previous studies, advocate the rhythmic nature of attentional process.

Fast-backward replay of sequentially memorized items in humans.

Storing temporal sequences of events (i.e., sequence memory) is fundamental to many cognitive functions. However, it is unknown how the sequence order information is maintained and represented in working memory and its behavioral significance, particularly in human subjects. We recorded electroencephalography (EEG) in combination with a temporal response function (TRF) method to dissociate item-specific neuronal reactivations. We demonstrate that serially remembered items are successively reactivated during memory retention. The sequential replay displays two interesting properties compared to the actual sequence. First, the item-by-item reactivation is compressed within a 200 - 400 ms window, suggesting that external events are associated within a plasticity-relevant window to facilitate memory consolidation. Second, the replay is in a temporally reversed order and is strongly related to the recency effect in behavior. This fast-backward replay, previously revealed in rat hippocampus and demonstrated here in human cortical activities, might constitute a general neural mechanism for sequence memory and learning.

Have you ever played the 'Memory Maze Challenge' game, or its predecessor from the 1980s, 'Simon'? Players must memorize a sequence of colored lights, and then reproduce the sequence by tapping the colors on a pad. The sequence becomes longer with each trial, making the task more and more difficult. One wrong response and the game is over. Storing and retrieving sequences is key to many cognitive processes, from following speech to hitting a tennis ball to recalling what you did last week. Such tasks require memorizing the order in which items occur as well as the items themselves. But how do we hold this information in memory? Huang et al. reveal the answer by using scalp electrodes to record the brain activity of healthy volunteers as they memorize and then recall a sequence. Memorizing, or encoding, each of the items in the sequence triggered a distinct pattern of brain activity. As the volunteers held the sequence in memory, their brains replayed these activity patterns one after the other. But this replay showed two non-intuitive features. First, it was speeded up relative to the original encoding. In fact, the brain compressed the entire sequence into about 200 to 400 milliseconds. Second, the brain replayed the sequence backwards. The activity pattern corresponding to the last item was replayed first, while that corresponding to the first item was replayed last. This 'fast-backward' replay may explain why we tend to recall items at the end of a list better than those in the middle, a phenomenon known as the recency effect. The results of Huang et al. suggest that when we hold a list of items in memory, the brain does not replay the list in its original form, like an echo. Instead, the brain restructures and reorganizes the list, compressing and reversing it. This process, which is also seen in rodents, helps the brain to incorporate the list of items into existing neuronal networks for memory storage.

Inhibition of canonical WNT/ß-catenin signaling is involved in leflunomide (LEF)-mediated cytotoxic effects on renal carcinoma cells.

Leflunomide (LEF), an inhibitor of dihydroorotate dehydrogenase (DHODH) in pyrimidine biosynthetic pathway, is an immunomodulatory agent approved for the treatment of rheumatoid arthritis. In this study, we show that LEF significantly reduced cell proliferation of renal carcinoma cells in a concentration-dependent manner. LEF at 50 µM induced S-phase arrest and autophagy. Higher doses of LEF (>50 µM) effectively induced cell apoptosis. Modulating the concentration of LEF resulted in distinct effects on the expression of regulatory proteins associated with cell cycle, apoptosis, and autophagy. In particular, high concentrations of LEF inhibited canonical WNT signaling by promoting nucleo-cytoplasmic shuttling and proteasome-dependent degradation of ß-catenin. Mechanistic studies showed that the repression of AKT activation partly accounted for LEF-mediated WNT inhibition. Gene expression microarray revealed that LEF treatment greatly inhibited the expression of FZD10 gene, a receptor mediating WNT/ß-catenin activation. In vivo xenograft study in NOD/SCID mice further validated the inhibitory effects of LEF on tumor growth and Wnt/ß-catenin signaling. However, LEF treatment also triggered cell autophagy and elevated the expression of WNT3a, which ameliorated its cytotoxic effects. The combination of LEF with a WNT inhibitor IWP-2 or autophagy inhibitor HCQ could yield an enhanced anti-tumor outcome. Taken together, these results identify the potential utility and pharmacological feature of LEF in the chemotherapy of renal cell carcinoma (RCC).

Hydrothermal Synthesis of BiFeO3 Nanoparticles for Visible Light Photocatalytic Applications.

Bismuth ferrite is a promising material for visible light response photocatalytic applications due to its narrow band gap. In this work, single crystalline BiFeO3 nanoparticles were prepared by a modified hydrothermal process. The effects of hydrothermal temperature, reaction time and precursor xerogel amoumt on the as-prepared BiFeO3 particle size and morphology were investigated by XRD, TEM and HRTEM. The XRD analysis reveals that single crystalline BiFeO3 particles can be obtained when the hydrothermal temperature is kept below 220 degrees C. TEM observation showed that the as-formed BFO particles are in a square or rectangle-like shape and that the particle size is increased with increasing hydrothermal temperature. The hydrothermal reaction time and the amount of xerogel could also influence the as-formed BFO particle morphology and size. The band gap of the as-prepared BFO nanoparticles was identified by UV-vis diffuse reflectance spectrum. The measurement of photodegradation of methyl orange dye in an aqueous solution revealed that the as-prepared BFO nanoparticles exhibit photocatalytic activity under visible light irradiation.

Induction of chemoresistance by all-trans retinoic acid via a noncanonical signaling in multiple myeloma cells.

Despite the successful application of all-trans retinoic acid (ATRA) in multiple myeloma treatment, ATRA-induced chemoresistance in the myeloma patients is very common in clinic. In this study, we evaluated the effect of ATRA on the expression of apurinic endonuclease/redox factor-1 (Ape/Ref-1) in the U266 and RPMI-8226 myeloma cells to explore the chemoresistance mechanism involved. ATRA treatment induced upregulation of Ape/Ref-1 via a noncanonical signaling pathway, leading to enhanced pro-survival activity counteracting melphalan (an alkylating agent). ATRA rapidly activated p38-MSK (mitogen- and stress activated protein kinase) cascade to phosphorylate cAMP response element-binding protein (CREB). Phosphorylated CREB was recruited to the Ape/Ref-1 promoter to evoke the gene expression. The stimulation of ATRA on Ape/Ref-1 expression was attenuated by either p38-MSK inhibitors or overexpression of dominant-negative MSK1 mutants. Moreover, ATRA-mediated Ape/Ref-1 upregulation was correlated with histone modification and activation of CBP/p300, an important cofactors for CREB transcriptional activity. C646, a competitive CBP/p300 inhibitor, abolished the upregulation of Ape/Ref-1 induced by ATRA. Intriguingly, CBP rather than p300 played a dominant role in the expression of Ape/Ref-1. Hence, our study suggests the existence of a noncanonical mechanism involving p38-MSK-CREB cascade and CBP induction to mediate ATRA-induced Ape/Ref-1 expression and acquired chemoresistance in myeloma cells.