MTH1 inhibition synergizes with ROS-inducing agents to trigger cervical cancer cells undergoing parthanatos.

Cervical cancer cells possess high levels of reactive oxygen species (ROS); thus, increasing oxidative stress above the toxicity threshold to induce cell death is a promising chemotherapeutic strategy. However, the underlying mechanisms of cell death are elusive, and efficacy and toxicity issues remain. Within DNA, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent base lesion repaired by 8-oxoguanine glycosylase 1 (OGG1)-initiated base excision repair. Cancer cells also express high levels of MutT homolog 1 (MTH1), which prevents DNA replication-induced incorporation of 8-oxoG into the genome by hydrolyzing 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Here, we revealed that ROS-inducing agents triggered cervical cancer to undergo parthanatos, which was mainly induced by massive DNA strand breaks resulting from overwhelming 8-oxoG excision by OGG1. Furthermore, the MTH1 inhibitor synergized with a relatively low dose of ROS-inducing agents by enhancing 8-oxoG loading in the DNA. In vivo, this drug combination suppressed the growth of tumor xenografts, and this inhibitory effect was significantly decreased in the absence of OGG1. Hence, the present study highlights the roles of base repair enzymes in cell death induction and suggests that the combination of lower doses of ROS-inducing agents with MTH1 inhibitors may be a more selective and safer strategy for cervical cancer chemotherapy.

Sub-chronic exposure to hexaconazole affects the lipid metabolism of rats through mTOR-PPAR-γ/SREBP1 signaling pathway mediated by oxidative stress.

Hexaconazole (Hex) is a widely used and high frequency detected triazole fungicide in agricultural products and environment which may pose potential toxicity to the nontargeted organisms. Hex had been reported to affect lipid homeostasis while the mechanism was undefined. This study aims to explore the characteristic lipidomic profiles and clarify the underlying signaling pathways of Hex-induced lipid metabolism disorder in rat liver. The results showed that sub-chronic exposure to environmental related concentrations of Hex caused histopathological changes, oxidative stress, fat accumulation, lipid biochemical parameter increase in rats. Moreover, the untargeted lipidomic analysis showed that the levels of TAG, PC, and PE and the pathway of glycerophospholipid metabolism were heavily altered by Hex. We further analyzed the lipid metabolism related genes and proteins which revealed that Hex exposure increased amount of lipogenesis by activating oxidative stress-mediated mTOR-PPAR-γ/SREBP1 signaling pathways. The imbalance of lipid homeostasis induced by Hex exposure might further lead to obesity, cardiovascular diseases (CVDs), and hyperlipidemia. Our results provided systematic and comprehensive evidence for the mechanism of Hex-induced lipid metabolism disorder at environmental concentrations and supplied a certain basis for its health risks assessment.

An Ultraflexible Electrode Array for Large-Scale Chronic Recording in the Nonhuman Primate Brain.

Single-unit (SU) recording in nonhuman primates (NHPs) is indispensible in the quest of how the brain works, yet electrodes currently used for the NHP brain are limited in signal longevity, stability, and spatial coverage. Using new structural materials, microfabrication, and penetration techniques, we develop a mechanically robust ultraflexible, 1 µm thin electrode array (MERF) that enables pial penetration and high-density, large-scale, and chronic recording of neurons along both vertical and horizontal cortical axes in the nonhuman primate brain. Recording from three monkeys yields 2,913 SUs from 1,065 functional recording channels (up to 240 days), with some SUs tracked for up to 2 months. Recording from the primary visual cortex (V1) reveals that neurons with similar orientation preferences for visual stimuli exhibited higher spike correlation. Furthermore, simultaneously recorded neurons in different cortical layers of the primary motor cortex (M1) show preferential firing for hand movements of different directions. Finally, it is shown that a linear decoder trained with neuronal spiking activity across M1 layers during monkey's hand movements can be used to achieve on-line control of cursor movement. Thus, the MERF electrode array offers a new tool for basic neuroscience studies and brain-machine interface (BMI) applications in the primate brain.

Effect of Processing on Reduction in Chiral Pesticide Hexaconazole for Kiwifruit Juice.

In this study, the residue levels of chiral pesticide hexaconazole during kiwifruit juice processing (peeling, homogenization, and sterilization) were investigated by using high-performance liquid chromatography (HPLC), and the dietary risk during these processes was also assessed. Hexaconazole was applied at dosages of 173.33 and 346.66 mg/L (recommended and double recommended dosage) in kiwifruit. In the peeling process, 87.7% to 89.2% of the residues were decreased after peeling. Levels of hexaconazole residues in homogenization and sterilization processes further increased from 0.49% to 24.3% and from 0.2% to 3.0%, respectively. Processing factors (PFs) for (+)- and (-)-hexaconazole after peeling, homogenization, and sterilization were 0.12, 0.88, 0.99 for low-dose treatment and 0.12, 0.87, 0.99 for high-dose treatment, respectively. The enantioselectivity of hexaconazole during these procedures was evaluated by enantiomeric fractions (EFs) values, which were around 0.5 throughout all the procedures, indicating that hexaconazole enantiomers had similar dissipation behaviors during kiwifruit juice processing. The RQc of hexaconazole in pre-peeling samples was significantly greater than 100% under two dosages, while the peeling process can notably decrease the values to an acceptable level. The results of this study could provide guidance for agriculture applications and kiwi commodity production to decrease the risk of hexaconazole residue.

Quantitative analysis of the current status and research trends of biochar research - A scientific bibliometric analysis based on global research achievements from 2003 to 2023.

Biochar has excellent physical and chemical properties such as porosity, high carbon content, high cation exchange capacity, and rich surface functional groups and has been widely used in environmental remediation. Over the past 20 years, although various reviews have described the application of biochar as an environmentally friendly multifunctional material in environmental remediation, no comprehensive summary and analysis of the research trends in this field exists. To promote the rapid and stable development of the field of biochar, the current state of research on biochar is clarified using the bibliometric method in this report, and potential development directions and challenges for the future are identified. All relevant biochar literature from 2003-2023 was collected from the Chinese National Knowledge Infrastructure and Web of Science Core Collection. A total of 6,119 published Chinese papers and 25,174 English papers were selected for the quantitative analysis. CiteSpace, VOSviewer, and Scimago graphics software was used to summarize the numbers of papers published over the years, as well as the countries, institutions, and authors that published the most articles. Secondly, using keyword co-occurrence and emergence analysis, the recognized research hotspots in different areas such as adsorbents, soil remediation, catalytic oxidation, supercapacitors, and "biochar-microbial" synergy were analyzed. Finally, the prospects and challenges of biochar were assessed to provide new perspectives for further promoting its development in technological, economic, environmental, and other aspects.

Optimal policy for uncertainty estimation concurrent with decision making.

Decision making often depends on vague information that leads to uncertainty, which is a quantity contingent not on choice but on probability distributions of sensory evidence and other cognitive variables. Uncertainty may be computed in parallel and interact with decision making. Here, we adapt the classic random-dot motion direction discrimination task to allow subjects to indicate their uncertainty without having to form a decision first. The subjects' choices and reaction times for perceptual decisions and uncertainty responses are measured, respectively. We then build a value-based model in which decisions are based on optimizing value computed from a drift-diffusion process. The model accounts for key features of subjects' behavior and the variation across the individuals. It explains how the addition of the uncertainty option affects perceptual decision making. Our work establishes a value-based theoretical framework for studying uncertainty and perceptual decisions that can be readily applied in future investigations of the underlying neural mechanism.

Stereoselective Iron-Catalyzed Alkylation of Enamides with Cyclopropanols via Oxidative C(sp2)-H Functionalization.

Established herein is a radical-mediated C-H alkylation of enamides with cyclopropanols. An environmentally benign catalytic system with iron salt and air is used to permit the oxidative coupling process. The protocol demonstrates a broad substrate scope, allowing the stereoselective synthesis of alkylated enamides. The value of this strategy is further reflected by late-stage diversification of complex cyclopropanol-containing molecules and downstream transformations. Mechanistic studies reveal the dual role of iron salt in the reaction.

Accumulation of evidence during decision making in OCD patients.

Decision-making often entails the accumulation of evidence. Previous studies suggested that people with obsessive-compulsive disorder (OCD) process decision-making differently from healthy controls. Both their compulsive behavior and obsessive thoughts may influence the evidence accumulation process, yet the previous studies disagreed on the reason. To address this question, we employed a probabilistic reasoning task in which subjects made two alternative forced choices by viewing a series of visual stimuli. These stimuli carried probabilistic information toward the choices. While the OCD patients achieved similar accuracy to the control, they took longer time and accumulated more evidence, especially in difficult trials in which the evidence strength was low. We further modeled the subjects' decision making as a leaky drifting diffusion process toward two collapsing bounds. The control group showed a higher drifting rate than the OCD group, indicating that the OCD group was less sensitive to evidence. Together, these results demonstrated that the OCD patients were less efficient than the control at transforming sensory information into evidence. However, their evidence accumulation was comparable to the healthy control, and they compensated for their decision-making accuracy with longer reaction times.

Reward salience but not spatial attention dominates the value representation in the orbitofrontal cortex.

The orbitofrontal cortex (OFC) encodes value and plays a key role in value-based decision-making. However, the attentional modulation of the OFC's value encoding is poorly understood. We trained two monkeys to detect a luminance change at a cued location between a pair of visual stimuli, which were over-trained pictures associated with different amounts of juice reward and, thus, different reward salience. Both the monkeys' behavior and the dorsolateral prefrontal cortex neuronal activities indicated that the monkeys actively directed their spatial attention toward the cued stimulus during the task. However, the OFC's neuronal responses were dominated by the stimulus with higher reward salience and encoded its value. The value of the less salient stimulus was only weakly represented regardless of spatial attention. The results demonstrate that reward and spatial attention are distinctly represented in the prefrontal cortex and the OFC maintains a stable representation of reward salience minimally affected by attention.

Celastrol Targets Cullin-Associated and Neddylation-Dissociated 1 to Prevent Fibroblast-Myofibroblast Transformation against Pulmonary Fibrosis.

Celastrol (CEL), a pentacyclic triterpene compound, has been proven to have a definite antipulmonary fibrosis effect. However, its direct targets for antipulmonary fibrosis remain unknown. In this study, we designed and synthesized a series of celastrol-based probes to identify the direct targets in human pulmonary fibroblasts using an activity-based protein profiling strategy. Among many fished targets, we identified a key protein, cullin-associated and neddylation-dissociated 1 (CAND1), which was involved in fibroblast-myofibroblast transformation (FMT). More importantly, we found that the inhibitory effect of celastrol on FMT is dependent on CAND1, through improving the interactions between CAND1 and Cullin1 to promote the activity of Skp1/Cullin1/F-box ubiquitin ligases. In silico studies and cysteine mutation experiments further demonstrated that Cys264 of CAND1 is the site for conjugation of celastrol. This reveals a new mechanism of celastrol against pulmonary fibrosis and may provide a novel therapeutic option for antipulmonary fibrosis.

Nontargeted metabolomics coupled with multivariate modelling techniques for discrimination of Cyclocarya paliurus (Batal.) Ijinskaja leaves from different geographic altitudes.

Altitude-associated nutrition-compositional evaluation is critical for quality control and value determination of plants. Herein, an exploratory study was applied to investigate the differences in the metabolites of Cyclocarya paliurus (CP) leaves from different altitudes (200-1000 m) using a UPLC-QTOF-MS-based metabolomics method, employed to create models for discrimination of CP leaves. On the one hand, 70 metabolites exhibiting significant distinctions within various components in different altitude environments were detected and identified, of which majority showed a close connection. High altitude environments with a decrease in temperature accompanied by enhanced UV-B radiation significantly influenced the profile of flavonoids and organic acids. On the other hand, the PLS-DA model (R2 = 0.994 and Q2 = 0.990) with the VIP variable selection method and P-value were selected to characterize fifteen potential differential metabolites. Moreover, the DD-SIMCA model involving the above-mentioned differential compounds showed both good specificity and accuracy of 100%. These results provide guidance for the discrimination of CP leaves from different geographic altitudes, which may be extended to improve the growing conditions of CP leaves.

Evidence accumulation occurs locally in the parietal cortex.

Decision making often entails evidence accumulation, a process that is represented by neural activities in a network of multiple brain areas. Yet, it has not been identified where exactly the accumulation originates. We reason that a candidate brain area should both represent evidence accumulation and information that is used to compute evidence. Therefore, we designed a two-stage probabilistic reasoning task in which the evidence for accumulation had to be first determined from sensory signals orthogonal to decisions. With a linear encoding model, we decomposed the responses of posterior parietal neurons to each stimulus into an early and a late component that represented two dissociable stages of decision making. The former reflected the transformation from sensory inputs to accumulable evidence, and the latter reflected the accumulation of evidence and the formation of decisions. The presence of both computational stages indicates that evidence accumulation signal in the parietal cortex is computed locally.

Linking oxidative DNA lesion 8-OxoG to tumor development and progression.

Cells of the aerobic metabolic organism are inevitably subjected to the damage from reactive oxygen species (ROS). ROS cause multiple forms of DNA damage, among which the oxidation product of guanine G 8-hydroxyguanine (8-oxoG) is the most frequent DNA oxidative damage, recognized by the specific glycosidase OGG1 that initiates the base excision repair pathway. If left unrepaired, 8-oxoG may pair with A instead of C, leading to a mutation of G: C to T: A during replication. Thus, the accumulation of 8-oxoG or the abnormal OGG1 repair is thought to affect gene function, which in turn leads to the development of tumor or aging-related diseases. However, a series of recent studies have shown that 8-oxoG tends to be produced in regulatory regions of the genome. 8-oxoG can be regarded as an epigenetic modification, while OGG1 is a specific reader of this information. Substrate recognition, binding or resection by OGG1 can cause DNA conformation changes or affect histone modifications, causing up-regulation or down-regulation of genes with different properties. Thus, in addition to the potential genotoxicity, the association of guanine oxidative damage with development of tumors is closely related to its aberrant initiation of gene expression through epigenetic mechanisms. In this review, we summarize the underlying mechanism of 8-oxoG and repair enzyme OGG1 in tumor development and progression, with aims to interpret the relationship between DNA oxidative damage and tumor from a new perspective, and provide new ideas and targets for tumor treatment.

Monkey plays Pac-Man with compositional strategies and hierarchical decision-making.

Humans can often handle daunting tasks with ease by developing a set of strategies to reduce decision-making into simpler problems. The ability to use heuristic strategies demands an advanced level of intelligence and has not been demonstrated in animals. Here, we trained macaque monkeys to play the classic video game Pac-Man. The monkeys' decision-making may be described with a strategy-based hierarchical decision-making model with over 90% accuracy. The model reveals that the monkeys adopted the take-the-best heuristic by using one dominating strategy for their decision-making at a time and formed compound strategies by assembling the basis strategies to handle particular game situations. With the model, the computationally complex but fully quantifiable Pac-Man behavior paradigm provides a new approach to understanding animals' advanced cognition.

Geometry of sequence working memory in macaque prefrontal cortex.

How the brain stores a sequence in memory remains largely unknown. We investigated the neural code underlying sequence working memory using two-photon calcium imaging to record thousands of neurons in the prefrontal cortex of macaque monkeys memorizing and then reproducing a sequence of locations after a delay. We discovered a regular geometrical organization: The high-dimensional neural state space during the delay could be decomposed into a sum of low-dimensional subspaces, each storing the spatial location at a given ordinal rank, which could be generalized to novel sequences and explain monkey behavior. The rank subspaces were distributed across large overlapping neural groups, and the integration of ordinal and spatial information occurred at the collective level rather than within single neurons. Thus, a simple representational geometry underlies sequence working memory.

Coronaviruses Nsp5 Antagonizes Porcine Gasdermin D-Mediated Pyroptosis by Cleaving Pore-Forming p30 Fragment.

Coronaviruses (CoVs) are a family of RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals and humans. Here, we use porcine epidemic diarrhea virus (PEDV) as a model of CoVs to illustrate the reciprocal regulation between CoV infection and pyroptosis. For the first time, we elucidate the molecular mechanism of porcine gasdermin D (pGSDMD)-mediated pyroptosis and demonstrate that amino acids R238, T239, and F240 within pGSDMD-p30 are critical for pyroptosis. Furthermore, 3C-like protease Nsp5 from SARS-CoV-2, MERS-CoV, PDCoV, and PEDV can cleave pGSDMD at the Q193-G194 junction to produce two fragments unable to trigger pyroptosis. The two cleaved fragments could not inhibit PEDV replication. In addition, Nsp5 from SARS-CoV-2 and MERS-CoV also cleave human GSDMD (hGSDMD). Therefore, we provide clear evidence that PEDV may utilize the Nsp5-GSDMD pathway to inhibit pyroptosis and, thus, facilitate viral replication during the initial period, suggesting an important strategy for the coronaviruses to sustain their infection. IMPORTANCE Recently, GSDMD has been reported as a key executioner for pyroptosis. This study first demonstrates the molecular mechanism of pGSDMD-mediated pyroptosis and that the pGSDMD-mediated pyroptosis protects host cells against PEDV infection. Notably, PEDV employs its Nsp5 to directly cleave pGSDMD in favor of its replication. We found that Nsp5 proteins from other coronaviruses, such as porcine deltacoronavirus, severe acute respiratory syndrome coronavirus 2, and Middle East respiratory syndrome coronavirus, also had the protease activity to cleave human and porcine GSDMD. Thus, we provide clear evidence that the coronaviruses might utilize Nsp5 to inhibit the host pyroptotic cell death and facilitate their replication during the initial period, an important strategy for their sustaining infection. We suppose that GSDMD is an appealing target for the design of anticoronavirus therapies.

Evolution and neural representation of mammalian cooperative behavior.

Cooperation is common in nature and is pivotal to the development of human society. However, the details of how and why cooperation evolved remain poorly understood. Cross-species investigation of cooperation may help to elucidate the evolution of cooperative strategies. Thus, we design an automated cooperative behavioral paradigm and quantitatively examine the cooperative abilities and strategies of mice, rats, and tree shrews. We find that social communication plays a key role in the establishment of cooperation and that increased cooperative ability and a more efficient cooperative strategy emerge as a function of the evolutionary hierarchy of the tested species. Moreover, we demonstrate that single-unit activities in the orbitofrontal and prelimbic cortex in rats represent neural signals that may be used to distinguish between the cooperative and non-cooperative tasks, and such signals are distinct from the reward signals. Both signals may represent distinct components of the internal drive for cooperation.

Variations in phenolic acids and antioxidant activity of navel orange at different growth stages.

Ripe navel orange has abundant amounts of phenolic compounds. Few studies monitored changes in these compounds during ripening. In this study, the effects of navel orange maturation on dynamic changes in antioxidant activity, total phenolic content (TPC), total flavonoid content (TFC) and phenolic acids were investigated. Five growth stages of navel orange were studied, and nine phenolic acids were detected via high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-QQQ-MS). Results showed that antioxidant activity, TFC and TPC decreased gradually with fruit ripening. The concentrations of most phenolic acids also declined during fruit maturation, except for free fractions of sinapic acid and bound fractions of ferulic and caffeic acids. Ferulic acid was the most dominant of all phenolic acids at all growth stages. Partial least-squares showed significant differences among fruits of different maturities. A significant correlation between antioxidant capacity, TPC, TFC and some phenolic acids was found.

Nontargeted metabolomics reveals the discrimination of Cyclocarya paliurus leaves brewed by different methods.

An original way of brewing Cyclocarya paliurus leaves, especially in China, is to steep leaves in hot water before people drink it directly. Recently, infusing tea leaves with cold water, a creative way in Taiwan, has become a popular way of making tea. This study was designed to investigate the differences in metabolites among three brewing methods (cold-brewing, steep-brewing, and boil-brewing) based on UPLC-QTOF-MS metabolomics experiments and the feasibility of cold-brewing methods for C. paliurus leaves. Unsupervised analysis (PCA) explained 54.6% (positive ion mode) and 57.4% (negative ion mode) of the total variance, whereas supervised analysis (OPLS-DA) with cross-validated R2Y and Q2 values > 0.5, could reveal potential metabolites with better discrimination among the three brewing methods. Fifteen potential differential metabolites were chosen and identified, and nine of them were further confirmed with reference standards. This study suggested that the cold-brewing method without an increase in temperature protected the phenol aromatic ring, thereby obtaining more phenolic acid compounds from C. paliurus leaves. These results provided a basis for making cold tea and promoting the development of cold tea with C. paliurus leaves as raw materials.

A neural network model of basal ganglia's decision-making circuitry.

The basal ganglia have been increasingly recognized as an important structure involved in decision making. Neurons in the basal ganglia were found to reflect the evidence accumulation process during decision making. However, it is not well understood how the direct and indirect pathways of the basal ganglia work together for decision making. Here, we create a recurrent neural network model that is composed of the direct and indirect pathways and test it with the classic random dot motion discrimination task. The direct pathway drives the outputs, which are modulated through a gating mechanism controlled by the indirect pathway. We train the network to learn the task and find that the network reproduces the accuracy and reaction time patterns of previous animal studies. Units in the model exhibit ramping activities that reflect evidence accumulation. Finally, we simulate manipulations of the direct and indirect pathways and find that the manipulations of the direct pathway mainly affect the choice while the manipulations of the indirect pathway affect the model's reaction time. These results suggest a potential circuitry mechanism of the basal ganglia's role in decision making with predictions that can be tested experimentally in the future.