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Behavioral flexibility relies on the brain's ability to switch rapidly between multiple tasks, even when the task rule is not explicitly cued but must be inferred through trial and error. The underlying neural circuit mechanism remains poorly understood. We investigated recurrent neural networks (RNNs) trained to perform an analog of the classic Wisconsin Card Sorting Test. The networks consist of two modules responsible for rule representation and sensorimotor mapping, respectively, where each module is comprised of a circuit with excitatory neurons and three major types of inhibitory neurons. We found that rule representation by self-sustained persistent activity across trials, error monitoring and gated sensorimotor mapping emerged from training. Systematic dissection of trained RNNs revealed a detailed circuit mechanism that is consistent across networks trained with different hyperparameters. The networks' dynamical trajectories for different rules resided in separate subspaces of population activity; the subspaces collapsed and performance was reduced to chance level when dendrite-targeting somatostatin-expressing interneurons were silenced, illustrating how a phenomenological description of representational subspaces is explained by a specific circuit mechanism.
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Modelos Neurológicos , Redes Neurais de Computação , Animais , Rede Nervosa/fisiologia , Neurônios/fisiologia , Interneurônios/fisiologia , Encéfalo/fisiologia , HumanosRESUMO
Interspecies comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of the strategies of female macaque monkeys to male and female humans on a variant of the Wisconsin Card Sorting Test (WCST), a widely studied and applied task that provides a multiattribute measure of cognitive function and depends on the frontal lobe. WCST performance requires the inference of a rule change given ambiguous feedback. We found that well-trained monkeys infer new rules three times more slowly than minimally instructed humans. Input-dependent hidden Markov model-generalized linear models were fit to their choices, revealing hidden states akin to feature-based attention in both species. Decision processes resembled a win-stay, lose-shift strategy with interspecies similarities as well as key differences. Monkeys and humans both test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidate choice options. We quantitatively show that perseveration, random exploration, and poor sensitivity to negative feedback account for the slower task-switching performance in monkeys.
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Macaca mulatta , Animais , Feminino , Masculino , Humanos , Adulto , Aprendizagem/fisiologia , Adulto Jovem , Especificidade da Espécie , Comportamento de Escolha/fisiologia , Tempo de Reação/fisiologiaRESUMO
The recent publications of the inter-areal connectomes for mouse, marmoset, and macaque cortex have allowed deeper comparisons across rodent vs. primate cortical organization. In general, these show that the mouse has very widespread, "all-to-all" inter-areal connectivity (i.e. a "highly dense" connectome in a graph theoretical framework), while primates have a more modular organization. In this review, we highlight the relevance of these differences to function, including the example of primary visual cortex (V1) which, in the mouse, is interconnected with all other areas, therefore including other primary sensory and frontal areas. We argue that this dense inter-areal connectivity benefits multimodal associations, at the cost of reduced functional segregation. Conversely, primates have expanded cortices with a modular connectivity structure, where V1 is almost exclusively interconnected with other visual cortices, themselves organized in relatively segregated streams, and hierarchically higher cortical areas such as prefrontal cortex provide top-down regulation for specifying precise information for working memory storage and manipulation. Increased complexity in cytoarchitecture, connectivity, dendritic spine density, and receptor expression additionally reveal a sharper hierarchical organization in primate cortex. Together, we argue that these primate specializations permit separable deconstruction and selective reconstruction of representations, which is essential to higher cognition.
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Callithrix , Cognição , Conectoma , Macaca , Animais , Camundongos , Cognição/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Córtex Cerebral/fisiologiaRESUMO
Ileostomy diverts the flow of feces, which can result in malnutrition in the distal part of the intestine. The diversity of the gut microbiota consequently decreases, ultimately leading to intestinal dysbiosis and dysfunction. This condition can readily result in diversion colitis (DC). Potential treatment strategies include interventions targeting the gut microbiota. In this case study, we effectively treated a patient with severe DC by ileostomy and allogeneic fecal microbiota transplantation (FMT). A 69-year-old man presented with a perforated malignant tumor in the descending colon and an iliac abscess. He underwent laparoscopic radical sigmoid colon tumor resection and prophylactic ileostomy. Follow-up colonoscopy 3 months postoperatively revealed diffuse intestinal mucosal congestion and edema along with granular inflammatory follicular hyperplasia, leading to a diagnosis of severe DC. After two rounds of allogeneic FMT, both the intestinal mucosal bleeding and edema significantly improved, as did the diversity of the gut microbiota. The positive outcome of allogeneic FMT in this case highlights the potential advantages that this procedure can offer patients with DC. However, few studies have focused on allogeneic FMT, and more in-depth research is needed to gain a better understanding.
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Colite , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Ileostomia , Humanos , Masculino , Idoso , Transplante de Microbiota Fecal/métodos , Colite/microbiologia , Colite/terapia , Transplante Homólogo/métodos , Resultado do Tratamento , ColonoscopiaRESUMO
Sclerosing mesenteritis (SM), an idiopathic nonneoplastic condition affecting 0.18% to 3.14% of the population, is characterized by chronic fat necrosis, inflammation, and fibrosis most commonly of the mesentery of the small intestine. Sclerosing mesenteritis typically presents in the fifth or sixth decade of life, where patients with a history of abdominal surgery and/or autoimmune disease may be at higher risk. While many patients are asymptomatic, clinical features and complications are related to the mass effect resulting from the inflammation and fibrosis involved in the pathogenesis of SM. When present, common signs, symptoms, and complications include abdominal pain, weight loss, diarrhea, palpable abdominal mass on examination, bowel obstruction, chylous ascites, and mesenteric vessel thrombosis. Although SM was historically diagnosed predominantly by biopsy, current practice has shifted away from this to computed tomography imaging of the abdomen, given the invasive nature of biopsy. However, certain conditions, including mesenteric neoplasia (lymphoma, metastatic carcinoid tumor, desmoid tumor, mesenteric carcinomatosis), can mimic SM on imaging, and if clinical suspicion is equivocal, a biopsy may be warranted for definitive diagnosis. Asymptomatic patients do not require treatment. For patients with pronounced symptoms or complicated SM, the combination of tamoxifen 10 mg twice daily and prednisone 40 mg daily is the first-line pharmacotherapy; no randomized controlled trial of this regimen has been performed. Rarely, surgery may be necessary in cases of persistent bowel obstruction refractory to medical management. Sclerosing mesenteritis has an overall benign course in most cases, but disease progression and fatal outcomes have been reported.
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Paniculite Peritoneal , Humanos , Paniculite Peritoneal/diagnóstico , Paniculite Peritoneal/terapia , Diagnóstico DiferencialRESUMO
BACKGROUND: Absent "organic" disease, dyspeptic symptoms may arise from abnormal gastric sensation, accommodation, motility or emptying (GE). Extensive gastric sensorimotor evaluation is rarely undertaken because testing is prolonged, invasive, poorly tolerated or unavailable. AIMS: To investigate whether gastric antral motor function, evaluated with scintigraphy, predicts GE. To explore whether motor testing with symptom recording predicts day-to-day symptoms in patients with dyspepsia. METHODS: GE was determined using a scintigraphic solid-meal protocol (296 kcal, 35% fat). Antral motility was estimated from 10 min of scintigraphic time-activity curves acquired 40 min after meal consumption. An antral motility index (MI) was derived from contraction amplitude and frequency. Intra-gastric distribution of the meal on scintograms at 1 h (IGD1) was determined. Meal-induced symptoms were evaluated by questionnaire. Patients completed the Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD) for 14 days. RESULTS: Twelve healthy participants and 23 prospectively recruited patients completed the study. Nine patients had delayed, and 2 had rapid, GE. In univariate analysis MI explained 42% of GE half-time. In multivariate analysis MI and GE half-time explained 25% of the variance in meal-induced symptoms. While scintigraphic evaluation of gastric motor function with symptom recording explained 80% of the variance in the GCSI-DD, meal-induced symptoms were the only significant predictor. However, among patients with delayed GE, MI, GE half-time, IGD1, and meal-induced symptoms all significantly predicted GCSI-DD. CONCLUSIONS: Antral motility predicts GE. In exploratory analyses, only meal-induced symptoms predicted daily symptoms among patients with dyspepsia. However, motor function also predicted symptoms in patients with delayed GE.
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Dispepsia , Esvaziamento Gástrico , Cintilografia , Humanos , Dispepsia/diagnóstico por imagem , Dispepsia/fisiopatologia , Feminino , Masculino , Adulto , Esvaziamento Gástrico/fisiologia , Pessoa de Meia-Idade , Cintilografia/métodos , Estudos Prospectivos , Motilidade Gastrointestinal/fisiologia , Gastroparesia/diagnóstico por imagem , Gastroparesia/fisiopatologia , Gastroparesia/diagnóstico , Adulto JovemRESUMO
Communication between insects and plants relies on the exchange of bioactive molecules that traverse the species interface. Although proteinic effectors have been extensively studied, our knowledge of other molecules involved in this process remains limited. In this study, we investigate the role of salivary microRNAs (miRNAs) from the rice planthopper Nilaparvata lugens in suppressing plant immunity. A total of three miRNAs were confirmed to be secreted into host plants during insect feeding. Notably, the sequence-conserved miR-7-5P is specifically expressed in the salivary glands of N. lugens and is secreted into saliva, distinguishing it significantly from homologues found in other insects. Silencing miR-7-5P negatively affects N. lugens feeding on rice plants, but not on artificial diets. The impaired feeding performance of miR-7-5P-silenced insects can be rescued by transgenic plants overexpressing miR-7-5P. Through target prediction and experimental testing, we demonstrate that miR-7-5P targets multiple plant genes, including the immune-associated bZIP transcription factor 43 (OsbZIP43). Infestation of rice plants by miR-7-5P-silenced insects leads to the increased expression of OsbZIP43, while the presence of miR-7-5P counteracts this upregulation effect. Furthermore, overexpressing OsbZIP43 confers plant resistance against insects which can be subverted by miR-7-5P. Our findings suggest a mechanism by which herbivorous insects have evolved salivary miRNAs to suppress plant immunity, expanding our understanding of cross-kingdom RNA interference between interacting organisms.
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Hemípteros , MicroRNAs , Oryza , Animais , Interferência de RNA , MicroRNAs/genética , MicroRNAs/metabolismo , Saliva , Hemípteros/fisiologia , Imunidade Vegetal/genética , Oryza/genéticaRESUMO
Saliva, an oral secretion primarily originating from salivary glands (SGs), exert critical roles in the ongoing evolutionary interaction between insects and plants. However, identifying insect salivary components poses challenges due to the tiny size of insects, low secretion amounts, and the propensity for degradation after secretion. In this study, we developed a transcriptome-based approach to comprehensively analyze the salivary proteins of the short-headed planthopper, Epeurysa nawaii, a species with unique feeding habits on bamboo. A total of 165 salivary proteins were identified, with 114 secretory genes highly and specifically expressed in SGs. Consistent with most phloem-feeding insects, digestive enzymes, calcium-binding proteins, oxidoreductases, and a few previously reported salivary effectors were ubiquitously distributed in E. nawaii saliva. However, we also identified a substantial portion of salivary proteins exhibiting taxonomy specificity, including 60 E. nawaii-specific and 62 Delphacidae-specific proteins. These taxonomy-restricted proteins potentially play a role in insect adaptation to specific host plants. Our study provides an efficient pipeline for salivary protein identification and serves as a valuable resource for the functional characterization of effectors.
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Hemípteros , Glândulas Salivares , Animais , Glândulas Salivares/metabolismo , Saliva/metabolismo , Hemípteros/metabolismo , Transcriptoma , Proteínas e Peptídeos Salivares/metabolismo , Proteínas de Insetos/metabolismoRESUMO
During foraging behavior, action values are persistently encoded in neural activity and updated depending on the history of choice outcomes. What is the neural mechanism for action value maintenance and updating? Here, we explore two contrasting network models: synaptic learning of action value versus neural integration. We show that both models can reproduce extant experimental data, but they yield distinct predictions about the underlying biological neural circuits. In particular, the neural integrator model but not the synaptic model requires that reward signals are mediated by neural pools selective for action alternatives and their projections are aligned with linear attractor axes in the valuation system. We demonstrate experimentally observable neural dynamical signatures and feasible perturbations to differentiate the two contrasting scenarios, suggesting that the synaptic model is a more robust candidate mechanism. Overall, this work provides a modeling framework to guide future experimental research on probabilistic foraging.
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Comportamento de Escolha , Recompensa , Encéfalo , Aprendizagem , Plasticidade Neuronal , Tomada de DecisõesRESUMO
In order to study the safe utilization of acid cadmium ï¼Cdï¼ contaminated soilï¼ light and moderate Cd-contaminated farmland in Shangluoï¼ Shaanxi Province was taken as the research objectï¼ and limeï¼ biocharï¼ and calcium magnesium phosphate fertilizer were applied. Through the wheat-maize rotation experimentï¼ the safe utilization effect of different amounts of passivator on Cd-contaminated soil was exploredï¼ and the best ratio of passivator was selected. The results showed thatï¼ â the soil quality could be improved to varying degrees by applying the passivator. â¡ After the application of amendmentsï¼ the grain yield of wheat and maize increased to different degrees. ⢠The lime 2 340 kg·hm-2 ï¼C3ï¼ treatment had the best effectï¼ which increased the soil pH of wheat and corn by 1.453 and 1.717 unitsï¼ respectivelyï¼ and reduced the available Cd content by 34.38% and 30.20%ï¼ respectively. ⣠The application of biochar 1 800 kg·hm-2 ï¼B2ï¼ treatment had the best effect on reducing the Cd contents in wheat rootsï¼ strawsï¼ and grainsï¼ which were significantly reduced by 53.60%ï¼ 38.86%ï¼ and 52.96%ï¼ respectivelyï¼ compared with that in CK. The Cd content in wheat grains was reduced to 0.09 mg·kg-1ï¼ which was lower than the limit value of wheat Cd ï¼0.1 mg·kg-1ï¼ specified in the "National food safety standard food pollutant limit" ï¼GB 2762-2017ï¼. The application of the biochar 1 260 kg·hm-2 ï¼B1ï¼ treatment had the best comprehensive effect on reducing the Cd contents of maize rootsï¼ strawsï¼ and grainsï¼ which were significantly reduced by 43.74%ï¼ 53.20%ï¼ and 94.57%ï¼ respectivelyï¼ compared with that in CK. The Cd content of maize grains was reduced to 0.001 9 mg·kg-1ï¼ which was far lower than the limit value of maize Cd ï¼0.1 mg·kg-1ï¼ specified in the "National food safety standard food pollutant limit" ï¼GB 2762-2017ï¼. Thereforeï¼ under the conditions of the field experimentï¼ considering the influence of various indexesï¼ biochar had the best effect on farmland soil in the wheat-maize rotation area with mild to moderate Cd pollution.
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Compostos de Cálcio , Poluentes Ambientais , Oryza , Óxidos , Poluentes do Solo , Fazendas , Cádmio/análise , Poluentes do Solo/análise , Carvão Vegetal/química , Solo/química , TriticumRESUMO
Introduction: The aim of this case-control study was to determine if exposure to tumor necrosis factor alpha inhibitors (TNFIs) or immunomodulators (thiopurines or methotrexate) was associated with development of primary gastrointestinal lymphoma (PGIL) in patients with chronic inflammatory conditions. Methods: Patients with PGIL and controls evaluated at a tertiary care center over 20 years were matched 1:3 using a medical record informatics search engine based on their chronic inflammatory condition (Crohn's disease [CD], ulcerative colitis [UC], rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis) and duration of follow-up. Patients who started on TNFI within 3 months of PGIL diagnosis were excluded. We extracted demographics, medical history, and medications used. Univariate models using conditional logistic regression were used due to the small number of matched pairs. Results: Twenty PGIL cases matched with 60 controls were followed for a mean 9.9â ±â 6.9 and 9.7â ±â 8.6 years, respectively. Mean age at time of PGIL diagnosis was 47.5â ±â 22.0 (standard deviation) years and the majority (75%) were males. The most common inflammatory diagnosis was inflammatory bowel disease (80% of cases; 45% with UC and 35% with CD). Development of PGIL was not associated with TNFI (odds ratio [OR]â =â 2.6; 95% confidence interval [CI] 0.69-11.01; Pâ =â .18), but with use of TNFI in combination with thiopurines (ORâ =â 8.93; 95% CI 1.43-80.25; Pâ =â .014). Risk of PGIL increased with every additional TNFI (2.277 (1.002-5.713); Pâ =â .0494). All cases exposed to multiple TNFI were also exposed to thiopurines. Use of thiopurines (alone or in combination) was the greatest risk factor (ORâ =â 6.32; 95% CI 1.55-37.05; Pâ =â 0.006) to develop PGIL. Conclusions: TNFI therapy was not associated with increased risk for PGIL unless used in combination with thiopurines and with every switch to a different TNFI.
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Granzymes are a family of proteases used by CD8 T cells to mediate cytotoxicity and other less-defined activities. The substrate and mechanism of action of many granzymes are unknown, although they diverge among the family members. In this study, we show that mouse CD8+ tumor-infiltrating lymphocytes (TILs) express a unique array of granzymes relative to CD8 T cells outside the tumor microenvironment in multiple tumor models. Granzyme F was one of the most highly upregulated genes in TILs and was exclusively detected in PD1/TIM3 double-positive CD8 TILs. To determine the function of granzyme F and to improve the cytotoxic response to leukemia, we constructed chimeric Ag receptor T cells to overexpress a single granzyme, granzyme F or the better-characterized granzyme A or B. Using these doubly recombinant T cells, we demonstrated that granzyme F expression improved T cell-mediated cytotoxicity against target leukemia cells and induced a form of cell death other than chimeric Ag receptor T cells expressing only endogenous granzymes or exogenous granzyme A or B. However, increasing expression of granzyme F also had a detrimental impact on the viability of the host T cells, decreasing their persistence in circulation in vivo. These results suggest a unique role for granzyme F as a marker of terminally differentiated CD8 T cells with increased cytotoxicity, but also increased self-directed cytotoxicity, suggesting a potential mechanism for the end of the terminal exhaustion pathway.
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Leucemia , Receptores de Antígenos Quiméricos , Animais , Camundongos , Linfócitos T CD8-Positivos , Granzimas , Leucemia/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Microambiente Tumoral , Citotoxicidade ImunológicaRESUMO
Deoxynivalenol (DON) is a common mycotoxin that is widely found in various foods and feeds, posing a potential threat to human and animal health. This study aimed to investigate the protective effect of the natural polyphenol piceatannol (PIC) against DON-induced damage in porcine intestinal epithelial cells (IPEC-J2 cells) and the underlying mechanism. The results showed that PIC promotes IPEC-J2 cell proliferation in a dose-dependent manner. Moreover, it not only significantly relieved DON-induced decreases in cell viability and proliferation but also reduced intracellular reactive oxygen species (ROS) production. Further studies demonstrated that PIC alleviated DON-induced oxidative stress damage by increasing the protein expression levels of the antioxidant factors NAD(P)H quinone oxidoreductase-1 (NQO1) and glutamate-cysteine ligase modifier subunit (GCLM), and the mRNA expression of catalase (CAT), Superoxide Dismutase 1 (SOD1), peroxiredoxin 3 (PRX3), and glutathione S-transferase alpha 4 (GSTα4). In addition, PIC inhibited the activation of the nuclear factor-B (NF-κB) pathway, downregulated the mRNA expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) to attenuate DON-induced inflammatory responses, and further mitigated DON-induced cellular intestinal barrier injury by regulating the protein expression of Occludin. These findings indicated that PIC had a significant protective effect against DON-induced damage. This study provides more understanding to support PIC as a feed additive for pig production.
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Células Epiteliais , NF-kappa B , Estilbenos , Tricotecenos , Suínos , Animais , Humanos , NF-kappa B/metabolismo , Linhagem Celular , RNA Mensageiro/metabolismoRESUMO
Three new cadinane sesquiterpenes (1-3) and three known sesquiterpenes were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and HRESIMS data. The structures of illiternins A-C (1-3) were confirmed by single crystal X-ray diffraction, allowing for the determination of their absolute configurations. Compounds 3 and 6 exhibited antiviral activity against Coxsackievirus B3 with IC50 values of 33.3 and 57.7 µM, respectively.
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Illicium , Sesquiterpenos , Illicium/química , Estrutura Molecular , Sesquiterpenos Policíclicos , Sesquiterpenos/químicaRESUMO
High-performance photocatalysts for catalytic reduction of CO2 are largely impeded by inefficient charge separation and surface activity. Reasonable design and efficient collaboration of multiple active sites are important for attaining high reactivity and product selectivity. Herein, Cu-Cu2O and Ag nanoparticles are confined as dual sites for assisting CO2 photoreduction to CH4 on TiO2. The introduction of Cu-Cu2O leads to an all-solid-state Z-scheme heterostructure on the TiO2 surface, which achieves efficient electron transfer to Cu2O and adsorption and activation of CO2. The confined nanometallic Ag further enhances the carrier's separation efficiency, promoting the conversion of activated CO2 molecules to â¢COOH and further conversion to CH4. Particularly, this strategy is highlighted on the TiO2 system for a photocatalytic reduction reaction of CO2 and H2O with a CH4 generation rate of 62.5 µmolâg-1âh-1 and an impressive selectivity of 97.49 %. This work provides new insights into developing robust catalysts through the artful design of synergistic catalytic sites for efficient photocatalytic CO2 conversion.
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Recent advances in connectomics and neurophysiology make it possible to probe whole-brain mechanisms of cognition and behavior. We developed a large-scale model of the multiregional mouse brain for a cardinal cognitive function called working memory, the brain's ability to internally hold and process information without sensory input. The model is built on mesoscopic connectome data for interareal cortical connections and endowed with a macroscopic gradient of measured parvalbumin-expressing interneuron density. We found that working memory coding is distributed yet exhibits modularity; the spatial pattern of mnemonic representation is determined by long-range cell type-specific targeting and density of cell classes. Cell type-specific graph measures predict the activity patterns and a core subnetwork for memory maintenance. The model shows numerous attractor states, which are self-sustained internal states (each engaging a distinct subset of areas). This work provides a framework to interpret large-scale recordings of brain activity during cognition, while highlighting the need for cell type-specific connectomics.