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Working memory, the brain’s ability to retain and manipulate information internally, has been traditionally associated with persistent neural firing in localized brain areas such as those in the frontal cortex (Fuster 1973, Funahashi et al., 1989; Goldman-Rakic 1995; Romo et al., 1999; Rigotti et al., 2013; Kopec et al., 2015; Inagaki et al., 2019). However, self-sustained neural persistent activity during working memory is present in multiple brain regions (Romo et al., 2004; Christophel et al., 2017; Leavitt et al., 2017; Sreenivasan and D’Esposito, 2019), the underlying mechanism is unknown. We developed an anatomically constrained large-scale computational model of the macaque cortex endowed with a macroscopic gradient of synaptic excitation, to investigate the origin of distributed working memory representation. We found that long-range inter-areal reverberation can support the emergence of persistent activity patterns across multiple cortical regions, by virtue of a robust bifurcation in space, even when none of isolated local areas is capable of generating persistent activity. The model uncovered a host of distinct persistent activity patterns (attractor states), and provides experimentally testable predictions that cannot be explained in local circuit models. Simulating cortical lesions reveals that distributed activity patters are resilient against simultaneous lesions of multiple cortical areas, but depend on areas that form the core of the entire cortex. This work provides a theoretical framework for identifying large-scale brain mechanisms and computational principles of distributed cognitive processes.

Introduction Central sensitization syndromes (CSS) comprise an overlapping group of clinical conditions with the core feature of “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Patients with CSS are known to have challenging interactions with healthcare providers contributing to psychological distress and increased healthcare utilization. CSS symptom severity has been associated with psychologic comorbidities, but little is known about how symptom severity relates to provider interactions. Methods We performed a cross-sectional survey among patients with CSS in our primary care practices to examine the relationship between CSS symptom severity and experiences with doctors. Results A total of 775 respondents completed the survey (775/5000; 15.5%) with 72% reporting high CSS symptom severity. About 44% of respondents had a prior diagnosis of fibromyalgia, 72% had migraines, and 28% had IBS. Patients with high CSS symptom severity were more likely to report that doctor(s) had often/always told them that they don’t need treatment when they feel like they do (OR = 3.6, 95% CI 1.9-7.5), that doctor(s) often/always don’t understand them (OR = 3.1, 95% CI 1.9-5.4), and that doctor(s) often/always seem annoyed with them when compared with respondents with low-moderate CSS symptom severity (OR = 4.8, 95% CI 2.2-12.5). Patients with high CSS symptom severity were at greater than 5 times odds of reporting being told that their symptoms were “all in their head” when compared to patients with low-moderate symptom severity (OR = 5.4, 95% CI 3.3-9.0). Conclusion Patients with CSS spectrum disorders experience frequent pain and decreased quality of life. A high degree of CSS symptom severity is associated with negative experiences with healthcare providers, which deters the establishment of a positive provider-patient relationship. Further research is needed to help understand symptom severity in CSS and harness the power of the therapeutic alliance as a treatment modality.

Begonia austroyunnanensis, a new species from Yunnan (China) is described and illustrated. This new species is similar to B. subhowii in having short erect stems, obliquely ovate leaves and white flowers, but can be distinguished by its stem, petioles and peduncle having conspicuous, red, linear dots and the much longer abaxial wing of the capsule. A detailed description, data on distribution, ecology and an illustration are provided.

Promoting photogenerated carriers separation and adjusting the activation path of the CO2 molecule are two effective solutions for improving the activity and selectivity of photocatalytic CO2 reduc...

Background Due to the paucity of targeted therapy for irritable bowel syndrome (IBS), many patients turn to dietary modifications for symptom management. The combination of five subgroups of poorly absorbed and rapidly fermented carbohydrates-fructans, galacto-oligosaccharides, lactose, excess fructose and polyols-are thought to trigger gastrointestinal symptoms and are referred to collectively as "FODMAPs". Aims To examine the biological plausibility and mechanisms by which foods high in specific FODMAP subgroups cause symptoms, and to use this information to explore the possibility of targeting select dietary components to allow for a more personalised approach to dietary adjustment METHODS: Recent literature was analysed via search databases including Medline, PubMed and Scopus. Results Lactose, fructans and galacto-oligosaccharides have strong biologic plausibility for symptom generation due to lack of hydrolases resulting in distention from osmosis and rapid fermentation. However, excess fructose and polyols may only cause symptoms in specific individuals when consumed in high doses, but this remains to be established. There is evidence to suggest that certain patient characteristics such as ethnicity may predict response to lactose, but differentiation of other subgroups is difficult prior to dietary manipulation. Conclusions While some clear mechanisms of action for symptom generation have been established, further research is needed to understand which patients will respond to specific FODMAP subgroup restriction. We suggest that clinicians consider in some patients a tailored, personalised "bottom-up" approach to the low-FODMAP diet, such as dietary restriction relevant to the patients' ethnicity, symptom profile and usual dietary intake.

Recently it has been proposed that information in working memory (WM) may not always be stored in persistent neuronal activity but can be maintained in 'activity-silent' hidden states, such as synaptic efficacies endowed with short-term synaptic plasticity. To test this idea computationally, we investigated recurrent neural network models trained to perform several WM-dependent tasks, in which WM representation emerges from learning and is not a priori assumed to depend on self-sustained persistent activity. We found that short-term synaptic plasticity can support the short-term maintenance of information, provided that the memory delay period is sufficiently short. However, in tasks that require actively manipulating information, persistent activity naturally emerges from learning, and the amount of persistent activity scales with the degree of manipulation required. These results shed insight into the current debate on WM encoding and suggest that persistent activity can vary markedly between short-term memory tasks with different cognitive demands.

The AZO films deposited on quartz glass by magnetron sputtering with different deposition time various from 30min to 120min.All of the obtained samples had a (002) diffraction peak range from 34.31 to 34.52°, while the mean grain size increased from 30.1nm (30min) to 56.1nm (120min) respectively. The XPS survey indicated the photoelectron peaks of Zn ,O and C elements occured. The optimal transmittance of the films reduced obviously from about 92% to 78% near 550nm with deposition time increased from 30min to 120min. And the average transmittance of AZO films prepared at 30, 60 and 90min was about 85% in the visible light region.

SMAD4 is a potent tumor suppressor and a central mediator of the TGFß signaling pathway. SMAD4 genetic loss is frequent in squamous cell carcinomas (SCCs). Reports of SMAD4 expression in SCCs vary significantly possibly due to inter-tumor heterogeneity or technical reasons. SMAD4 loss is an initiation event for SCCs. In tumor epithelial cells, SMAD4 loss causes increased proliferation, decreased apoptosis, and "Brca-like" genomic instability associated with DNA repair defects. SMAD4 loss also plays a role in the expansion of cancer stem cells. Epithelial SMAD4 loss causes overexpression of TGFß that is released into the tumor microenvironment and contributes to SCC progression through proinflammatory and immune evasive mechanisms. SMAD4 loss, while not a direct therapeutic target, is associated with multiple targetable pathways that require further therapeutic studies. Altogether, SMAD4 loss is a potential biomarker in SCCs that should be further studied for its values in prognostic and therapeutic predictions. Such information will potentially guide future biomarker-driven clinical trial designs and improve SCC patient outcomes.

Carcinomas of unknown primary (CUPs) have poor prognosis due to the paucity of data on their clinical characteristics and laboratory features, and empirical chemotherapy still remains the critical management for this kind of disease. This study aimed to present the knowledge of treating an elderly man with metastatic adenocarcinoma of unknown primary and also with a history of long-term hypertension and renal cysts. He was identified to harbor mesenchymal-epithelial transition factor (MET) gene amplification and neurotrophic tyrosine receptor kinase 1 (NTRK1) gene co-occurring mutation by targeted next-generation sequencing analysis upon the progression of empirical chemotherapy. He was then treated with a standard dose of crizotinib (250 mg, twice daily), which exhibited a satisfactory complete response (CR) of the targeted lesions after 1 month of treatment. When the number of renal cysts increased and renal inadequacy occurred after treatment for 2 months, crizotinib was reduced to half-dose (250 mg, once daily), and still conferred maintenance of CR for another 6.5 months and good quality life of the patient. These results suggested that treatments based on driver genes rather than primary tumor types could be a promising manipulation for achieving better treatment outcome, and a half-dose of crizotinib might be both effective and tolerable for MET-overexpressed CUPs with underlying renal diseases.

We assessed the roles of Smad7 in skin inflammation and wound healing using genetic and pharmacological approaches. In K5.TGFβ1/K5.Smad7 bigenic (double transgenic) mice, Smad7 transgene expression reversed transforming growth factor (TGF)-β1 transgene-induced inflammation, fibrosis, and subsequent epidermal hyperplasia and molecularly abolished TGF-β and NF-κB activation. Next, we produced recombinant human Smad7 protein with a Tat-tag (Tat-Smad7) that rapidly enters cells. Subcutaneous injection of Tat-Smad7 attenuated infiltration of F4/80+ and CD11b+ leukocytes and α-smooth muscle actin+ fibroblasts before attenuating epidermal hyperplasia in K5.TGFβ1 skin. Furthermore, topically applied Tat-Smad7 on K5.TGFβ1 skin wounds accelerated wound closure, with improved re-epithelialization and reductions in inflammation and fibrotic response. A short treatment with Tat-Smad7 was also sufficient to reduce TGF-β and NF-κB signaling in K5.TGFβ1 skin and wounds. Relevant to the clinic, we found that human diabetic wounds had elevated TGF-β and NF-κB signaling compared with normal skin. To assess the oncogenic risk of a potential Smad7-based therapy, we exposed K5.Smad7 skin to chemical carcinogenesis and found reduced myeloid leukocyte infiltration in tumors but not accelerated carcinogenesis compared with wild-type littermates. Our study suggests the feasibility of using exogenous Smad7 below an oncogenic level to alleviate skin inflammation and wound healing defects associated with excessive activation of TGF-β and NF-κB.

There is overwhelming evidence that functional gastrointestinal disorders (FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms (UGI Sx). Among patients with UGI Sx, approximately equal proportions (25%) of patients have delayed gastric emptying (GE), reduced gastric accommodation (GA), both impaired GE and GA, or neither, presumably due to increased gastric or duodenal sensitivity. Treatments targeted to the underlying pathophysiology utilize prokinetics, gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia (with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome (IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2D6, 2C19 and 3A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here; pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.

The primate cerebral cortex displays a hierarchy that extends from primary sensorimotor to association areas, supporting increasingly integrated function underpinned by a gradient of heterogeneity in the brain's microcircuits. The extent to which these hierarchical gradients are unique to primate or may reflect a conserved mammalian principle of brain organization remains unknown. Here we report the topographic similarity of large-scale gradients in cytoarchitecture, gene expression, interneuron cell densities, and long-range axonal connectivity, which vary from primary sensory to prefrontal areas of mouse cortex, highlighting an underappreciated spatial dimension of mouse cortical specialization. Using the T1-weighted:T2-weighted (T1w:T2w) magnetic resonance imaging map as a common spatial reference for comparison across species, we report interspecies agreement in a range of large-scale cortical gradients, including a significant correspondence between gene transcriptional maps in mouse cortex with their human orthologs in human cortex, as well as notable interspecies differences. Our results support the view of systematic structural variation across cortical areas as a core organizational principle that may underlie hierarchical specialization in mammalian brains.

The brain has the ability to flexibly perform many tasks, but the underlying mechanism cannot be elucidated in traditional experimental and modeling studies designed for one task at a time. Here, we trained single network models to perform 20 cognitive tasks that depend on working memory, decision making, categorization, and inhibitory control. We found that after training, recurrent units can develop into clusters that are functionally specialized for different cognitive processes, and we introduce a simple yet effective measure to quantify relationships between single-unit neural representations of tasks. Learning often gives rise to compositionality of task representations, a critical feature for cognitive flexibility, whereby one task can be performed by recombining instructions for other tasks. Finally, networks developed mixed task selectivity similar to recorded prefrontal neurons after learning multiple tasks sequentially with a continual-learning technique. This work provides a computational platform to investigate neural representations of many cognitive tasks.

In this work, N-methyl-2-pyrrolidonium (NMP) was acidized using hydrochloric acid to obtain [Hnmp]Cl first, which was then reacted with FeCl3 to prepare a series of inexpensive tunable [Hnmp]Cl·xFeCl3 (x = 0.2–2.0) ionic liquids (ILs) for the extractive and oxidative desulfurization of model oils. The Lewis acidities of these ILs were tested by the Fourier transform infrared (FT-IR) method, which indicated that when the x value of [Hnmp]Cl·xFeCl3 was above 1.0, the ILs exhibited Lewis acidity. The extraction results showed that the acidification of NMP reduced its dissolubility ability toward dibenzothiophene (DBT) and its Lewis acidity played a determining role in extractive desulfurization. In the catalytic oxidation removal process of the DBT model oil in the presence of H2O2, electron paramagnetic resonance (EPR) and scavenger experiments showed that the hydroxyl radical (˙OH) plays a key role and the superoxide anion radical (O2˙−) has a minor function. [Hnmp]Cl·1.5FeCl3 IL showed excellent recycling performance, which was due to its high dissolving capacity (23 700 ppm) for dibenzothiophene-sulfone (DBTO2).

Improving charge separation efficiency and accelerating surface reaction kinetics are two challenging issues for the graphitic carbon nitride (g-C3N4) photocatalyst. Surface atom decoration is a facile and efficacious strategy to modulate the electronic structure and then affect the local spatial charge separation of the photocatalyst. Here, we first reported a surface P atom grafting strategy for g-C3N4via P–N bond formation to effectively promote the local spatial charge separation and ample reactive sites. The post-calcination process allowed controllable grafting of P–OH at the corner-nitrogen sites in tri-s-triazine of g-C3N4, which resulted in an impurity state, and it acted as an electron capture center for local spatial charge separation and reactive sites. Thus, the surface N–P–OH bond modulation of g-C3N4 rendered nearly four-fold enhancement in the hydrogen evolution rate. The ability to build pure surface P–N motif modulation presents a promising strategy to realize the precise band engineering of modulated g-C3N4. These findings would deepen the understanding of the nonmetal atom decoration-related issues of g-C3N4-based materials.

Micranthanosides I and II (1–2), two diterpenoid glucosides featuring a new 1,10-secograyanane skeleton, thirteen new diterpenoid glycosides (3–15), and 21 known analogues were obtained from the ethanol extract of the leaves and twigs of Rhododendron micranthum. Micranthanoside XII (12) represent the first example of 3,5-epoxy-4,5-seco-ent-kaurane diterpenoid. The structures of these compounds were determined by spectroscopic data analysis and quantum chemical calculations. To clarify the chemical basis and provide reference for rational use of this medicinal plant, the antinociceptive and the anti-inflammatory activities of the compounds were tested. In the acetic acid-induced writhing test, compounds 17 and 19 showed significant antinociceptive activity at a dose of 3 mg kg−1 and compounds 2, 6 and 32 showed significant antinociceptive activity at a dose of 10 mg kg−1. Toxic reactions such as nausea and convulsion were observed when 17, 19, 29, and 31 at a dose of 10 mg kg−1 or 30 and 33 at a dose of 1 mg kg−1 were administered. The anti-inflammatory activities of the isolated compounds were evaluated by measuring the inhibitory effects of LPS-induced NO production in BV2 cells. At 10 μM, micranthanoside IX (9) and rhodomicranoside F (26) showed moderate anti-inflammatory activities with inhibition rates of 56.31% and 72.43%, respectively.

Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) have a dismal survival rate. The effects of the extracellular matrix (ECM) on cancer progression have been long studied, but the roles of specific integrins in the process of HNSCC metastasis remain to be dissected. This study aims to determine how HNSCC cells affect the production of laminin-binding integrins, and how these integrins participate in the ECM interactions necessary for a metastatic phenotype. Experimental design: Our laboratory has produced syngeneic mouse SCC cell lines, P029 and A223, derived from Keratin15+ stem cells with Smad4 loss and KrasG12D mutation. In syngeneic recipients, SCCs derived from P029 cells transplanted to the flank mouse skin produced spontaneous metastases to the lung while SCCs derived from A223 cells did not form metastases. Having the same genotype, these cell lines serve as models to examine cancer cell interactions with the ECM and resulting effects on invasion and metastasis. Bulk RNA sequencing (RNAseq) was performed to compare cultured metastatic P029 cells versus non-metastatic A223 cells and identify differentially expressed genes that regulate SCC cells and ECM interactions. Immunoassays and functional invasion assays were performed to evaluate ECM-cancer cell signaling and influence on cancer cell invasion in these two cell lines. Results: RNAseq analysis revealed that, relative to A223 cells, P029 cells have increased levels of integrins, the main mechanoreceptors for numerous ECM ligands and matrix proteins. Laminin-binding integrins, including integrins α4 and β6, were greater at the RNA and protein levels. Additionally, P029 cells expressed higher levels of fibronectin and laminin coding genes compared to non-metastatic A223 cells. Correlatively, high expression of these matrix proteins is associated with worse patient survival. Additionally, P029 SCC cells displayed differential gene expression of tight and apical junctions, PI3K signaling components, and regulators of cytoskeletal remodeling. Furthermore, ELISA and western blot analysis revealed that P029 has aberrant TGFβ-Smad signaling as indicated by the elevated release of TGFβ-1 protein and higher levels of phosphorylated Smad2 and Smad3 relative to non-metastatic A223. Treating P029 cells with TGFβ-1 significantly increased their motility and invasion. Conversely, migration and motility of P029 cells were radically reduced by the TGFβ inhibitor galunisertib. Additionally, the mouse cytokine array revealed that mouse plasma bearing P029 tumors had a greater circulation of CXCL16, MMP-9, proliferin, and serpin E1. These proteins are associated with ECM remodeling and metastasis in HNSCC. Conclusions: SCC cells with metastatic properties upregulate integrins which bind to non-collagen matrix proteins and have elevated invasive and migratory capacity contributed from activated TGFβ signaling. Citation Format: John Aleman, Khoa A. Nguyen, Yao Ke, Christian D. Young, Xiao-Jing Wang. Assessing the role of extracellular matrix-integrins in metastatic squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3834.

Promoting electron-hole separation and migration and lowering the overpotential of hydrogen evolution reactions are two effective solutions for improving photocatalytic hydrogen performance. Suitable co-catalyst and appropriate interfacial contacts can effectively lower overpotential and can also construct an electric field at the interface to increase the separation efficiency of the carriers. In this work, we design and fabricate a 2D-2D type of Ni2P co-catalyst modified with ZnIn2S4 for boosting the performance of photocatalytic hydrogen evolution. As a co-catalyst, the 2D Ni2P nanosheets exhibit a lower overpotential and smaller charge transfer resistance in hydrogen evolution reactions, and is much improved in both respects compared to Ni2P nanoparticles. Based on this, 2D/2D Ni2P/ZnIn2S4 nanohybrids with large contact regions and shorter transmission distances of the charges were fabricated, which effectively improve the separation of photo induced carriers and the interfacial charge transfer. By taking advantage of the above features, the fabricated 2D-2D Ni2P/ZnIn2S4hybrid exhibits a superior hydrogen evolution rate of 2066 μmol·h−1·g−1 under visible light irradiation, and the apparent quantum yield was 7.7% at 420 ± 20 nm. This activity far exceeds performance of the 0D/2D Ni2P/ZnIn2S4 hybrid, and is ascribed to better charge separation and accelerated surface reactions of the Ni2P nanosheets.

Thirteen compounds were isolated from the lipid-soluble extracts of Illicium ternstroemioides A. C. Smith, including eleven previously undescribed prenylated C

Four new monoterpene indole alkaloids (1–4) together with six known alkaloids (5–10) were isolated from the roots of Bousigonia mekongensis. Compounds 3 and 4 were the first examples of condylocarpan-adenine type alkaloids obtained from natural plant resource. Their structures were elucidated on the basis of spectroscopic data. All compounds were evaluated for their inhibiting glucose-induced mesanginal cell proliferation and protecting high glucose-evoked podocyte injury activities. (-)-demethoxycarbonyldihydrogambirtannine (5) can significantly antagonize glucose-induced podocyte injury with EC50 value of 6.5 ± 1.2 μM.

The construction of libraries of stereoisomers of natural products serves as an important approach to investigating the correlation between the stereostructure and biological activity. However, the total synthesis and isomerzation of polycyclic scaffolds with multiple chrial centers are rare. Spirooliganin (1), a new skeleton natural product isolated from the plant Illicium oligandrum, was structurally characterized by comprehensive analysis of NMR spectroscopic data and ECD which revealed an unprecedented 5–6–6–6–7 polycyclic framework with six chiral centers. Here we report a 17-step total synthesis to prepare a library of stereochemically diverse isomers of spirooliganin, including 16 diastereoisomers and 16 regioisomers. In addition to a regioselective hetero-Diels–Alder cycloaddition, the synthetic strategy involves a photo-induced stereoselective Diels–Alder reaction, which gives only the abnormal trans-fused product as rationalized by density functional theory calculations. Preliminary biological evaluation showed that spirooliganin and regioisomers 39 exhibited potent inhibition of Coxsackievirus B3. It also revealed the pharmacophore effect of the D-ring (16R,18R,24R, and 26R) for their antiviral activities., Library construction of stereochemically diverse isomers to investigate the relationship between stereoconfiguration and anti-coxsackie virus B3 activity.

Gastric emptying and gastric accommodation play a role in generation of upper gastrointestinal symptoms. Although both functions have been measured simultaneously using MRI or (99m)Tc SPECT methodology, the correlation of these two functions has not been evaluated simultaneously using a solid and liquid meal. To study relationships of whole or proximal stomach volumes to emptying, we concurrently measured postprandial gastric accommodation and emptying (over 4 h) of a (111)In-labeled mixed solid and liquid meal. A semiautomated method allowing selection of a segmentation threshold based on a grayscale image was used to measure volume of the proximal half of the stomach, defined as the top half of axial slices along the vertical length of the stomach. A correction factor derived from phantom studies was applied for upscatter from the (99m)Tc to the (111)In window. Relationships of time to emptying 10%, 25%, 50%, and 75% of the meal to fasting and postprandial gastric volumes were evaluated using Spearman correlation. Whole stomach fed and accommodation volumes were significantly correlated with all gastric emptying times (10%, 25%, and 50%). Proximal stomach fed volumes were similarly associated with 50% and 75% proximal gastric emptying. Fed proximal gastric volume was associated with 50% and 75% whole gastric emptying. Fed proximal accommodation volume was associated with 50% gastric emptying. Fasting gastric volumes were not significant determinants of emptying rates. In conclusion, postprandial gastric accommodation is significantly associated with the rate of gastric emptying, with higher gastric volumes associated with prolongation of emptying. Novel methods to measure proximal gastric accommodation and correct for radioisotope upscatter are described. NEW & NOTEWORTHY In vivo human studies evaluated concurrently the volume of the stomach during fasting and after a solid and liquid meal using a new SPECT-based method. Although fasting gastric volumes did not impact the rates of gastric emptying, both postprandial and accommodation volumes of the whole and proximal stomach were significantly correlated with gastric emptying. Larger stomach volumes were associated with slower gastric emptying.

Balancing instant gratification versus delayed, but better gratification is important for optimizing survival and reproductive success. Although psychologists and neuroscientists have long attempted to study delayed gratification through human psychological and brain activity monitoring, and animal research, little is known about its neural basis. We successfully trained mice to perform a waiting-and-water-reward delayed gratification task and used these animals in physiological recording and optical manipulation of neuronal activity during the task to explore its neural basis. Our results showed that the activity of DA neurons in ventral tegmental area (VTA) increases steadily during the waiting period. Optical activation vs. silencing of these neurons, respectively, extends or reduces the duration of waiting. To interpret this data, we developed a reinforcement learning (RL) model that reproduces our experimental observations. In this model, steady increases in DAergic activity signal the value of waiting and support the hypothesis that delayed gratification involves real-time deliberation.TEASERSustained ramping dopaminergic activation helps individuals to resist impulsivity and wait for laerger but later return.

Dynamics and functions of neural circuits depend on synaptic interactions mediated by receptors. Therefore, a comprehensive map of receptor organization is needed to understand how different functions may emerge across distinct cortical regions. Here we use in-vitro receptor autoradiography to measure the density of 14 neurotransmitter receptor types in 109 areas of macaque cortex. We integrate the receptor data with other anatomical, genetic and functional connectivity data into a common cortical space. We uncovered a principal gradient of increasing receptor expression per neuron aligned with cortical hierarchy from early sensory cortex to higher cognitive areas. A second gradient, primarily driven by 5-HT1A receptors, peaks in the anterior and subcallosal cingulate, suggesting that the macaque may be a promising animal model for major depressive disorder. The receptor gradients may enable rapid, reliable information processing in sensory cortical areas and slow, flexible integration of information in higher cognitive areas.

The main process of carbon dioxide (CO2) photoreduction is that excited electrons are transported to surface active sites to reduce adsorbed CO2 molecules. Obviously, electron transfer to the active site is one of the key steps in this process. However, current catalysts for CO2 adsorption, activation, and electron reduction occur in different locations, which greatly reduce the efficiency of photocatalysis. Herein, through a spontaneous chemical redox approach, the plasmonic photocatalysts of Au-BiOCl-OV with enhanced interfacial interaction were fabricated for visible light CO2 reduction through the simultaneous adsorption, activation and in situ reduction of CO2 without a sacrificial agent. By loading gold (Au) on the oxygen vacancy (OV), Au and BiOCl-OV formed a direct and tight interface contact, whose fine structure was confirmed by SEM, TEM, EPR and XPS, which not only effectively boosts the light utilization efficiency and the light carrier separation ability, but also can simultaneously adsorb, activate and in situ reduce carbon dioxide for highly efficient visible light photocatalysis. Thanks to the synergistic influence of Au and OV, Au-BiOCl-OV exhibits excellent photocatalytic performance without sacrificial agent and outstanding stability with a high CO and CH4 production yield, reaching 4.85 μmol g-1 h-1, which were 2.8 times higher than C-Au-BiOCl-OV (obtained by traditional NaBH4 reduction). This study proposes a new strategy for the production of high-performance collaborative catalysis in photocatalytic CO2 reduction.

Illihenin A (

Gastroparesis is defined by delayed gastric emptying with associated symptoms in the absence of mechanical obstruction.To evaluate pharmacokinetics and pharmacodynamics of felcisetrag, a highly selective 5-HTSingle-centre, placebo-controlled study of 36 participants receiving placebo, 0.1mg, 0.3mg or 1.0mg of felcisetrag I.V. infusion, daily, for 3 days. At baseline, each participant completed a 4h,Patients (22 idiopathic, 14 diabetic gastroparesis) were randomised to felcisetrag (0.1 mg, n = 10; 0.3 mg, n = 9; 1.0 mg, n = 7) or placebo (n = 10). Compared to placebo, felcisetrag significantly accelerated gastric emptying TI.V. felcisetrag significantly accelerated gastric, small bowel and colonic transit in patients with gastroparesis, and should be further evaluated for short-term treatment of gastric and intestinal motility disorders. ClinicalTrials.gov #NCT03281577.

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

Zero-dimensional (0D) black phosphorus quantum dots (BPQDs), the new derivatives of black phosphorus (BP) nanomaterials, have attracted considerable attention since they were first prepared in 2015. Compared to traditional two-dimensional (2D) BP nanosheets, BPQDs exhibit some unique properties and demonstrate great potential for a broad range of applications, especially in the field of biomedicine. Due to the rapid development and substantial research interest in this area, it is urgent to review the current advances, challenges and near-future possibilities of BPQD-related biomedical research, which will benefit the further development of this field. This review is mainly focused on the latest progress of BPQD related applications in the biomedical field, including photothermal therapy (PTT), photodynamic therapy (PDT), drug delivery, biological imaging, etc. The challenges and future prospects are also discussed.

Background: Tumor microenvironment (TME) significantly affects colorectal cancer (CRC) progression and therapeutic efficacy, particularly the infiltrating stromal components. This study aimed to profile the TME composition of tumor tissue and identify TME-related, especially stroma-related genes having prognosis value in CRC patients. Materials and Methods: We used ESTIMATE algorithm to assess stromal/immune component and divided 524 CRC cases of public dataset into high- and low-score groups. We analyzed effect of the score on prognosis and extracted the differential expression genes (DEGs) between groups, which were stromal- and/or immune-related genes, and performed prognostic investigation of the DEGs. Results: Higher stromal score was correlated with poor survival, whereas immune score was the opposite. By comparing global gene expression of cases with high vs. low stromal/immune scores, we extracted 474 stroma-related genes, 76 immune-related genes, and 498 intersection genes, which were explored by function enrichment and survival analysis. We identified the expression of five stroma-related genes (including ITGA7, PTPN14, SCG2, TNS1, and GRP) significantly associated with poorer survival, which were validated in the other two independent CRC cohorts. Conclusion: These results presented a comprehensive understanding of TME components and identified five stroma-related genes that predict poor outcomes in CRC patients.

Tocilizumab has been reported to attenuate the “cytokine storm” in COVID-19 patients. We attempted to verify the effectiveness and safety of tocilizumab therapy in COVID-19 and identify patients most likely to benefit from this treatment. We conducted a randomized, controlled, open-label multicenter trial among COVID-19 patients. The patients were randomly assigned in a 1:1 ratio to receive either tocilizumab in addition to standard care or standard care alone. The cure rate, changes of oxygen saturation and interference, and inflammation biomarkers were observed. Thirty-three patients were randomized to the tocilizumab group, and 32 patients to the control group. The cure rate in the tocilizumab group was higher than that in the control group, but the difference was not statistically significant (94.12% vs. 87.10%, rate difference 95% CI–7.19%–21.23%, P = 0.4133). The improvement in hypoxia for the tocilizumab group was higher from day 4 onward and statistically significant from day 12 (P = 0.0359). In moderate disease patients with bilateral pulmonary lesions, the hypoxia ameliorated earlier after tocilizumab treatment, and less patients (1/12, 8.33%) needed an increase of inhaled oxygen concentration compared with the controls (4/6, 66.67%; rate difference 95% CI–99.17% to–17.50%, P = 0.0217). No severe adverse events occurred. More mild temporary adverse events were recorded in tocilizumab recipients (20/34, 58.82%) than the controls (4/31, 12.90%). Tocilizumab can improve hypoxia without unacceptable side effect profile and significant influences on the time virus load becomes negative. For patients with bilateral pulmonary lesions and elevated IL-6 levels, tocilizumab could be recommended to improve outcome. Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11684-020-0824-3 and is accessible for authorized users.

SummaryDopamine is critical for working memory. However, its effects throughout the large-scale primate cortex are poorly understood. Here we report that dopamine receptor density per neuron, measured by receptor autoradiography in the macaque monkey cortex, displays a macroscopic gradient along the cortical hierarchy. We developed a connectome- and biophysically-based model for distributed working memory that incorporates multiple neuron types and a dopamine gradient. The model captures an inverted U-shaped dependence of working memory on dopamine. The spatial distribution of mnemonic persistent activity matches that observed in over 90 experimental studies. We show that dopamine filters out irrelevant stimuli by enhancing inhibition of pyramidal cell dendrites. The level of cortical dopamine can also determine whether memory encoding is through persistent activity or an internal synaptic state. Taken together, our work represents a cross-level understanding that links molecules, cell types, recurrent circuit dynamics and a core cognitive function distributed across the cortex.

cMYC (MYC) is a potent oncoprotein that is subject to post-translational modifications that affect its stability and activity. Here, we show that Serine 62 phosphorylation, which increases MYC stability and oncogenic activity, is elevated while Threonine 58 phosphorylation, which targets MYC for degradation, is decreased in squamous cell carcinoma (SCC). The oncogenic role of MYC in the development of SCC is unclear since studies have shown in normal skin that wild-type MYC overexpression can drive loss of stem cells and epidermal differentiation. To investigate whether and how altered MYC phosphorylation might affect SCC development, progression, and metastasis, we generated mice with inducible expression of MYCWT or MYCT58A in the basal layer of the skin epidermis. In the T58A mutant, MYC is stabilized with constitutive S62 phosphorylation. When challenged with DMBA/TPA-mediated carcinogenesis, MYCT58A mice had accelerated development of papillomas, increased conversion to malignant lesions, and increased metastasis as compared to MYCWT mice. In addition, MYCT58A-driven SCC displayed stem cell gene expression not observed with MYCWT, including increased expression of Lgr6, Sox2, and CD34. In support of MYCT58A enhancing stem cell phenotypes, its expression was associated with an increased number of BrdU long-term label-retaining cells, increased CD34 expression in hair follicles, and increased colony formation from neonatal keratinocytes. Together, these results indicate that altering MYC phosphorylation changes its oncogenic activity—instead of diminishing establishment and/or maintenance of epidermal stem cell populations like wild-type MYC, pS62-MYC enhances these populations and, under carcinogenic conditions, pS62-MYC expression results in aggressive tumor phenotypes.

Background Trichomes play a key role in the development of plants and exist in a wide variety of species. Results In this paper, it was reviewed that the structure and morphology characteristics of trichomes, alongside the biological functions and classical regulatory mechanisms of trichome development in plants. The environment factors, hormones, transcription factor, non-coding RNA, etc., play important roles in regulating the initialization, branching, growth, and development of trichomes. In addition, it was further investigated the atypical regulation mechanism in a non-model plant, found that regulating the growth and development of tea (Camellia sinensis) trichome is mainly affected by hormones and the novel regulation factors. Conclusions This review further displayed the complex and differential regulatory networks in trichome initiation and development, provided a reference for basic and applied research on trichomes in plants.

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.

INTRODUCTION: Previous studies in patients with irritable bowel syndrome (IBS) showed immune activation, secretion, and barrier dysfunction in duodenal, jejunal, or colorectal mucosa. This study aimed to measure ileal mucosal expression of genes and proteins associated with mucosal functions. METHODS: We measured by reverse transcription polymerase chain reaction messenger RNA (mRNA) expression of 78 genes (reflecting tight junction proteins, chemokines, innate immunity, ion channels, and transmitters) and 5 proteins (barrier, bile acid receptor, and ion exchanger) in terminal ileal mucosa from 11 patients with IBS-diarrhea (IBS-D), 17 patients with IBS-constipation (IBS-C), and 14 healthy controls. Fold changes in mRNA were calculated using 2(−Δ, ΔCT) formula. Group differences were measured using analysis of variance. Protein ratios relative to healthy controls were based on Western blot analysis. Nominal P values (P < 0.05) are reported. RESULTS: In ileal mucosal biopsies, significant differences of mRNA expression in IBS-D relative to IBS-C were upregulation of barrier proteins (TJP1, FN1, CLDN1, and CLDN12), repair function (TFF1), and cellular functions. In ileal mucosal biopsies, mRNA expression in IBS-C relative to healthy controls was reduced GPBAR1 receptor, myosin light chain kinase (MYLK in barrier function), and innate immunity (TLR3), but increased mRNA expression of cadherin cell adhesion mechanisms (CTNNB1) and transport genes SLC9A1 (Na-H exchanger [NHE1]) and INADL (indirect effect on ion transport). DISCUSSION: These data support a role of ileal mucosal dysfunction in IBS, including barrier dysfunction in IBS-D and alterations in absorption/secretion mechanisms in IBS-C.

Although cancer is the leading cause of disease-related mortality in children, the relative rarity of pediatric cancers poses a significant challenge for developing novel therapeutics to further improve prognosis. Patient-derived xenograft (PDX) models, which are usually developed from high-risk tumors, are a useful platform to study molecular driver events, identify biomarkers, and prioritize therapeutic agents. Here we develop PDX for Childhood Cancer Therapeutics (PCAT), a new integrated portal for pediatric cancer PDX models. Distinct from previously reported PDX portals, PCAT is focused on pediatric cancer models and provides intuitive interfaces for querying and data mining. The current release comprises 324 models and their associated clinical and genomic data, including gene expression, mutation, and copy number alteration. Importantly, PCAT curates preclinical testing results for 68 models and 79 therapeutic agents manually collected from individual agent testing studies published since 2008. To facilitate comparisons of patterns between patient tumors and PDX models, PCAT curates clinical and molecular data of patient tumors from the TARGET project. In addition, PCAT provides access to gene fusions identified in nearly 1,000 TARGET samples. PCAT was built using R-shiny and MySQL. The portal can be accessed at http://pcat.zhenglab.info or http://www.pedtranscriptome.org.

Whereas gastric emptying significantly predicts calorie intake, the association between gastric capacity and satiation and satiety is unclear. To study the associations between gastric volumes and ingestive behaviors with satiation and satiety in obesity, 62 healthy adult obese patients (57 female) with no eating disorders underwent measurements of satiety, as determined by kilocalories of ingestion at a buffet meal, and satiation by volume to comfortable fullness (VTF) and maximum tolerated volume (MTV), while drinking Ensure (30 mL/min). Fasting and postprandial gastric volumes were measured by validated single-photon emission computed tomography. We also measured eating [Weight Efficacy Life-Style Questionnaire score (WEL)] and exercise behaviors associated with obesity. Spearman correlation-assessed relationships of measured traits and linear regression analysis to identify predictors of satiation or satiety. The participants were aged 38 ± 10.1 yr and the body mass index (BMI) 36.8 ± 4.8 kg/m(2). Fasting gastric volume was significantly correlated with VTF (r(s) = 0.3, P = 0.03), but not with MTV or buffet meal kilocalorie ingestion. Regression analysis identified sex (P = 0.02, with males having significantly higher fasting gastric volume) and fasting gastric volume (0.04) as predictors of higher VTF. An increase in fasting gastric volume of 50 mL resulted in a 6-mL increase in VTF. Buffet meal intake was inversely related to the ability to resist the urge to eat; factors associated with ingestive behavior (increase in total WEL score) significantly correlated with satiety and gastric accommodation (P < 0.05). Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation. NEW & NOTEWORTHY Buffet meal intake was inversely related to the ability to resist the urge to overeat. Factors associated with ingestive behavior significantly correlated with satiety and gastric accommodation. Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.

In contrast to feedforward architecture commonly used in deep networks at the core of today’s AI revolution, the biological cortex is endowed with an abundance of feedback projections. Feedback signaling is often difficult to differentially identify, and its computational roles remain poorly understood. Here, we investigated a cognitive phenomenon, called categorical perception (CP), that reveals the influences of high-level category learning on low-level feature-based perception, as a putative signature of top-down signaling. By examining behavioral data from a visual motion delayed matching experiment in non-human primates, we found that, after categorization training, motion directions closer to (respectively, away from) a category center became more (less) difficult to discriminate. This distance-dependent discrimination performance change along the dimension relevant to the learned categories provides direct evidence for the CP phenomenon. To explain this experimental finding, we developed a neural circuit model that incorporated key neurophysiological findings in visual categorization, working memory and decision making. Our model accounts for the behavioral data indicative of CP, pinpoints its circuit basis, suggests novel experimentally testable predictions and provides a functional explanation for its existence. Our work shows that delayed matching paradigms in non-human primates combined with biologically-based modeling can serve as a promising model system for elucidating the neural mechanisms of CP, as a manifestation of top-down signaling in the cortex.Significant StatementCategorical perception is a cognitive phenomenon revealing the influences of high-level category learning on low-level feature-based perception. However, its underlying neural mechanisms are largely unknown. Here, we found behavioral evidence for this phenomenon from a visual motion delayed matching experiment in non-human primates. We developed a neural circuit model that can account for this behavioral data, pinpoints its circuit basis, suggests novel experimentally testable predictions and provides a functional explanation for its existence. Our work shows that delayed matching paradigms in non-human primates combined with biologically-based modeling can serve as a promising model system for elucidating the neural mechanisms of categorical perception, as a manifestation of top-down signaling in the cortex.