Miracle-dz/UniFAR-FTUs huggingface dataset:
CITCO Directly Binds to and Activates Human Pregnane X Receptor

The xenobiotic receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are activated by structurally diverse chemicals to regulate the expression of target genes, and they have overlapping regulation in terms of ligands and target genes. Receptor-selective agonists are, therefore, critical for studying the overlapping function of PXR and CAR. An early effort identified 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) as a selective human CAR (hCAR) agonist, and this has since been widely used to distinguish the function of hCAR from that of human PXR (hPXR). The selectivity was demonstrated in a green monkey kidney cell line, CV-1, in which CITCO displayed >100-fold selectivity for hCAR over hPXR. However, whether the selectivity observed in CV-1 cells also represented CITCO activity in liver cell models was not hitherto investigated. In this study, we showed that CITCO: 1) binds directly to hPXR; 2) activates hPXR in HepG2 cells, with activation being blocked by an hPXR-specific antagonist, SPA70; 3) does not activate mouse PXR; 4) depends on tryptophan-299 to activate hPXR; 5) recruits steroid receptor coactivator 1 to hPXR; 6) activates hPXR in HepaRG cell lines even when hCAR is knocked out; and 7) activates hPXR in primary human hepatocytes. Together, these data indicate that CITCO binds directly to the hPXR ligand-binding domain to activate hPXR. As CITCO has been widely used, its confirmation as a dual agonist for hCAR and hPXR is important for appropriately interpreting existing data and designing future experiments to understand the regulation of hPXR and hCAR. SIGNIFICANCE STATEMENT The results of this study demonstrate that 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is a dual agonist for human constitutive androstane receptor (hCAR) and human pregnane X receptor (hPXR). As CITCO has been widely used to activate hCAR, and hPXR and hCAR have distinct and overlapping biological functions, these results highlight the value of receptor-selective agonists and the importance of appropriately interpreting data in the context of receptor selectivity of such agonists.
From parts lists to functional significance—RNA–protein interactions in gene regulation

Hundreds of canonical RNA binding proteins facilitate diverse and essential RNA processing steps in cells forming a central regulatory point in gene expression. However, recent discoveries including the identification of a large number of noncanonical proteins bound to RNA have changed our view on RNA–protein interactions merely as necessary steps in RNA biogenesis. As the list of proteins interacting with RNA has expanded, so has the scope of regulation through RNA–protein interactions. In addition to facilitating RNA metabolism, RNA binding proteins help to form subcellular structures and membraneless organelles, and provide means to recruit components of macromolecular complexes to their sites of action. Moreover, RNA–protein interactions are not static in cells but the ribonucleoprotein (RNP) complexes are highly dynamic in response to cellular cues. The identification of novel proteins in complex with RNA and ways cells use these interactions to control cellular functions continues to broaden the scope of RNA regulation in cells and the current challenge is to move from cataloguing the components of RNPs into assigning them functions. This will not only facilitate our understanding of cellular homeostasis but may bring in key insights into human disease conditions where RNP components play a central role. This review brings together the classical view of regulation accomplished through RNA–protein interactions with the novel insights gained from the identification of RNA binding interactomes. We discuss the challenges in combining molecular mechanism with cellular functions on the journey towards a comprehensive understanding of the regulatory functions of RNA–protein interactions in cells.
How Academic Dentistry will Emerge from this Economic Crisis

Sompop Bencharit, DDS, MS, PhD, FACP, Assistant Professor, Department of Prosthodontics, School of Dentistry, Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, CB#7450, Chapel Hill, NC 27599-7450, USA, E-mail: Sompop_Bencharit@dentistry.unc. edu
Molecular Engineering of Fully-Conjugated sp2 Carbon-Linked Polymers for High-Efficiency Photocatalytic Hydrogen Evolution.

The manifold organic precursors offer a versatile platform for precisely tailoring the electronic properties of semiconducting polymers. In this study, three fully-conjugated sp 2 carbon-linked polymers were designed and synthesized for photocatalytic hydrogen evolution under visible-light illumination, by copolymerizing different C3-symmetric aromatic aldehydes as knots with the 1,4-phenylene diacetonitrile (PDAN) linker through the -C=C- condensation reaction. A maximum hydrogen evolution rate (HER) of 30.2 mmol g -1 h -1 was achieved over the polymer CTTP based on 2,4,6-triphenyl-1,3,5-triazine units linked by cyano substituted phenylene, with an apparent quantum yield (AQY) of 7.20 % at 420 nm. Increasing the degree of conjugation and planarity not only extended the visible-light absorption, but also stabilized the fully-conjugated sp 2 carbon-linked donor-acceptor (D-A) polymer. Incorporating additional electron-withdrawing triazine units into the D-A polymer to form multiple electron donors and acceptors can greatly promote exciton separation and charge transfer, thus significantly enhance the photocatalytic activity.
N400 event‐related brain potential as an index of real‐world and neurocognitive function in patients at clinical high risk for schizophrenia

The N400 event‐related potential is a neurophysiological index of cognitive processing of real‐world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This ‘N400 semantic priming effect’ is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real‐world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group.
The Effect of (1S,2R-((3-bromophenethyl)amino)-N-(4-chloro-2-trifluoromethylphenyl) cyclohexane-1-sulfonamide) on Botrytis cinerea through the Membrane Damage Mechanism

In recent years, Botrytis cinerea has led to serious yield losses because of its resistance to fungicides. Many sulfonamides with improved properties have been used. (1S,2R-((3-bromophenethyl)amino)-N-(4-chloro-2-trifluoromethylphenyl)cyclohexane-1-sulfonamide) (abbreviation: SYAUP-CN-26) is a new sulfonamide compound that has excellent activity against B. cinerea. This study investigated the effect of SYAUP-CN-26 on electric conductivity, nucleic acids leakage, malondialdehyde (MDA) content, and reducing sugars and membrane structure reduction of B. cinerea. The results showed that the cell membrane permeability of B. cinerea increased with increasing concentrations of SYAUP-CN-26; meanwhile, the sugar content decreased, the malondialdehyde content increased, and relative electric conductivity and nucleic acid substance leakage were observed in the cell after exposure to 19.263 mg/L SYAUP-CN-26 for 24 h. After 48 h of exposure to 1.823 mg/L and 19.263 mg/L SYAUP-CN-26, the cell membranes of B. cinerea mycelia were observed to be damaged under propidium iodide (PI) and transmission electron microscopy (TEM) observations. It is assumed that SYAUP-CN-26 was responsible for the damage of cell membrane. Overall, the results indicate that SYAUP-CN-26 could inhibit the growth of B. cinerea cells by damaging the cell membranes.
The metabotropic glutamate receptor subtype 1 regulates development and maintenance of lemniscal synaptic connectivity in the somatosensory thalamus

The metabotropic glutamate receptor subtype 1 (mGluR1) is a major subtype of group I mGluRs, which contributes to the development and plasticity of synapses in the brain. In the sensory thalamus, the thalamocortical neuron receives sensory afferents and massive feedback input from corticothalamic (CT) fibers. Notably, mGluR1 is more concentrated in CT synapses in the sensory thalamus. In the visual thalamus, mGluR1 maintains mature afferent synaptic connectivity. However, it is unknown whether mGluR1 contributes to strengthening of immature synapses or weakening of excess synapses during development and whether mGluR1 at CT synapses heterosynaptically regulates the development or refinement of afferent synapses. Here we investigated the effects of knocking out the gene encoding mGluR1 or pharmacologically blocking cortical activity on the development and maintenance of lemniscal synapses, i.e., the somatosensory afferent synapses, in the ventral posteromedial somatosensory thalamus. mGluR1-knockout (KO) mice exhibited delayed developmental strengthening as well as incomplete elimination and remodeling after maturation of lemniscal synapses. Similar to the phenotypes exhibited by mGluR1-KO mice, pharmacological blockade of somatosensory cortical activity from P12 or P21 for 1 week in wild-type mice perturbed elimination or maintenance of lemniscal synapses, respectively. The same manipulation in mGluR1-KO mice failed to induce additional abnormalities in lemniscal synaptic connectivity. These results suggest that activation of mGluR1, driven by CT input, regulates multiple stages of the development of lemniscal synapses, including strengthening, refinement, and maintenance in the somatosensory thalamus.
Restructuring of contralateral gray matter volume associated with cognition in patients with unilateral temporal lobe glioma before and after surgery

Glioma can cause variable alterations to the structure and function of the brain. However, there is a paucity of studies on the gray matter (GM) volume alterations in the brain region opposite the temporal glioma before and after surgery. Therefore, the present study was initiated to investigate the alternation in contralateral homotopic GM volume in patients with unilateral temporal lobe glioma and further, assess the relationship between GM volume alternations with cognition. Eight left temporal lobe glioma patients (LTPs), nine right temporal lobe glioma patients (RTPs), and 28 demographically matched healthy controls (HCs) were included. Using voxel‐based morphometry method, alternations in the contralateral homotopic GM volume in patients with unilateral temporal lobe glioma was determined. Furthermore, the correlation analysis was performed to explore the relationship between cognitive function and altered GM volume. In the preoperative analysis, compared to HCs, LTPs exhibited increased GM volume in right inferior temporal gyrus and right temporal pole (superior temporal gyrus), and, RTPs presented increased GM volume in left inferior temporal gyrus. In the postoperative analysis, compared to HCs, RTPs presented increased GM volume in left middle temporal gyrus. Furthermore, the increased GM volume was significantly positively correlated with the memory test but negatively correlated with the visuospatial test. This study preliminarily confirmed that there were compensatory changes in the GM volume in the contralateral temporal lobe in unilateral temporal lobe glioma patients. Furthermore, alterations of GM volume may be a mechanism for cognitive function compensation.
Postoperative narcotic use in patients with ovarian cancer on an Enhanced Recovery After Surgery (ERAS) pathway.

OBJECTIVES To determine the impact of an ERAS pathway on post-discharge narcotic use for patients with ovarian cancer undergoing open surgery. METHODS This was a retrospective cohort study of women who underwent open ovarian cancer surgeries in 2014 prior to ERAS ("pre-ERAS") and in 2016/2018 after ERAS was instituted ("ERAS"). Patients taking chronic narcotics were excluded. A statewide prescription monitoring program was used to identify narcotic prescriptions filled in the three months after surgery. Quantity of narcotic medication is referenced in morphine milligram equivalents (MME). RESULTS 42 pre-ERAS and 94 ERAS patients were included. The groups were similar in age, BMI, diabetes, tobacco use, mean number of prior abdominal/pelvic surgeries, and advanced stage disease. ERAS patients had a shorter hospital stay (6.7 days pre-ERAS vs 4.2 days ERAS, p = 0.003), used less narcotic in the 24 h prior to discharge (74.0 MME pre-ERAS vs 25.8 MME ERAS, p = 0.002), and filled prescriptions at time of discharge for less narcotic (519.9 MME pre-ERAS vs 339.7 MME ERAS, p = 0.011). After hospital discharge, ERAS patients filled fewer additional prescriptions (52.4% pre-ERAS, vs 29.4% ERAS, p = 0.012). In total, ERAS patients filled prescriptions for 55% fewer narcotics in the three months after surgery than the pre-ERAS group (1101.4 MME pre-ERAS vs 492.1 MME ERAS, p < 0.001). CONCLUSIONS Institution of an ERAS protocol appears to decrease the narcotic needs of patients in the three months after ovarian cancer surgery.
Pancreatoduodenectomy After Neoadjuvant Chemotherapy for Locally Advanced Pancreatic Cancer in the Presence of an Aberrant Right Hepatic Artery

Background/Aim: Locally advanced pancreatic head cancer remains an aggressive malignancy with a low likelihood of achieving resectability after neoadjuvant chemotherapy. Resection is even more difficult if anatomical variations of the blood supply are present. Case Report: We present the case of a 62-year-old male diagnosed with locally advanced pancreatic cancer in the presence of an aberrant right hepatic artery originating from the superior mesenteric artery. After completing six cycles of neoadjuvant chemotherapy consisting of irinotecan and oxaliplatin, resectability was achieved, the patient being submitted to pancreatoduodenectomy. Intraoperatively, the presence of an aberrant right hepatic artery originating from the superior mesenteric artery was confirmed. The postoperative course was uneventful, the patient being discharged on the eight postoperative day, while the histopathological studies confirmed the negativity of the resection margins. Conclusion: Resectability can be achieved after neoadjuvant chemotherapy for locally advanced pancreatic cancer. However, attention should be focused on the possibility of the presence of anatomical variations of the pancreatic and liver blood supply.
Neuroprotective effects of brain‐derived neurotrophic factor against amyloid beta 1‐40‐induced retinal and optic nerve damage

Brain‐derived neurotrophic factor (BDNF) could be considered a potential neuroprotective therapy in amyloid beta (Aβ)‐associated retinal and optic nerve degeneration. Hence, in this study we investigated the neuroprotective effect of BDNF against Aβ1‐40‐induced retinal and optic nerve injury. In this study, exposure to Aβ1‐40 was associated with retinal and optic nerve injury. TUNEL staining showed significant reduction in the apoptotic cell count in the BDNF‐treated group compared with Aβ1‐40 group. H&E‐stained retinal sections also showed a striking reduction in neuronal cells in the ganglion cell layer (GCL) of retinas fourteen days after Aβ1‐40 exposure. By contrast, number of retinal cells was preserved in the retinas of BDNF‐treated animals. After Aβ1‐40 exposure, visible axonal swelling was observed in optic nerve sections. However, the BDNF‐treated group showed fewer changes in optic nerve; axonal swelling was less frequent and less marked. In the present study, exposure to Aβ was associated with oxidative stress, whereas levels of retinal glutathione (GSH), superoxide dismutase (SOD) and catalase were significantly increased in BDNF‐treated than in Aβ1‐40‐treated rats. Both visual object recognition tests using an open‐field arena and a Morris water maze showed that BDNF improved rats’ ability to recognise visual cues (objects with different shapes) after Aβ1‐40 exposure, thus demonstrating that the visual performance of rats was relatively preserved following BDNF treatment. In conclusion, intravitreal treatment with BDNF prevents Aβ1‐40‐induced retinal cell apoptosis and axon loss in the optic nerve of rats by reducing retinal oxidative stress and restoring retinal BDNF levels.
Risk assessment of antimony, barium, beryllium, boron, bromine, lithium, nickel, strontium, thallium and uranium concentrations in the New Zealand diet

ABSTRACT Identifying and monitoring dietary toxicants is an important component of contemporary food safety systems. To characterise their potential dietary risks, analysis was undertaken of 10 elements: antimony, barium, beryllium, boron, bromine, lithium, nickel, strontium, thallium and uranium in 132 different food types. All 10 elements were reported as quantified in aportion of the analysed foods, with prevalence ranging from less than 1% for antimony to 98% for barium. Dietary exposure assessment was undertaken for 10 New Zealand population cohorts using apublished simulated diet, and proportionality of food groups to total exposure identified. Characterisation against health-based guidance values identified no dietary risk from exposures to beryllium, boron, bromine, lithium, strontium and uranium to any of the population cohorts. For antimony and thallium, the exposure range for infants was calculated to exceed the health-based guidance value, and for barium and nickel, all mean exposures were above the health-based guidance value for younger population cohorts. Although some conservatism in applying upper-bound mean exposures reduces the likelihood of asignificant dietary risk, further laboratory method development and analysis of these elements in the New Zealand diet would be beneficial to ensure protection of New Zealand public health.
The Influence of Tourists’ Experience of Quality of Street Foods on Destination’s Image, Life Satisfaction, and Word of Mouth: The Moderating Impact of Food Neophobia

Due to growing food-related tourism, there is increasing interest about street foods worldwide, including South Korea. Many types of food-related experiences have been considered as one of the significant elements to develop positive perceptions about a destination, and street food has been recognized as a critical clue for encouraging tourists to a destination. Previous scholars mentioned street food as a public health risk element as well as a significant factor to attract tourists’ attention. Therefore, this study aims to find out how experiential quality of street foods is related to the destination image, life satisfaction, and word of mouth as perceived by tourists in night markets of South Korea. Data was collected from 325 foreigners who visited night markets and have experienced street foods in Korea. This study demonstrates the results of the influence of quality of street foods on tourist experience, on destination image, on life satisfaction, and on word of mouth in Korea. In addition, the result shows a moderating impact of food neophobia on the formulated relationships. There are statistically significant differences between groups with high neophobia perception and low neophobia perception of street foods. Based on the results of this study, we propose not only academic implications for future studies, but also managerial implications for food enterprises and food tourism organizers related to street food.
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.
Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine

Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine w/w. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops® dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses.