Xanthan gum-capped Chromia Nanoparticles (XG-CrNPs): A promising nanoprobe for the detection of heavy metal ions.

The present study reports on the selective and sensitive detection of metals using xanthan gum-capped chromia nanoparticles (XG-CrNPs). The nanoparticles were synthesized by the chemical reduction method using sodium borohydride and xanthan gum as the reducing and capping agents, respectively. The synthesis of XG-CrNPs was confirmed by the appearance of the two absorption peaks at 272 nm and 371 nm in the UV-visible region. The nanoparticles have been extensively characterized by FTIR, TEM-EDX, XRD, and TGA analyses. The well-dispersed XG-CrNPs exhibited a quasi-spherical structure with an average particle size of 3 nm. A significantly low amount (2 µg/L) of XG-CrNPs was used for selective and sensitive detection of heavy metal ions. It showed excellent metal detecting properties by quenching its band gap signal which was extraordinarily conspicuous for Co(II), Hg(II), and Cd(II) in comparison to other metal ions like Ag(I), Ba(II), Mg(II), Mn(II), Ni(II), and Zn(II). The limit of detection of Co(II), Cd(II), and Hg(II) with this nanoprobe was found to be 2.167 µM, 1.065 µM, and 0.601 µM respectively. The nanoparticles manifested higher shelf-life and can be reused up to three consecutive cycles where most of its activity was conserved even after being used. Thus, it may find use in metal sensor devices for the detection of hazardous metals.

Psychometric evaluation of the Chinese version of the burnout syndrome assessment scale in nurses.

Objective: This study aimed to translate the Burnout Syndrome Assessment Scale (BOSAS) into Chinese and validate its reliability and validity among Chinese emergency department and ICU nurses. Methods: The scale was translated into Chinese using Brislin's translation principle. A total of 626 nurses from Jiangxi, Zhejiang, and Fujian provinces in China participated in an online questionnaire survey. The survey included the general information questionnaire for nurses developed by the research team and the Chinese version of the Burnout Syndrome Assessment Scale. Reliability and validity of the Chinese version of the scale were analyzed using SPSS.25 and AMOS.24 software. Results: The Chinese version of the Burnout Syndrome Assessment Scale consists of a total of 20 items, encompassing two dimensions: personal burnout and job burnout. This structure is consistent with the original English version of the scale. The Chinese version of BOSAS demonstrated high internal consistency, with a Cronbach's α coefficient of 0.941. Additionally, the scale exhibited good split-half reliability (0.765) and test-retest reliability (0.871). The content validity index (S-CVI) was 0.971, indicating strong content validity. Exploratory factor analysis confirmed the same 2-factor structure as the original scale, and confirmatory factor analysis further validated this structure, with all fit indices indicating appropriateness. Conclusion: The Burnout Syndrome Assessment Scale has been successfully introduced and its reliability and validity have been verified in Chinese emergency department and ICU nurses.

Proteomic and metabolomic insights into seed germination of Ferula assa-foetida.

Cold stratification is known to affect the speed of seed germination; however, its regulation at the molecular level in Ferula assa-foetida remains ambiguous. Here, we used cold stratification (4 °C in the dark) to induce germination in F. assa-foetida and adopted a proteomic and metabolomic approach to understand the molecular mechanism of germination. Compared to the control, we identified 209 non-redundant proteins and 96 metabolites in germinated F. assa-foetida seed. Results highlight the common and unique regulatory mechanisms like signaling cascade, reactivation of energy metabolism, activation of ROS scavenging system, DNA repair, gene expression cascade, cytoskeleton, and cell wall modulation in F. assa-foetida germination. A protein-protein interaction network identifies 18 hub protein species central to the interactome and could be a key player in F. assa-foetida germination. Further, the predominant metabolic pathways like glucosinolate biosynthesis, arginine and proline metabolism, cysteine and methionine metabolism, aminoacyl-tRNA biosynthesis, and carotenoid biosynthesis in germinating seed may indicate the regulation of carbon and nitrogen metabolism is prime essential to maintain the physiology of germinating seedlings. The findings of this study provide a better understanding of cold stratification-induced seed germination, which might be utilized for genetic modification and traditional breeding of Ferula assa-foetida. SIGNIFICANCE: Seed germination is the fundamental checkpoint for plant growth and development, which has ecological significance. Ferula assa-foetida L., commonly known as "asafoetida," is a medicinal and food crop with huge therapeutic potential. To date, our understanding of F. assa-foetida seed germination is rudimentary. Therefore, studying the molecular mechanism that governs dormancy decay and the onset of germination in F. assa-foetida is essential for understanding the basic principle of seed germination, which could offer to improve genetic modification and traditional breeding.

Unconventional Activation of IRE1 Enhances TH17 Responses and Promotes Airway Neutrophilia.

Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with TH17 responses. However, how UPRs participate in the deregulation of TH17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in TH17 cells relative to naïve CD4+ T cells. Cytokine (e.g. IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse TH17 cells. Ern1 (encoding IRE1)-deficiency decreases the expression of ER stress factors and impairs the differentiation and cytokine secretion of TH17 cells. Genetic ablation of Ern1 leads to alleviated TH17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances TH17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of TH17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in TH17-biased TH2-low asthma.

Heavy metal association with chronic kidney disease of unknown cause in central India-results from a case-control study.

BACKGROUND: Chronic Kidney Disease of unknown cause (CKDu) a disease of exclusion, and remains unexplained in various parts of the world, including India. Previous studies have reported mixed findings about the role of heavy metals or agrochemicals in CKDu. These studies compared CKDu with healthy controls but lacked subjects with CKD as controls. The purpose of this study was to test the hypothesis whether heavy metals, i.e. Arsenic (As), Cadmium (Cd), Lead (Pb), and Chromium (Cr) are associated with CKDu, in central India. METHODS: The study was conducted in a case-control manner at a tertiary care hospital. CKDu cases (n = 60) were compared with CKD (n = 62) and healthy subjects (n = 54). Blood and urine levels of As, Cd, Pb, and Cr were measured by Inductively Coupled Plasma- Optical Emission Spectrometry. Pesticide use, painkillers, smoking, and alcohol addiction were also evaluated. The median blood and urine metal levels were compared among the groups by the Kruskal-Wallis rank sum test. RESULTS: CKDu had significantly higher pesticide and surface water usage as a source of drinking water. Blood As levels (median, IQR) were significantly higher in CKDu 91.97 (1.3-132.7) µg/L compared to CKD 4.5 (0.0-58.8) µg/L and healthy subjects 39.01 (4.8-67.4) µg/L (p < 0.001) On multinominal regression age and sex adjusted blood As was independently associated with CKDu[ OR 1.013 (95%CI 1.003-1.024) P < .05].Blood and urinary Cd, Pb, and Cr were higher in CKD compared to CKDu (p > .05). Urinary Cd, Pb and Cr were undetectable in healthy subjects and were significantly higher in CKDu and CKD compared to healthy subjects (P = < 0.001). There was a significant correlation of Cd, Pb and Cr in blood and urine with each other in CKDu and CKD subjects as compared to healthy subjects. Surface water use also associated with CKDu [OR 3.178 (95%CI 1.029-9.818) p < .05). CONCLUSION: The study showed an independent association of age and sex adjusted blood As with CKDu in this Indian cohort. Subjects with renal dysfunction (CKDu and CKD) were found to have significantly higher metal burden of Pb, Cd, As, and Cr as compared to healthy controls. CKDu subjects had significantly higher pesticide and surface water usage, which may be the source of differential As exposure in these subjects.

Comparison of propofol and desflurane for postoperative neurocognitive function in patients with aneurysmal subarachnoid hemorrhage: A prospective randomized trial.

Background: Following aneurysmal subarachnoid hemorrhage, 40-50% of survivors experience cognitive dysfunction, which affects their quality of life. Anesthetic agents play a pivotal role in aneurysm surgeries. However, substantial evidence regarding their effects on neurocognitive function is lacking. This study evaluated the effects of propofol and desflurane on postoperative neurocognitive function and serum S-100B levels. Methods: One hundred patients were equally randomized to receive either propofol (Group P) or desflurane (Group D). Cognitive function was assessed using the Montreal Cognitive Assessment scale at three different time points: Preoperatively, at the time of discharge, and one month after surgery. Perioperative serum levels of S-100B were also measured. Results: The preoperative mean cognitive score in Group P was 21.64 + 4.46 and in Group D was 21.66 + 4.07 (P = 0.79). At discharge, a significant decrease in cognitive scores was observed compared to preoperative scores (Group P- 20.91 + 3.94, P = 0.03 and Group D-19.28 + 4.22, P = 0.00); however, scores were comparable between the two groups (P = 0.09). One month following surgery, mean cognitive scores were 22.63 + 3.57 in Group P and 20.74 + 3.89 in Group D, and the difference was significant (P = 0.04). Higher memory and orientation scores were observed in Group P than in Group D at one month (P < 0.05) in the subgroup analysis. Both groups had similar serum S-100B levels. Conclusion: The mean cognitive scores one month after surgery improved significantly with propofol compared with desflurane, but without clinical significance. Individual domain analysis demonstrated that orientation and memory scores were better preserved with propofol.

A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells.

Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15-18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes.

Specific connectivity optimizes learning in thalamocortical loops.

Thalamocortical loops have a central role in cognition and motor control, but precisely how they contribute to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for the thalamus in shaping cortical dynamics through learning. Since signals undergo a compression from the cortex to the thalamus, we hypothesized that the computational role of the thalamus depends critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic projections specialized to communicate an efference copy of the cortical output benefit motor control, while communicating the modes of highest variance is optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination tasks and found corticothalamic communication consistent with these predictions. These results suggest that the thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.

Post Cholecystectomy Bile Duct Injury in an Acute Setting: Categorization, Triaging, and Management Algorithm.

Background Postcholecystectomy bile duct injury (BDI) is a management challenge with significant morbidity, mortality, and effects on long-term quality of life. Early referral to a specialized hepatobiliary center and appropriate early management are crucial to improving outcomes and overall quality of life. In this retrospective analysis, we examined patients who were managed at our center over the past 10 years and proposed a triage and management algorithm for BDI in acute settings. Methods Patients referred to our center with BDI from January 2011 to December 2020 were reviewed retrospectively. The primary objective of initial management is to control sepsis and minimize BDI-related morbidity and mortality. All the patients were resuscitated with intravenous fluid, antibiotics (preferably culture-based), correction of electrolyte deficiencies, and organ support if required. A triage module and management algorithm were framed based on our experience. All the patients were triaged based on the presence or absence of bile leaks. Each group was further subdivided into red, yellow, and green zones (depending on the presence of sepsis, organ failure, and associated injuries), and the results were analyzed as per the proposed algorithm. Results One hundred twenty-eight patients with acute BDI were referred to us during the study period, and 116 patients had BDI with a bile leak and 12 patients were without a bile leak. Out of bile leak patients, 106 patients (91.38%) had sepsis with or without organ failure (red and yellow zone) and required invasive intervention in the form of PCD insertion (n=99, 85.34%) and/or laparotomy, lavage, and drainage (n=7, 6.03%). Another 10 patients (8.62%) had controlled external biliary fistula (green zone), of which four were managed with antibiotics, four underwent endoscopic retrograde cholangiopancreatography stenting, and only two (1.7%) patients could undergo Roux-en-Y hepaticojejunostomy upfront due to late referral. Among patients with BDI without bile leaks, nine (75%) had cholangitis (red and yellow zones). Out of these, five required PTBD along with antibiotics and four were managed with antibiotics alone. Only three (25%) patients in this group could undergo definitive repair without any restriction on the timing of referral and were sepsis-free at presentation (green zone). A total of nine patients had a vascular injury, and four of them required digital subtraction angiography and coil embolization. There were three (2.34%) mortalities; all were in the red zone of rest and had successful initial management. In total, five patients were managed with early repair in the acute setting, and the rest underwent definitive intervention at subsequent admissions after being converted to green zone patients with initial management. Conclusion The presented categorization, triaging, and management algorithm provides optimum insight to understand the severity, simplify these complex scenarios, expedite the decision-making process, and thus enhance patient outcomes in early acute settings following BDI.

Caudal duplication syndrome: A rare entity.

The rare caudal duplication syn drome is a spectrum of anomalie s primarily involving par tial or compl ete dupl ication of organ s comp risin g the gastro intest ina l, genitourinary and distal neu ral tube system s. These findings are considered to be a result of aberrant embryogenesis. We hereby report a case of an adult female with comple te duplicat ion o f the genital and ur inary systems (ureth ra and bladder), hindgut a nd lower end of vertebral col umn with no functional impairment. She presented in her first pregnancy at 36 weeks gestation, in labo ur. To the author's knowle dge this is the first case of caudal duplication syn drom e with pregnanc y fro m Pakistan.

Identification of novel potential cathepsin-B inhibitors through pharmacophore-based virtual screening, molecular docking, and dynamics simulation studies for the treatment of Alzheimer's disease.

Cathepsin B is a cysteine protease lysosomal enzyme involved in several physiological functions. Overexpression of the enzyme enhances its proteolytic activity and causes the breakdown of amyloid precursor protein (APP) into neurotoxic amyloid ß (Aß), a characteristic hallmark of Alzheimer's disease (AD). Therefore, inhibition of the enzyme is a crucial therapeutic aspect for treating the disease. Combined structure and ligand-based drug design strategies were employed in the current study to identify the novel potential cathepsin B inhibitors. Five different pharmacophore models were developed and used for the screening of the ZINC-15 database. The obtained hits were analyzed for the presence of duplicates, interfering PAINS moieties, and structural similarities based on Tanimoto's coefficient. The molecular docking study was performed to screen hits with better target binding affinity. The top seven hits were selected and were further evaluated based on their predicted ADME properties. The resulting best hits, ZINC827855702, ZINC123282431, and ZINC95386847, were finally subjected to molecular dynamics simulation studies to determine the stability of the protein-ligand complex during the run. ZINC123282431 was obtained as the virtual lead compound for cathepsin B inhibition and may be a promising novel anti-Alzheimer agent.

Evaluating Static Bone Cysts (SBCs) Through Long-Term Volumetric Analysis Using CBCT: A Study with 6-Month Follow-Up.

Background: Salivary gland bone defects are static lesions which are rare entities, generally asymptomatic and found in routine imaging exams. However, in atypical cases or when misdiagnosed, surgical intervention is carried out. Purpose: a) The study is intended to investigate the frequency of SBC's and to describe the radiological characteristics of its subtypes; b) To evaluate the efficacy of volumetric analysis tool in CBCT and; c) To describe the confirmative role of CBCT in the diagnosis of SBC's without the need for surgical intervention. Material and Methods: The study was conducted on 11 subjects with SBC detected on 3304 panoramic radiographs. CBCT images for each patient were captured at baseline and at an interval of 6 months. Radiographic sub-types of SBC based on the relationship to mandibular canal and bucco-lingual expansion were studied. Files in DICOM format were transferred into OnDemand 3D program (Cybermed Co, Seoul, Korea) and volumes in mm3 of the cavities were measured by 2 observers at both intervals. Inter and intra reliability of volumetric measurements between observers was compared using correlation coefficient and student t test. Results: There were 8 males and 3 females who had SBC in this study (age range: 22-70 years). According to the relationship of SBC with mandibular canal, most SBCs were Type 1 (63.5 %) followed by Type 2 & 3 (18.5 %) each. The total volume of SBC in patients ranged from 146 mm3 to 650 mm3 (mean: 332.5 mm3). There was no significant difference between observers for volume measurements at baseline and at 6 months interval (p>0.05). Conclusions: Based on the results of this study, CBCT should be considered as a definitive diagnostic modality for volumetric analysis of SBCs. Over diagnosis, unnecessary surgical exploration and agony to patients can be avoided using this tool. Key words:Stafne bone cavity, CBCT, Volumetric analysis, salivary gland, panoramic radiography.

The Impact of an Intern's Clinical Guidebook on Easing the Transition of New Interns Into the United States Healthcare System.

This study explores the efficacy of an intern's clinical guidebook in facilitating the transition of categorical internal medicine interns into the United States healthcare system. New interns, particularly foreign medical graduates, face multifaceted challenges during their initial year of residency. The research, conducted at Ascension Saint Joseph Hospital in Chicago, employed a quasi-experimental pre-post design involving 20 interns. Participants were provided with an intern's clinical guidebook, and their knowledge was assessed through pre and post exams. Results demonstrated a statistically significant improvement in overall knowledge, with mean scores increasing from 65% to 77.37%. Subgroup analysis revealed similar improvements among both male and female interns. Data confidentiality and ethical considerations were prioritized, with participant data anonymized and stored securely. Despite limitations, this study highlights the guidebook's potential to enhance intern education and improve the quality of care provided during the crucial transition period. Further research is recommended to validate and extend these findings.

ER stress and ERO1: Potential therapeutic targets for inherited myopathies.

Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1 demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP.

Exploring luminescent carbon dots derived from syrup bottle waste and curcumin for potential antimicrobial and bioimaging applications.

In this study, we utilized a navel hybrid material, prepared by fusing fluorescent Carbon Dots SyCDs, derived from syrup bottles, with curcumin. This innovative approach not only offers significant advancements in antimicrobial activity and bioimaging but also represents a stride in sustainable and eco-friendly nanotechnology. The core of our study is the development of an efficient, cost-effective, and environmentally conscious method for synthesizing SyCDs. This is achieved by repurposing waste syrup bottles, thus addressing the pressing issue of plastic waste. The incorporation of curcumin, renowned for its biological properties, enhances the luminescent characteristics of SyCDs and augments their functionality. This combination overcomes the inherent limitations of curcumin when used in isolation. The hybrid material exhibits enhanced antimicrobial properties and proves to be a potent alternative to conventional fluorescent dyes for bioimaging, marking a substantial leap in the field of sustainable nanomaterials. Our work not only demonstrates the versatile applications of luminescent SyCDs in health and environmental science but also underscores the potential of sustainable approaches in addressing global environmental challenges. This study, represents a significant contribution to the domain of sustainable nanotechnology, highlighting the transformative power of integrating waste management with advanced material science.

Laser-assisted synthesis of nano-hydroxyapatite and functionalization with bone active molecules for bone regeneration.

The main goal of bone tissue engineering research is to replace the allogenic and autologous bone graft substitutes that can promote bone repair. Owing to excellent biocompatibility and osteoconductivity, hydroxyapatite is in extensive research and high demand for both medical and non-medical applications. Although various methods have been developed for the synthesis of hydroxyapatite, in the present study we have shown the use of nanosecond laser energy in the wet precipitation method of nano-hydroxyapatite (nHAP) synthesis without using ammonium solution or any other chemicals for pH maintenance. Here, the present study aimed to fabricate the nanohydroxyapatite using a nanosecond laser. The X-ray diffraction and Fourier transform infrared spectroscopy have confirmed the hydroxyapatite formation under laser irradiation in less time without aging. A transmission electron microscopy confirmed the nano size of synthesized nHAP, which is comparable to conventional nHAP. The length and width of the laser-assisted nHAP were found to be in the range of 50-200 nm and 15-20 nm, respectively, at various laser parameters. The crystallite size obtained by Debye Scherrer formulae was found to be in the range of ∼ 16-36 nm. In addition, laser-assisted nHAP based composite cryogel (nanohydroxyapatite/gelatin/collagen I) was synthesized and impregnated with bioactive molecules (bone morphogenic protein and zoledronic acid) that demonstrated significant osteogenic potential both in vitro in cell experiment and in vivo rat muscle pouch model (abdomen and tibia muscles). Dual-energy X-ray analysis, micro-CT, and histological analysis confirmed ectopic bone regeneration. Micro-CT based histomorphometry showed a higher amount (more than 10-fold) of mineralization for animal groups implanted with composite cryogels loaded with bioactive molecules compared to only composite cryogels groups. Our findings thus demonstrate a controlled and rapid synthetic method for the synthesis of nHAP with various physical, chemical, and biological properties exhibited as comparable to conventionally synthesized nHAP.

Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine.

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.

Anti-proliferative, -migratory and -clonogenic effects of long-lasting nitric oxide release in HepG2 cells.

Nitric oxide (NO) holds promise as a cytotoxic agent against tumors, but its gaseous nature and short half-life hinder direct administration to tumor tissues. Herein, we present novel 6,9-disubstituted purine derivatives designed to ensure sustained NO release, followed by study of their significant anti-proliferative, anti-migratory, and anti-clonogenic effects on HepG2 cell lines, highlighting NO release as a potent effector for treating hepatocellular carcinoma.

Dynamics of striatal action selection and reinforcement learning.

Spiny projection neurons (SPNs) in dorsal striatum are often proposed as a locus of reinforcement learning in the basal ganglia. Here, we identify and resolve a fundamental inconsistency between striatal reinforcement learning models and known SPN synaptic plasticity rules. Direct-pathway (dSPN) and indirect-pathway (iSPN) neurons, which promote and suppress actions, respectively, exhibit synaptic plasticity that reinforces activity associated with elevated or suppressed dopamine release. We show that iSPN plasticity prevents successful learning, as it reinforces activity patterns associated with negative outcomes. However, this pathological behavior is reversed if functionally opponent dSPNs and iSPNs, which promote and suppress the current behavior, are simultaneously activated by efferent input following action selection. This prediction is supported by striatal recordings and contrasts with prior models of SPN representations. In our model, learning and action selection signals can be multiplexed without interference, enabling learning algorithms beyond those of standard temporal difference models.