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Solution-phase bottom up self-assembly of nanocrystals into superstructures such as ordered superlattices is an attractive strategy to generate functional materials of increasing complexity, including very recent advances that incorporate strong interparticle electronic coupling. While the self-assembly kinetics in these systems have been elucidated and related to the product characteristics, the weak interparticle bonding interactions suggest the superstructures formed could continue to order within the solution long after the primary nucleation and growth have occurred, even though the mechanism of annealing remains to be elucidated. Here, we use a combination of Bragg coherent diffractive imaging and x-ray photon correlation spectroscopy to create real-space maps of supercrystalline order along with a real-time view of the strain fluctuations in aging strongly coupled nanocrystal superlattices while they remain suspended and immobilized in solution. By combining the results, we deduce that the self-assembled superstructures are polycrystalline, initially comprising multiple nucleation sites, and that shear avalanches at grain boundaries continue to increase crystallinity long after growth has substantially slowed. This multimodal approach should be generalizable to characterize a breadth of materials in situ in their native chemical environments, thus extending the reach of high-resolution coherent x-ray characterization to the benefit of a much wider range of physical systems.

IntroductionThe development and maintenance of the skeletal muscle is crucial for the support of daily function. Heat, when applied locally, has shown substantial promise in the maintenance of the muscle. The purpose of this study was to determine the combined effects of local heat application and acute resistance exercise on gene expression associated with the human muscle growth program.Materials and methodsParticipants (n = 12, 26 ± 7 years, 1.77 ± 0.07 m, 79.6 ± 15.4 kg, and 16.1 ± 11.6 %BF) completed an acute bilateral bout of resistance exercise consisting of leg press (11 ± 2 reps; 170 ± 37 kg) and leg extension (11 ± 1 reps; 58 ± 18 kg). Participants wore a thermal wrap containing circulating fluid (40°C, exercise + heat; EX + HT) during the entire experimental period and 4 h post-exercise, while the other leg served as an exercise-only (EX) control. Biopsies of the vastus lateralis were collected (Pre, Post, and 4hPost) for gene expression analyses.ResultsIntramuscular temperatures increased (Post, +2.2°C ± 0.7°C, and p < 0.001; 4hPost, +2.5°C ± 0.6°C, and p < 0.001) and were greater in the EX + HT leg post-exercise (+0.35°C ± 0.3°C, and p = 0.005) and after 4hPost (+2.1°C ± 0.8°C and p < 0.001). MYO-D1 mRNA was greater in the EX + HT leg vs. the EX (fold change = 2.74 ± 0.42 vs. 1.70 ± 0.28, p = 0.037). No other genes demonstrated temperature sensitivity when comparing both legs (p > 0.05). mRNA associated with the negative regulator, myostatin (MSTN), decreased post-exercise (p = 0.001) and after 4 h (p = 0.001). mRNA associated with proteolysis decreased post-exercise (FBXO32, p = 0.001; FOXO3a, p = 0.001) and after 4 h (FBXO32, p = 0.001; FOXO3a, p = 0.027).ConclusionThe elevated transcription of the myogenic differentiation factor 1 (MYO-D1) after exercise in the heated condition may provide a mechanism by which muscle growth could be enhanced.

Understanding the interactions between drugs and enzymes is crucial for designing effective therapeutics. This study employed a combination of molecular docking and molecular dynamics (MD) simulations to evaluate the binding affinity, stability, and dynamic behavior of two new compounds (compound 1 and compound 2) compared to vancomycin and meropenem against Staphylococcus aureus and Serratia marcescens bacterial enzymes. Molecular docking studies provided insights into the binding interactions and affinities of these compounds, revealing that both compound 1 and compound 2 exhibit promising binding profiles. In particular, compound 1 demonstrated lower binding energies with key enzymes from Staphylococcus aureus compared to vancomycin, suggesting enhanced potential. MD simulations further elucidated the dynamic stability of these complexes. Results indicated that compound 1 maintains consistent binding modes with low RMSD and RMSF values, implying stable interactions. In contrast, vancomycin exhibited high RMSD and RMSF values in some enzyme complexes, reflecting potential instability. Compound 2 showed competitive stability and binding behavior compared to meropenem, with comparable RMSD and RMSF values across various enzyme targets. These findings highlight the potential of compound 1 and compound 2 as viable candidates for further development, offering insights into their stability and efficacy as new therapeutic agents.

Large language models like ChatGPT can learn in-context (ICL) from examples. Studies showed that, due to ICL, ChatGPT achieves impressive performance in various natural language processing tasks. However, to the best of our knowledge, this is the first study that assesses ChatGPT's effectiveness in annotating a dataset for training instructor models in intelligent tutoring systems (ITSs). The task of an ITS instructor model is to automatically provide effective tutoring instruction given a student's state, mimicking human instructors. These models are typically implemented as hardcoded rules, requiring expertise, and limiting their ability to generalize and personalize instructions. These problems could be mitigated by utilizing machine learning (ML). However, developing ML models requires a large dataset of student states annotated by corresponding tutoring instructions. Using human experts to annotate such a dataset is expensive, time-consuming, and requires pedagogical expertise. Thus, this study explores ChatGPT's potential to act as a pedagogy expert annotator. Using prompt engineering, we created a list of instructions a tutor could recommend to a student. We manually filtered this list and instructed ChatGPT to select the appropriate instruction from the list for the given student's state. We manually analyzed ChatGPT's responses that could be considered incorrectly annotated. Our results indicate that using ChatGPT as an annotator is an effective alternative to human experts. The contributions of our work are (1) a novel dataset annotation methodology for the ITS, (2) a publicly available dataset of student states annotated with tutoring instructions, and (3) a list of possible tutoring instructions.

Introduction Treatment for abdominal pain in patients with chronic pancreatitis (CP) remains challenging in the setting of central nervous system sensitisation, a phenomenon of remodelling and neuronal hyperexcitability resulting from persistent pain stimuli. This is suspected to render affected individuals less likely to respond to conventional therapies. Endotherapy or surgical decompression is offered to patients with pancreatic duct obstruction. However, the response to treatment is unpredictable. Pancreatic quantitative sensory testing (P-QST), an investigative technique of standardised stimulations to test the pain system in CP, has been used for phenotyping patients into three mutually exclusive groups: no central sensitisation, segmental sensitisation (pancreatic viscerotome) and widespread hyperalgesia suggestive of supraspinal central sensitisation. We will test the predictive capability of the pretreatment P-QST phenotype to predict the likelihood of pain improvement following invasive treatment for painful CP.Methods and analysis This observational clinical trial will enrol 150 patients from the University of Pittsburgh, Johns Hopkins and Indiana University. Participants will undergo pretreatment phenotyping with P-QST. Treatment will be pancreatic endotherapy or surgery for clearance of painful pancreatic duct obstruction. Primary outcome: average pain score over the preceding 7 days measured by Numeric Rating Scale at 6 months postintervention. Secondary outcomes will include changes in opioid use during follow-up, and patient-reported outcomes in pain and quality of life at 3, 6 and 12 months after the intervention. Exploratory outcomes will include creation of a model for individualised prediction of response to invasive treatment.Ethics and dissemination The trial will evaluate the ability of P-QST to predict response to invasive treatment for painful CP and develop a predictive model for individualised prediction of treatment response for widespread use. This trial was approved by the University of Pittsburgh Institutional Review Board. Data and results will be reported and disseminated in conjunction with National Institutes of Health policies.Trial registration number NCT04996628.

Background: Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterised by acute episodes of non-pruritic skin and submucosal swelling caused by increase in vascular permeability. Objective: Here we present the first complex analysis of the National HAE Slovakian cohort with the detection of 12 previously un-published genetic variants in SERPING1 gene. Methods: In patients diagnosed with hereditary angioedema caused by deficiency or dysfunction of C1 inhibitor (C1–INH-HAE) based on clinical manifestation and complement measurements, SERPING1 gene was tested by DNA sequencing (Sanger sequencing/massive parallel sequencing) and/or multiplex ligation-dependent probe amplification for detection of large rearrangements. Results: The Slovakian national cohort consisted of 132 living patients with confirmed HAE. We identified 51 index cases (32 families, 19 sporadic patients/112 adults, 20 children). One hundred seventeen patients had HAE caused by deficiency of C1 inhibitor (C1–INH-HAE-1) and 15 patients had HAE caused by dysfunction of C1 inhibitor (C1–INH-HAE-2). The prevalence of HAE in Slovakia has recently been calculated to 1:41 280 which is higher than average calculated prevalence. The estimated incidence was 1:1360 000. Molecular-genetic testing of the SERPING1 gene found 22 unique causal variants in 26 index cases, including 12 previously undescribed and unreported. Conclusion: The first complex report about epidemiology and genetics of the Slovakian national HAE cohort expands the knowledge of the C1–INH-HAE genetics. Twelve novel causal variants were present in the half of the index cases. A higher percentage of inframe variants comparing to other studies was observed. Heterozygous deletion of exon 3 found in a large C1–INH-HAE-1 family probably causes the dysregulation of the splicing isoforms balance and leads to the decrease of full-length C1–INH level.

Background/objectiveSmoking prevalence in patients with chronic pancreatitis [CP] is high. We aimed to understand lifetime history of smoking and cohort trends in CP patients to inform effective strategies for smoking cessation.MethodData on 317 CP patients from the North American Pancreatitis Study 2 [NAPS2] Continuation and Validation Study and the NAPS2 Ancillary Study were analyzed. Smoking history was assessed for each phase of life from the onset of smoking to study enrollment. Data on second-hand smoke and drinking history were also collected. We compared demographic factors, drinking history, pain level and pancreas morphology by smoking status at age 25 (non-smoking,

Nataliya Korol,1 Oksana M Holovko-Kamoshenkova,1 Mikhailo Slivka,1 Oleksandra Pallah,2 Mykhailo Yu Onysko,1 Andriy Kryvovyaz,1 Nadiya V Boyko,2 Olha V Yaremko,3 Ruslan Mariychuk4 1Organic Chemistry Department, Educational and Research Institute of Chemistry and Ecology, Uzhhorod National University, Uzhhorod, Ukraine; 2Department of Clinical and Laboratory Diagnostics and Pharmacology, Faculty of Dentistry, Uzhhorod National University, Uzhhorod, Ukraine; 3Department of Microbiology and Virology, Lviv National Stepan Gzhytsky University of Veterinary Medicine and Biotechnology, Lviv, Ukraine; 4Department of Ecology, Faculty of Humanities and Natural Science, University of Presov, Presov, Slovak RepublicCorrespondence: Nataliya Korol, Organic Chemistry Department, Educational and Research Institute of Chemistry and Ecology, Uzhhorod National University, Tomchaniia Street, 13, Uzhhorod, 88001, Ukraine, Tel +380 95 704 34 56, Email nataliya.korol@uzhnu.edu.uaIntroduction: Heterocyclic compounds have diverse biological activities and potential in drug development. This study aims to synthesize novel compounds with two 1,2,4-triazole cores and evaluate their biological properties, particularly their inhibitory activity against thymidine phosphorylase (TP), an enzyme involved in various physiological processes.Methods: The compounds were synthesized by reacting 5,5’-butane-bis-1,2,4-triazole derivatives with prenyl bromide. Characterization involved various techniques, including spectroscopy and elemental analysis. Antimicrobial potential was evaluated against bacteria and fungi, with comparative antibiotics as references. Inhibitory activity against TP was assessed, and molecular docking studies were conducted.Results: Six compounds were successfully synthesized and their structures confirmed. The synthesized triazole derivatives exhibited high biological activity, with compounds 2 and 6 showing the most promising TP inhibition. Molecular docking studies revealed interactions between compound 2 and TP, involving nine amino acids.Discussion: The synthesis of novel compounds with two 1,2,4-triazole cores contributes significantly to bis-triazole research. These compounds have potential as anti-tumor agents due to their inhibitory activity against TP, a crucial enzyme in tumor growth and metastasis. Comparative evaluation against antibiotics highlights their potency. Docking results provide insights into their interactions with TP, supporting their potential as potent TP inhibitors. Further research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and optimizing their activities.Conclusion: The synthesized compounds with two 1,2,4-triazole cores exhibit significant biological activity, including strong TP inhibition and broad-spectrum antimicrobial effects. These findings emphasize their potential as anti-tumor agents and the need for further exploration and optimization. Future research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and developing more potent bis-triazole derivatives for drug discovery efforts. The combined results from assays and docking studies support the therapeutic potential of these compounds as anti-tumor agents.Keywords: alkylations, antitumor agents, heterocycles, hydrogen bonds, molecular modelling

Abstract Chronic pancreatitis is a debilitating disease affecting millions worldwide. These patients suffer from bouts of severe pain that are minimally relieved by pain medications and may necessitate major surgeries with high morbidity and mortality. Previously, we demonstrated that “chemical pancreatectomy,” a pancreatic intraductal infusion of dilute acetic acid solution, ablated the exocrine pancreas while preserving the endocrine pancreas. Notably, chemical pancreatectomy resolved chronic inflammation, alleviated allodynia in the cerulein pancreatitis model, and improved glucose homeostasis. Herein, we extensively tested the feasibility of a chemical pancreatectomy in NHPs and validated our previously published pilot study. We did serial computed tomography (CT) scans of the abdomen and pelvis, analyzed dorsal root ganglia, measured serum enzymes, and performed histological and ultrastructural assessments and pancreatic endocrine function assays. Based on serial CT scans, chemical pancreatectomy led to the loss of pancreatic volume. Immunohistochemistry and transmission electron microscopy demonstrated exocrine pancreatic ablation with endocrine islet preservation. Importantly, chemical pancreatectomy did not increase pro-nociceptive markers in harvested dorsal root ganglia. Also, chemical pancreatectomy improved insulin secretion to supranormal levels in vivo and in vitro. Thus, this study may provide a foundation for translating this procedure to patients with chronic pancreatitis or other conditions requiring a pancreatectomy.

Glycans of MVs are proposed to be candidates for mediating targeting specificity or at least promoting it. In contrast to exosomes, glycomic studies of MVs are largely absent. We studied the glycoprofile of endothelial cell-derived MVs using 21 plant lectins, and the results show the dominance of oligolactosamines and their α2-6-sialylated forms as N-glycans and low levels of α2-3-sialylated glycans. The low levels of α2-3-sialosides could not be explained by the action of extracellular glycosidases. Additionally, the level of some Man-containing glycans was also decreased in MVs. Spatial masking as the causative relationship between these low level glycans (as glycosphingolipids) by integral proteins or proteoglycans (thus, their lack of interaction with lectins) seems unlikely. The results suggest that integral proteins do not pass randomly into MVs, but instead only some types, differing in terms of their specific glycosylation, are integrated into MVs.

This study aims to characterize the proteome composition of organ-derived protein extracts from rabbits. Protein isolation was performed using soft homogenization and size exclusion via ultrafiltration. The proteome analysis of the ultrafiltrates was conducted using gel electrophoresis, and the mass spectrometry data were subjected to gene ontology analysis. Proteomic profiling revealed comprehensive protein profiles associated with RNA regulation, fatty acid binding, inflammatory response, oxidative stress, and metabolism. Additionally, our results demonstrate the presence of abundant small proteins, as observed in the mass spectrometry datasets. Small proteins and peptides are crucial in transcription modulation and various biological processes. The protein networks identified in the ultrafiltrates have the potential to enhance and complement biological therapeutic interventions. Data are available via ProteomeXchange with identifier PXD050039.