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Background/Objectives: Tuberculosis (TB) remains a major global health threat. Current administration methods for anti-TB drugs, including oral or intravenous, suffer from systemic side effects, low lung distribution, and poor patient compliance. Dry powder inhalers (DPIs) offer a promising alternative. This study investigates the aerodynamic performance of co-spray-dried DPIs containing rifampin or pyrazinamide and amino acids by using machine learning. Methods: Firstly, 72 formulations were prepared by varying drug-amino acid combinations, molar ratios, and spray-drying parameters. Subsequently, the aerodynamic performance of all 72 formulations was evaluated using a Next Generation Impactor, and the solid-state characterizations of optimal DPIs were carried out. Finally, four machine learning (ML) models were successfully developed and were utilized to predict the fine particle dose (FPD), FPF, MMAD, and geometric standard deviation (GSD) of DPIs based on the high-quality in-house data above. Results: Key results showed that the aerodynamic performance of DPIs was highly dependent on the specific drug-amino acid combination, with rifampin-L-lysine acetate and pyrazinamide-L-leucine formulations achieving the highest fine particle fraction (FPF, 73.37%, 87.74%) and optimal mass median aerodynamic diameter (MMAD, 2.59 µm, 1.88 µm). Notably, XGBoost (v3.1.3) exhibited the best predictive performance, with R2 values ranging from 0.894 to 0.991 in the testing set for the four prediction tasks. Meanwhile, SHapley Additive exPlanations (v0.50.0) was used for model interpretability analysis. The molecular weights and LogP of the drug and amino acid were identified as two of the most important features affecting the prediction of FPD, FPF, MMAD, and GSD. Conclusions: This work demonstrates the feasibility of ML in accelerating the development of inhalable spray-dried anti-TB drugs by enabling the prediction of DPI formulations.

Background Metabolic reprogramming is a hallmark in cancer. Pyrimidine metabolism (PM), a part of nucleotide metabolism, has been shown to be associated with the progression of various cancers, and the prognostic predictive ability of pyrimidine metabolism-related genes (PMG) in breast cancer has not been elucidated. This paper was designed to identify pyrimidine metabolism-related prognostic marker of breast cancer and potential targeted therapeutic options. Methods The cohort in the TCGA-BRCA dataset was used for patient information, and 108 pyrimidine metabolism-related genes were identified from the MSigDB KEGG pathways. We identified PM clusters in breast cancer and established a PM risk score model based on 10 pyrimidine metabolism-related genes. The status of immune infiltration was assessed in different groups. Further we identified the relevant hub gene and analyzed its significance for breast cancer metastasis and explored patterns of combination therapy. Results We identified three types of PM clusters in breast cancer and clarified that PM cluster C with inferior prognosis possessed activation of tumor proliferation-associated pathways. The high-risk group in PM risk score model was found to be characterized by an immunosuppressive microenvironment. The hub gene POLR2C (RNA polymerase II subunit C) was further identified and verified as a potential prognostic marker. Furthermore, targeting POLR2C in combination with anti-PD-1 and anti-angiogenic therapies demonstrated a promising tumor suppression effect, suggesting a potential therapeutic direction. Conclusions These findings provide additional insights into the link between breast cancer and PMG, offering potential strategies for breast cancer management and treatment.

Nearly all essential nuclear processes act on DNA packaged into arrays of nucleosomes. However, our understanding of how these processes (for example, DNA replication, RNA transcription, chromatin extrusion and nucleosome remodeling) occur on individual chromatin arrays remains unresolved. Here, to address this deficit, we present SAMOSA-ChAAT: a massively multiplex single-molecule footprinting approach to map the primary structure of individual, reconstituted chromatin templates subject to virtually any chromatin-associated reaction. We apply this method to distinguish between competing models for chromatin remodeling by the essential imitation switch (ISWI) ATPase SNF2h: nucleosome-density-dependent spacing versus fixed-linker-length nucleosome clamping. First, we perform in vivo single-molecule nucleosome footprinting in murine embryonic stem cells, to discover that ISWI-catalyzed nucleosome spacing correlates with the underlying nucleosome density of specific epigenomic domains. To establish causality, we apply SAMOSA-ChAAT to quantify the activities of ISWI ATPase SNF2h and its parent complex ACF on reconstituted nucleosomal arrays of varying nucleosome density, at single-molecule resolution. We demonstrate that ISWI remodelers operate as density-dependent, length-sensing nucleosome sliders, whose ability to program DNA accessibility is dictated by single-molecule nucleosome density. We propose that the long-observed, context-specific regulatory effects of ISWI complexes can be explained in part by the sensing of nucleosome density within epigenomic domains. More generally, our approach promises molecule-precise views of the essential processes that shape nuclear physiology. Here authors present SAMOSA-ChAAT, a method for resolving how chromatin-interacting proteins restructure individual chromatin fibers, in high throughput and at scale. They provide evidence that the imitation switch family remodeling enzymes sense nucleosome density to program internucleosomal spacing on individual molecules.

In recent years, self-assembled peptide nanotechnology has attracted a great deal of attention for its ability to form various regular and ordered structures with diverse and practical functions. Self-assembled peptides can exist in different environments and are a kind of medical bio-regenerative material with unique structures. These materials have good biocompatibility and controllability and can form nanoparticles, nanofibers and hydrogels to perform specific morphological functions, which are widely used in biomedical and material science fields. In this paper, the properties of self-assembled peptides, their influencing factors and the nanostructures that they form are reviewed, and the applications of self-assembled peptides as drug carriers are highlighted. Finally, the prospects and challenges for developing self-assembled peptide nanomaterials are briefly discussed.

BackgroundThe efficacy of computed tomography-based multiple body composition parameters in assessing disease behavior and prognosis has not been comprehensively evaluated in Crohn’s disease. This study aimed to assess the association of body composition parameters with disease behavior and outcomes in Crohn’s disease and to compare the efficacies of indexes derived from body and lumbar spinal heights in body composition analysis.ResultsOne hundred twenty-two patients with confirmed Crohn’s disease diagnoses and abdominal computed tomography scans were retrospectively included in this study. Skeletal muscle, visceral, and subcutaneous fat indexes were calculated by dividing each type of tissue area by height2 and lumbar spinal height2. Parameters reflecting the distribution of adiposity were also assessed. Principal component analysis was used to deal with parameters with multicollinearity. Patients were grouped according to their disease behavior (inflammatory vs. structuring/penetrating) and outcomes. Adverse outcome included need for intestinal surgery or anti-TNF therapy. Predictors of disease course from multiple parameters were evaluated using multivariate analysis. Indexes derived from body and lumbar spinal heights were strongly correlated (r, 0.934–0.995; p < 0.001). Low skeletal muscle-related parameters were significantly associated with complicated disease behavior in multivariate analysis (p = 0.048). Complicated disease behavior (p < 0.001) and adipose tissue parameters-related first principal component (p = 0.029) were independent biomarkers for predicting adverse outcomes.ConclusionsSkeletal muscle and adipose tissue principle component were associated with complicated Crohn’s disease behavior and adverse outcome, respectively. Indexes derived from body and lumbar spinal heights have similar efficacies in body composition analysis.

Scabrol B and Scabrol C, two newly identified iridoid derivatives (1 and 2) and six known compounds (3–8), were extracted from the roots of Patrinia scabra. The structures of these derivatives, including their absolute configurations, were elucidated via comprehensive NMR analysis, chemical derivatization, and quantum chemical ECD calculations. All isolated compounds were evaluated for their anti-renal fibrosis activity. The results demonstrate that compounds 1 and 2 showed dose-dependent protective effects against renal fibrosis in vitro by reducing the expression of fibronectin, collagen I, and alpha-smooth muscle actin (α-SMA) in NRK-49f cells mediated by TGF-β1.

A bidirectional quasi-endfire patch antenna with a low elevation angle has promising applications for wireless communication systems that are vehicle-based, airborne, and shipborne. In this paper, the shortened patch resonators and open patch resonator are integrated to form a bidirectional quasi-endfire patch antenna with low elevation angle. The open patch resonator operates with a TM20 mode to realize bidirectional radiation. The two shortened patch resonators operate with a TM01 mode coupled with a TM20 mode to control the phase difference between them at a suitable angle, so that the shortened patch resonators act as directors to tilt the dual beams toward the endfire direction and achieve low elevation angle. Compared with reported patch antennas with dual beams, the proposed antenna has the lowest elevation angle and a compact structure. For demonstration purposes, an antenna prototype operating at 3.5 GHz is fabricated and measured, exhibiting a low elevation angle of ±28°, a −10 dB impedance matching bandwidth from 3.44 GHz to 3.61 GHz, and a size of 1.36 λ0 × 0.57 λ0 with a profile of 0.036 λ0. A prototype with two pair of shortened patch directors further reduces the elevation angle to ±19° with the size of 2.3 λ0 × 0.57 λ0.

ObjectiveTo evaluate the changes in magnetic resonance imaging-based body composition parameters during follow-ups in patients with Crohn's disease (CD).MethodsBetween November 1, 2017, and June 30, 2021, patients diagnosed with CD, who underwent two or more magnetic resonance enterography (MRE) scans at our institution were retrospectively reviewed. The baseline and one subsequent follow-up scan for each patient were paired to form longitudinal comparisons. Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) indexes were calculated from tissue areas measured at the third lumbar vertebra level per scan, standardized by dividing the height2 and lumbar height2 (heightL1–L5). We also assessed the correlation between changes in VAT to total adipose tissue ratio (VA/TA index) and CD activity scores (5-point MRE classification) using Spearman’s correlation analysis. A multivariate linear regression model was used to adjust for the follow-up duration and treatment type.ResultsOverall, 49 patients (with 49 paired scans) were enrolled. VA/TA index changes were negatively correlated with changes in skeletal muscle index (SMI; r =  − 0.339, p < 0.05). The VA/TA index (52.69 ± 10.66% vs. 49.18 ± 10.80%, p < 0.001) and the total MRE score (8.0 ± 3.9 vs. 5.7 ± 3.4, p < 0.001) decreased significantly during follow-up, regardless of follow-up duration and treatment type (both p > 0.05). Changes in total MRE score were negatively correlated with SMI changes (r =  − 0.408, p < 0.01) but positively correlated with VA/TA index changes (r = 0.479, p < 0.01).ConclusionAn increase in SMI and a decrease in VA/TA index could reflect improved nutritional and inflammatory status.

The spontaneous phenomena known as liquid–liquid phase separation (LLPS) is caused by weak interactions between substances. Under specific circumstances, macromolecules like proteins and nucleic acids can dynamically aggregate to form biomolecular condensates. This phenomenon offers a novel perspective on the intricate spatiotemporal coordination within living cells. Recent research has shown that LLPS is crucial for the initiation and progression of cancer, mainly by influencing multiple cellular activities such as metabolism, autophagy, stress responses, immune reactions, transcriptional regulation and intracellular signaling pathways, etc. Dysregulation of LLPS significantly affects the proliferation, metastasis, and therapeutic resistance of hepatocellular carcinoma (HCC) cells. Here, we introduce recent advances in understanding how LLPS regulates HCC-associated signaling pathways. Furthermore, we discuss the molecular mechanisms underlying the LLPS of oncogenic signaling molecules and its potential implication. Finally, we summarize several feasible approaches for treating HCC by targeting LLPS. These findings have the potential to establish a novel theoretical framework and therapeutic hypothesis for cancer treatment, thus providing more precise and individualized clinical strategies and significantly enhance patient prognosis and overall survival rates.

Background Premature loss of primary molars can be treated with a band loop space maintainer (SM). However, fabricating a conventional band loop SM requires multiple clinical and laboratory procedures, which can potentially affect the accuracy of the SM. Moreover, the conventional SM is unable to fully restore masticatory function and maintain the vertical dimension of the edentulous space. In this current study, a fully digital workflow to fabricate a semi-rigid bridge SM made from polyetheretherketone (PEEK) has been described and evaluated for its clinical effectiveness. Methods A total of 15 children (eight males and seven females) between the ages of 4–8 years, who experienced the premature loss of a single primary molar, were included in this study. Digital impressions were taken using the CEREC CAD/CAM chair system and imported into CAD software to design the semi-rigid bridge SM, which was fabricated using PEEK block as the maintainer material. The digital SM was tried-in and bonded to the abutment with resin cement. The edentulous space was measured immediately after bonding (T0) and 1 month (T1), 3 months (T2), and 6 months (T3) after treatment. The periodontal condition and mobility of the SM and abutment were also examined. Results The use of digital impressions resulted in a decreased occurrence of the pharyngeal reflex. The digital semi-rigid bridge SM, fabricated with PEEK, was both convenient and aesthetically pleasing, and successfully restored the anatomy and masticatory function of the missing primary molar. None of the 15 semi-rigid bridge SMs or abutments became loose or fell off during the study, and only one child presented with gingivitis. Furthermore, the difference in the edentulous space at T0, T1, T2, and T3 was not statistically significant (all P > 0.05). Conclusions The digital semi-rigid bridge SM fabricated with PEEK was clinically effective in maintaining the missing space and had advantages over the traditional band/crown loop SM.