Liquid Crystalline Nanoparticles via Polymerization-Induced Self-Assembly: Morphology Evolution and Function Regulation.

Liquid crystalline nanoparticles (LC NPs) are a kind of polymer NPs with LC mesogens, which can form special anisotropic morphologies due to the influence of LC ordering. Owing to the stimuli-responsiveness of the LC blocks, LC NPs show abundant morphology evolution behaviors in response to external regulation. LC NPs have great application potential in nano-devices, drug delivery, special fibers and other fields. Polymerization-induced self-assembly (PISA) method can synthesize LC NPs at high solid content, reducing the harsh demand for reaction solvent of the LC polymers, being a better choice for large-scale production. In this review, we introduced recent research progress of PISA-LC NPs by dividing them into several parts according to the LC mesogen, and discussed the improvement of experimental conditions and the potential application of these polymers.

Analysis of Related Risk Factors and Prognostic Factors of Gastric Cancer with Liver Metastasis: A SEER and External Validation Based Study.

Background: Gastric cancer (GC) has a poor prognosis, particularly in patients with liver metastasis (LM). This study aims to identify relevant factors associated with the occurrence of LM in GC patients and factors influencing the prognosis of gastric cancer with liver metastasis (GCLM) patients, in addition to developing diagnostic and prognostic nomograms specifically. Patients and Methods: Overall, 6184 training data were from the Surveillance, Epidemiology, and End Results (SEER) database from 2011 to 2015. 1527 validation data were from our hospital between January 2018 and December 2022. Logistic regression was used to identify the risk factors associated with the occurrence of LM in GC patients, Cox regression was used to confirm the prognostic factors of GCLM patients. Two nomogram models were established to predict the risk and overall survival (OS) of patients with GCLM. The performance of the two models was evaluated using the area under the curve (AUC), concordance index (C-index), and calibration curves. Results: A nomogram included five independent factors from multivariate logistic regression: sex, lymph node removal, chemotherapy, T stage and N stage were constructed to calculate the possibility of LM. Internal and external verifications of AUC were 0.786 and 0.885, respectively. The other nomogram included four independent factors from multivariate Cox regression: surgery at primary site, surgery at other site, chemotherapy, and N stage were constructed to predict OS. C-index for internal and external validations were 0.714 and 0.702, respectively, and the calibration curves demonstrated the robust discriminative ability of the models. Conclusion: Based on the SEER database and validation data, we defined effective nomogram models to predict risk and OS in patients with GCLM. They have important value in clinical decision-making and personalized treatment.

Killing of Staphylococcus aureus persisters by a multitarget natural product chrysomycin A.

Staphylococcus aureus poses a severe public health problem as one of the vital causative agents of healthcare- and community-acquired infections. There is a globally urgent need for new drugs with a novel mode of action (MoA) to combat S. aureus biofilms and persisters that tolerate antibiotic treatment. We demonstrate that a benzonaphthopyranone glycoside, chrysomycin A (ChryA), is a rapid bactericide that is highly active against S. aureus persisters, robustly eradicates biofilms in vitro, and shows a sustainable killing efficacy in vivo. ChryA was suggested to target multiple critical cellular processes. A wide range of genetic and biochemical approaches showed that ChryA directly binds to GlmU and DapD, involved in the biosynthetic pathways for the cell wall peptidoglycan and lysine precursors, respectively, and inhibits the acetyltransferase activities by competition with their mutual substrate acetyl-CoA. Our study provides an effective antimicrobial strategy combining multiple MoAs onto a single small molecule for treatments of S. aureus persistent infections.

Novel citrinin derivatives from fungus Penicillium sp. TW131-64 and their antimicrobial activities.

Six new citrinin derivatives (1, 2, 4, 10, 11, and 16), along with fourteen known analogues, were acquired from Penicillium sp. TW131-64, a marine-derived fungus strain. The chemical structures of new compounds were identified through adopting various spectroscopic methods in combination with X-ray diffraction technology and comparison of the experimental electronic circular dichroism (ECD) with calculated ones. Among them, compounds 1-4 were nitrogen-containing citrinin derivatives existing in enantiomers which were resolved by chiral chromatography. A putative biosynthetic pathway for compounds 1-4 was proposed. Additionally, the antimicrobial activities of these compounds were detected by the broth microdilution assays. Citrinin derivatives 1, 2, 4 and their corresponding enantiomers (1a, 2a, 4a, 1b, 2b, and 4b) exhibited potent antimicrobial activities towards Helicobacter pylori standard strains and multidrug-resistant strains (MIC values ranging from 0.25 to 8 µg/mL), which were comparable or even better than metronidazole. Moreover, compounds 1a and 1b also showed remarkable broad antimicrobial effects towards Staphylococcus aureus, Enterococcus faecalis, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus subtilis, vancomycin-resistant Enterococcus faecium (VRE), and Candida albicans. In summary, our studies demonstrated that citrinin enantiomers 1a-4a and 1b-4b, especially 1a and 1b, can be lead compounds in the research and development (R & D) of novel antimicrobial drugs. KEY POINTS: • 3 novel nitrogen-containing citrinin derivatives (1, 2, 4) were isolated. • citrinin derivatives 1-4 in enantiomers were resolved by chiral chromatography. • citrinin derivatives 1a and 1b showed broad and significant antimicrobial effects.

A combined index constructed based on NLR and PLR is associated with in-hospital mortality risk in patients with acute myocardial infarction.

OBJECTIVE: To explore the validity of the neutrophil-to-lymphocyte ratio (NLR) combined with the platelet-to-lymphocyte ratio (PLR) in predicting the short-term prognosis of acute myocardial infarction (AMI). METHODS: We collected the data from a total of 3,246 clinical AMI patients hospitalized in the Second Affiliated Hospital of Dalian Medical University from December 2015 to December 2021. All patients underwent routine blood examination within 2 hours of admission. Outcome was defined as all-cause mortality during hospitalization. A total of 94 pairs of patients were generated by propensity score matching (PSM), and a combined NLR-based and PLR-based indicators was constructed according to receiver operating characteristic (ROC) curves and multivariate logistic regression analysis. RESULTS: We finally generated 94 pairs of patients by PSM, and analyzed NLR and PLR in those patients using ROC curves, and converted NLR (optimal cut-off = 5.094) and PLR (optimal cut-off = 165.413) into binary variables according to optimal cut-offs, defined as NLR grouping (5.094 vs. > 5.094, ≤ 5.094 = 0, > 5.094 = 1) and PLR grouping (165.413 vs. > 165.413, ≤ 165.413 = 0, > 165.413 = 1). We constructed a combined indicator (NLR grouping + PLR grouping) based on the results of multivariate logistic regression. Combined indicator has four conditions [Y1 = 0.887 (NLR grouping = 0; PLR grouping = 0); Y2 = 0.949 (NLR grouping = 0; PLR grouping = 1); Y3 = 0.972 (NLR grouping = 1; PLR grouping = 0); and Y4 = 0.988 (NLR grouping = 1; PLR grouping = 1)]. Univariate logistic regression showed that the risk of in-hospital death was significantly increased when the combined indicator of patients was in Y3 (OR = 4.968, 95% CI 2.215-11.141, P < 0.0001) and Y4 (OR = 10.473, 95% CI 4.610-23.793, P < 0.0001). Combined indicator constructed by NLR grouping and PLR grouping can better predict the risk of in-hospital mortality in AMI patients and help clinical cardiologists to more finely care for and treat these high-risk groups to improve their short-term prognostic outcomes.

Colloidal crystals of monodisperse fluoro-nanoparticles by aqueous polymerization-induced self-assembly.

Here, we prepared monodisperse fluorinated nanospheres with the diameter regulated from 100 to 200 nm and PDI of the diameter lower than 0.05 via polymerization-induced self-assembly (PISA). Mono/multilayered 2D and large-scale ordered 3D lattices were formed by solvent evaporation-induced colloidal self-assembly. This work shows the promising application of PISA in colloidal self-assembly.

Aculeaxanthones A-E, new xanthones from the marine-derived fungus Aspergillus aculeatinus WHUF0198.

Introduction: Dimeric natural products are widespread in plants and microorganisms, which usually have complex structures and exhibit greater bioactivities than their corresponding monomers. In this study, we report five new dimeric tetrahydroxanthones, aculeaxanthones A-E (4-8), along with the homodimeric tetrahydroxanthone secalonic acid D (1), chrysoxanthones B and C (2 and 3), and 4-4'-secalonic acid D (9), from different fermentation batches of the title fungus. Methods: A part of the culture was added to a total of 60 flasks containing 300 ml each of number II fungus liquid medium and culture 4 weeks in a static state at 28˚C. The liquid phase (18 L) and mycelia was separated from the fungal culture by filtering. A crude extract was obtained from the mycelia by ultrasound using acetone. To obtain a dry extract (18 g), the liquid phase combined with the crude extract were further extracted by EtOAc and concentrated in vacuo. The MIC of anaerobic bacteria was examined by a broth microdilution assay. To obtain MICs for aerobic bacteria, the agar dilution streak method recommended in Clinical and Laboratory Standards Institute document (CLSI) M07-A10 was used. Compounds 1-9 was tested against the Bel-7402, A-549 and HCT-116 cell lines according to MTT assay. Results and Discussion: The structures of these compounds were elucidated on the base of 1D and 2D NMR and HR-ESIMS data, and the absolute configurations of the new xanthones 4-8 were determined by conformational analysis and time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations. Compounds 1-9 were tested for cytotoxicity against the Bel-7402, A549, and HCT-116 cancer cell lines. Of the dimeric tetrahydroxanthone derivatives, only compound 6 provided cytotoxicity effect against Bel-7402 cell line (IC50, 1.96 µM). Additionally, antimicrobial activity was evaluated for all dimeric tetrahydroxanthones, including four Gram-positive bacteria including Enterococcus faecium ATCC 19434, Bacillus subtilis 168, Staphylococcus aureus ATCC 25923 and MRSA USA300; four Gram-negative bacteria, including Helicobacter pylori 129, G27, as well as 26,695, and multi drug-resistant strain H. pylori 159, and one Mycobacterium M. smegmatis ATCC 607. However, only compound 1 performed activities against H. pylori G27, H. pylori 26695, H. pylori 129, H. pylori 159, S. aureus USA300, and B. subtilis 168 with MIC values of 4.0, 4.0, 2.0, 2.0, 2.0 and 1.0 µg/mL, respectively.

In situ generation and evolution of polymer toroids by liquid crystallization-assisted seeded dispersion polymerization.

An effective method is presented for preparing high solid content azobenzene-containing triblock copolymer toroidal assemblies by liquid crystallization-assisted seeded dispersion polymerization. Vesicles are prepared via polymerization-induced self-assembly (PISA), and used as seeds for further chain extension. By introducing smectic liquid crystalline (LC) ordering into the core-forming block, toroids are formed in situ during the polymerization. The morphological transformation from toroids to barrels is observed under ultraviolet irradiation due to the photo-isomerization of the azobenzene mesogens. This strategy expands the scope of tunable anisotropic morphologies for potential functional nanomaterials based on a LC copolymer by seeded dispersion polymerization.

Iboga-type alkaloids with Indolizidino[8,7-b]Indole scaffold and bisindole alkaloids from Tabernaemontana bufalina Lour.

Phytochemical investigation on the aerial parts of Tabernaemontana bufalina Lour. (Apocynaceae) led to the identification of four undescribed monoterpenoid indole alkaloids named taberbufamines A-D, an undescribed natural product, and fourteen known indole alkaloids. The structures of the undescribed alkaloids were established by spectroscopic and computational methods, and their absolute configurations were further determined by quantum chemical TDDFT calculations and the experimental ECD spectra. Taberbufamines A and B possessed an uncommon skeleton incorporating an indolizidino [8,7-b]indole motif with a 2-hydroxymethyl-butyl group attached at the pyrrolidine ring. Biosynthetically, Taberbufamines A and B might be derived from iboga-type alkaloid through rearrangement. Vobatensine C showed significant bioactivity against A-549, Bel-7402, and HCT-116 cells with IC50 values of 2.61, 1.19, and 1.74 µM, respectively. Ervahanine A showed antimicrobial activity against Bacillus subtilis, Mycobacterium smegmatis, and Helicobacter pylori with MIC values of 4, 8, and 16 µg/mL, respectively. 19(S)-hydroxyibogamine was shown as butyrylcholinesterase inhibitor (IC50 of 20.06 µM) and α-glycosidase inhibitor (IC50 of 17.18 µM), while tabernamine, ervahanine B, and ervadivaricatine B only showed α-glycosidase inhibitory activities with IC50 values in the range of 0.95-4.61 µM.

Polymeric nanostructures based on azobenzene and their biomedical applications: synthesis, self-assembly and stimuli-responsiveness.

Amphiphilic polymers can self-assemble to form nanoparticles with different structures under suitable conditions. Polymer nanoparticles functionalized with aromatic azo groups are endowed with photo-responsive properties. In recent years, a variety of photoresponsive polymers and nanoparticles have been developed based on azobenzene, using different molecular design strategies and synthetic routes. This article reviews the progress of this rapidly developing research field, focusing on the structure, synthesis, assembly and response of photo-responsive polymer assemblies. According to the molecular structure, photo-responsive polymers can be divided into linear polymers containing azobenzene in a side chain, linear polymers containing azobenzene in the main chain, linear polymers containing azobenzene in an end group, branched polymers containing azobenzene and supramolecular polymers containing azobenzene. These systems have broad biomedical application prospects in the field of drug delivery and imaging applications.

New diketopiperazine alkaloid and polyketides from marine-derived fungus Penicillium sp. TW58-16 with antibacterial activity against Helicobacter pylori.

Marine-derived fungi can usually produce structurally novel and biologically potent metabolites. In this study, a new diketopiperazine alkaloid (1) and two new polyketides (10 and 11), along with 8 known diketopiperazine alkaloids (2-9) were isolated from marine-derived fungus Penicillium sp. TW58-16. Their structures were fully elucidated by analyzing UV, IR, HR-ESI-MS, 1D, and 2D NMR spectroscopic data. The absolute configurations of the new compounds 1, 10 and 11 were ascertained by X-ray diffraction (Cu Kα radiation) and comparing their CD data with those reported. In addition, the antibacterial activities of these compounds against Helicobacter pylori in vitro were assessed. Results showed that compounds 3, 6, 8 and 9 displayed moderate antibacterial activity against standard strains and drug-resistant clinical isolates of H. pylori in vitro. This result demonstrates that diketopiperazine alkaloids could be lead compounds to be explored for the treatment of H. pylori infection.

Development of a Predictive Model for Screening Patients with Psoriasis at Increased Risk of Psoriatic Arthritis.

INTRODUCTION: This study aimed to develop a predictive model based on ultrasound variables which can be used to screen patients with psoriasis who are prone to progress to psoriatic arthritis (PsA) in clinical practice. METHODS: This is a cross-sectional study conducted in a single center from October 2018 to November 2020. All subjects (non-PsA group, PsA group, and control group) underwent an ultrasound examination and their ultrasound abnormalities were recorded. On the basis of statistical analysis and clinical experts' advice, several variables were selected for modelling. We used logistic regression to establish the prediction model. To assess the discrimination and accuracy of this model, internal validation and external validation were performed. RESULTS: A total of 852 patients with psoriasis but without PsA, 261 patients with PsA, and 86 healthy volunteers were included. Ultimately, the predictive model consisted of six variables, namely hand joint power Doppler (PD) signals (grade 0: OR 2.94, 95% CI 1.94-4.47; grade ≥ 1: OR 109.30, 95% CI 14.35-832.27; P < 0.001), wrist joint synovial thickening (grade 1: OR 1.29, 95% CI 0.69-2.43; grade 2: OR 4.30, 95% CI 1.92-9.65; grade 3: OR 11.05, 95% CI 1.01-120.64; P = 0.001), knee joint PD signals (grade 0: OR 1.01, 95% CI 0.56-1.80; grade ≥ 1: OR 14.77, 95% CI 3.99-54.69; P < 0.001), toe joint PD signals (grade 0: OR 1.18, 95% CI 0.78-1.79; grade ≥ 1: OR 5.74, 95% CI 2.84-11.63; P < 0.001), quadriceps tendon and patellar tendon enthesitis (OR 1.95, 95% CI 1.36-2.78, P < 0.001), Achilles tendon and plantar aponeurosis enthesitis (OR 1.63, 95% CI 1.14-2.32, P = 0.007). C-index for the predictive model was 0.80 (95% CI 0.76-0.83). After bootstrapping validation (1000 times), it was confirmed to be 0.79. The external validation showed the accuracy of the predictive model is 0.87 (95% CI 0.69-0.95). CONCLUSION: This study succeeded in developing a predictive model with a high degree of accuracy to predict the risk of PsA in patients with psoriasis.

Psoriatic arthritis often occurs in the population of patients with psoriasis. It brings a huge burden and pain to patients. At present, the diagnosis for psoriatic arthritis is very challenging. Numerous research studies have begun to focus on identifying patients with psoriasis at increased risk of psoriatic arthritis. Among a lot of modalities, ultrasound has been considered as a sensitive and convenient tool for screening early psoriatic arthritis. Our study successfully established a predictive model based on ultrasound variables to screen patients with psoriasis at high risk of transiting to psoriatic arthritis. After internal and external validation, it showed great accuracy and generalizability. We recommend that clinicians perform ultrasound screening of patients with psoriasis in clinical routine and get their risk value of transiting to psoriatic arthritis by using this model. For those patients with a high risk of progression to psoriatic arthritis, clinicians should refer them to a rheumatology department as soon as possible so that they could have access to early and effective management which might bring them good clinical and imaging outcomes.

Nomogram Model for Dynamic and Individual Prediction of Cardiac Response and Survival for Light Chain Amyloidosis in 737 Patients With Cardiac Involvement.

OBJECTIVE: Light chain amyloidosis (AL) with cardiac involvement is associated with poor prognosis. The existing prognostic assessment system does not consider treatment-related factors, and there is currently no effective system for predicting the response. The purpose of this study was to build an individualized, dynamic assessment model for cardiac response and overall survival (OS) for AL patients with cardiac involvement. METHODS: The records of 737 AL patients with cardiac involvement were collected through cooperation with 18 hospitals in the Chinese Registration Network for Light-chain Amyloidosis (CRENLA). We used univariate and multivariate analyses to evaluate the prognostic factors for OS and cardiac response. Then, two nomogram models were developed to predict OS and cardiac response in AL patients with cardiac involvement. RESULTS: A nomogram including four independent factors from the multivariate Cox proportional hazards analysis-Mayo staging, courses of treatment, hematologic response, and cardiac response-was constructed to calculate the possibility of achieving survival by adding all the points associated with four variables. The higher the score, the more likely death would occur. The other nomogram model included the courses of treatment, hematological response, and different treatment regimens, and was correlated with cardiac response. The higher the score, the more likely a cardiac response would occur. CONCLUSION: In conclusion, based on the large Chinese cohort of patients with AL and cardiac involvement, we identified nomogram models to predict cardiac response and OS. These models are more individualized and dynamic, and therefore, they have important clinical application value.

Long-Duration Tracking of Cervical-Spine Kinematics With Ultrasound.

Cervical-spine (C-spine) pathoanatomy is commonly evaluated by plane radiographs, computed tomography (CT), or magnetic resonance imaging (MRI); however, these modalities are unable to directly measure the dynamic mechanical properties of the functional spinal units (FSU) comprising the C-spine that account for its functional performance. We have developed an ultrasound-based technique that provides a non-invasive, real-time, quantitative, in vivo assessment of C-spine kinematics and FSU viscoelastic properties. The fidelity of the derived measurements is predicated on accurate tracking of vertebral motion over a prolonged time duration. The purpose of this work was to present a bundle adjustment method that enables accurate tracking of the relative motion of contiguous cervical vertebrae from ultrasound radio-frequency data. The tracking method was validated using both a plastic anatomical model of a cervical vertebra undergoing prescribed displacements and also human cadaveric C-spine specimens subjected to physiologically relevant loading configurations. While the velocity of motion and thickness of the surrounding soft tissue envelope affected accuracy, using the bundle adjustment method, B-mode ultrasound was capable of accurately tracking vertebral motion under clinically relevant physiologic conditions. Therefore, B-mode ultrasound can be used to evaluate in vivo real-time C-spine kinematics and FSU mechanical properties in environments where radiographs, CT, or MRI cannot be used.

Correlation of Soft Tissue Swelling and Timing to Surgery With Acute Wound Complications for Operatively Treated Ankle and Other Lower Extremity Fractures.

BACKGROUND: Considerable debate exists regarding how soft-tissue edema should influence timing of surgery for ankle and other lower extremity fractures. Assessment of swelling is subjective, and timing varies among surgeons. However, timing of surgery is one of the few modifiable factors in fracture care. Ultrasonography can objectively measure swelling and help determine optimal timing. The purposes of this study were to determine whether objective measures of swelling, timing to surgery, and patient-specific risk factors correlated with wound complications and to try to create a prediction model for postoperative wound complications based on identified modifiable and nonmodifiable risk factors. METHODS: Patients with closed ankle and other lower extremity fractures requiring surgery with an uninjured, contralateral extremity were included. Demographic information and sonographic measurements on both lower extremities were obtained pre-operatively. Subjects were followed for 3 months and wound complications were documented. A predictive algorithm of independent risk factors was constructed, determining wound complication risk. Given that patients with ankle fractures made up the majority of the study cohort (75/93 or 80%), a separate statistical analysis was performed on this group. A total of 93 subjects completed the study, with 75/93 sustaining ankle fractures. RESULTS: Overall wound complication rate was 18.3%. Timing to surgery showed no correlation with wound complications. A heel-pad edema index >1.4 was independently associated with wound complications. Subgroup analysis of ankle fractures demonstrated a 3.4× increase in wound complications with a heel-pad edema index >1.4. Tobacco history and BMI >25 were independent predictors of wound complications. An algorithm was established based on heel-pad edema index, BMI >25, and tobacco history. Patients with none of the 3 factors had a 3% probability of a wound complication. Patients with 1/3, 2/3 and 3/3 factors had a 12-36%, 60-86% and 96% probability of a wound complication, respectively. CONCLUSIONS: Timing to surgery had no correlation with wound complications. Heel-pad edema index >1.4, BMI >25, and tobacco-use correlated with wound complications. When separately analyzing the cohort that sustained ankle fractures, the heel-pad edema index of >1.4 was still demonstrated to be predictive of wound complications corresponding to a 3.4× increase in wound complication rates (11.1% vs 37.5%). Risk of wound complications significantly increased with each factor. In patients with increased BMI and/or tobacco use, resolution of heel edema may significantly reduce wound complications in lower extremity trauma. LEVEL OF EVIDENCE: Level II, prognostic, prospective cohort study.

Sensitivity and stability analysis of a nonlinear material model of cervical intervertebral disc under cyclic loads using the finite element method.

It is known that the human spine exhibits non-linear behavior, and its intervertebral discs play a role in the mechanism of internal load transfer. It is important to simulate its nonlinear behavior in computational models for better delineation of intrinsic responses, especially during cyclic loading activities, a mode pertinent to civilian and military populations. For developing a robust “material model” of the disc, this study used experimental tensile-compressive cyclic loading responses from four human cadaver cervical functional spinal units. Disc deformations were measured using an ultrasound system at 42 samples per second. Using experimental data, a three-network non-linear “material model” was developed using an optimization procedure and finite-element analysis. The model used 12 parameters to capture loading and unloading in tension and compression, including hysteresis. A sensitivity analysis performed to test the robustness of the “material model” indicated that seven of the 12 parameters were sensitive to tension, compressive, or both loading modes. Stability analysis was also performed under nine different loading conditions. The developed “material model” is robust and stable to capture intervertebral disc responses in tensile-compressive cyclic loading and can be used in future finite-element models.