Phytoplankton-chytrid-zooplankton dynamics via a reaction-diffusion-advection mycoloop model.

Mycoloop is an important aquatic food web composed of phytoplankton, chytrids (one dominant group of parasites in aquatic ecosystems), and zooplankton. Chytrids infect phytoplankton and fragment them for easy consumption by zooplankton. The free-living chytrid zoospores are also a food resource for zooplankton. A dynamic reaction-diffusion-advection mycoloop model is proposed to describe the Phytoplankton-chytrid-zooplankton interactions in a poorly mixed aquatic environment. We analyze the dynamics of the mycoloop model to obtain dissipativity, steady state solutions, and persistence. We rigorously derive several critical thresholds for phytoplankton or zooplankton invasion and chytrid transmission among phytoplankton. Numerical diagrams show that varying ecological factors affect the formation and breakup of the mycoloop, and zooplankton can inhibit chytrid transmission among phytoplankton. Furthermore, this study suggests that mycoloop may either control or cause phytoplankton blooms.

Modelling phytoplankton-virus interactions: phytoplankton blooms and lytic virus transmission.

A dynamic reaction-diffusion model of four variables is proposed to describe the spread of lytic viruses among phytoplankton in a poorly mixed aquatic environment. The basic ecological reproductive index for phytoplankton invasion and the basic reproduction number for virus transmission are derived to characterize the phytoplankton growth and virus transmission dynamics. The theoretical and numerical results from the model show that the spread of lytic viruses effectively controls phytoplankton blooms. This validates the observations and experimental results of Emiliana huxleyi-lytic virus interactions. The studies also indicate that the lytic virus transmission cannot occur in a low-light or oligotrophic aquatic environment.

Dipeptidyl peptidase-1 inhibition with brensocatib reduces the activity of all major neutrophil serine proteases in patients with bronchiectasis: results from the WILLOW trial.

BACKGROUND: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction. METHODS: The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib's effect and identify potential correlated effects. RESULTS: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG. CONCLUSIONS: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients. TRIAL REGISTRATION: The study was approved by the corresponding ethical review boards of all participating centers. The trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events.

Exploring the role of LIAS-related cuproptosis in systemic lupus erythematosus.

BACKGROUND: Cuproptosis is a novel mode of cell death, which is strongly related to energy metabolism in mitochondria and regulated by protein lipoylation. Currently, the molecular mechanisms of cuproptosis-related genes (CRGs) involved in systemic lupus erythematosus (SLE) largely remained unclear, our study is aimed to explore the mechanisms of cuproptosis and CRGs involved in SLE. METHODS: Bulk RNA-seq datasets were collected to display the expressions of CRGs in peripheral blood mononuclear cells (PBMCs) of SLE and healthy individuals, and then ROC analysis was used to establish the diagnostic models of CRGs. Next, the immune infiltration analyses were applied to reveal the difference of immune cells infiltration in LIAS-low and LIAS-high group. Additionally, WGCNA analysis was performed to find the gene modules significantly correlated with the LIAS expression level. We also performed the functional enrichment analyses for LIAS-related gene modules to determine the potential pathways involved in the development of SLE. Finally, scRNA-seq dataset was used to cluster immune cell subsets, reveal the activated pathways, and study cell-cell interactions in LIAS-low and LIAS-high cells. RESULT: We found CDKN2A was significantly increased and LIAS was significantly decreased in SLE patients compared with healthy individuals. The AUC score showed that LIAS had a great diagnostic value than other CRGs. Additionally, the results of immune infiltration analyses showed that immune cells proportion were diverse in LIAS-low and LIAS-high samples. The gene sets related to LIAS expression level were involved in dephosphorylation of JAK1 by SHP1, phosphorylation of STAT2, cytokine signaling in immune system, expression of interferon-alpha and beta, inhibition of JAK kinase activity by SOCS1/3, and so on. Finally, the results of cell-cell communication showed that CCL- (CCL5 + CCR1) and ANNEXIN- (ANXA1 + FPR1) might play an essential role in the communication network between LIAS-low and LIAS-high cells. CONCLUSION: Above findings inferred that LIAS-mediated cuproptosis might involve in a comprehensive cellular and molecular mechanism to cause the occurrence and development of SLE.

Synthesis and Self-Assembly of Thermoresponsive Biohybrid Graft Copolymers Based on a Combination of Passerini Multicomponent Reaction and Molecular Recognition.

Amphiphilic graft copolymers exhibit fascinating self-assembly behaviors. Their molecular architectures significantly affect the morphology and functionality of the self-assemblies. Considering the potential application of amphiphilic graft copolymers in the fabrication of nanocarriers, it is essential to synthesize well-defined graft copolymers with desired functional groups. Herein, the Passerini reaction and molecular recognition are introduced to the synthesis of functional thermoresponsive graft copolymers. A bifunctional monomer 2-((adamantan-1-yl)amino)-1-(4-((2-bromo-2-methylpropanoyl)oxy)phenyl)-2-oxoethyl methacrylate (ABMA) with a bromo group for atom transfer radical polymerization (ATRP) and an adamantyl group for molecular recognition is synthesized through the Passerini reaction. The graft copolymers are prepared by reversible addition-fragmentation transfer (RAFT) copolymerization of ABMA and oligo(ethylene glycol) methyl ether methacrylate (OEGMA) followed by RAFT end group removal and ATRP of di(ethylene glycol)methyl ether methacrylate (DEGMA) initiated by the ABMA units. The graft copolymer P(OEGMA-co-ABMA)-g-PDEGMA can be functionalized with ß-cyclodextrin modified peptides, affording a thermoresponsive biohybrid graft copolymer. At a temperature above its lower critical solution temperature, the biohybrid graft copolymer self-assembles into peptide-modified polymersomes.

Dynamics of Stoichiometric Autotroph-Mixotroph-Bacteria Interactions in the Epilimnion.

Autotrophs, mixotrophs and bacteria exhibit complex interrelationships containing multiple ecological mechanisms. A mathematical model based on ecological stoichiometry is proposed to describe the interactions among them. Some dynamic analysis and numerical simulations of this model are presented. The roles of autotrophs and mixotrophs in controlling bacterioplankton are explored to examine the experiments and hypotheses of Medina-Sánchez, Villar-Argaiz and Carrillo for La Caldera Lake. Our results show that the dual control (bottom-up control and top-down control) of bacteria by mixotrophs is a key reason for the ratio of bacterial and phytoplankton biomass in La Caldera Lake to deviate from the general tendency. The numerical bifurcation diagrams suggest that the competition between phytoplankton and bacteria for nutrients can also be an important factor for the decrease of the bacterial biomass in an oligotrophic lake.

A model of algal growth depending on nutrients and inorganic carbon in a poorly mixed water column.

A reaction-diffusion-advection model is proposed to describe the growth of algae depending on both nutrients and inorganic carbon in a poorly mixed water column. Nutrients from the water bottom and inorganic carbon from the water surface form an asymmetric resource supply mechanism for the algal growth. The existence and stability of semi-trivial steady state and positive steady state of the model are proved, and a threshold condition for the regime shift from extinction to survival of algae is established. The influence of environmental parameters on the vertical distribution of algae is investigated in the water column. It is shown that the vertical distribution of algae can exhibit many different profiles under the combined limitation of nutrients and inorganic carbon.

Therapeutic administration of inhaled INS1009, a treprostinil prodrug formulation, inhibits bleomycin-induced pulmonary fibrosis in rats.

Idiopathic pulmonary fibrosis is a progressive and lethal disease and while there are now two approved drugs (Esbriet® and Ofev®) additional effective treatments are still needed. Recently, prostacyclin analogs such as iloprost and treprostinil (TRE) have been shown to exert some protection against bleomycin-induced pulmonary fibrosis in mice when administered in a prophylactic regimen. In this study, we evaluated the effect of the inhaled treprostinil prodrug hexadecyl-treprostinil (C16TR) formulated in a lipid nanoparticle (INS1009) administered therapeutically in a fibrotic rat model. Male Fischer 344 rats challenged with intra-tracheal saline instillation were then treated with daily inhaled phosphate buffered saline (PBS) while rats challenged with bleomycin sulfate (3.5-4.0 mg/kg) instillation were treated with either daily inhaled PBS, daily inhaled INS1009 (10, 30, or 100 µg/kg), or twice-daily orally with the anti-fibrotic compound pirfenidone (100 mg/kg). Dosing started on day 10 post-bleomycin challenge and continued until day 27 after bleomycin. Lungs were harvested 24 h after the last dose of treatment for evaluation of lung hydroxyproline content and pulmonary histology. Lung hydroxyproline content increased from 421 µg/lung lobe in saline challenged and PBS treated animals to 673 µg/lung lobe in bleomycin challenged and PBS treated rats. Treatment of bleomycin challenged rats with 10, 30, or 100 µg/kg INS1009 dose-dependently reduced lung hydroxyproline content to 563, 501, and 451 µg/lung lobe, respectively, and pirfenidone decreased hydroxyproline content to 522 µg/lung lobe. Histologically, both INS1009 (100 µg/kg) and pirfenidone (100 mg/kg) reduced the severity of subepithelial fibrosis. Single dose pharmacokinetic (PK) studies of inhaled INS1009 in bleomycin challenged rats showed dose-dependent increases in lung C16TR concentration and plasma TRE on day 10 post-bleomycin challenge. Multiple dose PK studies of inhaled INS1009 showed dose-dependent increases only in lung C16TR concentration on day 27 post-bleomycin challenge. We also investigated the effects of TRE on the cytokine transforming growth factor-ß1 (TGF-ß1)-stimulated collagen gene and protein expressions in cultured human lung fibroblasts, assessed by real-time PCR and Sirius Red staining, respectively. In human fibroblasts, TRE (0.001-10 µM) inhibited TGF-ß1 (20 ng/mL)-induced expression of collagen mRNA and protein in a concentration-dependent manner. These results demonstrated that inhaled INS1009, administered in a therapeutic dosing paradigm, dose-dependently (10-100 µg/kg) inhibited bleomycin-induced pulmonary fibrosis in rats. This effect may involve direct actions of TRE in suppressing collagen expression in lung fibroblasts.

A mathematical model of algae growth in a pelagic-benthic coupled shallow aquatic ecosystem.

A coupled system of ordinary differential equations and partial differential equations is proposed to describe the interaction of pelagic algae, benthic algae and one essential nutrient in an oligotrophic shallow aquatic ecosystem with ample supply of light. The existence and uniqueness of non-negative steady states are completely determined for all possible parameter range, and these results characterize sharp threshold conditions for the regime shift from extinction to coexistence of pelagic and benthic algae. The influence of environmental parameters on algal biomass density is also considered, which is an important indicator of algal blooms. Our studies suggest that the nutrient recycling from loss of algal biomass may be an important factor in the algal blooms process; and the presence of benthic algae may limit the pelagic algal biomass density as they consume common resources even if the sediment nutrient level is high.

IGF-1 C Domain-Modified Hydrogel Enhances Cell Therapy for AKI.

Low cell retention and engraftment after transplantation limit the successful application of stem cell therapy for AKI. Engineered microenvironments consisting of a hydrogel matrix and growth factors have been increasingly successful in controlling stem cell fate by mimicking native stem cell niche components. Here, we synthesized a bioactive hydrogel by immobilizing the C domain peptide of IGF-1 (IGF-1C) on chitosan, and we hypothesized that this hydrogel could provide a favorable niche for adipose-derived mesenchymal stem cells (ADSCs) and thereby enhance cell survival in an AKI model. In vitro studies demonstrated that compared with no hydrogel or chitosan hydrogel only, the chitosan-IGF-1C hydrogel increased cell viability through paracrine effects. In vivo, cotransplantation of the chitosan-IGF-1C hydrogel and ADSCs in ischemic kidneys ameliorated renal function, likely by the observed promotion of stem cell survival and angiogenesis, as visualized by bioluminescence imaging and attenuation of fibrosis. In conclusion, IGF-1C immobilized on a chitosan hydrogel provides an artificial microenvironment for ADSCs and may be a promising therapeutic approach for AKI.

[Effect and mechanism of gastrodin inhibiting ß-amyloid plaques in brain of mice].

This study was designed to investigate the effect of gastrodin（GAS） against ß-amyloid plaques in 5×FAD Alzheimer's disease（AD） transgenic mice, and utilize 117 cell model（over-expression of Aß and ß-secretase） to explore the underlying mechanism. 5×FAD mice model were randomly divided into three groups, including GAS-high dose group(GAS-H, 200 mg·kg(-1)·d(-1)), GAS-middle dose group(GAS-M, 100 mg·kg(-1)·d(-1)) and GAS-low dose group(GAS-L, 50 mg·kg(-1)·d(-1)). Meanwhile, the wild type mice were used in the control group. After being treated with GAS for three months, 5×FAD mice were evaluated by Morris water maze for the learning and memory ability and by ELISA for Aß in the cerebral homogenate. Then, Aß plaques in the hippocampus and cortex of 5×FAD mice were observed and analyzed with immunohistochemical staining. The cell apoptosis rate and the cell viability were determined in vitro, after the cells were treated with different concentrations of GAS(10, 25, 50 and 100 µmol·L(-1)). Furthermore, Intracelluar/extracelluar Aß were determined by ELISA. Effects of GAS on BACE（ß-secretase site APP cleaving enzyme） m RNA and protein expression were analyzed in 117 cell models by Q-PCR and Western blotting. The results suggest that GAS is able to restore the learning and memory capacity of 5×FAD mice, and reduce Aß in the cerebral homogenate and Aß plaques in the brain. Compared with the untreated transgenic positive group, Aß plaques were declined in hippocampus and cortex of GAS-H group by 93.28% and 88.88%, and Aß was reduced in the cerebral homogenate by 55.74%. In vitro study suggests a dose-dependent effect of GAS in reducing Aß in 117 cell models. When the cells were treated with 100 µmol·L(-1) GAS, extracelluar Aß and intracellular Aß of 117 cells were reduced by 63.1% and 49.1%. BACE expression was largely suppressed in m RNA by 32.9%（P < 0.01）. At 50 µmol·L(-1) GAS, the protein level was declined by 47.9%（P < 0.05）. In conclusion, GAS inhibits Aß production and accumulation by inhibiting ß-secretase.

[Transfection of thymidine phosphorylase cDNA with lentiviral vector enhances the anticancer effect of 5'-deoxy-5-fluorouridine on colorectal cancer cell lines HT29 and LS174T].

OBJECTIVE: To explore the changes of anticancer efficiency of 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-Fu) in colorectal cancer cell line HT29 and LS174T cells after transfection of thymidine phosphorylase (TP) cDNA with a lentiviral vector. METHODS: TP cDNA was transfected into human colorectal cancer cell lines HT29 and LS174T with the lentiviral vector pLenti6.3-MCS-IRES2-EGFP, and the transfection efficiency of the two cell lines passed 5 generations was analyzed by flow cytometry. The expression of TP protein and the relative quantitative expression of TP mRNA in these 2 cell lines were detected by Western blot and RT-PCR, respectively. The 50% inhibitory concentration (IC50) of 5'-DFUR and 5-Fu in both HT29 and LS174T parent cells and TP-transfected cells were assessed by MTS assay. Finally, the concentration of converted 5-Fu was detected by high performance liquid chromatography (HPLC) either in the medium containing a series of concentrations of 5'-DFUR, in which HT29/HT29-TP or LS174T/LS174T-TP cells were cultured, or in the cell culture lysates. RESULTS: The HT29 and LS174T cells transfected with human TP cDNA were monitored for 5 generations, and their transfection efficiency was about 95.0%. Immunohistochemical staining showed that both the parent cells and TP-transfected HT29 and LS174T cells were TP-positive, while vector-transfected cells were TP-negative. Western blotting showed that the TP protein expression in HT29-TP and LS174T-TP cells were significantly increased compared with that in their parents cells. The relative quantity (RQ) values of TP mRNA in HT29-TP and LS174T-TP cells were 8.45 ± 0.15 and 2 615.02 ± 253.97, respectively, which were significantly higher than that in their parents cells (P < 0.01). The IC50 values of 5'-DFUR on HT29-TP cells and its parents cell were (14.33 ± 0.74) µmol/L and (707.66 ± 5.66) µmol/L, respectively (P < 0.05), while (0.59 ± 0.11) µmol/L in LS174T-TP cells and (239.20 ± 21.83) µmol/L in its parent cells, respectively (P < 0.05). The IC50 values of 5-Fu of HT29-TP cells and its parents cells were (5.42 ± 0.75) µmol/L and (14.19 ± 0.97) µmol/L, respectively (P < 0.05), while (4.41 ± 0.96)µmol/L in LS174T-TP cells and (16.42 ± 2.12)µmol/L in its parents cells, respectively (P < 0.05). The HPLC results showed that the 5-Fu concentration detected from media contained a series of concentrations of 5'-DFUR for culturing HT29-TP and LS174T-TP cells were 12.2 to 28.7-folds and 13.1 to 23.6-folds, respectively, higher than that in their parents cells, (P < 0.01 for all). Otherwise, just a little of 5-Fu was detected in the two TP-transfected cells lysate, about 0.9% to 4.2% of 5-Fu detected in the media of the same cultured cells, whereas no 5-Fu was detected in the two parent cell lysates. CONCLUSIONS: Transfection of TP cDNA into colorectal cancer cell lines HT29 and LS174T with lentiviral vector can improve the expression of both TP mRNA and TP protein levels in passaged cells, enhance the conversion of 5-Fu from 5'-DFUR in the medium, and result in an enhanced anticancer effect on these two cell lines.

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.

Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcγ receptor (FcγR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FcγRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FcγRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3(+) regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FcγR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FcγR-expressing immune cells, and facilitate subsequent antitumor immunity.

[Screening of 10 types of Chinese herbal compounds inhibiting Abeta and their possible related mechanism in vitro].

This study is to screen the Chinese herbal compounds which could inhibit the production of Abeta and investigate the underlying mechanism. Ten types of compounds which have potential value in the treatment of AD were selected as initial screening trial. The cell models which used could overexpress Abeta and beta-secretases or Abeta and gamma-secretases. Extracellular Abeta was determined by ELISA after the cell models treated with different concentrations of compounds (0.5-100 micromol x L(-1)), separately. Then the compounds were selected which could inhibit extracellular Abeta and their best concentration ranges were decided, too. Furthermore, the cell viability and apoptosis rate, the level of intracellular Abeta, beta and gamma-secretases were determined after the cell models treated with different concentrations of selected compounds. The results showed that 4 of the 10 compounds could reduce the level of extracellular Abeta; they were cryptotanshinone, astragalosides, gastrodin and paeoniflorin, and their best concentration ranges were 0.5-5.0, 0.5-5.0, 5.0-50, 1.0-25 micromol x L(-1), respectively. Further study indicated that the 4 selected compounds were nontoxic to the cellular models and lowering intracellular Abeta were more effective compared with extracellular; of which astragalosides and gastrodin showed dose-dependent inhibition to the activities of beta and gamma-secretases, with the maximum inhibiting rates of 78.2% and 80.3%, respectively. In conclusion, cryptotanshinone, astragalosides, gastrodin and paeoniflorin could inhibit the expression and secretion of Abeta, and the underlying inhibiting mechanism of astragalosides and gastrodin were related with the reduction of the beta and gamma-secretase activities, respectively.

Mycoloop: Modeling phytoplankton-chytrid-zooplankton interactions in aquatic food webs.

A dynamic model is proposed to describe a mycoloop in aquatic food webs. The model consists of phytoplankton, chytrids and zooplankton. It characterizes that zooplankton consume both phytoplankton and free-living chytrid spores, and that chytrids infect phytoplankton. The dynamics of the model are investigated containing the dissipativity, existence and stability of equilibria, and persistence. The ecological reproductive indexes for phytoplankton or zooplankton invasion and basic reproduction numbers for chytrid transmission are derived. The parameter values of the model are estimated based on experimental data. Numerical simulations explore the effects of the mycoloop on phytoplankton blooms and chytrid transmission. This research reveals that the mycoloop structure increases or reduces phytoplankton blooms, and controls the spread of chytrids among phytoplankton.

Experimental study on failure mode and fracture evolution characteristics of red shale in Kaiyang Phosphorus mining area.

In order to study the failure mode and fracture evolution characteristics of red shale in Kaiyang Phosphorus mining area, conventional triaxial compression mechanical tests of red shale with different bedding dip angles were carried out by using DSTD-1000 electro-hydraulic servo rock mechanics experiment system. Based on the laboratory test results, the conventional triaxial particle flow simulation of red shale samples with different bedding dip angles was carried out using discrete element PFC2D. The results show that: (1) the failure mode of red shale is controlled by bedrock when the bedding dip angle is 0° and 60° ~ 90°. When the bedding dip angle is 15° ~ 45°, the rock failure mode is controlled by bedding. The compressive strength of rock is the minimum when the bedding dip angle is 30°and the maximum at 0°, which is about 2 times of the minimum. (2) In the failure process of red shale, the cracks with different bedding dip angles show slow growth stage, accelerated growth stage and stable stage with axial strain. The whole failure process is dominated by tensile cracks, accompanied by a few shear cracks. (3) The type of displacement field varies with the bedding dip angle: tensile failure and shear failure are the main displacement field types at 15° ~ 45°, and mixed failure is often the main mode at 60° ~ 90°and 0°. The research results provide the basis and reference for the safety control of red shale roadway.

Identification of inflammatory markers as indicators for disease progression in primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that affects various systems in the body, resulting in symptoms such as dry eyes and mouth, pain, and fatigue. Inflammation plays a critical role in pSS and its associated complications, with chronic inflammation being a common occurrence in patients with pSS. This review of the literature highlights inflammatory markers that could serve as indicators to predict disease progression in pSS. Laboratory markers are frequently and significantly increased in pSS patients, including erythrocyte sedimentation rate, C-reactive protein, complement proteins, S100 proteins, cytokines (IFNs, CD40 ligand, soluble CD25, rheumatoid factors, interleukins, and TNF-α), and chemokines (CXCL13, CXCL10, CCL2, CXCL11, and CCL25). These inflammatory markers can be used as prognostic indicators for disease progression in pSS. In conclusion, the results from the studies reported in this review indicate that high levels of inflammatory markers may serve as markers for disease progression of pSS, which, in turn, may be valuable in predicting disease outcome.

Development and validation of a nomogram for predicting depressive symptoms in dentistry patients: A cross-sectional study.

Depressive symptoms are frequently occur among dentistry patients, many of whom struggle with dental anxiety and poor oral conditions. Identifying the factors that influence these symptoms can enable dentists to recognize and address mental health concerns more effectively. This study aimed to investigate the factors associated with depressive symptoms in dentistry patients and develop a clinical tool, a nomogram, to assist dentists in predicting these symptoms. Methods: After exclusion of ineligible participants, a total of 1355 patients from the dentistry department were included. The patients were randomly assigned to training and validation sets at a 2:1 ratio. The LASSO regression method was initially employed to select highly influrtial features. This was followed by the application of a multi-factor logistic regression to determine independent factors and construct a nomogram. And it was evaluated by 4 methods and 2 indicators. The nomograms were formulated based on questionnaire data collected from dentistry patients. Nomogram2 incorporated factors such as medical burden, personality traits (extraversion, conscientiousness, and emotional stability), life purpose, and life satisfaction. In the training set, Nomogram2 exhibited a Concordance index (C-index) of 0.805 and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.805 (95% CI: 0.775-0.835). In the validation set, Nomogram2 demonstrated an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.810 (0.768-0.851) and a Concordance index (C-index) of 0.810. Similarly, Nomogram1 achieved an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.816 (0.788-0.845) and a Concordance index (C-index) of 0.816 in the training set, and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.824 (95% CI: 0.784-0.864) and a Concordance index (C-index) of 0.824 in the validation set. Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) indicated that Nomogram1, which included oral-related factors (oral health and dental anxiety), outperformed Nomogram2. We developed a nomogram to predict depressive symptoms in dentistry patients. Importantly, this nomogram can serve as a valuable psychometric tool for dentists, facilitating the assessment of their patients' mental health and enabling more tailored treatment plans.

A gene delivery system with autophagy blockade for enhanced anti-angiogenic therapy against Fusobacterium nucleatum-associated colorectal cancer.

Anti-angiogenesis has emerged a promising strategy against colorectal cancer (CRC). However, the efficacy of anti-angiogenic therapy is greatly compromised by the up-regulated autophagy levels resulting from the evolutionary resistance mechanism and the presence of Fusobacterium nucleatum (F. nucleatum) in CRC. Herein, we report a cationic polymer capable of blocking autophagic flux to deliver plasmid DNA (pDNA) encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) for enhanced anti-angiogenic therapy against F. nucleatum-associated CRC. The autophagy-inhibiting cationic polymer, referred to as PNHCQ, is synthesized by conjugating hydroxychloroquine (HCQ) into 3,3'-diaminodipropylamine-pendant poly(ß-benzyl-L-aspartate) (PAsp(Nors)), which can be assembled and electrostatically interacted with sFlt-1 plasmid to form PNHCQ/sFlt-1 polyplexes. Hydrophobic HCQ modification not only boosts transfection efficiency but confers autophagy inhibition activity to the polymer. Hyaluronic acid (HA) coating is further introduced to afford PNHCQ/sFlt-1@HA for improved tumor targeting without compromising on transfection. Consequently, PNHCQ/sFlt-1@HA demonstrates significant anti-tumor efficacy in F. nucleatum-colocalized HT29 mouse xenograft model by simultaneously exerting anti-angiogenic effects through sFlt-1 expression and down-regulating autophagy levels exacerbated by F. nucleatum challenge. The combination of anti-angiogenic gene delivery and overall autophagy blockade effectively sensitizes CRC tumors to anti-angiogenesis, providing an innovative approach for enhanced anti-angiogenic therapy against F. nucleatum-resident CRC. STATEMENT OF SIGNIFICANCE: Up-regulated autophagy level within tumors is considered responsible for the impaired efficacy of clinic antiangiogenic therapy against CRC colonized with pathogenic F. nucleatum. To tackle this problem, an autophagy-inhibiting cationic polymer is developed to enable efficient intracellular delivery of plasmid DNA encoding soluble FMS-like tyrosine kinase-1 (sFlt-1) and enhance anti-angiogenic therapy against F. nucleatum-associated CRC. HA coating that can be degraded by tumor-enriching hyaluronidase is further introduced for improved tumor targeting without compromising transfection efficiency. The well-orchestrated polyplexes achieve considerable tumor accumulation, efficient in vivo transfection, and effectively reinforce the sensitivity of CRC to the sFlt-1-derived anti-angiogenic effects by significantly blocking overall autophagy flux exacerbated by F. nucleatum challenge, thus harvesting robust antitumor outcomes against F. nucleatum-resident CRC.

Remotely Controllable Supramolecular Nanomedicine for Drug-Resistant Colorectal Cancer Therapy Caused by Fusobacterium nucleatum.

Fusobacterium nucleatum (Fn) existing in the community of colorectal cancer (CRC) promotes CRC progression and causes chemotherapy resistance. Despite great efforts that have been made to overcome Fn-induced chemotherapy resistance by co-delivering antibacterial agents and chemotherapeutic drugs, increasing the drug-loading capacity and enabling controlled release of drugs remain challenging. In this study, a novel supramolecular upconversion nanoparticle (SUNP) is constructed by incorporating a positively charged polymer (PAMAM-LA-CD) with Fn inhibition capacity, a negatively charged platinum (IV) oxaliplatin prodrug (OXA-COOH), upconversion nanoparticle (UCNPs) and polyethylene glycol-azobenzene (PEG-Azo) to enhance drug-loading and enable on-demand drug release for drug-resistant CRC treatment. SUNPs exhibit high drug-loading capacity (30.8%) and good structural stability under normal physiological conditions, while disassembled upon exogenous NIR excitation and endogenous azo reductase in the CRC microenvironment to trigger drug release. In vitro and in vivo studies demonstrate that SUNPs presented good biocompatibility and robust performance to overcome chemoresistance, thereby significantly inhibiting Fn-infected cancer cell proliferation. This study leverages multiple dynamic chemical designs to integrate both advantages of drug loading and release in a single system, which provides a promising candidate for precision therapy of bacterial-related drug-resistant cancers.