Electrically-driven drug delivery into deep cutaneous tissue by conductive microneedles for fungal infection eradication and protective immunity.

Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using in vitro and ex vivo models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue.

Carboxyl-Group-Bearing Metal Corroles of Cobalt, Manganese and Copper for Electrocatalytic Hydrogen Evolution.

5,15-bis(perfluorophenyl)-10-(4-carboxyphenyl) corrole and its Co(III), Mn(III), and Cu(III) corrole complexes were synthesized. The electrocatalytic hydrogen evolution reaction (HER) of these metal corrole complexes was investigated using different proton sources (AcOH, trifluoroacetic acid, and TsOH) in an organic dimethylformamide solvent. The electrocatalytic HER may proceed through EECC, EECEC, or EEECEC pathways (where E represents electron transfer and C represents proton binding) depending on the acidity and concentration of the proton source used. The Co corrole complex exhibits remarkable hydrogen production performance, achieving a turnover frequency of 201 s-1 and a catalytic efficiency of 1.00. The examined metal corrole complexes also exhibit good HER activity in aqueous solution, with their catalytic activity following an order of 1-Co > 1-Cu > 1-Mn in both organic and aqueous phases.

Validation of the 2018 (New) ENMC Classification Criteria for Dermatomyositis in Chinese Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVES: To validate the 2018 European Neuromuscular Centre classification (ENMC) criteria, compare its performance to the 1975 Bohan & Peter (B&P) and 2017 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for dermatomyositis (DM), and describe characteristics of different myositis-specific autoantibody (MSA)-positive patients defined by the ENMC-DM criteria. METHODS: Medical records and data on MSAs and muscle biopsies were retrospectively obtained from 1370 Chinese patients with idiopathic inflammatory myopathy (IIM) between 2008 and 2020. Patients were diagnosed with DM by at least two rheumatologists and classified according to the ENMC-DM, EULAR/ACR, and B&P criteria. RESULTS: Of the 1370 patients, 857, 671, 693, and 913 were diagnosed with DM using the specialists' gold standard, ENMC-DM, EULAR/ACR, and B&P criteria, respectively. Significant between-group differences were observed in the clinical symptoms, serum creatine kinase levels, and MSAs (P < 0.05). Based on muscle biopsy data, the B&P criteria had the highest sensitivity (94%) but lowest specificity (65%). Without muscle biopsy data, the ENMC-DM criteria had the highest specificity (92%) but lowest sensitivity (61%). The sensitivity and specificity of the EULAR/ACR criteria were intermediate (72% and 86%, respectively) regardless of muscle biopsy data availability. With MSA data, the sensitivity and specificity of the ENMC-DM criteria were 73% and 91% and increased to 76% and 97%, respectively, with both muscle biopsy and MSA data. CONCLUSIONS: The ENMC-DM criteria had higher specificity than the other criteria, especially in the absence of muscle biopsy data. Sensitivity and specificity improved when both muscle biopsy and MSA data were available. Key Points • Idiopathic inflammatory myopathy presents diagnostic challenges due to its variable features and dermatomyositis has distinct subtypes based on myositis-specific autoantibodies (MSAs) with unique clinical phenotypes. • This study validates the ENMC-DM criteria in Chinese patients and provides a comprehensive comparison with the B&P and EULAR/ACR criteria. • It demonstrates that the new ENMC-DM criteria exhibit higher specificity, especially noteworthy in cases without muscle biopsy, and the study further highlights the improved sensitivity and specificity when combining muscle biopsy and MSAs, offering a refined approach for accurate DM classification.

Correlation Between Intrinsic Capacity and Muscle Strength and Quality in Older Patients with Cardiovascular Disease: A Cross-Sectional Study.

Background: Cardiovascular disease (CVD) has become the leading cause of death worldwide. High muscle mass can reduce the incidence and mortality of CVD. In recent years, increasing attention has been given to the relationship between intrinsic capacity (IC) and CVD. This study aims to explore the relationship between the decline of IC, muscle strength, and muscle quality in older patients with CVD, providing a new method and basis for early recognition of IC decline in the older adults. Methods: This cross-sectional study included 475 older individuals from communities in Zhejiang. General data were collected, and a comprehensive geriatric assessment (CGA) was conducted. Participants with CVD were divided into three groups: IC retention, IC impairment, and IC significantly impaired. Bioelectrical impedance analysis (BIA) measurements were completed. Student's t-test or non-parametric tests (Mann-Whitney) were used to analyze the correlation between IC and muscle-related indicators. The best cutoff values were obtained using ROC curve analysis. Results: Compared to non-CVD patients, CVD patients were older, more educated, and had higher rates of polypharmacy and comorbidity. IC decreased more significantly in CVD patients. Age (P=0.001), Fried (P=0.024), and GDS-5 (P=0.002) increased with the severity of IC decline. ADL (P=0.002), MMSE (P=0.000), MNA-SF (P=0.000), SARC-Calf (P=0.026), waist circumference (P=0.037), and muscle quality (P=0.010) decreased with the decline in IC. When IC decreased, the cutoff values for hand grip strength, waist circumference, and muscle quality were 25.45 kg, 72.55 cm, and 3.05, respectively. When IC decreased significantly, the cutoff values were 17.15 kg, 71.55 cm, and 2.28, respectively. Conclusion: The results of this study showed that in patients with CVD, the hand grip strength and muscle quality of patients with IC injury were lower than those of patients with IC retention.

Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer.

The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

Pilot-scale study of enhanced thermophilic anaerobic digestion of food waste with the addition of trace elements.

Thermophilic anaerobic digestion (AD) offers many benefits for food waste treatment but is seldom adopted in industrial plants due to instability issue, particularly under higher loading conditions. This study thus conducted a 160-day continuous operation of a pilot-scale thermophilic AD system on-site. Results from the experiments showed that the system could operate under relatively lower loading but failed when the loading reached up to 5.69 kg·COD/(m3·d). Volatile fatty acids increased to 6000 mg/L at the corresponding hydraulic retention time of 15 days. Trace elements were then introduced, which restored higher process stability by reducing volatile fatty acids to 400 mg/L. The mass balance and materials decomposition resutls revealed the system's strong resilience. Methanoculleus (92.52 %) and Methanomassiliicoccus (6.55 %) were the dominant methanogens, a phenomenon rarely observed in similar thermophilic systems. This system may tolerate more stressful conditions, as the loading limits had not been reached with the addition of trace elements.

Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial.

BACKGROUND: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases. METHODS: For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing. RESULTS: Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia. INTERPRETATION: The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted. FUNDING: Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center.

Molecular mechanism of a coastal cyanobacterium Synechococcus sp. PCC 7002 adapting to changing phosphate concentrations.

Phosphorus concentration on the surface of seawater varies greatly with different environments, especially in coastal. The molecular mechanism by which cyanobacteria adapt to fluctuating phosphorus bioavailability is still unclear. In this study, transcriptomes and gene knockouts were used to investigate the adaptive molecular mechanism of a model coastal cyanobacterium Synechococcus sp. PCC 7002 during periods of phosphorus starvation and phosphorus recovery (adding sufficient phosphorus after phosphorus starvation). The findings indicated that phosphorus deficiency affected the photosynthesis, ribosome synthesis, and bacterial motility pathways, which recommenced after phosphorus was resupplied. Even more, most of the metabolic pathways of cyanobacteria were enhanced after phosphorus recovery compared to the control which was kept in continuous phosphorus replete conditions. Based on transcriptome, 54 genes potentially related to phosphorus-deficiency adaptation were selected and knocked out individually or in combination. It was found that five mutants showed weak growth phenotype under phosphorus deficiency, indicating the importance of the genes (A0076, A0549-50, A1094, A1320, A1895) in the adaptation of phosphorus deficiency. Three mutants were found to grow better than the wild type under phosphorus deficiency, suggesting that the products of these genes (A0079, A0340, A2284-86) might influence the adaptation to phosphorus deficiency. Bioinformatics analysis revealed that cyanobacteria exposed to highly fluctuating phosphorus concentrations have more sophisticated phosphorus acquisition strategies. These results elucidated that Synechococcus sp. PCC 7002 have variable phosphorus response mechanisms to adapt to fluctuating phosphorus concentration, providing a novel perspective of how cyanobacteria may respond to the complex and dynamic environments. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00244-y.

Importance of the enhanced cooling system for more spherical ablation zones: Numerical simulation, ex vivo and in vivo validation.

INTRODUCTION: This study aimed to investigate the efficacy of a small-gauge microwave ablation antenna (MWA) with an enhanced cooling system (ECS) for generating more spherical ablation zones. METHODS: A comparison was made between two types of microwave ablation antennas, one with ECS and the other with a conventional cooling system (CCS). The finite element method was used to simulate in vivo ablation. Two types of antennas were used to create MWA zones for 5, 8, 10 min at 50, 60, and 80 W in ex vivo bovine livers (n = 6) and 5 min at 60 W in vivo porcine livers (n = 16). The overtreatment ratio, ablation aspect ratio, carbonization area, and other characteristcs of antennas were measured and compared using numerical simulation and gross pathologic examination. RESULTS: In numerical simulation, the ECS antenna demonstrated a lower overtreatment ratio than the CCS antenna (1.38 vs 1.43 at 50 W 5 min, 1.19 vs 1.35 at 50 W 8 min, 1.13 vs 1.32 at 50 W 10 min, 1.28 vs 1.38 at 60 W 5 min, 1.14 vs 1.32 at 60 W 8 min, 1.10 vs 1.30 at 60 W 10 min). The experiments revealed that the ECS antenna generated ablation zones with a more significant aspect ratio (0.92 ± 0.03 vs 0.72 ± 0.01 at 50 W 5 min, 0.95 ± 0.02 vs 0.70 ± 0.01 at 50 W 8 min, 0.96 ± 0.01 vs 0.71 ± 0.04 at 50 W 10 min, 0.96 ± 0.01 vs 0.73 ± 0.02 at 60 W 5 min, 0.94 ± 0.03 vs 0.71 ± 0.03 at 60 W 8 min, 0.96 ± 0.02 vs 0.69 ± 0.04 at 60 W 10 min) and a smaller carbonization area (0.00 ± 0.00 cm2 vs 0.54 ± 0.06 cm2 at 50 W 5 min, 0.13 ± 0.03 cm2 vs 0.61 ± 0.09 cm2 at 50 W 8 min, 0.23 ± 0.05 cm2 vs 0.73 ± 0.05 m2 at 50 W 10 min, 0.00 ± 0.00 cm2 vs 1.59 ± 0.41 cm2 at 60 W 5 min, 0.23 ± 0.22 cm2 vs 2.11 ± 0.63 cm2 at 60 W 8 min, 0.57 ± 0.09 cm2 vs 2.55 ± 0.51 cm2 at 60 W 10 min). Intraoperative ultrasound images revealed a hypoechoic area instead of a hyperechoic area near the antenna. Hematoxylin-eosin staining of the dissected tissue revealed a correlation between the edge of the ablation zone and that of the hypoechoic area. CONCLUSIONS: The ECS antenna can produce more spherical ablation zones with less charring and a clearer intraoperative ultrasound image of the ablation area than the CCS antenna.

Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors.

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women. Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators (SERMs) has been associated with various clinical drawbacks. We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein, called HKUOT-S2 protein (32 kDa), from Dioscorea opposita Thunb that can accelerate bone defect healing. Here, we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors (ERs) ERα, ERß, and GPR30 expressions in vivo. Also, HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers, ALP, and RUNX2 expressions, ALP activity, and osteoblast biomineralization in vitro. Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions, osteoblasts differentiation, and functions. Finally, we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties. Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis. Currently, there is no or limited data if any, on osteoanabolic SERMs. The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

Geriatric syndrome awareness and its determinants in China: a cross-sectional study.

BACKGROUND: This study aims to investigate the awareness rate of six common geriatric syndromes and related influencing factors among the older adults aged 65 and above in China. METHODS: This is a multicenter cross-sectional study involving 6,653 participants aged 65 and older from four regions who completed a questionnaire on geriatric syndrome awareness. The questionnaire covered demographic data, health information, medication usage, and an assessment scale for knowledge of six geriatric syndromes (GS Awareness Scale). RESULTS: A total of 6,653 respondents were surveyed, with 5,318 valid questionnaires collected (79.93%), including 1,311 from Zhejiang (24.7%), 1,356 from Beijing (25.5%), 1,373 from Sichuan (25.8%), and 1,278 from Fujian (24.0%). The highest awareness was for falls, with 3,295 individuals (62.0%), followed by dementia with 2,929 individuals (55.1%), malnutrition with 2,907 individuals (54.7%), frailty with 2,156 individuals (40.5%), urinary incontinence with 2,006 individuals (37.7%), and sarcopenia with 1,914 individuals (36.0%). Univariate analysis showed that factors such as region, age, marital status, living situation, educational level, source of respondents, income status, and smoking had statistically significant differences in awareness rates (P < 0.05). Multivariate logistic regression results indicated that the source of respondents significantly affected the awareness rates (P < 0.05), with the older adults from rural areas having an increased risk of lower awareness compared to urban areas; age also significantly influenced the awareness rates (P < 0.05), with older age groups (76-85, 86-95 years) having a higher risk of reduced awareness compared to those aged 65-75 years. CONCLUSIONS: The awareness of common geriatric syndromes among the older adults population aged 65 years and older in China is notably low. Consequently, there exists a critical need to enhance the formulation of policies regarding geriatric syndromes across various regions, aiming to elevate health literacy among this demographic.

Response of Elymus nutans Griseb. seedling physiology and endogenous hormones to drought and salt stress.

Elymus nutans Griseb. (E. nutans), a pioneer plant for the restoration of high quality pasture and vegetation, is widely used to establish artificial grasslands and ecologically restore arid and salinized soils. To investigate the effects of drought stress and salt stress on the physiology and endogenous hormones of E. nutans seedlings, this experiment configured the same environmental water potential (0 (CK), - 0.04, - 0.14, - 0.29, - 0.49, - 0.73, and - 1.02 MPa) of PEG-6000 and NaCl stress to investigate the effects of drought stress and salt stress, respectively, on E. nutans seedlings under the same environmental water potential. The results showed that although the physiological indices and endogenous hormones of the E. nutans seedlings responded differently to drought stress and salt stress under the same environmental water potential, the physiological indices of E. nutans shoots and roots were comprehensively evaluated using the genus function method, and the physiological indices of the E. nutans seedlings under the same environmental water potential exhibited better salt tolerance than drought tolerance. The changes in endogenous hormones of the E. nutans seedlings under drought stress were analyzed to find that treatment with gibberellic acid (GA3), gibberellin A7 (GA7), 6-benzyladenine (6-BA), 6-(y,y-dimethylallylaminopurine) (2.IP), trans-zeatin (TZ), kinetin (KT), dihydrozeatin (DHZ), indole acetic acid (IAA), and 2,6-dichloroisonicotininc acid (INA) was more effective than those under drought stress. By analyzing the amplitude of changes in the endogenous hormones in E. nutans seedlings, the amplitude of changes in the contents of GA3, GA7, 6-BA, 2.IP, TZ, KT, DHZ, IAA, isopentenyl adenosine (IPA), indole-3-butyric acid (IBA), naphthalene acetic acid (NAA), and abscisic acid was larger in drought stress compared with salt stress, which could be because the endogenous hormones are important for the drought tolerance of E. nutans itself. The amplitude of the changes in the contents of DHZ, TZR, salicylic acid, and jasmonic acid was larger in salt stress compared with drought stress. Changes in the content of melatonin were larger in salt stress compared with drought stress, which could indicate that endogenous hormones and substances are important for the salt tolerance of E. nutans itself.

Berberine ameliorates endothelial progenitor cell function and wound healing in vitro and in vivo via the miR-21-3p/RRAGB axis for venous leg ulcers.

Purpose: Venous leg ulcers (VLUs) are prevalent chronic wounds with limited treatment options. This study aimed to investigate the potential of berberine to enhance endothelial progenitor cell (EPC) function in VLU healing. Methods: Histopathological changes and inflammatory cytokine levels in a deep venous thrombosis (DVT) mouse model were assessed using HE staining and ELISA assays. A luciferase reporter assay was employed to identify the miR-21-3p and RRAGB targeting relationship. EPC proliferation, migration, and tube formation were evaluated through CCK-8, Transwell, and tubule formation assays, while the mTOR pathway and autophagy-related proteins were analyzed by immunofluorescence staining and western blotting. Results: Berberine significantly improved EPC functions, such as proliferation, migration, and tube formation in vitro, and enhanced in vivo EPC-mediated wound healing in a DVT mouse model. Furthermore, miR-21-3p was downregulated in EPCs from VLU patients, and its overexpression improved model EPC functions. Mechanistically, RRAGB, which regulates the mTOR pathway, was identified as a potential miR-21-3p target in EPCs. Overexpression of RRAGB inhibited autophagic activity and impaired EPC function. Conclusion: Berberine shows promise in ameliorating EPC function and promoting wound healing in VLUs. The regulation of the miR-21-3p/RRAGB axis by berberine could offer a promising therapeutic approach for managing VLUs.

Development of a base editor for convenient and multiplex genome editing in cyanobacteria.

Cyanobacteria are important primary producers, contributing to 25% of the global carbon fixation through photosynthesis. They serve as model organisms to study the photosynthesis, and are important cell factories for synthetic biology. To enable efficient genetic dissection and metabolic engineering in cyanobacteria, effective and accurate genetic manipulation tools are required. However, genetic manipulation in cyanobacteria by the conventional homologous recombination-based method and the recently developed CRISPR-Cas gene editing system require complicated cloning steps, especially during multi-site editing and single base mutation. This restricts the extensive research on cyanobacteria and reduces its application potential. In this study, a highly efficient and convenient cytosine base editing system was developed which allows rapid and precise C → T point mutation and gene inactivation in the genomes of Synechocystis and Anabaena. This base editing system also enables efficient multiplex editing and can be easily cured after editing by sucrose counter-selection. This work will expand the knowledge base regarding the engineering of cyanobacteria. The findings of this study will encourage the biotechnological applications of cyanobacteria.

Necroptosis enhances 'don't eat me' signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 'don't eat me' signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial-mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.

A global transcriptional activator involved in the iron homeostasis in cyanobacteria.

Cyanobacteria use a series of adaptation strategies and a complicated regulatory network to maintain intracellular iron (Fe) homeostasis. Here, a global activator named IutR has been identified through three-dimensional chromosome organization and transcriptome analysis in a model cyanobacterium Synechocystis sp. PCC 6803. Inactivation of all three homologous IutR-encoding genes resulted in an impaired tolerance of Synechocystis to Fe deficiency and loss of the responses of Fe uptake-related genes to Fe-deplete conditions. Protein-promoter interaction assays confirmed the direct binding of IutR with the promoters of genes related to Fe uptake, and chromatin immunoprecipitation sequencing analysis further revealed that in addition to Fe uptake, IutR could regulate many other physiological processes involved in intracellular Fe homeostasis. These results proved that IutR is an important transcriptional activator, which is essential for cyanobacteria to induce Fe-deficiency response genes. This study provides in-depth insights into the complicated Fe-deficient signaling network and the molecular mechanism of cyanobacteria adaptation to Fe-deficient environments.

Nano-lamellar H-ZSM-5 molecular sieves for enhanced indoor air purification: Synthesis and adsorption characterization.

BACKGROUND: The rapid growth of cities has been accompanied by problems with urban air quality, making air pollution challenging to manage. In this situation, people focus on indoor building materials to improve air quality. OBJECTIVE: In this paper, a novel bola-type surfactant was synthesized and used as a template, using ethyl orthosilicate and sodium meta-aluminate as the silicon and aluminum source, in the ratio of n(NaOH): n(NaAIO2): n(SiO2): n(SDA): n(H2O) as 30:2.5:120:5:4800. METHODS: Hydrothermal preparation of ZSM-5 molecular sieves with a nanosheet structure (H-ZSM-5) was accomplished. The manufactured lamellar ZSM-5 molecular sieves were examined using X-ray diffraction, transmission electron microscopy, scanning electron microscopy, and adsorption and desorption techniques. RESULTS: Traditional microporous ZSM-5 had a considerably lower static adsorption of formaldehyde molecules. The findings demonstrated that the nano-lamellar H-ZSM-5 molecular sieve can purify and eliminate larger molecular VOCs inside because it has the ability to adsorb larger molecular diameter VOCs. Additionally, the effectiveness of the adsorption was assessed using toluene vapour molecules with higher molecular diameters. CONCLUSION: The findings demonstrate that the nanosheet H-ZSM-5 molecular sieve can remove bigger molecule VOCs from indoor air and can be utilised to purify indoor spaces. This study offers a fresh approach to indoor environmental cleanup by demonstrating the capability of nano-lamellar H-ZSM-5 molecular sieves for molecular adsorption.

Psychosocial and psychological interventions for schizophrenia relapse prevention: A bibliometric analysis.

Various psychosocial and psychological interventions have been developed to reduce schizophrenia relapse prevention. A better understanding of these active interventions is important for clinical practice and for meaningful allocation of resources. However, no bibliometric analysis of this area has been conducted. Studies were retrieved from the Web of Science Core Collection database. The publication outputs and cooperation of institutions were visualized with Origin 2021. Global cooperation was visualized using ArcGIS Pro3.0. VOSviewer was used to generate visualizations of network of authors and keywords. The number of annual publications generally showed a fluctuating upward trend over the past 20 years. Germany published the most relevant articles (361, 26.76%). The Technical University of Munich was the most productive institution (70, 9.86%). Leucht Stefan published the most articles (46, 6.48%) and had the highest number of citations (4,375 citations). Schizophrenia Research published the most studies (39, 5.49%). Keywords were roughly classified into three clusters: cognitive behavioral therapy (CBT), family interventions and family psychoeducation and other factors related to interventions. The findings provided the current status of research on psychosocial and psychological interventions for schizophrenia relapse prevention from a bibliometric perspective. Recent research has mainly focused on CBT, family interventions and family psychoeducation.

Phase 1 study of azacitidine in combination with quizartinib in patients with FLT3 or CBL mutated MDS and MDS/MPN.

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0-38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.