High radiation efficiency and tunable resonance planar double-turn spiral antenna for manipulation of nitrogen-vacancy centers.

Nitrogen-vacancy (NV) centers in diamond are promising quantum sensors, where microwave antennas play a crucial role in manipulating the spin states accurately. Conventional microwave antennas often struggle to balance radiation efficiency and bandwidth. To address this challenge, we design a planar double-turn spiral antenna (PDTSA), based on the ring microstrip antenna (RMA). PDTSA demonstrates an ∼4.5-fold increase in radiation efficiency compared to RMA. In addition, the PDTSA allows linear tunability of the resonance frequency up to 500 MHz by adjusting the spiral input length. This feature addresses the limitations of a narrow working frequency range, which are typically caused by the narrowband in high-radiation-efficiency antennas. The experimental results show that at an absolute input power of 1 W, the PDTSA increases the Rabi frequency from 1.72 to 8.06 MHz compared to the RMA. This enhancement accelerates quantum state manipulation and reduces phase accumulation errors. These characteristics make PDTSA suitable for applications in quantum sensing and precision measurements using NV centers.

Modeling high-risk Wilms tumors enables the discovery of therapeutic vulnerability.

Wilms tumor (WT) is the most common pediatric kidney cancer treated with standard chemotherapy. However, less-differentiated blastemal type of WT often relapses. To model the high-risk WT for therapeutic intervention, we introduce pluripotency factors into WiT49, a mixed-type WT cell line, to generate partially reprogrammed cells, namely WiT49-PRCs. When implanted into the kidney capsule in mice, WiT49-PRCs form kidney tumors and develop both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrate that WiT49-PRCs recapitulate blastemal-predominant WTs. Moreover, drug screening in isogeneic WiT49 and WiT49-PRCs leads to the identification of epithelial- or blastemal-predominant WT-sensitive drugs, whose selectivity is validated in patient-derived xenografts (PDXs). Histone deacetylase (HDAC) inhibitors (e.g., panobinostat and romidepsin) are found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRCs serve as a blastemal-predominant WT model for therapeutic intervention to treat patients with high-risk WT.

Geographic Socioeconomic Influences on Disease Activity in Rheumatoid Arthritis in an Academic and Safety Net Hospital System.

OBJECTIVE: The objective of this study was to analyze the impact of the Area Deprivation Index (ADI) on disease activity and cardiovascular comorbidity in rheumatoid arthritis (RA). METHODS: A retrospective analysis of adult patients with RA was conducted to highlight differences in academic and safety net hospital clinics. Demographics, RA medication history, patient portal engagement, primary care presence, emergency or inpatient visits, RA disease activity and functional scores, Charlson Comorbidity Index (CCI), and cardiovascular disease (CVD) presence were captured. The ADI rank was assigned using nine-digit zip codes. Patients were stratified by the upper versus lower ADI decile group and matched by age, sex, race, ethnicity, insurance, and CCI using propensity score analysis. RESULTS: Patients with RA from the academic practice (n = 542) and the safety net hospital (n = 496) were assessed. In the academic cohort, those with high ADI scores (>8, more deprivation) had higher RA disease activity scores (Routine Assessment of Patient Index Data 3 mean ± SD: high 13.83 ± 6.94 vs low 11.17 ± 7.37, P < 0.0001; Clinical Disease Activity Index mean ± SD: high 11.97 ± 11.74 vs low 9.40 ± 7.97, P < 0.05), more functional impairment (Multidimensional Health Assessment Questionnaire mean ± SD: high 2.99 ± 2.29 vs low 2.34 ± 2.23, P < 0.01), lower MyChart use (P < 0.001), and different smoking history (P < 0.01) compared to those with low ADI scores (<3, less deprivation). In the safety net cohort, there was a statistically significant difference only in smoking status (P < 0.05). CVD was not significantly different in either cohort. CONCLUSION: The absence of differences in RA disease activity and functional impairment in patients suggests that the ADI may not be as effective at predicting RA disease activity specifically in a safety net health care context. Identifying the discrepancies between the two systems may elucidate areas of improvement for patient care.

CRISPR-AMRtracker: A novel toolkit to monitor the antimicrobial resistance gene transfer in fecal microbiota.

The spread of antibiotic resistance genes (ARGs), particularly those carried on plasmids, poses a major risk to global health. However, the extent and frequency of ARGs transfer in microbial communities among human, animal, and environmental sectors is not well understood due to a lack of effective tracking tools. We have developed a novel fluorescent tracing tool, CRISPR-AMRtracker, to study ARG transfer. It combines CRISPR/Cas9 fluorescence tagging, fluorescence-activated cell sorting, 16S rRNA gene sequencing, and microbial community analysis. CRISPR-AMRtracker integrates a fluorescent tag immediately downstream of ARGs, enabling the tracking of ARG transfer without compromising the host cell's antibiotic susceptibility, fitness, conjugation, and transposition. Notably, our experiments demonstrate that sfGFP-tagged plasmid-borne mcr-1 can transfer across diverse bacterial species within fecal samples. This innovative approach holds the potential to illuminate the dynamics of ARG dissemination and provide valuable insights to shape effective strategies in mitigating the escalating threat of antibiotic resistance.

MiR-30c suppresses the proliferation, metastasis and polarity reversal of tumor cell clusters by targeting MTDH in invasive micropapillary carcinoma of the breast.

Purpose: Invasive micropapillary carcinoma (IMPC) of the breast has a high propensity for lymphovascular invasion and axillary lymph node metastasis and displays an 'inside-out' growth pattern, but the molecular mechanism of invasion, metastasis and cell polarity reversal in IMPC is unclear. Methods: and Patients: Cell growth curves, tumor sphere formation assays, transwell assays, mouse xenograft model and immunofluorescence were evaluated to investigate the effects of miR-30c and MTDH. Dual luciferase reporter assays was performed to confirm that the MTDH (metadherin) 3'UTR bound to miR-30c. MiRNA in situ hybridization (ISH) and immunohistochemistry (IHC) were carried out on IMPC patient tissues for miR-30c and MTDH expression, respectively. Results: We found miR-30c as a tumor suppressor gene in cell proliferation, metastasis and polarity reversal of IMPC. Overexpression of miR-30c inhibited cell growth and metastasis in vitro and in vivo. MiR-30c could directly target the MTDH 3'UTR. MiR-30c overexpression inhibited breast cancer cell proliferation, invasion and metastasis by targeting MTDH. Moreover, miR-30c/MTDH axis could also regulate cell polarity reversal of IMPC. By ISH and IHC analyses, miR-30c and MTDH were significantly correlated with tumor size, lymph nodule status and tumor grade, the 'inside-out' growth pattern, overall survival (OS) and disease-free survival (DFS) in IMPC patients. Conclusions: Overall, miR-30c/MTDH axis was responsible for tumor proliferation, metastasis and polarity reversal. It may provide promising therapeutic targets and prognostic biomarkers for patients with IMPC.

15-Gene Expression Profile and PRAME as Integrated Prognostic Test for Uveal Melanoma: First Report of Collaborative Ocular Oncology Group Study No. 2 (COOG2.1).

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier.MATERIALS AND METHODSThis study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR], 5.95 [95% CI, 4.43 to 7.99]; P < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.CONCLUSIONIn the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with UM.

UV-assisted synthesis of ultra-small GO-Austar for efficient PTT therapeutic architectonic construction.

Conventional Au nanomaterial synthesis typically necessitates the involvement of extensive surfactants and reducing agents, leading to a certain amount of chemical waste and biological toxicity. In this study, we innovatively employed ultra-small graphene oxide as a reducing agent and surfactant for the in situ generation of small Au nanoparticles under ultraviolet irradiation (UV) at ambient conditions. After ultra-small GO-Au seeds were successfully synthesized, we fabricated small star-like Au nanoparticles on the surface of GO, in which GO effectively prevented Austar from aggregation. To further use GO-Austar for cancer PTT therapy, through the modification of reduced human serum albumin-folic acid conjugate (rHSA-FA) and loading IR780, the final probe GO-Austar@rHSA-FA@IR780 was prepared. The prepared probe showed excellent biocompatibility and superb phototoxicity towards MGC-803 cells in vitro. In vivo, the final probe dramatically increased tumor temperature up to 58.6 °C after 5 minutes of irradiation by an 808 nm laser, significantly inhibiting tumor growth and nearly eradicating subcutaneous tumors in mice. This research provides a novel and simple method for the synthesis of GO-Au nanocomposites, showcasing significant potential in biological applications.

Association Between Substance Abuse and Mental Illness Symptoms Screener (SAMISS) Scores and HIV Care Continuum Outcomes in People Newly Diagnosed with HIV in the US South.

Mental illness (MI) and substance use (SU) are highly prevalent among people with HIV (PWH) and impact care outcomes. The Substance Abuse and Mental Illness Symptoms Screener (SAMISS) is a validated screener for MI and SU, but it is unknown how screening results at entry to care correlate with subsequent HIV outcomes. This is a retrospective chart review of individuals newly diagnosed with HIV between 2016 and 2019 in a Southern US, safety-net clinic. Baseline demographics, HIV risk factors, socioeconomic variables, and SAMISS screening scores were collected. Outcomes included retention in care, achieving virologic suppression (VS), and continuous VS. Data analyses included stepwise Cox and logistic multivariate regression modeling. Among the 544 newly diagnosed PWH, mean age was 35, 76% were male, 46% non-Hispanic Black, 40% Hispanic/other. Overall, 35% screened positive for SU and 41% for MI. A positive SU (odds ratio (OR) 0.66, p = 0.04) or MI (OR 0.65, p = 0.03) SAMISS screening was associated with lower retention in care in univariate analysis, but was not statistically significant after adjusting for other variables. Positive SAMISS screening for SU and MI were both associated with reduced continuous VS in univariate and multivariate analyses (SU: adjusted OR (aOR) 0.67, p = 0.05; MI: aOR 0.66, p = 0.03). SAMISS is a useful tool for prospectively identifying individuals at risk for low retention in care and for not achieving sustained VS. Future interventions guided by SAMISS may improve HIV care continuum outcomes.

Bio-orthogonal engineered peptide: A multi-functional strategy for the gene therapy of osteoporotic bone loss.

Osteoporosis is a degenerative disease affecting millions of elderly people globally and increases the risk of bone fractures due to the reduced bone density. Drugs are normally prescribed to treat osteoporosis, especially after surgical treatment of osteoporotic fractures. However, many anti-osteoporotic drugs produce deleterious side effects. The recent development of gene therapy utilizing oligonucleotides (ONs) has spurred the development of new therapies for osteoporosis. Nevertheless, most ONs lack the capability of cell penetration and lysosome escape and hence, intracellular delivery of ON remains a challenge. Herein, a novel strategy is demonstrated to efficiently deliver ON to cells by combining ON with the cell-penetrating peptide (CPP) via the bio-orthogonal click reaction. Several dopamine (DOPA) groups are also introduced into the fabricated peptide to scavenge intracellular reactive oxygen species (ROS). Owing to favorable properties such as good cytocompatibility, cell penetration, lysosome escape, ROS scavenging, and osteoclastogenesis suppression, the hybrid CPP-DOPA-ON peptide improves the osteoporotic conditions significantly in vivo even when bone implants are involved. This strategy has great potential in the treatment of osteoporosis and potentially broadens the scope of gene therapy.

Confining Prepared Ultrasmall Nanozymes Loading ATO for Lung Cancer Catalytic Therapy/Immunotherapy.

Nanozymes with inherent enzyme-mimicking catalytic properties combat malignant tumor progression via catalytic therapy, while the therapeutic efficacy still needs to be improved. In this work, ultrasmall platinum nanozymes (nPt) in a confined domain of a wormlike pore channel in gold nanobipyramidal-mesoporous silica dioxide nanocomposites, producing nanozyme carriers AP-mSi with photoenhanced peroxidase ability, are innovatively synthesized. Afterward, based on the prepared AP-mSi, a lung-cancer nanozymes probe (AP-HAI) is ingeniously produced by removing the SiO2 template, modifying human serum albumin, and loading atovaquone molecules (ATO) as well as IR780. Under NIR light irradiation, inner AuP and IR780 collaborate for photothermal process, thus facilitating the peroxidase-like catalytic process of H2 O2 . Additionally, loaded ATO, a cell respiration inhibitor, can impair tumor respiration metabolism and cause oxygen retention, hence enhancing IR780's photodynamic therapy (PDT) effectiveness. As a result, IR780's PDT and nPt nanozymes' photoenhanced peroxidase-like ability endow probes a high ROS productivity, eliciting antitumor immune responses to destroy tumor tissue. Systematic studies reveal that the obvious reactive oxygen species (ROS) generation is obtained by the strategy of using nPt nanozymes and reducing oxygen consumption by ATO, which in turn enables lung-cancer synergetic catalytic therapy/immunogenic-cell-death-based immunotherapy. The results of this work would provide theoretical justification for the practical use of photoenhanced nanozyme probes.

Implementation of CYP2C19 genotyping and clinical outcomes following percutaneous coronary intervention in East Asian patients treated with oral P2Y12 inhibitors.

BACKGROUND: The CYP2C19 loss-of-function variants have significant impact on response to clopidogrel. The efficacy and safety of tailored antiplatelet therapy under the guidance of CYP2C19 genetic polymorphisms remains elusive for patients undergoing percutaneous coronary intervention (PCI). OBJECTIVES: The aims of the present study were to investigate the impact of clinical implementation of CYP2C19 genotyping on the selection of oral P2Y12 inhibitor therapy following PCI, and to estimate the risk of adverse outcomes for patients with different genotype status treated with alternative or traditional P2Y12 inhibitor. METHODS: Data from a single-center registry enrolling 41,090 consecutive PCI patients treated with dual antiplatelet therapy after PCI were analyzed. Risk of major adverse cardiovascular events (MACEs) and bleeding events within 12 months after PCI were compared across CYP2C19 genotype and antiplatelet therapy groups using Cox proportional hazards models. RESULTS: CYP2C19 genotyping was successfully achieved for 9081 patients, of whom baseline characteristics significantly differed from non-genotyped patients. A higher proportion of genotyped patients were prescribed ticagrelor compared with non-genotyped patients (27.0 % vs. 15.5 %, P < 0.001). CYP2C19 metabolic status was an independent predictor for use of ticagrelor (P < 0.001). Ticagrelor was significantly associated with a lower risk of MACEs in poor metabolizers (adjusted hazard ratio 0.62, 95 % confidence interval 0.42 to 0.92, P = 0.017), but not in intermediate metabolizers or normal metabolizers. The interaction was not statistically significant (P for interaction = 0.252). CONCLUSIONS: Genotype information on CYP2C19 metabolic status was associated with an increase in the use of potent antiplatelet therapy in PCI patients. Patients prescribed with clopidogrel has a higher risk of MACEs among poor metabolizers, which suggested the potential application of genotype-guided P2Y12 inhibitor selection for improving clinical outcomes.

Visual analysis based on CiteSpace software: a bibliometric study of atrial myxoma.

Objective: To use CiteSpace and VOSviewer visual metrology to analyze the research status, frontier hotspots, and trends in research on atrial myxoma. Methods: The Web of Science core collection database was used to retrieve relevant literature on atrial myxoma from 2001 to 2022. CiteSpace software was used to analyze keywords with a co-occurrence network, co-polymerization class, and burst terms, and a corresponding visual atlas was drawn for analysis. Results: A total of 893 valid articles were included. The country with the highest number of articles was the United States (n = 186). The organization with the highest number of articles was the Mayo Clinic (n = 15). The author with the highest number of articles was Yuan SM (n = 12). The highest cited author was Reynen K (n = 312). The highest cited journal was Annals of Thoracic Surgery (n = 1,067). The most frequently cited literature was published in the New England Journal of Medicine in 1995, which was cited 233 times. The keywords co-occurrence, copolymerization analysis, and Burst analysis revealed that the main research focuses were surgical methods, case reports, and genetic and molecular level studies on the pathogenesis of myxoma. Conclusions: This bibliometric analysis revealed that the main research topics and hotspots in atrial myxoma included surgical methods, case reports, genetic and molecular studies.

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells.

Proteasome subunit alpha type-2 (PSMA2) is a critical component of the 20S proteasome, which is the core particle of the 26S proteasome complex and is involved in cellular protein quality control by recognizing and recycling defective proteins. PSMA2 expression dysregulation has been detected in different human diseases and viral infections. No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. METHODS: We used SOMAScan, an aptamer-based multiplexed technique, to measure >1300 human proteins to determine the impact of PSMA2 KD on A549 human lung epithelial cells. RESULTS: PSMA2 KD resulted in significant dysregulation of 52 cellular proteins involved in different bio-functions, including cellular movement and development, cell death and survival, and cancer. The immune system and signal transduction were the most affected cellular functions. PSMA2 KD caused dysregulation of several signaling pathways involved in immune response, cytokine signaling, organismal growth and development, cellular stress and injury (including autophagy and unfolded protein response), and cancer responses. CONCLUSIONS: In summary, this study helps us better understand the importance of PSMA2 in different cellular functions, signaling pathways, and human diseases.

Up-regulation of Dsg2 confered stem cells with malignancy through wnt/ß-catenin signaling pathway.

In the previous study, we originally developed cancer stem cells (CSCs) models from mouse induced pluripotent stem cells (miPSCs) by culturing miPSCs in the conditioned medium of cancer cell lines, which mimiced as carcinoma microenvironment. However, the molecular mechanism of conversion in detail remains to be uncovered. Microarray analysis of the CSCs models in this study revealed Dsg2, one of the members of the desmosomal cadherin family, was up-regulated when compared with the original miPSCs. Moreover, the expression of key factors in Wnt/ß-catenin signaling pathway were also found up-regulated in one of the CSCs models, named miPS-LLCcm. An autocrine loop was implied between Dsg2 and Wnt/ß-catenin signaling pathway when miPSCs were treated with Wnt/ß-catenin signaling pathway activators, Wnt3a and CHIR99021, and when the CSCs model were treated with inhibitors, IWR-1 and IWP-2. Furthermore, the ability of proliferation and self-renewal in the CSCs model was markedly decreased in vitro and in vivo when Dsg2 gene was knocked down by shRNA. Our results showed that the Wnt/ß-catenin signaling pathway is activated by the up-regulation of Dsg2 expresssion during the conversion of miPSCs into CSCs implying a potential mechanism of the tranformation of stem cells into malignant phenotype.

MiR-101: An Important Regulator of Gene Expression and Tumor Ecosystem.

MiRNAs are small single-stranded non-coding RNAs. MiRNA contributes to the transcriptional and post-transcriptional regulation of mRNA in different cell types, including mRNA transcription inhibition and mRNA decay and phenotypes via the effect of several essential oncogenic processes and tumor microenvironment. MiR-101 is a highly conserved miRNA that was found to alter the expression in various human cancers. MiR-101 has been reported to have tumor oncogenic and suppressive effects to regulate tumorigenesis and tumor progression. In this review, we summarize the new findings about the roles of miR-101 in cancers and the underlying mechanisms of targeting genes degradation and microenvironment regulation, which will improve biological understanding and design of novel therapeutics.

Diptoindonesin G is a middle domain HSP90 modulator for cancer treatment.

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (Kd = 0.13 ± 0.02 µM) without inducing heat shock response. This is likely because dip G does not interfere with the HSP90-HSF1 interaction like N-terminal inhibitors, maintaining HSF1 in a transcriptionally silent state. We found that binding of dip G to HSP90 promotes degradation of HSP90 client protein estrogen receptor α (ER), a major oncogenic driver protein in most breast cancers. Mutations in the ER ligand-binding domain (LBD) are an established mechanism of endocrine resistance and decrease the binding affinity of mainstay endocrine therapies targeting ER, reducing their ability to promote ER degradation or transcriptionally silence ER. Because dip G binds to HSP90 and does not bind to the LBD of ER, unlike endocrine therapies, it is insensitive to ER LBD mutations that drive endocrine resistance. Additionally, we determined that dip G promoted degradation of WT and mutant ER with similar efficacy, downregulated ER- and mutant ER-regulated gene expression, and inhibited WT and mutant cell proliferation. Our data suggest that dip G is not only a molecular probe to study HSP90 biology and the HSP90 conformation cycle, but also a new therapeutic avenue for various cancers, particularly endocrine-resistant breast cancer harboring ER LBD mutations.

Recognition of cyclic dinucleotides and folates by human SLC19A1.

Cyclic dinucleotides (CDNs) are ubiquitous signalling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, through cyclic GMP-AMP synthase after detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogues, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is dependent on the solute carrier SLC19A122,23. Moreover, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs, folate and antifolate is unclear. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate and a new-generation antifolate drug. The structural and mutagenesis results demonstrate that hSLC19A1 uses unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, whereas folate and antifolate bind as a monomer and occupy a distinct pocket of the cavity. Moreover, the structures enable accurate mapping and potential mechanistic interpretation of hSLC19A1 with loss-of-activity and disease-related mutations. Our research provides a framework for understanding the mechanism of SLC19-family transporters and is a foundation for the development of potential therapeutics.

Recent developments of sonodynamic therapy in antibacterial application.

The rapid emergence of pathogenic bacteria poses a serious threat to global health. Notably, traditional antibiotic therapies suffer from the risk of strengthening bacterial drug resistance. Sonodynamic therapy (SDT) combining sonosensitizers and low-intensity ultrasound (US) has broadened the way towards treating drug-resistant bacteria. The allure of this therapy emerges from the capacity to focus the US energy on bacterial infection sites buried deep in tissues, locally activating the sonosensitizers to produce cytotoxic reactive oxygen species (ROS) with the ability to induce bacterial death. The past decade has witnessed the rapid development of antibacterial SDT owing to their excellent penetration, favorable biocompatibility and specific targeting ability. This review summarizes available sonosensitizers for antibacterial SDT, and digs into innovative biotechnologies to improve SDT efficiency, such as enhancing the targeting ability of sonosensitizers, image-guided assisted SDT, improvement of hypoxia and combination of SDT with other therapies. Finally, we conclude with the present challenges and provide insights into the future research of antibacterial SDT.

Peptidomics comparison of plant-based meat alternatives and processed meat after in vitro digestion.

Plant-based meat alternatives (PMAs) is a new type of food that meets people's health needs, but the lack of awareness of its nutritional properties limits product development and promotion. Here, we compared the similarities and differences of the nutritional properties of PMAs and meat before and after in vitro simulation of gastrointestinal digestion by chemical composition analysis, peptidomics and bioactivity tests. The molecular weights of Plant-based meat alternatives derived peptides (PDPs) as well as meat-derived peptides (MDPs) in the beef and pork groups were mainly concentrated in the low mass range from 800 Da to 1500 Da. The principal component analysis indicated that the composition of MDPs in the beef and pork groups significantly differed from PDPs but overlapped slightly with the chicken group. Also, there were very few common peptides among them. The proportion of high-biological-scoring peptides (33.3%-40%) in PDPs was more than that in MDPs (4.8%-20.8%). PDPs were predicted to have higher antibacterial activity than others. PDPs and MDPs showed a certain antioxidant capacity and angiotensin converting enzyme inhibitory activity (62.2%-92.5%) in vitro. Some peptides weakly inhibited the growth of Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 25923) while promoting the growth of probiotics. This research provides a theoretical basis for in-depth exploration of the nutritional characteristics of PMAs.