Genetically engineered CD276-anchoring biomimetic nanovesicles target senescent escaped tumor cells to overcome chemoresistant and immunosuppressive breast cancer.

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

CAR-T therapy pulmonary adverse event profile: a pharmacovigilance study based on FAERS database (2017-2023).

Background: Chimeric antigen receptor T-cell (CAR-T) therapy, a rapidly emerging treatment for cancer that has gained momentum since its approval by the FDA in 2017, involves the genetic engineering of patients' T cells to target tumors. Although significant therapeutic benefits have been observed, life-threatening adverse pulmonary events have been reported. Methods: Using SAS 9.4 with MedDRA 26.1, we retrospectively analyzed data from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database, covering the period from 2017 to 2023. The analysis included the Reporting Odds Ratio Proportional Reporting Ratio Information Component and Empirical Bayes Geometric Mean to assess the association between CAR-T cell therapy and adverse pulmonary events (PAEs). Results: The FAERS database recorded 9,400 adverse events (AEs) pertaining to CAR-T therapies, of which 940 (10%) were PAEs. Among these CAR-T cell-related AEs, hypoxia was the most frequently reported (344 cases), followed by respiratory failure (127 cases). Notably, different CAR-T cell treatments demonstrated varying degrees of association with PAEs. Specifically, Tisa-cel was associated with severe events including respiratory failure and hypoxia, whereas Axi-cel was strongly correlated with both hypoxia and tachypnea. Additionally, other CAR-T therapies, namely, Brexu-cel, Liso-cel, Ide-cel, and Cilta-cel, have also been linked to distinct PAEs. Notably, the majority of these PAEs occurred within the first 30 days post-treatment. The fatality rates varied among the different CAR-T therapies, with Tisa-cel exhibiting the highest fatality rate (43.6%), followed by Ide-cel (18.8%). Conclusion: This study comprehensively analyzed the PAEs reported in the FAERS database among recipients of CAR-T cell therapy, revealing conditions such as hypoxia, respiratory failure, pleural effusion, and atelectasis. These CAR-T cell therapy-associated events are clinically significant and merit the attention of clinicians and researchers.

A genome-wide investigation of the mechanism underlying the effect of exogenous boron application on sugar content and overall quality of "Benihoppe" strawberries.

In recent years, the widespread application of growth regulators and nutrients to boost yield and quality of strawberry fruits has led to the rapid growth of strawberry industry globally. Although the effects of major nutrients on strawberry yield have been widely studied, investigations into the effect of trace elements such as boron remain limited. This study examined the effect of boron application on the yield and quality of "Benihoppe" strawberry fruits. Nutrient solutions with varying boron concentrations (0, 0.024, 0.048, 0.072, and 0.096 mM) were applied to the plants, and their effect on fruit quality was evaluated. The results indicated that boron application enhanced the yield per plant, nutrient composition (total amino acid and vitamin C content), antioxidant properties (total phenol) and volatile components (esters) in strawberry fruits. Specifically, treatment with 0.048 mM boron concentration significantly increased the accumulation of soluble sugars, such as sucrose, whose concentration was 154.29% higher than that of the control treated with 0 mM concentration. This enhancement is attributable to the regulated expression of sucrose phosphate synthase (maker-Fvb2-2-augustus-gene-229.38) and ß-fructofuranosidase-1/2/3 (augustus-masked-Fvb5-4-processed-gene-2.0, maker-Fvb5-3-augustus-gene-272.30, and maker-Fvb5-1-augustus-gene-0.37) genes, which play crucial roles in sugar metabolism and enzyme activity. Overall, boron application enhanced the quality of "Benihoppe" strawberries. The findings of this study offer substantial theoretical and practical guidance for using boron fertilizers in strawberry farming.

High-performance electrochemical immunosensor based on bimetallic gold/silver functionalized carbon spheres for CYFRA 21-1 detection and information protection.

Bimetallic nanomaterial-based systems have been widely utilized across various fields due to their remarkable expandability and flexibility, including nanomedicine, diagnostics, and molecular information technology. Here, we constructed an electrochemical immunosensor using bimetallic gold/silver functionalized carbon spheres (AuAg@CSs) and mesoporous silica nanoparticles (MSNs) for the sensitive determination of cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1) and ensuring information protection for textual data. The AuAg@CSs demonstrated exceptional catalytic activity towards hydrogen peroxide, generating a significant current signal. The introduction of CYFRA 21-1 facilitated the binding of MSNs, thereby forming a sandwich-type electrochemical immunosensor that resulted in a notable decrease in current. Notably, the detection limit for CYFRA 21-1 was determined to be 31 fg mL-1, accompanied by high selectivity. Furthermore, extensive textual information can be encrypted and concealed within the current responses of the electrochemical nanosensing system. By establishing a threshold, these current signals can be represented as a series of binary strings, which can subsequently be segmented into shorter strings. Through information coding methods, these shorter binary strings can be assembled and decrypted, ultimately merging into meaningful textual content. This study promotes the synthesis and multifunctional application of bimetallic nanomaterials, providing innovative solutions to enhance the sensing sensitivity of electrochemical immunosensors and paving the way for advancements in molecular digitization.

Regulation of Lead Iodide Crystallization and Distribution for Efficient Perovskite Solar Cells.

At present, the power conversion efficiency (PCE) of perovskite solar cells (PSCs) has reached 26.1%. Polycrystalline perovskite films prepared by sequential deposition are often accompanied by excess PbI2. Although excess PbI2 can reduce the internal defects of the perovskites and promote charge transfer, excess PbI2 is unevenly distributed in the perovskites and easily decomposed into the composite center of charge. Therefore, the growth and distribution of PbI2 crystals can be regulated by introducing 4-fluoroaniline (4-FLA) as an additive into the precursor of PbI2. We observe that the presence of an amino group in 4-FLA leads to a reduction in the strength of van der Waals forces between PbI2 layer structures, thereby facilitating the uniform dispersion of excess PbI2 within the perovskites. Additionally, 4-FLA is restricted from being embedded in the PbI2 layer due to the steric hindrance of 4-FLA and the hydrogen bond interaction between nitrogen atoms and PbI2. Therefore, it leads to better dispersion of PbI2, resulting in better passivation and device efficiency. Based on the hydrophobicity of the benzene ring, the modified perovskite film shows excellent hydrophobicity. Ultimately, we achieved 21.63% PCE and 1.16V VOC. This provides an effective strategy for regulating excess PbI2 to achieve efficient and stable PSCs.

miR-19-3p/GRSF1/COX1 axis attenuates early brain injury via maintaining mitochondrial function after subarachnoid haemorrhage.

BACKGROUND: Guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein, which is eventually localised to mitochondria and promotes the translation of cytochrome C oxidase 1 (COX1) mRNA. However, the role of the miR-19-3p/GRSF1/COX1 axis has not been investigated in an experimental subarachnoid haemorrhage (SAH) model. Thus, we investigated the role of the miR-19-3p/GRSF1/COX1 axis in a SAH-induced early brain injury (EBI) course. METHODS: Primary neurons were treated with oxyhaemoglobin (OxyHb) to simulate in vitro SAH. The rat SAH model was established by injecting autologous arterial blood into the optic chiasma cisterna. The GRSF1 level was downregulated or upregulated by treating the rats and neurons with lentivirus-GRSF1 shRNA (Lenti-GRSF1 shRNA) or lentivirus-GRSF1 (Lenti-GRSF1). RESULTS: The miR-19-3p level was upregulated and the protein levels of GRSF1 and COX1 were both downregulated in SAH brain tissue. GRSF1 silence decreased and GRSF1 overexpression increased the protein levels of GRSF1 and COX1 in primary neurons and brain tissue, respectively. Lenti-GRSF1 shRNA aggravated, but Lenti-GRSF1 alleviated, the indicators of neuronal injury and neurological impairment in both in vitro and in vivo SAH conditions. In addition, miR-19-3p mimic reduced the protein levels of GRSF1 and COX1 in cultured neurons while miR-19-3p inhibitor increased them. More importantly, Lenti-GRSF1 significantly relieved mitochondrial damage of neurons exposed to OxyHb or induced by SAH and was beneficial to maintaining mitochondrial integrity. Lenti-GRSF1 shRNA treatment, conversely, aggravated mitochondrial damage in neurons. CONCLUSION: The miR-19-3p/GRSF1/COX1 axis may serve as an underlying target for inhibiting SAH-induced EBI by maintaining mitochondrial integrity.

Urinary Thioproline and Thioprolinyl Glycine as Specific Biomarkers of Formaldehyde Exposure in Humans.

Assessment of personal formaldehyde (FA) exposure is most commonly carried out using formate as a biomarker, as it is the major product from FA metabolism. However, formate could also have originated from the metabolism of other endogenous and exogenous substances or from dietary intake, which may give rise to overestimated results with regard to FA exposure. We have developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with an isotope-dilution method for rigorous quantitation of two major urinary FA conjugation products: thioproline (SPro) and thioprolinyl glycine (SPro-Gly), formed in the reaction between FA and endogenous cysteine or cysteinyl glycine, respectively, as marker molecules to assess personal FA exposure. Using this newly developed method, we measured the FA exposure levels in cigarette smokers, occupants of a chemistry research laboratory and typical domestic household, and visitors to a Chinese temple with a Pearson correlation coefficient greater than 0.94, showing a strong linear correlation between urinary adduct levels and the airborne FA level. It is believed that quantitation of urinary SPro and SPro-Gly may represent a noninvasive, interference-free method for assessing personal FA exposure.

New Analytical Paradigm to Determine Concentration of Brown Carbon and Its Sample-by-Sample Mass Absorption Efficiency.

Brown carbon (BrC) has a substantial direct radiative effect, but current estimates of its impact on radiative balance are highly uncertain due to a lack of measurements of its light-absorbing properties, such as mass absorption efficiency (MAE). Here, we present a new analytical paradigm based on a Bayesian inference (BI) model that takes multiwavelength aethalometer measurements and total carbon data to resolve the concentrations of black carbon and BrC, and MAEs of BrC on a sample-by-sample basis. Hourly MAEs, unattainable in previous studies, can now be calculated, enabling the first-time observation of the darkening-bleaching dynamics of BrC in response to photochemical transformation. We demonstrate the application of this BI model to analyze measurements collected over one year (2021-2022) in Hong Kong. Diel variations in MAE370 nm of BrC reveal a darkening-to-bleaching transition occurring between 8 and 10 O'clock when the solar irradiance ranges from 30 to 400 W m-2. Furthermore, we consistently observe an increase in MAE370 nm of BrC with nitrogen oxide concentrations, suggesting the enhanced formation of nitrogenous organics. This BI model-based data analysis would bring forth a breakthrough in amassing observation data of BrC and its MAEs in diverse ambient environments and with high time resolution.

Intracranial pressure variability associates with 3-month outcomes in spontaneous intracerebral hemorrhage: a retrospective analysis of 597 patients.

BACKGROUND AND OBJECTIVE: Spontaneous intracerebral hemorrhage (ICH) is a devastating type of stroke but most favorable treatments to improve patients' neurological outcomes are not clear. Invasive intracranial pressure (ICP) monitoring is a common treatment of ICH, but whether ICH patients could benefit from ICP monitoring is controversial. ICP variability (IPV) has been shown to correlate with poor outcomes in patients with subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI), but this association has not been clearly elucidated in ICH patients. We hypothesized that 72 hour-IPV from time of ICP probe implantation is associated with outcomes in ICH patients. METHODS: A retrospective chart review analysis of adult ICH patients, who received ICP monitoring at Huashan Hospital Fudan University between Jan. 2008 and Jan. 2023, was performed. We included ICH patients within 6 hours of signs or symptoms onset. Outcomes of ICH patients were assessed using 3-month mRS, and were dichotomized into poor (mRS 4 to 6) and good (mRS 0 to 3) outcome group. ICPs were recorded from the implantation of invasive ICP probe until it was removed. ICP was analyzed in the acute period, from 0 to 72 hours after ICP implantation. IPV was analyzed by SD (Standard deviation), CV (Coefficient of variation) and SV (Successive variation) of ICP. RESULTS: We analyzed 597 patients' charts. The 1st ICP assessment, immediately after ICP implantation, at median 117 minutes (interquartile range, 82-231 minutes) after admission was mean 20.5±7.8 mmHg. The 2nd ICP assessment, on NICU arrival after operation, was mean 14.6±8.3 mmHg. Poor outcomes occurred in 213 patients (35.68%). In univariate analysis, univariate quintile analysis or multivariate analysis, ICPSD, ICPCV and ICPSV were associated with poor outcomes. CONCLUSIONS: IPV during the first 72 hours after ICP implantation in patients with ICH was independently associated with poor functional outcome at 3-month. Stabilization of IPV during hyperacute and acute period maybe a potential therapeutic target to improve functional outcomes of these patients.

Effects of dexmedetomidine on renal function, inflammatory markers, and cognitive functioning in elderly patients undergoing hip replacement surgery.

OBJECTIVE: To investigate the effects of dexmedetomidine on renal function, inflammatory markers, and cognitive outcome, and to identify factors influencing early postoperative cognitive dysfunction (POCD) in elderly patients undergoing hip replacement surgery. METHODS: A retrospective analysis was conducted on 162 elderly patients who underwent hip replacement surgery at Cangzhou Central Hospital from March 2022 to May 2023. Patients were divided into a control group (without dexmedetomidine) and an experimental group (with dexmedetomidine). Measurements included creatinine (Cr), blood urea nitrogen (BUN), interleukin 1ß (IL-1ß), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), Montreal Cognitive Assessment (MoCA) score, and the incidence of POCD seven days postoperatively. Univariate and logistic regression analyses were employed to investigate the predictors of early POCD. RESULTS: Significant differences were observed between the groups in terms of renal function, inflammatory markers, and cognitive outcome (Cr, BUN, IL-1ß, TNF-α, IL-6 and MoCA scores) (all P<0.05). The experimental group showed a significantly lower incidence of POCD at seven days post-surgery (P<0.05). Logistic regression identified having a neuron-specific enolase (NSE) level seven days post-surgery ≥7.0 pg/ml as a risk factor for early POCD (P=0.001, OR=3.987, 95% CI: 1.789-8.886), whereas intraoperative use of dexmedetomidine was a protective factor (P=0.041, OR=0.424, 95% CI: 0.187-0.964). CONCLUSION: The use of dexmedetomidine in hip replacement surgery can mitigate postoperative renal injury and inflammatory response, enhance cognitive outcome, and significantly reduce the incidence and risk of early POCD in elderly patients.

NIR light-triggered bursting of double-emulsion drops (DEDs) for microdroplet generation.

Microdroplets have significant applications in microbiology, pharmaceuticals, cosmetics, and synthetic materials. Herein, we present for the first time, a near-infrared (NIR)-light-triggered double-emulsion drop (DED) bursting method for generating a large number of micro-droplets with a size of several microns. Under the irradiation of NIR light, the inner water phase of the DED containing a trace amount of Prussian blue (PB) rapidly heats up and evaporates rapidly to generate microbubbles due to the photothermal property of PB. By controlling the light intensity, the DED could be inflated by the constant coalescence of microbubbles, which then burst immediately and tear the middle oil phase to form a large number of microdroplets. The performance of the microdroplets generated by NIR-light-triggered DED bursting was investigated by varying the oil shell thickness (HO), oil phase viscosity (ηO) and oil type. HO and ηO were the key factors affecting the generation of microdroplets. DEDs with lower HO and ηO generated lower polydispersity and a large number of microdroplets via NIR-triggered DED bursting. The proportion of microdroplets of sizes below 10 µm reached up to 95%. Furthermore, camellia oil, as the middle oil phase of the DEDs, generated lower polydispersity and a large number of microdroplets measuring several microns. The as-developed bursting method has great potential to generate micro-droplets for micro-/nano- and biotechnology applications.

Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications.

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

Exploring emission spatiotemporal pattern and potential reduction capacity in China's aviation sector: Flight trajectory optimization perspective.

China's rapid expansion of civil aviation has led to an increase in pollution-related issues, causing adverse health effects on populations near airports and downwind. Accurately quantifying aviation emissions is essential for effective emission management. Here, we developed a high-resolution aviation emissions inventory for China by employing a bottom-up approach that relied on daily flight schedules. By using the Aeronautical Information Publication (AIP) to reproduce real-world flight routes rather than conventional great-circle routes, we improved the accuracy of emissions and investigated the potential for reducing these emissions. Our findings demonstrated substantial variations in domestic civil aviation emissions both spatially and temporally. Emissions peaked in most provinces during Chinese holidays, particularly the Chinese Lunar New Year and summer holidays, highlighting the importance of detailed activity data for accurate emissions calculations. Therefore, we recommend extensive utilization of real-world flight routes, particularly in areas with limited Automatic Dependent Surveillance-Broadcast (ADS-B) coverage since they provide more accurate representations of actual flight trajectories. Our study also identified regions like Shaanxi, Sichuan, Beijing, and their surroundings having considerable potential for emission reduction due to substantial deviations from great-circle routes. This approach can enhance the accuracy and spatiotemporal resolution of aviation emissions at national and global scales throughout the year, without relying on extensive, long-term real-time flight trajectories. Additionally, it provides a unique way to quantify the potential for emission reductions across provinces in civil aviation, ultimately contributing to mitigating pollution-related health impacts from aviation emissions and promoting a more sustainable aviation industry.

Comparison of the Accuracy of HSV1 and HSV2 Antibody Tests with PCR in the Diagnosis of Recurrent Genital Herpes.

Objective: To assess the accuracy of HSV1and HSV2 antibody testing in identifying genital herpes infection. Methods: A cohort of 299 patients previously diagnosed with recurrent genital herpes, confirmed via PCR, were tested using ELISA for HSV1 and HSV2 IgM and IgG antibodies. The study compared the accuracy of HSV1 and HSV2 antibody tests in diagnosing genital herpes. Results: Among 299 patients, 14 tested positives for HSV1 DNA. Of these, 9 had HSV1 IgG antibodies, but none had HSV2 IgG antibody. Among 278 patients with HSV2 DNA, 149 had HSV1 IgG, 9 had HSV2 IgG, and 97 had both. Seven patients had both HSV1 and HSV2 DNA; 3 had HSV1 IgG, 1 had HSV2 IgG, and 3 had both. The accuracy of HSV1 IgG for HSV1 infection was 64.2%, and for HSV1 and HSV2 co-infection, 85.7%. The accuracy of HSV2 IgG for HSV2 infection was 38.1%, and for HSV1 and HSV2 co-infection, 57.1%. The combined antibody positivity accuracy was 34.9%. Conclusion: Genital herpes is primarily caused by HSV2 (92.98%). A smaller percentage is HSV1 (4.67%) or co-infection (2.34%). Despite relatively low diagnostic accuracy (34.9-85.7%) for antibody detection, combined antibody testing is necessary. Herpes DNA testing is recommended for accurate diagnosis. Absence of antibodies does not rule out genital herpes and clinical assessment is essential.

HTINet2: herb-target prediction via knowledge graph embedding and residual-like graph neural network.

Target identification is one of the crucial tasks in drug research and development, as it aids in uncovering the action mechanism of herbs/drugs and discovering new therapeutic targets. Although multiple algorithms of herb target prediction have been proposed, due to the incompleteness of clinical knowledge and the limitation of unsupervised models, accurate identification for herb targets still faces huge challenges of data and models. To address this, we proposed a deep learning-based target prediction framework termed HTINet2, which designed three key modules, namely, traditional Chinese medicine (TCM) and clinical knowledge graph embedding, residual graph representation learning, and supervised target prediction. In the first module, we constructed a large-scale knowledge graph that covers the TCM properties and clinical treatment knowledge of herbs, and designed a component of deep knowledge embedding to learn the deep knowledge embedding of herbs and targets. In the remaining two modules, we designed a residual-like graph convolution network to capture the deep interactions among herbs and targets, and a Bayesian personalized ranking loss to conduct supervised training and target prediction. Finally, we designed comprehensive experiments, of which comparison with baselines indicated the excellent performance of HTINet2 (HR@10 increased by 122.7% and NDCG@10 by 35.7%), ablation experiments illustrated the positive effect of our designed modules of HTINet2, and case study demonstrated the reliability of the predicted targets of Artemisia annua and Coptis chinensis based on the knowledge base, literature, and molecular docking.

Pain perception enhancement in consecutive second-eye phacoemulsification cataract surgeries under topical anesthesia.

Cataract is the main cause of visual impairment and blindness worldwide while the only effective cure for cataract is still surgery. Consecutive phacoemulsification under topical anesthesia has been the routine procedure for cataract surgery. However, patients often grumbled that they felt more painful during the second-eye surgery compared to the first-eye surgery. The intraoperative pain experience has negative influence on satisfaction and willingness for second-eye cataract surgery of patients with bilateral cataracts. Intraoperative ocular pain is a complicated process induced by the nociceptors activation in the peripheral nervous system. Immunological, neuropsychological, and pharmacological factors work together in the enhancement of intraoperative pain. Accumulating published literatures have focused on the pain enhancement during the second-eye phacoemulsification surgeries. In this review, we searched PubMed database for articles associated with pain perception differences between consecutive cataract surgeries published up to Feb. 1, 2024. We summarized the recent research progress in mechanisms and interventions for pain perception enhancement in consecutive second-eye phacoemulsification cataract surgeries. This review aimed to provide novel insights into strategies for improving patients' intraoperative experience in second-eye cataract surgeries.

Crown ether dopant to reduce ion suppression and improve detection in the liquid microjunction surface sampling probe.

RATIONALE: Sodium and potassium are required in agar media for the growth of some microorganisms (e.g., marine bacteria). However, alkali cations are a significant source of contamination for mass spectrometry causing ion suppression and adduct formation. Conventionally, salts can be removed before mass spectrometric analysis with appropriate and often lengthy sample preparation. The direct mass spectrometric sampling of bacterial colonies grown on agar media seeks to minimize or eliminate sample preparation to improve workflow. However, this may exacerbate ion suppression and contamination since these metal cations will degrade spectral quality and limit the rapid profiling of microbial metabolites. Different approaches are needed to sequester sodium and potassium ions to minimize unwanted background interferences. Herein, we use crown ethers (CEs) in combination with a liquid microjunction surface sampling probe (LMJ-SSP) to directly sample the surface of the bacterial colonies from two marine bacteria species (Pseudoalteromonas rubra DSM6842 and Pseudoalteromonas tunicata DSM 14096). CEs (e.g., 18-crown-6 or 15-crown-5) are added to the carrier solvent of the LMJ-SSP, the chemical noise is reduced, and spectra are easier to interpret. METHODS: The liquid microjunction formed at the tip of LMJ-SSP was used to directly touch bacterial colonies on agar. The carrier solvent was either methanol (100%) or methanol: H2O (50:49.9%) with or without 0.01% CEs. Information-theoretic measures are employed to investigate qualitative changes between spectra before and after adding CEs. RESULTS: Our work demonstrates the capability of CEs to reduce background interferences within the direct profiling of bacterial colonies from agar plates. The data obtained from both P. rubra DSM6842 and P. tunicata DSM 14096 show that CEs can be used to mitigate the salty background and improve compound detection. CONCLUSION: Our approach can be implemented in natural product discovery using LMJ-SSP to allow fast and accurate detection of interesting/novel compounds.

UNSEG: unsupervised segmentation of cells and their nuclei in complex tissue samples.

Multiplexed imaging technologies have made it possible to interrogate complex tissue microenvironments at sub-cellular resolution within their native spatial context. However, proper quantification of this complexity requires the ability to easily and accurately segment cells into their sub-cellular compartments. Within the supervised learning paradigm, deep learning-based segmentation methods demonstrating human level performance have emerged. However, limited work has been done in developing such generalist methods within the unsupervised context. Here we present an easy-to-use unsupervised segmentation (UNSEG) method that achieves deep learning level performance without requiring any training data via leveraging a Bayesian-like framework, and nucleus and cell membrane markers. We show that UNSEG is internally consistent and better at generalizing to the complexity of tissue morphology than current deep learning methods, allowing it to unambiguously identify the cytoplasmic compartment of a cell, and localize molecules to their correct sub-cellular compartment. We also introduce a perturbed watershed algorithm for stably and automatically segmenting a cluster of cell nuclei into individual nuclei that increases the accuracy of classical watershed. Finally, we demonstrate the efficacy of UNSEG on a high-quality annotated gastrointestinal tissue dataset we have generated, on publicly available datasets, and in a range of practical scenarios.

Transition metals-based electrocatalysts on super-flat substrate for perovskite photovoltaic hydrogen production with 13.75% solar to hydrogen efficiency.

Harnessing the inexhaustible solar energy for water splitting is regarded one of the most promising strategies for hydrogen production. However, sluggish kinetics of oxygen evolution reaction (OER) and expensive photovoltaics have hindered commercial viability. Here, an adhesive-free electrodeposition process is developed for in-situ preparation of earth-abundant electrocatalysts on super-flat indium tin oxide (ITO) substrate. NiFe hydroxide exhibited prominent OER performance, achieving an ultra-low overpotential of 236 mV at 10 mA/cm2 in alkaline solution. With the superior OER activity, we achieved an unassisted solar water splitting by series connected perovskite solar cells (PSCs) of 2 cm2 aperture area with NiFe/ITO//Pt electrodes, yielding overall solar to hydrogen (STH) efficiency of 13.75 %. Furthermore, we upscaled the monolithic facility to utilize perovskite solar module for large-scale hydrogen production and maintained an approximate operating current of 20 mA. This creative strategy contributes to the decrease of industrial manufacturing expenses for perovskite-based photovoltaic-electrochemical (PV-EC) hydrogen production, further accelerating the conversion and utilization of carbon-free energy.

An autoantibody profile identified by human genome-wide protein arrays in rheumatoid arthritis.

Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)-negative and early-stage RA are still to be improved. We aimed to screen autoantibodies in ACPA-negative patients and evaluated their diagnostic performance. The human genome-wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti-ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA-negative RA, including anti-ANAPC15, anti-LSP1, anti-APBB1, anti-parathymosin, and anti-UBL7. Anti-parathymosin showed the highest prevalence of 46.2% (p = 0.016) in ACPA-negative early stage (<2 years) RA. To further improve the diagnostic efficacy, a prediction model was constructed with 44 autoantibodies. With increased threshold for RA calling, the specificity of the model is 90.8%, while the sensitivity is 66.1% (87.8% in ACPA-positive RA and 23.8% in ACPA-negative RA) in independent testing patients. Therefore, HuProt arrays identified RA-associated autoantibodies that might become possible diagnostic markers, especially in early stage ACPA-negative RA.