Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Dynamic Stomach Model-Capillary Electrophoresis-ICPMS for Evaluation of Release and Transformation Behaviors of Arsenic Species from Microplastics during Digestion.

Microplastics (MPs) can act as carriers of environmental arsenic species into the stomach with food and release arsenic species during digestion, which threatens human health. Herein, an integrated dynamic stomach model (DSM)-capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICPMS) is developed for online monitoring of the release and transformation behaviors of arsenic species loaded on MPs (As-MPs) in the simulated human stomach. The 3D-printed DSM with a soft stomach chamber enables the behaviors of gastric peristalsis, gastric and salivary fluid addition, pH adjustment, and gastric emptying (GE) to be controlled by a self-written program after oral ingestion of food with As-MPs. The gastric extract during digestion is introduced into the spiral channel to remove the large particulate impurity and online filtered to obtain the clarified arsenic-containing solution for subsequent speciation analysis of arsenic by CE-ICPMS. The digestion conditions and pretreatment processes of DSM are tracked and validated, and the release rates of As-MPs digested by DSM are compared with those digested by the static stomach model and DSM without GE. The release rate of inorganic arsenic on MPs is higher than that of organic arsenic throughout the gastric digestion process, and 8% of As(V) is reduced to As(III). The detection limits for As(III), DMA, MMA, and As(V) are 0.5-0.9 µg L-1 using DSM-CE-ICPMS, along with precisions of ≤8%. This present method provides an integrated and convenient tool for evaluating the release and transformation of As-MPs during human gastric digestion and provides a reference for exploring the interactions between MPs and metals/metalloids in the human body.

Micropeptides: potential treatment strategies for cancer.

Some noncoding RNAs (ncRNAs) carry open reading frames (ORFs) that can be translated into micropeptides, although noncoding RNAs (ncRNAs) have been previously assumed to constitute a class of RNA transcripts without coding capacity. Furthermore, recent studies have revealed that ncRNA-derived micropeptides exhibit regulatory functions in the development of many tumours. Although some of these micropeptides inhibit tumour growth, others promote it. Understanding the role of ncRNA-encoded micropeptides in cancer poses new challenges for cancer research, but also offers promising prospects for cancer therapy. In this review, we summarize the types of ncRNAs that can encode micropeptides, highlighting recent technical developments that have made it easier to research micropeptides, such as ribosome analysis, mass spectrometry, bioinformatics methods, and CRISPR/Cas9. Furthermore, based on the distribution of micropeptides in different subcellular locations, we explain the biological functions of micropeptides in different human cancers and discuss their underestimated potential as diagnostic biomarkers and anticancer therapeutic targets in clinical applications, information that may contribute to the discovery and development of new micropeptide-based tools for early diagnosis and anticancer drug development.

A hydrodynamic-based dual-function microfluidic chip for high throughput discriminating tumor cells.

A hydrodynamic-based microfluidic chip consisted of two function units that could not only separate tumor cells (TCs) from whole blood but also remove residual blood cells was designed. The separation of TCs was achieved by a straight contraction-expansion array (CEA) microchannel on the front end of the chip. The addition of contractive structure brought a micro-vortex like Dean vortex that promoted cell focusing in the channel, while when cells entered the dilated region, the wall-induced lift force generated by the channel wall gave cells a push away from the wall. As the wall-induced lift force is proportional to the third power of the cell diameter, TCs with larger diameter will have a larger lateral migration under the wall-induced lift force, realizing the separation of TCs from blood sample. Fluorescent particles with diameters of 19.3 µm and 4.5 µm were used to simulate TCs and red blood cells, respectively, to verify the separation capacity of the proposed CEA microchannel for particles with different diameter. And a separation efficiency 98.7% for 19.3 µm particles and a removal rate 96.2% for 4.5 µm particles was observed at sample flow rate of 10 µL min-1 and sheath flow rate of 190 µL min-1. In addition, a separation efficiency about 96.1% for MCF-7 cells (stained with DiI) and removal rates of 96.2% for red blood cells (RBCs) and 98.7% for white blood cells (WBCs) were also obtained under the same condition. However, on account of the large number of blood cells in the blood, there will be a large number of blood cells remained in the isolated TCs, so a purification unit based on hydrodynamic filtration (HDF) was added after the separation microchannel. The purification channel is a size-dictated cell filter that can remove residual blood cells but retain TCs, thus achieving the purification of TCs. Combined the CEA microchannel and the purifier, the microchip facilitates sorting of MCF-7 cells from whole blood with a separation rate about 95.3% and a removal rate over 99.99% for blood cells at a sample flow rate of 10 µL min-1, sheath flow rate of 190 µL min-1 and washing flow rate of 63 µL min-1.

Phase 1 Study of Bortezomib, Fludarabine, and Melphalan, With or Without Total Marrow Irradiation, as Allogeneic Hematopoietic Stem Cell Transplant Conditioning for High-risk or Relapsed/Refractory Multiple Myeloma.

OBJECTIVES: We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. METHODS: Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). RESULTS: Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m2; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m2) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m2), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. CONCLUSIONS: TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.

A Portable Microplasma Optical Emission Spectrometric Device with Online Digestion Function for Field and Sensitive Determination of Lead in Biological Samples.

Accurate detection and screening of Pb in biological samples is helpful to assess the risk associated with lead pollution to human health. However, conventional atomic spectroscopic instruments are bulky and cumbersome, requiring additional sample pretreatment equipment, and difficult to perform field analysis with. Herein, a portable point discharge (PD) microplasma-optical emission spectrometric (OES) device with online digestion function is designed for field and sensitive determination of lead in biological samples. With rice as a model, online digestion of a batch of six 50 mg samples can be achieved in the HNO3 and H2O2 system within 25 min by a temperature control and timing module. Compared to the conventional microwave digestion, the digestion efficiency of this device reaches 97%. Pb in digestion solution is converted into volatile species by hydride generation (HG) and directly introduced into PD-OES for excitation and detection by a self-designed rotatable and telescopic cutoff gas sampling column. Six samples can be successively detected in 2 min, and argon consumption of the whole process is only <800 mL. Under the optimized conditions, the detection limit of Pb is 0.018 mg kg-1 (0.9 µg L-1) and precision is 3.6%. The accuracy and practicability of the present device are verified by measuring several certified reference materials and real biological samples. By virtue of small size (23.5 × 17 × 8.5 cm3), lightweight (2.5 kg), and low energy consumption (24.3 W), the present device provides a convenient tool for field analysis of toxic elements in biological samples.

Potential role of glutathione S­transferase M1 gene polymorphism in kidney calcium oxalate stone formation.

BACKGROUND: The purpose of this study was to look into the effects of glutathione S-transferase M1 (GSTM1) gene polymorphism on the formation of kidney calcium oxalate stones. METHODS: A total of 159 patients with kidney calcium oxalate stones were included in this study as a case group. One hundred and three healthy individuals were included in the control group. The age, gender, and levels of calcium (Ca), uric acid (UA), creatinine (Cr), and urinary creatinine (Ucr) are tracked. Peripheral blood samples are used to perform a polymerase chain reaction to identify the glutathione S-transferase (GST) gene polymorphism (PCR). A commercial kit was used in this study to measure the levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC), and 8-hydroxydeoxyguanosine (8-OHdG) in peripheral blood. RESULTS: There was no difference in age or gender distribution between the case and control groups (P > 0.05). The Cr, Ucr, Ca, UA, 8-OHdG, MDA, NO, and T-AOC in the case group were significantly higher than those in the control group (P < 0.001). The Hardy-Weinberg genetic equilibrium test showed no difference between the case group (P = 0.23) and the control group (P = 0.09). In the case group, the 8-OHdG and NO in GSTM1 null genotype were significantly higher than those in GSTM1 genotype (P < 0.05), but there was no significant difference in MDA and T-AOC (P > 0.05). Multivariate regression analysis showed that the GSTM1 null genotype was positively correlated with 8-OHdG (P < 0.001) and NO (P < 0.001). CONCLUSIONS: GSTM1 gene polymorphism might be a detecting risk factor for kidney calcium oxalate stone formation. TRIAL REGISTRATION: ChiCTR2100051300.

Impact of early heparin therapy on outcomes in patients with solid malignancy associated sepsis: a marginal structural model causal analyse.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear. Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables. Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41-0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26-0.68); hospital mortality HR 0.70, 95% CI 0.50-0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34-0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26-0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50-0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16-0.69). Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Endocytosis-mediated entry of a caterpillar effector into plants is countered by Jasmonate.

Insects and pathogens release effectors into plant cells to weaken the host defense or immune response. While the imports of some bacterial and fungal effectors into plants have been previously characterized, the mechanisms of how caterpillar effectors enter plant cells remain a mystery. Using live cell imaging and real-time protein tracking, we show that HARP1, an effector from the oral secretions of cotton bollworm (Helicoverpa armigera), enters plant cells via protein-mediated endocytosis. The entry of HARP1 into a plant cell depends on its interaction with vesicle trafficking components including CTL1, PATL2, and TET8. The plant defense hormone jasmonate (JA) restricts HARP1 import by inhibiting endocytosis and HARP1 loading into endosomes. Combined with the previous report that HARP1 inhibits JA signaling output in host plants, it unveils that the effector and JA establish a defense and counter-defense loop reflecting the robust arms race between plants and insects.

Chromatic Plasmonic Polarizer-Based Synapse for All-Optical Convolutional Neural Network.

Emerging memory devices have been demonstrated as artificial synapses for neural networks. However, the process of rewriting these synapses is often inefficient, in terms of hardware and energy usage. Herein, we present a novel surface plasmon resonance polarizer-based all-optical synapse for realizing convolutional filters and optical convolutional neural networks. The synaptic device comprises nanoscale crossed gold arrays with varying vertical and horizontal arms that respond strongly to the incident light's polarization angle. The presented synapse in an optical convolutional neural network achieved excellent performance in four different convolutional results for classifying the Modified National Institute of Standards and Technology (MNIST) handwritten digit data set. After training on 1,000 images, the network achieved a classification accuracy of over 98% when tested on a separate set of 10,000 images. This presents a promising approach for designing artificial neural networks with efficient hardware and energy consumption, low cost, and scalable fabrication.

Results of a Phase II Trial of Allogeneic Hematopoietic Stem Cell Transplantation Using 90Y-Ibritumomab Tiuxetan (Zevalin) in Combination With Fludarabine and Melphalan in Patients With High-Risk B-Cell Non-Hodgkin's Lymphoma.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (B-cell NHL). However, relapse remains a major cause of treatment failure, especially in patients with either positron emission tomography (PET)-positive and/or chemoresistant disease prior to alloHCT. 90Y-ibritumomab tiuxetan (Zevalin) is a radiolabeled anti-CD20 antibody which is a safe and effective therapy in multiple histologic subtypes of B-cell NHL and has also been incorporated in both autologous HCT (autoHCT) and alloHCT conditioning regimens. OBJECTIVES: The purpose of this study was to evaluate the efficacy and confirm the safety of the radiolabeled anti-CD20 antibody ibritumomab tiuxetan (Zevalin) combined with the reduced intensity conditioning (RIC) regimen of fludarabine and melphalan (Flu/Mel) in patients with high-risk B-cell NHL. STUDY DESIGN: We conducted a phase II trial (NCT00577278) of Zevalin with Flu/Mel in patients with high-risk B-cell NHL. We enrolled 41 patients from October 2007 to April 2014, all of whom had either a fully matched sibling or 8/8 or 7/8 matched unrelated donor (MUD). Patients received 111In-Zevalin (5.0 mCi) on day -21 pre-HCT, followed by 90Y-Zevalin (0.4 mCi/kg) on day -14. Fludarabine (25 mg/m2 daily) was given from days -9 to -5 and melphalan (140 mg/m2) was administered on day -4. All patients received rituximab 250 mg/m2 on day +8 and an additional dose on either day +1 or -21 depending on the baseline rituximab level. Patients with a low rituximab level were given rituximab on days -21 and -15. All patients received tacrolimus/sirolimus (T/S) with or without methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis starting on day -3, and stem cells were infused on day 0. RESULTS: The 2-year overall survival (OS) and progression-free survival (PFS) for all patients were 63% and 61%, respectively. The incidence of relapse at 2 years was 20%. Nonrelapse mortality (NRM) at day +100 and 1 year were 5% and 12%, respectively. The overall cumulative incidence of grade II-IV and III-IV acute GVHD (aGVHD) were 44% and 15%, respectively. Extensive chronic GVHD (cGVHD) occurred in 44% of patients. On univariate analysis, histology (diffuse large B cell lymphoma (DLBCL) vs. others) was negatively predictive for OS (P = .0013) and PFS (P = .0004), while histology (DLBCL vs. others, P = .0128) predicted for relapse. PET positivity pre-HCT did not correlate with any of the efficacy endpoints. CONCLUSION: Addition of Zevalin to Flu/Mel is safe and effective in high-risk NHL and met the prespecific endpoint. Results were suboptimal in patients with DLBCL.

Naringenin: A flavanone with anti-inflammatory and anti-infective properties.

Although a growing body of research has recently shown how crucial inflammation and infection are to all major diseases, several of the medications currently available on the market have various unfavourable side effects, necessitating the development of alternative therapeutic choices. Researchers are increasingly interested in alternative medications or active components derived from natural sources. Naringenin is a commonly consumed flavonoid found in many plants, and since it was discovered to have nutritional benefits, it has been utilized to treat inflammation and infections caused by particular bacteria or viruses. However, the absence of adequate clinical data and naringenin's poor solubility and stability severely restrict its usage as a medicinal agent. In this article, we discuss naringenin's effects and mechanisms of action on autoimmune-induced inflammation, bacterial infections, and viral infections based on recent research. We also present a few suggestions for enhancing naringenin's solubility, stability, and bioavailability. This paper emphasizes the potential use of naringenin as an anti-inflammatory and anti-infective agent and the next prophylactic substance for the treatment of various inflammatory and infectious diseases, even though some mechanisms of action are still unclear, and offers some theoretical support for its clinical application.

One-Pot Pretreatment Coupled to Microplasma Optical Emission Spectrometry for Field and Sensitive Determination of Inorganic Mercury and Methylmercury in Fish.

Field and sensitive analysis of mercury species in seafood is helpful to assess the risk of human exposure to mercury, but the cumbersome pretreatment process is time-consuming and laborious. Herein, a simple one-pot pretreatment system is designed for extraction, separation, and enrichment of inorganic mercury (Hg(II)) and methylmercury (MeHg) in fish, and coupled to dielectric barrier discharge (DBD) microplasma optical emission spectrometry (OES). Both Hg(II) and MeHg species in fish can be effectively extracted by tetramethylammonium hydroxide under ultrasound, then separated from the fish matrix by vapor generation and photochemical vapor generation, and finally enriched on the activated carbon electrode tips. Mercury trapped on the activated carbon electrode tips can be rapidly released to produce OES under the DBD microplasma excitation for quantitative analysis. The pretreatment and analysis of a batch of 12 samples are completed within 50 min, and the extraction efficiency of total mercury is up to 90% for 100 mg of freeze-dried fish or 86% for 1 g of fresh fish. Under the optimized conditions, the detection limits are 2 µg kg-1 for Hg(II) and 1.2 µg kg-1 for MeHg in freeze-dried fish, and precisions are 3.2% for Hg(II) and 3.9% for MeHg. The present method is applied to the analysis of the certified reference material and real marine fishes, giving rise to spiked recoveries of 95-103%. The present system hardly leads to MeHg and Hg(II) transforming into each other during extraction, providing a simple, convenient, and low-cost analytical tool to evaluate the risk of mercury species in fish.

Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Chronic Obstructive Pulmonary Disease Patients With High Peripheral Blood Eosinophil Counts Have Better Predicted Improvement in 6MWD After Rehabilitation: A PRELIMINARY STUDY.

PURPOSE: The objective of this investigation was to determine whether chronic obstructive pulmonary disease (COPD) patients with high blood eosinophil (EOS) counts had better improvement in 6-min walk test (6MWT) after pulmonary rehabilitation (PR). METHODS: Fifty COPD patients were randomly assigned to either the rehabilitation group (RG) or the control group (CG). Patients in the RG (8 wk PR + routine medication) and the CG (routine medication) were followed for 32 wk. According to the blood EOS level, the RG was divided into an EOS ≥ 200 cells/µL group and EOS < 200 cells/µL group. The 6MWT distance, Borg Scale, and COPD Assessment Test (CAT) were evaluated before intervention and 8 wk and 32 wk later. RESULTS: After the 8-wk intervention, 37 patients (19 RG/18 CG) completed the study. At 8-wk and 32-wk follow-up from baseline, a statistically significant difference was found between these two groups in the 6MWT, Borg Scale, and CAT. Compared with baseline, the 6MWT in the RG increased 49.1 ± 40.2 m (95% CI, 29.7-68.5, P < .001) at 8 wk and 60.8 ± 42.1 m (95% CI, 40.5-81.6, P < .001) at 32 wk. In addition, the improvement of 6MWT in the EOS ≥ 200 cells/µL RG group was higher than that in the EOS < 200 cells/µL group (40.1 ± 17.6 m, 95% CI, 36.8-43.4; P = .036) at 32-wk follow-up from baseline. CONCLUSION: An 8-wk PR can improve the exercise capacity of COPD patients, and the benefits persistent for 24 wk. The improvement in the 6MWT was more significant in COPD patients with a high blood EOS count.

Unique Probiotic Properties and Bioactive Metabolites of Saccharomyces boulardii.

Saccharomyces boulardii (S. boulardii) is a probiotic and is widely used to improve the nutritional and functional value of food. This study aimed to compare the probiotic properties of S. boulardii and Saccharomyces cerevisiae. A series of in vitro probiotic experiments was performed, including simulated gastrointestinal digestion, bile salt tolerance, hydrophobicity, self-aggregation, and antioxidant and antibacterial properties. Self-aggregation and hydrophobic properties of S. boulardii were relatively poor, but they showed high tolerance, antioxidant properties, and broad antibacterial properties. In addition, non-targeted metabolomics was used to comprehensively analyze the active metabolites of S. boulardii and the metabolic differences between S. boulardii and S. cerevisiae were compared. Saccharomyces boulardii produced many bioactive metabolites, which generally showed antioxidant, antibacterial, antitumor, anti-inflammatory, and other properties. In contrast to S. cerevisiae, S. boulardii produced phenyllactic acid and 2-hydroxyisocaproic acid. There were also significant differences in their metabolic pathways. These results may be of great significance in the medical and food industries and provide a basis for understanding the metabolism of S. boulardii. It also shows that metabolomics is an effective and novel method for screening microbial functional metabolites and identifying functional differences between similar microorganisms.

Dynorphin promotes stress-induced depressive behaviors by inhibiting ventral pallidal neurons in rats.

AIM: Endogenous dynorphin signaling via kappa opioid receptors (KORs) plays a key role in producing the depressive and aversive consequences of stress. We investigated the behavioral effects of the dynorphin/KOR system in the ventral pallidum (VP) and studied the underlying mechanisms. METHODS: To investigate the effects of dynorphin on the VP, we conducted behavioral experiments after microinjection of drugs or shRNA and brain-slice electrophysiological recordings. Histological tracing and molecular biological experiments were used to identify the distribution of KORs and the possible sources of dynorphin projections to the VP. RESULTS: An elevated dynorphin concentration and increased KOR activity were observed in the VP after acute stress. Infusion of dynorphin-A into the VP produced depressive-like phenotypes including anhedonia and despair and anxiety behaviors, but did not alter locomotor behavior. Mechanistically, dynorphin had an inhibitory effect on VP neurons-reducing their firing rate and inhibiting excitatory transmission-through direct activation of KORs and modulation of downstream G-protein-gated inwardly rectifying potassium (GIRK) channels and high-voltage gated calcium channels (VGCCs). Tracing revealed direct innervation of VP neurons by dynorphin-positive projections; potential sources of these dynorphinergic projections include the nucleus accumbens, amygdala, and hypothalamus. Blockade of dynorphin/KOR signaling in the VP by drugs or viral knock-down of KORs significantly reduced despair behavior in rats. CONCLUSIONS: Endogenous dynorphinergic modulation of the VP plays a critical role in mediating depressive reactions to stress.

MoS2-Covalent Organic Framework Composite as a Bifunctional Supporter for the Determination of Trace Nickel by Photochemical Vapor Generation-Microplasma Optical Emission Spectrometry.

A microplasma-based optical emission spectrometry (OES) system has emerged as a potential tool for field analysis of heavy metal pollution due to its features of portability and low energy consumption, while the development of an efficient sample introduction approach against matrix interference is crucial to meet the requirements of complex sample analysis. Herein, a MoS2-covalent organic framework (COF) composite serves as a bifunctional supporter for efficient sample separation/enrichment and photochemical vapor generation (PVG) enhancement, thereby achieving highly selective and sensitive detection of heavy metals in environmental water by dielectric barrier discharge (DBD) microplasma-OES. With trace nickel analysis as a model, the MoS2-COF composite with a large specific surface area and a porous structure can not only efficiently separate and enrich nickel ions from a sample matrix through electrostatic interaction and coordination to reduce the interference of coexisting ions but also significantly improve the subsequent PVG efficiency due to the formed heterojunction and more negative reduction potential. Under optimized conditions, a linear range of 0.1-10 µg L-1 along with a detection limit of 0.03 µg L-1 is obtained for nickel. Compared with direct PVG, the tolerance to coexisting ions is greatly enhanced, and the detection limit is also improved by 43-fold. The accuracy and practicability of the present PVG-DBD-OES system are verified by measuring several certified reference materials and real water samples. MoS2-COF as a bifunctional supporter promotes the performance of the PVG-DBD-OES system in terms of anti-interference ability and detection sensitivity, especially for robust and efficient on-site analysis of complex samples.