How I diagnose and treat organizing pneumonia in hematopoietic cell transplant recipients.

ABSTRACT: Organizing pneumonia (OP) is a known noninfectious pulmonary complication following allogeneic hematopoietic cell transplant (HCT) and represents a significant risk factor for nonrelapse mortality in HCT recipients. Unlike bronchiolitis obliterans syndrome, it is not universally acknowledged as a distinctive pulmonary manifestation of chronic graft-versus-host disease (cGVHD) and, therefore, its diagnostic criteria and management approach are lacking. Given its shared similar clinical features and radiological and histologic findings to OP in the non-HCT population, the diagnostic approach and treatment strategy for OP in HCT recipients is largely adapted from the non-HCT population. In this article, we aim to enhance the understanding of OP within the context of cGVHD following HCT and distinguish its clinical features and treatment strategy from non-HCT counterparts, thereby reinforcing its recognition as a pulmonary manifestation of graft-versus-host disease. We will propose the diagnostic criteria and outline our approach in diagnosis and treatment strategy, highlighting the potential challenges that may arise in each process. Finally, we will discuss knowledge gaps in this field and identify the area of need for future research.

Observation of the exceptional-point-enhanced Sagnac effect.

Exceptional points (EPs) are special spectral degeneracies of non-Hermitian Hamiltonians that govern the dynamics of open systems. At an EP, two or more eigenvalues, and the corresponding eigenstates, coalesce1-3. Recently, it was predicted that operation of an optical gyroscope near an EP results in improved response to rotations4,5. However, the performance of such a system has not been examined experimentally. Here we introduce a precisely controllable physical system for the study of non-Hermitian physics and nonlinear optics in high-quality-factor microresonators. Because this system dissipatively couples counter-propagating lightwaves within the resonator, it also functions as a sensitive gyroscope for the measurement of rotations. We use our system to investigate the predicted EP-enhanced Sagnac effect4,5 and observe a four-fold increase in the Sagnac scale factor by directly measuring rotations applied to the resonator. The level of enhancement can be controlled by adjusting the system bias relative to the EP, and modelling results confirm the observed enhancement. Moreover, we characterize the sensitivity of the gyroscope near the EP. Besides verifying EP physics, this work is important for the understanding of optical gyroscopes.

Antiferroelectric Heterostructures Memristors with Unique Resistive Switching Mechanisms and Properties.

A novel antiferroelectric material, PbSnO3 (PSO), was introduced into a resistive random access memory (RRAM) to reveal its resistive switching (RS) properties. It exhibits outstanding electrical performance with a large memory window (>104), narrow switching voltage distribution (±2 V), and low power consumption. Using high-resolution transmission electron microscopy, we observed the antiferroelectric properties and remanent polarization of the PSO thin films. The in-plane shear strains in the monoclinic PSO layer are attributed to oxygen octahedral tilts, resulting in misfit dislocations and grain boundaries at the PSO/SRO interface. Furthermore, the incoherent grain boundaries between the orthorhombic and monoclinic phases are assumed to be the primary paths of Ag+ filaments. Therefore, the RS behavior is primarily dominated by antiferroelectric polarization and defect mechanisms for the PSO structures. The RS behavior of antiferroelectric heterostructures controlled by switching spontaneous polarization and strain, defects, and surface chemistry reactions can facilitate the development of new antiferroelectric device systems.

Unraveling the Structure-Property-Performance Relationships of Fused-Ring Nonfullerene Acceptors: Toward a C-Shaped ortho-Benzodipyrrole-Based Acceptor for Highly Efficient Organic Photovoltaics.

The high-performance Y6-based nonfullerene acceptors (NFAs) feature a C-shaped A-DA'D-A-type molecular architecture with a central electron-deficient thiadiazole (Tz) A' unit. In this work, we designed and synthesized a new A-D-A-type NFA, termed CB16, having a C-shaped ortho-benzodipyrrole-based skeleton of Y6 but with the Tz unit eliminated. When processed with nonhalogenated xylene without using any additives, the binary PM6:CB16 devices display a remarkable power conversion efficiency (PCE) of 18.32% with a high open-circuit voltage (Voc) of 0.92 V, surpassing the performance of the corresponding Y6-based devices. In contrast, similarly synthesized SB16, featuring an S-shaped para-benzodipyrrole-based skeleton, yields a low PCE of 0.15% due to the strong side-chain aggregation of SB16. The C-shaped A-DNBND-A skeleton in CB16 and the Y6-series NFAs constitutes the essential structural foundation for achieving exceptional device performance. The central Tz moiety or other A' units can be employed to finely adjust intermolecular interactions. The single-crystal X-ray structure reveals that ortho-benzodipyrrole-embedded A-DNBND-A plays an important role in the formation of a 3D elliptical network packing for efficient charge transport. Solution structures of the PM6:NFAs detected by small- and wide-angle X-ray scattering (SWAXS) indicate that removing the Tz unit in the C-shaped skeleton could reduce the self-packing of CB16, thereby enhancing the complexing and networking with PM6 in the spin-coating solution and the subsequent device film. Elucidating the structure-property-performance relationships of A-DA'D-A-type NFAs in this work paves the way for the future development of structurally simplified A-D-A-type NFAs.

Uniform, Strain-Free, Large-Scale Graphene and h-BN Monolayers Enabled by Hydrogel Substrates.

Translation of the unique properties of 2D monolayers from non-scalable micron-sized samples to macroscopic scale is a longstanding challenge obstructed by the substrate-induced strains, interface nonuniformities, and sample-to-sample variations inherent to the scalable fabrication methods. So far, the most successful strategies to reduce strain in graphene are the reduction of the interface roughness and lattice mismatch by using hexagonal boron nitride (h-BN), with the drawback of limited uniformity and applicability to other 2D monolayers, and liquid water, which is not compatible with electronic devices. This work demonstrates a new class of substrates based on hydrogels that overcome these limitations and excel h-BN and water substrates at strain relaxation enabling superiorly uniform and reproducible centimeter-sized sheets of unstrained monolayers. The ultimate strain relaxation and uniformity are rationalized by the extreme structural adaptability of the hydrogel surface owing to its high liquid content and low Young's modulus, and are universal to all 2D materials irrespective of their crystalline structure. Such platforms can be integrated into field effect transistors and demonstrate enhanced charge carrier mobilities in graphene. These results present a universal strategy for attaining uniform and strain-free sheets of 2D materials and underline the opportunities enabled by interfacing them with soft matter.

Amorphous Ni-Fe-Mo Oxides Coupled with Crystalline Metallic Domains for Enhanced Electrocatalytic Oxygen Evolution by Promoted Lattice-Oxygen Participation.

The crystalline/amorphous heterophase nanostructures are promising functional materials for biomedicals, catalysis, energy conversion, and storage. Despite great progress is achieved, facile synthesis of crystalline metal/amorphous multinary metal oxides nanohybrids remains challenging, and their electrocatalytic oxygen evolution reaction (OER) performance along with the catalytic mechanism are not systematically investigated. Herein, two kinds of ultrafine crystalline metal domains coupled with amorphous Ni-Fe-Mo oxides heterophase nanohybrids, including Ni/Ni0.5-a Fe0.5 Mo1.5 Ox and Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox , are fabricated through controllable reduction of amorphous Ni0.5 Fe0.5 Mo1.5 Ox precursors by simply tuning the amount of used reductant. Due to the suited component in metal domains, the special structure with dense crystalline/amorphous interfaces, and strong electronic coupling of their components, the resultant Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox nanohybrids show greatly enhanced OER activity with a low overpotential (278 mV) to reach 10 mA cm-2 current density and ultrahigh turnover frequency (38160 h-1 ), outperforming Ni/Ni0.5-a Fe0.5 Mo1.5 Ox , Ni0.5 Fe0.5 Mo1.5 Ox precursors, commercial IrO2 , and most of recently reported OER catalysts. Also, such Ni-FeNi3 /Ni0.5-b Fe0.5-y Mo1.5 Ox nanohybrids manifest good catalytic stability. As revealed by a series of spectroscopy and electrochemical analyses, their OER mechanism follows the lattice-oxygen-mediated (LOM) pathway. This work may shed light on the design of advanced heterophase nanohybrids, and promote their applications in water splitting, metal-air batteries, or other clean energy fields.

iProbiotics: a machine learning platform for rapid identification of probiotic properties from whole-genome primary sequences.

Lactic acid bacteria consortia are commonly present in food, and some of these bacteria possess probiotic properties. However, discovery and experimental validation of probiotics require extensive time and effort. Therefore, it is of great interest to develop effective screening methods for identifying probiotics. Advances in sequencing technology have generated massive genomic data, enabling us to create a machine learning-based platform for such purpose in this work. This study first selected a comprehensive probiotics genome dataset from the probiotic database (PROBIO) and literature surveys. Then, k-mer (from 2 to 8) compositional analysis was performed, revealing diverse oligonucleotide composition in strain genomes and apparently more probiotic (P-) features in probiotic genomes than non-probiotic genomes. To reduce noise and improve computational efficiency, 87 376 k-mers were refined by an incremental feature selection (IFS) method, and the model achieved the maximum accuracy level at 184 core features, with a high prediction accuracy (97.77%) and area under the curve (98.00%). Functional genomic analysis using annotations from gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Rapid Annotation using Subsystem Technology (RAST) databases, as well as analysis of genes associated with host gastrointestinal survival/settlement, carbohydrate utilization, drug resistance and virulence factors, revealed that the distribution of P-features was biased toward genes/pathways related to probiotic function. Our results suggest that the role of probiotics is not determined by a single gene, but by a combination of k-mer genomic components, providing new insights into the identification and underlying mechanisms of probiotics. This work created a novel and free online bioinformatic tool, iProbiotics, which would facilitate rapid screening for probiotics.

High Serum Galectin-3 Level as a Potential Biomarker of Peripheral Artery Disease in Patients Undergoing Hemodialysis.

Background: Galectin-3 is implicated in the pathogenesis of inflammation and atherosclerosis. Peripheral arterial disease (PAD), characterized by a reduced ankle-brachial index (ABI), is a prognostic marker for mortality in patients on hemodialysis. We investigated the relationship between serum galectin-3 levels and PAD in patients undergoing regular hemodialysis. Methods: We carried out a cross-sectional study at a medical center, involving 92 participants. Serum galectin-3 levels were assessed by a commercially available enzyme-linked immunosorbent assay. ABI measurement was done with an automatic device based on oscillometry. Participants were categorized into two groups, normal and low ABI, based on a 0.9 cut-off point. Results: Eighteen patients (19.6%) exhibited a low ABI. In individuals with low ABIs, we observed a greater prevalence of diabetes mellitus, elevated serum C-reactive protein (CRP) levels, increased galectin-3 levels, and lower serum creatinine levels. Furthermore, serum galectin-3 levels (odds ratio [OR]: 1.056, 95% confidence interval [CI]: 1.003-1.112, p = 0.037) and CRP (per 0.1 mg/dL increment, OR: 1.195, 95% CI: 1.032-1.383, p = 0.017) were identified as independent predictors of PAD. Serum galectin-3 and log-transformed CRP levels were also independently and significantly negatively correlated with the left and right ABI values. Conclusions: Serum galectin-3 levels correlate with PAD in patients undergoing maintenance hemodialysis.

Comparison of the Efficacy of HSK3486 and Propofol for Induction of General Anesthesia in Adults: A Multicenter, Randomized, Double-blind, Controlled, Phase 3 Noninferiority Trial.

BACKGROUND: Propofol is an intravenous anesthetic associated with hypotension, respiratory depression, and injection-site pain. HSK3486 injectable emulsion (ciprofol) is a 2,6-disubstituted phenol derivative with fast onset and quick, stable recovery. Previous studies support HSK3486 as an effective, safe anesthetic with substantially less injection-site pain than propofol. The primary objective of this study was to investigate the noninferiority of HSK3486 compared with propofol in successful general anesthesia induction. METHODS: Two hundred fifty-five participants were enrolled in HSK3486-304, a multicenter, randomized (2:1), double-blind, propofol-controlled, phase 3 study evaluating HSK3486 for general anesthesia induction in adults undergoing elective surgery with tracheal intubation. The primary endpoint was successful anesthesia induction, defined as 1 or less on the Modified Observer's Assessment of Alertness/Sedation scale. Key secondary endpoints were proportion of participants with injection-site pain on the Numerical Rating Scale of 1 or greater and a composite endpoint, including the proportion of participants successfully induced while maintaining the desired anesthetic depth and without substantial cardiac and respiratory events. Safety endpoints included adverse events, abnormal vital signs, and injection-site pain. RESULTS: Two hundred fifty-one participants (HSK3486, n = 168; propofol, n = 83) were included in the analyses. General anesthesia was successfully induced in 97.0% versus 97.6% of participants with HSK3486 and propofol, respectively. The difference in success rate was -0.57% (95% CI, -5.4 to 4.2%); the noninferiority boundary of -8% was not crossed. Thirty participants (18.0%) had injection-site pain with HSK3486 versus 64 (77.1%) with propofol (P < 0.0001). Eighty-one participants (48.2%) with HSK3486 versus 42 (50.6%) with propofol (P = 0.8780) satisfied the composite endpoint. When injection-site pain was excluded, the incidence of treatment-emergent adverse events related to study drug was 17.9% for HSK3486 and 14.5% for propofol. CONCLUSIONS: The study met its primary objective and endpoint, demonstrating noninferiority of HSK3486 compared with propofol in successful anesthetic induction. Substantially less injection-site pain was associated with HSK3486 than with propofol.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Metagenomic analysis revealed the potential of lactic acid bacteria in improving natural saline-alkali land.

Management and improving saline-alkali land is necessary for sustainable agricultural development. We conducted a field experiment to investigate the effects of spraying lactic acid bacteria (LAB) on the cucumber and tomato plant soils. Three treatments were designed, including spraying of water, viable or sterilized LAB preparations to the soils of cucumber and tomato plants every 20 days. Spraying sterilized or viable LAB could reduce the soil pH, with a more obvious effect by using viable LAB, particularly after multiple applications. Metagenomic sequencing revealed that the soil microbiota in LAB-treated groups had higher alpha-diversity and more nitrogen-fixing bacteria compared with the water-treated groups. Both viable and sterilized LAB, but not water application, increased the complexity of the soil microbiota interactive network. The LAB-treated subgroups were enriched in some KEGG pathways compared with water or sterilized LAB subgroups, such as environmental information processing-related pathways in cucumber plant; and metabolism-related pathways in tomato plant, respectively. Redundancy analysis revealed association between some soil physico-chemical parameters (namely soil pH and total nitrogen) and bacterial biomarkers (namely Rhodocyclaceae, Pseudomonadaceae, Gemmatimonadaceae, and Nitrosomonadales). Our study demonstrated that LAB is a suitable strategy for decreasing soil pH and improving the microbial communities in saline-alkali land.

4-(Triethoxysilyl)butanoic acid as a self-assembled monolayer for surface modification of titanium dioxide.

In this study, the carboxy silane 4-(triethoxysilyl)butanoic acid (TESBA) was used to modify titanium dioxide (TiO2) to create a self-assembled monolayer (SAM) and then directionally immobilize a capture antibody using protein A. We selected the amino silane (3-aminopropyl)triethoxysilane (APTES) to perform a comparative analysis with TESBA, and employed glutaraldehyde (GA) as the control. The modification and detection effects and the limit of detection (LOD) were evaluated by detecting human immunoglobulin G (IgG). The average normalized sensitivity of the dual-grating coupler waveguide biosensor was 49.63 ± 0.27 RIU-1 and the optimum resolution was 1.30 × 10-6 RIU. When the SAM was prepared using TESBA and APTES followed by GA, the LOD was 4.59 × 10-7 g mL-1 and 5.29 × 10-7 g mL-1, respectively. We analyzed the modification and detection effects by the t-test and concluded that the differences in the modification effects using TESBA and APTES followed by GA were significant and the differences in the detection effects using TESBA and APTES followed by GA were insignificant. The use of TESBA as the SAM led to the modification effect being superior to that obtained using APTES followed by GA. The detection effect using TESBA was as outstanding as that using APTES followed by GA. Our findings demonstrate the feasibility and effectiveness of using TESBA as the SAM to carboxylate the surface of TiO2, thereby enabling immobilization of biomolecules for human IgG detection.

Neutrophils impaired by anti-galectin-3 antibodies elicit inflammation of endothelial cells to aggregate the development of lupus cutaneous vasculitis.

OBJECTIVES: To investigate whether the interplay of anti-galectin-3 antibodies (anti-Gal3 Abs) with neutrophils contributes to the development of lupus cutaneous vasculitis. METHODS: Enzyme-linked immunosorbent assay was used to determine the serum level of anti-Gal3 Abs in lupus patients. Flow cytometry, quantitative PCR and western blot were performed to investigate the expression of cell surface receptors, proinflammatory cytokines and signalling molecules in neutrophils stimulated by serum from lupus patients or healthy controls (HCs) or anti-Gal3 Ab, respectively. Immunofluorescence was performed to visualise the formation of neutrophil extracellular traps (NETs). Human umbilical vein endothelial cells were co-cultured with the supernatants from neutrophils stimulated by anti-Gal3 Ab, and cytokine production was measured at mRNA and protein levels. Immunohistochemistry was adopted to reveal the distribution of Gal3, cytokines and myeloperoxidase within lupus skin lesions. REULTS: Serum levels of anti-Gal3 Abs were negatively correlated with peripheral counts of neutrophils. Anti-Gal3 Abs positive sera from SLE patients accelerated neutrophil death, altered cell phenotype and promoted formation of NETs with the involvement of p38 MAPK pathway. Supernatants collected from neutrophils co-cultured with anti-Gal3 Ab provoked endothelial cells to produce cytokines such as IL-1, ICAM-1, SELE and particularly IL-6. Consistently, IL-6 was higher in SLE patients with anti-Gal3 Ab positive sera and enriched in the area of vascular inflammation together with enhanced expression of Gal3 protein and infiltration of neutrophils. CONCLUSIONS: Overall, these findings suggested that neutrophils were crucial mediators in anti-Gal3 Ab induced lupus cutaneous vasculitis.

Growth and thermal maturation of the Toba magma reservoir.

The Toba volcanic system in Indonesia has produced two of the largest eruptions (>2,000 km3 dense-rock equivalent [DRE] each) on Earth since the Quaternary. U-Pb crystallization ages of zircon span a period of ∼600 ky before each eruptive event, and in the run-up to each eruption, the mean and variance of the zircons' U content decrease. To quantify the process of accumulation of eruptible magma underneath the Toba caldera, we integrated these observations with thermal and geochemical modeling. We show that caldera-forming eruptions at Toba are the result of progressive thermal maturation of the upper crustal magma reservoir, which grows and chemically homogenizes, by sustained magma influx at average volumetric rates between 0.008 and 0.01 km3/y over the past 2.2 My. Protracted thermal pulses related to magma-recharge events prime the system for eruption without necessarily requiring an increased magma-recharge rate before the two supereruptions. If the rate of magma input was maintained since the last supereruption of Toba at 75 ka, eruptible magma is currently accumulating at a minimum rate of ∼4.2 km3 per millennium, and the current estimate of the total volume of potentially eruptible magma available today is a minimum of ∼315 km3 Our approach to evaluate magma flux and the rate of eruptible magma accumulation is applicable to other volcanic systems capable of producing supereruptions and thereby could help in assessing the potential of active volcanic systems to feed supereruptions.

Probiotic Bifidobacterium animalis ssp. lactis Probio-M8 improves the fermentation and probiotic properties of fermented milk.

Probiotics are increasingly used as starter cultures to produce fermented dairy products; however, few studies have investigated the role of probiotics in milk fermentation metabolism. The current study aimed to investigate whether adding Bifidobacterium animalis ssp. lactis Probio-M8 (Probio-M8) as a starter culture strain could improve milk fermentation by comparing the physicochemical characteristics and metabolomes of fermented milks produced by a commercial starter culture with and without Probio-M8. Our results showed that adding Probio-M8 shortened the milk fermentation time and improved the fermented milk texture and stability. Metabolomics analyses revealed that adding Probio-M8 affected mostly organic acid, AA, and fatty acid metabolism in milk fermentation. Targeted quantitative analyses revealed significant increases in various metabolites related to the sensory quality, nutritive value, and health benefits of the probiotic fermented milk, including 5 organic acids (acetic acid, lactic acid, citric acid, succinic acid, and tartaric acid), 5 EAA (valine, arginine, leucine, isoleucine, and lysine), glutamic acid, and 2 essential fatty acids (α-linolenic acid and docosahexaenoic acid). Thus, applying probiotics in milk fermentation is desirable. This study has generated useful information for developing novel functional dairy products.

The interaction between Lactobacillus delbrueckii ssp. bulgaricus M58 and Streptococcus thermophilus S10 can enhanced texture and flavor profile of fermented milk: Insights from metabolomics analysis.

Lactobacillus delbrueckii ssp. bulgaricus M58 (M58) and Streptococcus thermophilus S10 (S10) are 2 dairy starter strains known for their favorable fermentation characteristics. Therefore, this research aimed to study the effects of 1-d low-temperature ripening on the physicochemical properties and metabolomics of fermented milk. Initially, the performance of single (M58 or S10) and dual (M58+S10) strain fermentation was assessed, revealing that the M58+S10 combination resulted in a shortened fermentation time, a stable gel structure, and desirable viscosity, suggesting positive strain interactions. Subsequently, non-targeted metabolomics analyses using LC-MS and GC-MS were performed to comparatively analyze M58+S10 fermented milk samples collected at the end of fermentation and after 1-d low-temperature ripening. The results showed a significant increase in almost all small peptides and dodecanedioic acid in the samples after one day of ripening, while there was a substantial decrease in indole and amino acid metabolites. Moreover, notable increases were observed in high-quality flavor compounds, such as geraniol, delta-nonalactone, 1-hexanol,2-ethyl-, methyl jasmonate, and undecanal. This study provides valuable insights into the fermentation characteristics of the dual bacterial starter consisting of M58 and S10 strains and highlights the specific contribution of the low-temperature ripening step to the overall quality of fermented milk.

Co-culturing Bifidobacterium animalis ssp. lactis with Lactobacillus helveticus accelerates its growth and fermentation in milk through metabolic interactions.

[Objective] This study aimed to investigate the interaction between Lactobacillus helveticus H9 (H9) and Bifidobacterium animalis ssp. lactis Probio-M8 (M8) through metabolomics analysis, focusing on understanding how co-culturing these strains can enhance bacterial growth and metabolism, thereby shortening the fermentation cycle and improving efficiency. [Methods] The H9 and M8 strains were cultured individually and in combination (1:1 ratio) in milk. The fermented milk metabolomes were analyzed using solid-phase microextraction-gas chromatography-mass spectrometry. [Results] In the dual-strain fermentation, the M8 strain exhibited a 2.33-fold increase in viable bacterial count compared with single-strain fermentation. Additionally, the dual-strain fermentation resulted in greater metabolite abundance and diversity. Notably, the dual-strain fermented milk showed significantly elevated levels of metabolites, including 5-methyl-2-hexanone, (E)-3-octen-2-one, acetic acid, alanine, and 3-hydroxy-butanal. [Conclusion] Our results demonstrated that co-culturing the M8 and H9 strains accelerated growth and fermentation efficiency. This enhancement effect is likely attributed to the strong proteolytic ability of the H9 strain, which hydrolyzes casein to produce small molecular peptides, alanine, tyrosine, and other growth-promoting factors. The insights gained from this study have significant implications for probiotics and the dairy industry, potentially leading to shorter fermentation cycles, enhanced cost-effectiveness, and improved nutritional and functional properties of future fermented milk products. Additionally, these findings may contribute to advancements in probiotic research and applications.

Shotgun metagenomic analysis of microbiota dynamics during long-term backslopping fermentation of traditional fermented milk in a controlled laboratory environment.

Traditional fermented milks are produced through an inoculation process that involves the deliberate introduction of microorganisms that have been adapted and perpetuated across successive generations. However, the changes in the microbiota of traditional fermented milk during long-term inoculation fermentation in a laboratory environment remain unclear. In this study, we collected 5 samples of traditional fermented milk samples from 5 different counties in Tibet (3 kurut products) and Xinjiang (2 tarag products) of China, which served as starter cultures for a 9-mo continuous inoculation fermentation experiment. We analyzed the inter- and intra-population variations in the microbial communities of the collected samples, representing their macrodiversity and microdiversity, using shotgun metagenomic sequencing. Across all samples, we obtained a total of 186 high-quality metagenomic-assembled genomes, including 7 genera and 13 species with a relative abundance of more than 1%. The majority of these genomes were annotated as Lactobacillus helveticus (60.46%), Enterococcus durans (9.52%), and Limosilactobacillus fermentum (6.23%). We observed significant differences in species composition and abundance among the 5 initial inoculants. During the long-term inoculation fermentation, we found an overall increasing trend in species diversity, composition, and abundances of carbohydrate metabolism module-encoding genes in the fermented milk bacterial metagenome, while the fermented milk virome exhibited a relatively narrow range of variation. Lactobacillus helveticus, a dominant species in traditional fermented milk, displayed high stability during the long-term inoculation fermentation. Our study provides valuable insights for the industrial production of traditional fermented milk.

Dynamic Changes of the Gut Microbiota and Its Functional Metagenomic Potential during the Development of Non-Small Cell Lung Cancer.

The gut microbiota plays a significant role in tumor pathogenesis by regulating the host metabolism and immune response, and there are few studies focused on tracking changes in the gut microbiota from the onset of lung cancer. Therefore, the aim of our study is combining preclinical and clinical research to thoroughly analyze the signatures of fecal microbiota in lung cancer, which will be useful for early diagnosis and predicting the therapeutic efficacy of lung cancer. The first part of this study analyzed the fecal metagenomic differences between patients with non-small cell lung cancer and healthy subjects, and the second part of this work constructed a murine lung cancer model to monitor changes in mouse fecal metagenomics and T cell immunology during lung cancer progression. We found that the fecal microbiota was altered in both humans and mice with lung cancer, characterized by a significantly reduced microbial diversity and number of beneficial microbes, with increases in potential pathogens. The fecal level of Akkermansia muciniphila and the gut metabolic module of the secondary bile acid metabolism were diminished in both humans and mice with lung cancer compared with healthy subjects. Splenomegaly was observed in the lung cancer mice. Flow cytometer analysis of the splenocytes revealed substantial alterations in the proportions of T cell subsets in the lung cancer mice, characterized by significant increases in CD4+Foxp3+CD25+ T regulatory cells (p < 0.05) while significant decreases in CD3+ T cells (p < 0.001), CD4+ T cells (p < 0.001), and the CD4+/CD8+ ratio (p < 0.01). Vertical and longitudinal analyses of the fecal microbiota of the two mouse groups identified some lung cancer biomarkers (including Acutalibacter timonensis, Lachnospiraceae bacterium NSJ-38 sp014337195, etc.). The fecal microbiota of the lung cancer mice had a reduced metagenomic potential for neurotransmitters (melatonin, γ-aminobutyric acid, and histamine) compared with healthy mice. In summary, this study found that the diversity, structure, and composition of gut microbiota vary between cancer and healthy conditions, ultimately leading to changes in the potential for functional metagenomics.

Cardiac-to-Bronchial Fistula in Hepatocellular Carcinoma: A Case Report.

Hepatocellular carcinoma (HCC) stands as a significant contributor to cancer-related mortality globally. While the acute and often fatal manifestations of locally advanced HCC primarily present within the abdomen, it is crucial to recognize that the respiratory and circulatory systems can also fall victim due to the liver's unique anatomical position within the body. Here, we present the case of a 63-year-old male recently diagnosed with locally advanced HCC with vascular invasion. Shortly after receiving target therapy and focal radiotherapy, the patient developed repeated secondary infections and a persistent diaphragmatic defect. As the necrotic tissue invaded the pleural space, subsequent tumor-to-bronchial and tumor-to-cardiac fistulas emerged, resulting in an abnormal connection between the respiratory and cardiovascular systems, leading to massive air emboli in circulation. This report highlights the risk of supradiaphragmatic complications in HCC patients with post-treatment secondary infections, particularly in patients predisposed to developing diaphragmatic defects.