Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.

Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. However, BDQ also inhibits human ATP synthase3. At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs.

Lactate-lactylation-HSPA6 axis promotes PRRSV replication by impairing IFN-ß production.

Lactate, traditionally considered a metabolic by-product, has recently been identified as a substrate for the induction of lactylation, a newly identified epigenetic modification that plays an important role in the regulation of host gene expression. Our previous study showed that lactate levels were significantly elevated in cells infected with the porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has devastated the swine industry worldwide for over 30 years. However, the role of elevated lactate in PRRSV infections remains unknown. In this study, we found that lactate was required for optimal PRRSV proliferation, and PRRSV infection increased cellular lactylation in a dose-dependent manner. Using the Cleavage Under Targets and Tagmentation (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by negatively modulating interferon (IFN)-ß induction. Mechanistically, HSPA6 impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), thereby hindering the production of IFN-ß. Taken together, these results indicate that the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing IFN-ß induction, providing new therapeutic targets for the prevention and control of PRRSV infection. The results presented here also link lactylation to the virus life cycle, improving our understanding of epigenetic regulation in viral infection.IMPORTANCEAs a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-ß production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.

CsiR-mediated signal transduction pathway in response to low iron conditions promotes Escherichia coli K1 invasion and penetration of the blood-brain barrier.

Escherichia coli K1 is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli K1 meningitis remains unclear. Blood-brain barrier (BBB) penetration is a crucial step in E. coli meningitis development. Here, we uncovered the crucial role of CsiR, a GntR family regulator, in E. coli K1 virulence. During infection, csiR expression was induced due to the derepression by Fur in the blood and human brain microvascular endothelial cells (HBMECs). CsiR positively regulated ilvB expression, which is associated with branched chain amino acid synthesis. Furthermore, we revealed that IlvB activated the FAK/PI3 K pathway of HBMECs to induce actin cytoskeleton rearrangements, thereby promoting the bacterial invasion and penetration of the BBB. Overall, this study reveals a CsiR-mediated virulence regulation pathway in E. coli K1, which may provide a useful target for the prevention or therapy of E. coli meningitis.

Uropathogenic Escherichia coli subverts host autophagic defenses by stalling pre-autophagosomal structures to escape lysosome exocytosis.

Urinary tract infections are primarily caused by uropathogenic Escherichia coli (UPEC). UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and escapes into the cytosol by disrupting fusiform vesicle membrane using outer membrane phospholipase PldA, and establishes biofilm-like intracellular bacterial communities (IBCs) for protection from host immune clearance. Cytosolic UPEC is captured by autophagy to form autophagosomes, then transport to lysosomes, triggering the spontaneous exocytosis of lysosomes. The mechanism by which UPEC evades autophagy to recognize and form IBCs remains unclear. Here, we demonstrate that by inhibiting autophagic flux, UPEC PldA reduces the lysosome exocytosis of BECs. By reducing intracellular PI3P levels, UPEC PldA increases the accumulation of NDP52 granules and decreases the targeting of NDP52 to autophagy, hence stalling pre-autophagosome structures. Thus, our results uncover a critical role for PldA to inhibit autophagic flux, favoring UPEC escapes from lysosome exocytosis, thereby contributing to acute UTI.

miR-451a suppresses the proliferation and migration of high-grade serous ovarian cancer by targeting RAB5A through the Ras/Raf/MEK/ERK pathway.

BACKGROUND: Ovarian cancer is one of the most common cancers in women. Profiles changes of microRNAs (miRNAs) are closely linked to malignant tumors. In the present study, we investigated expression of miR-451a in high-grade serous ovarian cancer (HGSOC). We also investigated the potential pathological roles and the likely mechanism of miR-451a in the development of HGSOC using animal models and cell lines. METHODS: Using bioinformatics techniques and a real-time PCR, we analyzed differently expressed miRNAs in HGSOC compared to normal tissue. MTT (i.e. 3-[4, 5-dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), EDU (i.e. 5-ethynyl-2'-deoxyuridine) and transwell assays were performed to investigate the effect of miR-451a on the proliferation and migration of HGSOC SKOV-3 cells. A dual luciferase reporter assay was performed to verify the targeting relationship of miR-451 and RAB5A (one of the Rab GTPase proteins that regulates endocytosis and vesicle transport). Also, we analyzed levels of the RAB5A mRNA and protein by real-time PCR, western blotting and immunohistochemistry assays in HGSOC cells and tissues. Finally, we performed in vivo experiments using HGSOC mice. RESULTS: miR-451a was substantially upregulated in HGSOC and associated with favorable clinical characteristics. miR-451a knockdown significantly increased growth and metastasis of HGSOC cell line SKOV-3 through Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. In addition, RAB5A, an early endosome marker, was shown to be a direct target of miR-451a. Moreover, RAB5A is correlated with unfavorable clinical features and shows independent prognostic significance in HGSOC. CONCLUSIONS: We found that the miR-451a/RAB5A axis is associated with tumorigenesis and progression through the Ras/Raf/MEK/ERK pathway, providing prognostic indicators and therapeutic targets for patients with HGSOC.

Limited effects of xylem anatomy on embolism resistance in cycad leaves.

Drought-induced xylem embolism is a primary cause of plant mortality. Although c. 70% of cycads are threatened by extinction and extant cycads diversified during a period of increasing aridification, the vulnerability of cycads to embolism spread has been overlooked. We quantified the vulnerability to drought-induced embolism, pressure-volume curves, in situ water potentials, and a suite of xylem anatomical traits of leaf pinnae and rachises for 20 cycad species. We tested whether anatomical traits were linked to hydraulic safety in cycads. Compared with other major vascular plant clades, cycads exhibited similar embolism resistance to angiosperms and pteridophytes but were more vulnerable to embolism than noncycad gymnosperms. All 20 cycads had both tracheids and vessels, the proportions of which were unrelated to embolism resistance. Only vessel pit membrane fraction was positively correlated to embolism resistance, contrary to angiosperms. Water potential at turgor loss was significantly correlated to embolism resistance among cycads. Our results show that cycads exhibit low resistance to xylem embolism and that xylem anatomical traits - particularly vessels - may influence embolism resistance together with tracheids. This study highlights the importance of understanding the mechanisms of drought resistance in evolutionarily unique and threatened lineages like the cycads.

Insidious transmission of Mycobacterium tuberculosis in Ordos, China: a molecular epidemiology study.

BACKGROUND: In this study, we conducted this population-based study to evaluate the genetic diversity and clustering rate of Mycobacterium tuberculosis (MTB) strains using the whole-genome sequencing (WGS), to better understand its transmission in Ordos. METHODS: All patients with culture-positive TB notified in Ordos from January 2021 to December 2022 were recruited. WGS was performed to analyze single-nucleotide polymorphism (SNP) and to identify genotypic drug susceptibilities of MTB isolates. RESULTS: Overall, a total of 186 patients were included in the present study, of whom 35 (18.8%) had no symptoms suggestive of active TB. Lineage 2 was the predominant MTB sublineage, accounting for 186 of isolates tested. When the pairwise SNP difference ≤ 12 was used as the cutoff for WGS-based clusters, we identified 17 genotypic clusters, and 38 isolates belonged to these 17 clusters, resulting in a clustering rate of 20.4%. The Beijing genotype was an independent factor associating with genomic-clustering (adjusted OR 4.219, 95% CI 0.962-18.502). The overall sensitivity on WGS-based resistance prediction was 85.7% for rifampicin, 73.1% for isoniazid, 60.0% for Ethambutol, 72.7% for streptomycin, and 72.7% for fluoroquinolones. CONCLUSION: To conclude, the present study demonstrates the extensive recent transmission of Beijing genotype strains in the community of Ordos. The failure to provide a comprehensive pattern of transmission indicated the missed diagnosis of active TB within the community. A substantial proportion of subclinical TB cases are recognized in the bacteria-positive cases, emphasizing that we must interrupt transmission by finding people with active TB before they infect others.

MMSyn: A New Multimodal Deep Learning Framework for Enhanced Prediction of Synergistic Drug Combinations.

Combination therapy is a promising strategy for the successful treatment of cancer. The large number of possible combinations, however, mean that it is laborious and expensive to screen for synergistic drug combinations in vitro. Nevertheless, because of the availability of high-throughput screening data and advances in computational techniques, deep learning (DL) can be a useful tool for the prediction of synergistic drug combinations. In this study, we proposed a multimodal DL framework, MMSyn, for the prediction of synergistic drug combinations. First, features embedded in the drug molecules were extracted: structure, fingerprint, and string encoding. Then, gene expression data, DNA copy number, and pathway activity were used to describe cancer cell lines. Finally, these processed features were integrated using an attention mechanism and an interaction module and then input into a multilayer perceptron to predict drug synergy. Experimental results showed that our method outperformed five state-of-the-art DL methods and three traditional machine learning models for drug combination prediction. We verified that MMSyn achieved superior performance in stratified cross-validation settings using both the drug combination and cell line data. Moreover, we performed a set of ablation experiments to illustrate the effectiveness of each component and the efficacy of our model. In addition, our visual representation and case studies further confirmed the effectiveness of our model. All results showed that MMSyn can be used as a powerful tool for the prediction of synergistic drug combinations.

In vitro susceptibility of nontuberculous mycobacteria in China.

OBJECTIVES: This study aimed to measure the prevalence of resistance to antimicrobial agents, and explore the risk factors associated with drug resistance by using nontuberculous Mycobacteria (NTM) isolates from China. METHODS: A total of 335 NTM isolates were included in our analysis. Broth dilution method was used to determine in vitro drug susceptibility of NTM isolates. RESULTS: Clarithromycin (CLA) was the most potent drug for Mycobacterium intracellulare (MI). The resistance rate of 244 MI isolates to CLA was 21%, yielding a minimum inhibitory concentrations (MIC)50 and MIC90 of 8 and 64 mg/L, respectively. 51% of 244 MI isolates exhibited resistance to amikacin (AMK). For 91 Mycobacterium abscessus complex (MABC) isolates, 6 (7%) and 49 (54%) isolates were categorized as resistant to CLA at day 3 and 14, respectively. The resistance rate to CLA for Mycobacterium abscessus subspecies abscessus (MAA) was dramatically higher than that for Mycobacterium abscessus subspecies massiliense (MAM). Additionally, the percentage of patients presenting fever in the CLA-susceptible group was significantly higher than that in the CLA-resistant group. CONCLUSIONS: Our data demonstrate that approximate one fifth of MI isolates are resistant to CLA. We have identified a higher proportion of CLA-resistant MAA isolates than MAM. The patients caused by CLA-resistant MI are at low risk for presenting with fever relative to CLA-susceptible group.

A framework for longitudinal latent factor modelling of treatment response in clinical trials with applications to Psoriatic Arthritis and Rheumatoid Arthritis.

OBJECTIVE: Clinical trials involve the collection of a wealth of data, comprising multiple diverse measurements performed at baseline and follow-up visits over the course of a trial. The most common primary analysis is restricted to a single, potentially composite endpoint at one time point. While such an analytical focus promotes simple and replicable conclusions, it does not necessarily fully capture the multi-faceted effects of a drug in a complex disease setting. Therefore, to complement existing approaches, we set out here to design a longitudinal multivariate analytical framework that accepts as input an entire clinical trial database, comprising all measurements, patients, and time points across multiple trials. METHODS: Our framework composes probabilistic principal component analysis with a longitudinal linear mixed effects model, thereby enabling clinical interpretation of multivariate results, while handling data missing at random, and incorporating covariates and covariance structure in a computationally efficient and principled way. RESULTS: We illustrate our approach by applying it to four phase III clinical trials of secukinumab in Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA). We identify three clinically plausible latent factors that collectively explain 74.5% of empirical variation in the longitudinal patient database. We estimate longitudinal trajectories of these factors, thereby enabling joint characterisation of disease progression and drug effect. We perform benchmarking experiments demonstrating our method's competitive performance at estimating average treatment effects compared to existing statistical and machine learning methods, and showing that our modular approach leads to relatively computationally efficient model fitting. CONCLUSION: Our multivariate longitudinal framework has the potential to illuminate the properties of existing composite endpoint methods, and to enable the development of novel clinical endpoints that provide enhanced and complementary perspectives on treatment response.

Cloning, expression of porcine GSDME and identification of its site cleaved by caspase-3.

As a member of the gasdermin family, gasdermin E (GSDME) is specifically cleaved by caspase-3, resulting in pyroptosis. To date, the biological characteristics and functions of human and mouse GSDME have been extensively studied; however, little is known of porcine GSDME (pGSDME). In this study, the full-length pGSDME-FL was cloned, which encodes 495 amino acids (aa) that have closely evolutionary relationships to the homolog of camelus, aquatic mammals, cattle and goat. Moreover, pGSDME was detected at different levels of expression in 21 tissues and 5 pig-derived cell lines tested by qRT-PCR, with the highest expression levels in mesenteric lymph nodes and PK-15 cell lines. Anti-pGSDME polyclonal antibody (pAb) with good specificity was generated by expressing the truncated recombinant protein pGSDME-1-208 and immunizing the rabbits. By western blot analysis using highly specific anti-pGSDME polyclonal antibody (pAb) prepared as primary antibody, it was not only confirmed that paclitaxel and cisplatin were positive stimuli to pGSDME cleavage and caspase-3 activation, but also identified the aspartate (D268) at position 268th of pGSDME as a cleavage site of caspase-3, and the overexpressed pGSDME-1-268 possesses cytotoxicity to HEK-293T cells, indicating that pGSDME-1-268 may contain active domains and involve pGSDME-mediated pyroptosis. These results lay a foundation for further investigating the function of pGSDME, especially its role in pyroptosis and its interaction with pathogens.

Mycobacterium tuberculosis protein kinase G acts as an unusual ubiquitinating enzyme to impair host immunity.

Upon Mycobacterium tuberculosis (Mtb) infection, protein kinase G (PknG), a eukaryotic-type serine-threonine protein kinase (STPK), is secreted into host macrophages to promote intracellular survival of the pathogen. However, the mechanisms underlying this PknG-host interaction remain unclear. Here, we demonstrate that PknG serves both as a ubiquitin-activating enzyme (E1) and a ubiquitin ligase (E3) to trigger the ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF-ß-activated kinase 1 (TAK1), thereby inhibiting the activation of NF-κB signaling and host innate responses. PknG promotes the attachment of ubiquitin (Ub) to the ubiquitin-conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82-Ub), rather than the usual C86-Ub thiol-ester bond. PknG induces the discharge of Ub from UbcH7 by acting as an isopeptidase, before attaching Ub to its substrates. These results demonstrate that PknG acts as an unusual ubiquitinating enzyme to remove key components of the innate immunity system, thus providing a potential target for tuberculosis treatment.

Real-time recombinase-aided amplification assay for rapid amplification of the IS1081 gene of Mycobacterium tuberculosis.

Mycobacterium tuberculosis (MTB), the etiological agent of tuberculosis (TB), is the leading cause of death due to a single infectious agent worldwide. Rapid and accurate diagnosis of MTB is critical for controlling TB especially in resource-limited countries, since any diagnosis delay increases the chances of transmission. Here, a real-time recombinase-aided amplification (RAA) assay targeting conserved positions in IS1081 gene of MTB, is successfully established to detect MTB. The intact workflow was completed within 30 min at 42 °C with no cross-reactivity observed for non-tuberculous mycobacteria and other clinical bacteria, and the detection limit for recombinant plasmid of MTB IS1081 was 163 copies/reaction at 95% probability, which was approximately 1.5-fold increase in analytical sensitivity for the detection of MTB, compared to conventional quantitative real-time PCR (qPCR; 244 copies/reaction). Furthermore, the result of clinical performance evaluation revealed an increased sensitivity of RAA assay relative to qPCR was majorly noted in the specimens with low bacteria loads. Our results demonstrate that the developed real-time RAA assay is a convenient, sensitive, and low-cost diagnostic tool for the rapid detection of MTB.

Coordination of intertracheid pit traits and climate effects among cycads.

Interconduit pit membranes, which are permeable regions in the primary cell wall that connect to adjacent conduits, play a crucial role in water relations and the movement of nutrients between xylem conduits. However, how pit membrane characteristics might influence water-carbon coupling remains poorly investigated in cycads. We examined pit characteristics, the anatomical and photosynthetic traits of 13 cycads from a common garden, to determine if pit traits and their coordination are related to water relations and carbon economy. We found that the pit traits of cycads were highly variable and that cycads exhibited a similar tradeoff between pit density and pit area as other plant lineages. Unlike other plant lineages (1) pit membranes, pit apertures, and pit shapes of cycads were not coordinated as in angiosperms; (2) cycads exhibited larger pit membrane areas but lower pit densities relative to ferns and angiosperms, but smaller and similar pit membrane densities to non-cycad gymnosperms; (3) cycad pit membrane areas and densities were partially coordinated with anatomical traits, with hydraulic supply of the rachis positively coordinated with photosynthesis, whereas pit aperture areas and fractions were negatively coordinated with photosynthetic traits; (4) cycad pit traits reflected adaptation to wetter habitats for Cycadaceae and drier habitats for Zamiaceae. The large variation in pit traits, the unique pit membrane size and density, and the partial coordination of pit traits with anatomical and physiological traits of the rachis and pinna among cycads may have facilitated their dominance in a variety of ecosystems from the Mesozoic to modern times.

Rapid Mycobacterium abscessus antimicrobial susceptibility testing based on antibiotic treatment response mapping via Raman Microspectroscopy.

OBJECTIVES: Antimicrobial susceptibility tests (ASTs) are pivotal tools for detecting and combating infections caused by multidrug-resistant rapidly growing mycobacteria (RGM) but are time-consuming and labor-intensive. DESIGN: We used a Mycobacterium abscessus-based RGM model to develop a rapid (24-h) AST from the beginning of the strain culture, the Clinical Antimicrobials Susceptibility Test Ramanometry for RGM (CAST-R-RGM). The ASTs obtained for 21 clarithromycin (CLA)-treated and 18 linezolid (LZD)-treated RGM isolates. RESULTS: CAST-R-RGM employs D2O-probed Raman microspectroscopy to monitor RGM metabolic activity, while also revealing bacterial antimicrobial drug resistance mechanisms. The results of clarithromycin (CLA)-treated and linezolid (LZD)-treated RGM isolates exhibited 90% and 83% categorical agreement, respectively, with conventional AST results of the same isolates. Furthermore, comparisons of time- and concentration-dependent Raman results between CLA- and LZD-treated RGM strains revealed distinct metabolic profiles after 48-h and 72-h drug treatments, despite similar profiles obtained for both drugs after 24-h treatments. CONCLUSIONS: Ultimately, the rapid, accurate, and low-cost CAST-R-RGM assay offers advantages over conventional culture-based ASTs that warrant its use as a tool for improving patient treatment outcomes and revealing bacterial drug resistance mechanisms.

Systematic investigation of simultaneous copper biosorption and nitrogen removal from wastewater by an aerobic denitrifying bacterium of auto-aggregation.

Finding effective methods for simultaneous removal of eutrophic nutrients and heavy metals has attracted increasing concerns for the environmental remediation. Herein, a novel auto-aggregating aerobic denitrifying strain (Aeromonas veronii YL-41) was isolated with capacities for copper tolerance and biosorption. The denitrification efficiency and nitrogen removal pathway of the strain were investigated by nitrogen balance analysis and amplification of key denitrification functional genes. Moreover, the changes in the auto-aggregation properties of the strain caused by extracellular polymeric substances (EPS) production were focused on. The biosorption capacity and mechanisms of copper tolerance during denitrification were further explored by measuring changes in copper tolerance and adsorption indices, as well as by variations in extracellular functional groups. The strain showed extremely strong total nitrogen removal ability, with 67.5%, 82.08% and 78.48% of total nitrogen removal when NH4+-N, NO2--N, and NO3--N were used as the only initial nitrogen source, respectively. The successful amplification of napA, nirK, norR, and nosZ genes further demonstrated that the strain accomplished nitrate removal through a complete aerobic denitrification pathway. The production of protein-rich EPS of up to 23.31 mg/g and an auto-aggregation index of up to 76.42% may confer a strong biofilm-forming potential to the strain. Under the stress of 20 mg/L copper ions, the removal of nitrate-nitrogen was still as high as 71.4%. In addition, the strain could achieve an efficient removal of 96.9% of copper ions at an initial concentration of 80 mg/L. Scanning electron microscopy and deconvolution analysis of characteristic peaks confirmed that the strains encapsulate heavy metals by secreting EPS and, meanwhile, form strong hydrogen bonding structures to enhance intermolecular forces to resist copper ion stress. This study provides an innovative and effective biological approach for the synergistic bioaugmentation removal of eutrophic substances and heavy metals from aquatic environments.

Osteogenic mesenchymal stem cells/progenitors in the periodontium.

Periodontitis is the major cause of tooth loss in adults and is mainly characterized by alveolar bone destruction. Elucidating the mesenchymal stem cell (MSC)/progenitor populations of alveolar bone formation will provide valuable insights into regenerative approaches to clinical practice, such as endogenous regeneration and stem-cell-based tissue engineering therapies. Classically, MSCs residing in the bone marrow, periosteum, periodontal ligament (PDL), and even the gingiva are considered to be osteogenic progenitors. Furthermore, the contributions of MSCs expressing specific markers, including Gli1, Axin2, PTHrP, LepR, and α-SMA, to alveolar bone formation have been studied using cell lineage tracing and gene knockout models. In this review, we describe the MSCs/progenitors of alveolar bone and the biological properties of different subpopulations of MSCs involved in alveolar bone development, remodeling, injury repair, and regeneration.

Clinical characteristics and predictive model of pulmonary tuberculosis patients with pulmonary fungal coinfection.

BACKGROUND: In clinical settings, pulmonary tuberculosis (PTB) patients were often found to have pulmonary fungal coinfection. This study aimed to assess the clinical characteristics of patients suffering from coinfection with TB and pulmonary fungal and construct a predictive model for evaluating the probability of pulmonary fungal coinfection in patients with pulmonary tuberculosis. METHODS: The present case-control study retrospectively collected information from 286 patients affected by PTB who received treatment from December 6,2016- December 6,2021 at Beijing Chest Hospital, Capital Medical University. As control subjects, patients with sex and address corresponding to those of the case subjects were included in the study in a ratio of 1:1. These 286 patients were randomly divided into the training and internal validation sets in a ratio of 3:1. Chi-square test and logistic regression analysis were performed for the training set, and a predictive model was developed using the selected predictors. Bootstrapping was performed for internal validation. RESULTS: Seven variables [illness course, pulmonary cavitation, broad-spectrum antibiotics use for at least 1 week, chemotherapy or immunosuppressants, surgery, bacterial pneumonia, and hypoproteinemia] were validated and used to develop a predictive model which showed good discrimination capability for both training set [area under the curve (AUC) = 0.860, 95% confidence interval (CI) = 0.811-0.909] and internal validation set (AUC = 0.884, 95% CI = 0.799-0.970). The calibration curves also showed that the probabilities predicted using the predictive model had satisfactory consistency with the actual probability for both training and internal validation sets. CONCLUSIONS: We developed a predictive model that can predict the probability of pulmonary fungal coinfection in pulmonary tuberculosis patients. It showed potential clinical utility.

Thymus and lung mucosa-associated lymphoid tissue lymphoma with adenocarcinoma of the lung: a case report and literature review.

BACKGROUND: Mucosa-associated lymphoid tissue (MALT) lymphoma is a common, low-grade, malignant B-cell lymphoma. However, simultaneous MALT lymphoma in the thymus and lung is extremely rare, and concomitant adenocarcinoma of the lung is even rarer. Herein, we report a rare case of a collision tumor in which MALT lymphoma was found in both the thymus and lung with Sjögren's syndrome (SS) and adenocarcinoma in the lung. CASE PRESENTATION: A physical examination of a 32-year-old woman revealed an anterior superior mediastinal space-occupying lesion, and chest computed tomography (CT) indicated a nodular ground-glass opacity and irregular mixed-density focus in the right lung. All lung cancer-related tumor biomarkers were within normal ranges. The thymus and part of the lung tissue were surgically resected. The histopathology and molecular examinations confirmed MALT lymphoma of the thymus and lung with lung adenocarcinoma. SS was also diagnosed. No special postoperative treatment was performed for the MALT lymphoma, and the patient underwent immunosuppressive therapy for SS after 4 months of follow-up observation. CONCLUSIONS: MALT lymphoma of the thymus and lung tissues has no specific presentation on imaging and is difficult to differentiate from common malignant tumors, and the definite diagnoses of these tumors are highly dependent on histopathological examination in combination with molecular testing and cytogenetics. SS may be an important potential condition for the occurrence of MALT lymphoma in the thymus and lung. Additional similar cases are needed to clarify the biological pathways and potential molecular mechanisms of rare lymphomas and collision tumors.

Antioxidative and Mitochondrial Protection in Retinal Pigment Epithelium: New Light Source in Action.

Low-color-temperature light-emitting diodes (LEDs) (called 1900 K LEDs for short) have the potential to become a healthy light source due to their blue-free property. Our previous research demonstrated that these LEDs posed no harm to retinal cells and even protected the ocular surface. Treatment targeting the retinal pigment epithelium (RPE) is a promising direction for age-related macular degeneration (AMD). Nevertheless, no study has evaluated the protective effects of these LEDs on RPE. Therefore, we used the ARPE-19 cell line and zebrafish to explore the protective effects of 1900 K LEDs. Our results showed that the 1900 K LEDs could increase the cell vitality of ARPE-19 cells at different irradiances, with the most pronounced effect at 10 W/m2. Moreover, the protective effect increased with time. Pretreatment with 1900 K LEDs could protect the RPE from death after hydrogen peroxide (H2O2) damage by reducing reactive oxygen species (ROS) generation and mitochondrial damage caused by H2O2. In addition, we preliminarily demonstrated that irradiation with 1900 K LEDs in zebrafish did not cause retinal damage. To sum up, we provide evidence for the protective effects of 1900 K LEDs on the RPE, laying the foundation for future light therapy using these LEDs.