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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, with more than 800,000 deaths each year, and its 5-year survival rate is less than 12%. The role of the HN1 gene in HCC has remained elusive, despite its upregulation in various cancer types. In our investigation, we identified HN1's heightened expression in HCC tissues, which, upon overexpression, fosters cell proliferation, migration, and invasion, unveiling its role as an oncogene in HCC. In addition, silencing HN1 diminished the viability and metastasis of HCC cells, whereas HN1 overexpression stimulated their growth and invasion. Gene expression profiling revealed HN1 silencing downregulated 379 genes and upregulated 130 genes, and suppressive proteins associated with the lipogenic signaling pathway networks. Notably, suppressing HN1 markedly decreased the expression levels of SREBP1 and SREBP2, whereas elevating HN1 had the converse effect. This dual modulation of HN1 affected lipid formation, hindering it upon HN1 silencing and promoting it upon HN1 overexpression. Moreover, HN1 triggers the Akt pathway, fostering tumorigenesis via SREBP1-mediated lipogenesis and silencing HN1 effectively curbed HCC tumor growth in mouse xenograft models by deactivating SREBP-1, emphasizing the potential of HN1 as a therapeutic target, impacting both external and internal factors, it holds promise as an effective therapeutic strategy for HCC.

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The shell of Hermetia illucens L. contains considerable amounts of chitin, which has various biological activities. So far, few studies have focused on chitin of Hermetia illucens L. as a source of chitosan and oligosaccharides. There is great potential for utilizing Hermetia illucens L. chitin to produce chitosan films in biomaterials. We studied different extraction conditions for chitin and extracted it from black soldier fly (BSF) (Hermetia illucens L.). Three processing steps were adopted: (1) demineralization, (2) deproteinization, and (3) decolorization. The chemical components (moisture, ash, protein, fat, residual protein, and residual mineral contents) and physicochemical characteristics of the chitin and chitosan extracted under these three conditions were determined. In addition, Fourier transform infrared spectroscopy and X-ray diffraction were used to analyze the extracted chitin and commercial samples, and the results showed that demineralization-deproteinization-decolorization treatments could achieve the highest chitin yield (7.18 ±â€¯0.11 %), chitosan yield (64.22 ±â€¯0.79 %), and the best purity (residual protein 0.56 ±â€¯0.01 % and residual ash 0.58 ±â€¯0.04 %), making it the best treatment method. Using this method, the residues produced from farmed BSF can be recycled and used as a new source of chitin.

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This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78-0.92), 0.76 (95% CI 0.68-0.84), and 0.89 (95% CI 0.84-0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86-1.00), 0.79 (95% CI 0.68-0.91), and 0.96 (95% CI 0.90-1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72-0.96), 0.75 (95% CI 0.62-0.87), and 0.86 (95% CI 0.75-0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients.

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In the past decades, various methods, such as chemical sensing, X-ray screening, and spectroscopy, have been employed to detect explosives for environmental protection and national public security. However, achieving ultrahigh sensitivity for detection, which is crucial for some practical applications, remains challenging. This study employs scanning transmission electron microscopy and electron energy loss spectroscopy (STEM-EELS) to detect individual ∼200 nm explosive nanoparticles of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX). The vibrational modes of HMX were acquired for each single nanoparticle under the aloof STEM-EELS mode, which ensures damage-free detection. Detailed comparisons with Raman and infrared spectra validate the acquired data's origin. This work highlights STEM-EELS as an effective tool in explosives detection, offering ultrahigh sensitivity, damage-free, and nanometer spatial resolution, with potential applications in environmental protection, public security, and criminal investigations.

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Background: Patients undergoing painless egg retrieval are prone to preoperative anxiety, and whether preoperative anxiety induces postoperative nausea and vomiting (PONV) is debated. The primary objective of this prospective, randomized, controlled study was to compare the clinical effect of ondansetron in preventing PONV for patients with and without preoperative anxiety. The secondary objective was to investigate whether preoperative anxiety was associated with PONV. Methods: The self-rating anxiety scale (SAS) was used to assess the anxiety patients undergoing painless egg retrieval. Patients with a SAS standard score of 50-60 were selected to the anxiety group (n=105); and patients with a SAS standard score of 25-35 were assigned to the non-anxiety group (n=104). Venous blood samples of both groups of patients were obtained during admission and 1 hour after surgery, and all serotonin (5-HT) levels were tested using an enzyme-linked immunosorbent assay. The anxiety group was then randomly assigned into two subgroups: ondansetron (AO group, n=53) and placebo saline (AS group, n=52). Similarly, patients in the non-anxiety group were also randomly assigned to one of two subgroups: ondansetron (NO group, n=51) and placebo saline (NS group, n=53). The AO and NO groups received 8 mg (4 mL) of intravenous ondansetron 15 minutes before surgery, while the AS and NS groups received an equivalent volume (4 mL) of normal saline. We then analyzed the vital signs, risk factors for nausea and vomiting, intraoperative anesthetic doses, incidences of nausea and vomiting in 24 hours after surgery, serum 5-HT level before and after surgery, other adverse responses, pain scores, and satisfaction. Results: A total of 200 patients eventually completed this study. The serum 5-HT values in the anxiety group were higher before and after surgery than in the non-anxiety group (P<0.05), but there was no significant difference in serum 5-HT before and after surgery in the same group (P>0.05). The incidence of PONV was more significant in the AS group than in the NS group (P<0.05). The incidence of PONV was also higher in the AS group than in the AO group (P<0.05). Still, there was no statistically significant difference between the NO and NS groups (P>0.05). There were no significant differences between the four groups in vital signs, risk factors for nausea and vomiting, intraoperative anesthetic doses, other adverse responses and pain scores (P>0.05). Patients in the AS group had lower satisfaction scores than those in the other three groups (P<0.05). Conclusions: Patients experiencing preoperative anxiety have a greater risk of PONV following painless egg retrieval compared to those without preoperative anxiety. Ondansetron can reduce the occurrence of PONV in patients with preoperative anxiety, but it has no discernible preventative effect in non-anxious patients. Trial Registration: Chinese Clinical Trial Registry ChiCTR2400079504.

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Our intensive surveys of wild drosophilids in East and Southeast Asia discovered a great species diversity (more than 100 putatively new species) of the genus Dichaetophora, which is currently comprised of 67 formally described species assigned into five species groups, i.e., agbo, tenuicauda, acutissima, sinensis and trilobita. In the present study, we delimited species from a huge amount of samples of Dichaetophora and allied taxa (the genus Mulgravea and the subgenus Dudaica of Drosophila) collected from a wide range of the Oriental and east Palearctic regions. We first sorted all specimens into morpho-species, and representative specimen(s) selected from each morpho-species were subjected to barcoding of COI (the cytochrome c oxidase subunit I gene) sequences. The applied ASAP (Assemble Species by Automatic Partitioning) analysis estimated a total of 166 to 168 MOTUs (molecular operational taxonomic units). Integrating this result with morphological evidence from re-examined, detailed structures of male terminalia, we recognized a total of 144 (109 new and 35 known) species in our sample. Out of them, 83 species representing the supraspecific taxa of Dichaetophora, Mulgravea and Dudaica were selected, along with 33 species from major genera and subgenera of Drosophila in the tribe Drosophilini, as in-group and four species from the tribe Colocasiomyini as out-group for phylogenetic reconstruction based on 12 nuclear gene markers. In the trees constructed by the maximum likelihood and Bayesian inference methods, the three focal taxa (i.e., Dichaetophora, Mulgravea and Dudaica) formed a clade provisionally called the "pan-Dichaetophora". Within this large clade, the agbo, tenuicauda, sinensis and trilobita groups of Dichaetophora, Mulgravea and Dudaica were recovered as monophyletic groups, but Dichaetophora and its acutissima group were regarded as paraphyletic. In addition, two clusters were recognized among ungrouped species of Dichaetophora. Thus, the present study has uncovered some issues concerning the taxonomy of the pan-Dichaetophora. Such issues will be addressed elsewhere in the phylogenetic reclassification of the pan-Dichaetophora, along with descriptions/redescriptions of a large number of new/known species delimited in the present study.

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Color-tunable room temperature phosphorescence (RTP) materials possess potential applications in multicolor imaging, multichannel anticounterfeiting, and information encryption. Herein, we synthesized two zero-dimensional cadmium-organic halides, (H-aepy)2CdX4 (referred to as CdX-aepy; X = Cl-, Br-; aepy = 3-(2-aminoethyl)pyridine), both of which exhibit long-lived excitation wavelength- and time-dependent RTP. Experimental and theoretical results suggest that the multicolor RTP can be ascribed to the coemission of pristine H-aepy ligands and halogen-affected H-aepys, supporting that suitably introducing halogens can be an efficient strategy for constructing multicolor RTP materials. Additionally, we also demonstrate that the two phosphors can be applied in multichannel anticounterfeiting and information encryption. This work reports two hybrids with color-tunable RTP, as well as provides new insight into the effect of halogens on the regulation of RTP.

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Introduction: Accurate reference genomes are fundamental to understanding biological evolution, biodiversity, hereditary phenomena and diseases. However, many assembled nuclear chromosomes are often contaminated by organelle genomes, which will mislead bioinformatic analysis, and genomic and transcriptomic data interpretation. Methods: To address this issue, we developed a tool named Chlomito, aiming at precise identification and elimination of organelle genome contamination from nuclear genome assembly. Compared to conventional approaches, Chlomito utilized new metrics, alignment length coverage ratio (ALCR) and sequencing depth ratio (SDR), thereby effectively distinguishing true organelle genome sequences from those transferred into nuclear genomes via horizontal gene transfer (HGT). Results: The accuracy of Chlomito was tested using sequencing data from Plum, Mango and Arabidopsis. The results confirmed that Chlomito can accurately detect contigs originating from the organelle genomes, and the identified contigs covered most regions of the organelle reference genomes, demonstrating efficiency and precision of Chlomito. Considering user convenience, we further packaged this method into a Docker image, simplified the data processing workflow. Discussion: Overall, Chlomito provides an efficient, accurate and convenient method for identifying and removing contigs derived from organelle genomes in genomic assembly data, contributing to the improvement of genome assembly quality.

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Mechanical stimuli can affect plant growth, development, and defenses. The role of water spray stimulation, as a prevalent mechanical stimulus in the environment, in crop growth and defense cannot be overlooked. In this study, the effects of water spray on tomato plant growth and defense against the chewing herbivore Helicoverpa armigera and necrotrophic fungus Botrytis cinerea were investigated. Suprathreshold water spray stimulus (LS) was found to enhance tomato plant defenses against pests and pathogens while concurrently modifying plant architecture. The results of the phytohormone and chemical metabolite analysis revealed that LS improved the plant defense response via jasmonic acid (JA) signaling. LS significantly elevated the level of a pivotal defensive metabolite, chlorogenic acid, and reduced the emissions of volatile organic compounds (VOCs) from tomato plants, thereby defending against pest and pathogen attacks. The most obvious finding to emerge from this study is that LS enhances tomato plant defenses against biotic stresses, which will pave the way for further work on the application of mechanical stimuli for pest management.

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BACKGROUND: This study aimed to identify the causative genetic variant in a Chinese family with orofacial clefts. METHODS: We retrospectively analyzed the clinical information of a family with orofacial clefts. Then, we performed an etiological genetic analysis of the family using whole exome sequencing analysis and Sanger sequencing. We created a hybrid code-shifting mutation cell line (293T-462het) and evaluated its impact on cell proliferation, migration, and apoptosis, as well as E-cadherin and vimentin expression. RESULTS: Whole exome sequencing revealed a novel heterozygous variant c.1386del (p.A462Pfs*28) in the interferon regulatory transcription factor 6 (IRF6) gene in a family with orofacial clefts. Sanger sequencing further confirmed that this heterozygous variant was the genetic cause of orofacial clefts in this family. The c.1386del variant of IRF6 was classified as likely pathogenic. The heterozygous mutation IRF6 (c.1386del) enhanced cell proliferation and migration while inhibiting cell apoptosis and regulating the expression of E-cadherin and vimentin. CONCLUSION: This study identified a novel c.1386del mutation in the IRF6 gene and explored how this mutation leads to lip and palate defects. Our results provide a solid theoretical foundation for future genetic detection of these orofacial defects.

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Introduction: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (cTACE) remains suboptimal. This study investigated the efficacy and safety of modified TACE using low-dose chemotherapy with blank microspheres (BMS-TACE) plus low-dose lenvatinib (LD-LEN) and microwave ablation (MWA) in patients with large unresectable HCC. Methods: In this prospective, single-arm, phase 2 study, patients with unresectable HCC exceeding the up-to-seven criteria, with maximum tumor diameter ≥7 cm, and without macrovascular invasion or extrahepatic metastases, received initial BMS-TACE (lipiodol, low-dose doxorubicin, and lobaplatin up to 30 mg each, and blank microspheres; subsequently modified and repeated in most patients) plus LD-LEN (4-8 mg/day) and MWA. The primary endpoint was downstaging rate (DSR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: From November 2019 to March 2022, 43 patients were enrolled. Median follow-up was 21.2 months. Median largest tumor diameter was 11.2 cm (interquartile range [IQR], 7-25). Following BMS-TACE and LD-LEN, downstaging occurred in 37 (86.0%) patients, 32 of whom received MWA, and 8 of whom had a complete response (CR) without MWA. ORR was 93.0% (CR in 32 [74.4%] and partial response in 8 [18.6%] patients). The 1-, 2-, and 3-year PFS rates were 57.5%, 25.9%, and 18.1%, respectively (median PFS, 14.7 months [95% CI: 8.1-19.5]). The 1-, 2-, and 3-year OS rates were 85.8%, 67.7%, and 61.6%, respectively (median OS, 36.4 months [95% CI: 26.8-not reached]). After BMS-TACE, a significant decline in CD11b+/CD33+/HLA-DR- myeloid-derived suppressor cells and early elevation in CXCR5+/CD8+ and CXCR5+/CD4+ T cells were observed (both p < 0.05). Conclusion: BMS-TACE plus LD-LEN and MWA resulted in promising efficacy and tolerable toxicity in patients with large unresectable HCC exceeding the up-to-seven criteria with a maximum tumor diameter ≥7 cm and without macrovascular invasion or extrahepatic metastases.

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BACKGROUND: Gestational diabetes mellitus (GDM) significantly impacts maternal and infant health both immediately and over the long term, yet effective early diagnostic biomarkers are currently lacking. Thus, it is essential to identify early diagnostic biomarkers for GDM risk screening. Extrachromosomal circular DNA (eccDNA), being more stable than linear DNA and involved in disease pathologies, is a viable biomarker candidate for diverse conditions. In this study, eccDNA biomarkers identified for early diagnosis and assessment of GDM risk were explored. METHODS: Using Circle-seq, we identified plasma eccDNA profiles in five pregnant women who later developed GDM and five matched healthy controls at 11-13 weeks of gestation. These profiles were subsequently analyzed through bioinformatics and validated through outward PCR combined with Sanger sequencing. Furthermore, candidate eccDNA was validated by quantitative PCR (qPCR) in a larger cohort of 70 women who developed GDM and 70 normal glucose-tolerant (NGT) subjects. A ROC curve assessed the eccDNA's diagnostic potential for GDM. RESULTS: 2217 eccDNAs were differentially detected between future GDM patients and controls, with 1289 increased and 928 decreased in abundance. KEGG analysis linked eccDNA genes mainly to GDM-related pathways such as Rap1, MAPK, and PI3K-Akt, and Insulin resistance, among others. Validation confirmed a significant decrease in eccDNA PRDM16circle in the plasma of 70 women who developed GDM compared to 70 NGT women, consistent with the eccDNA-seq results. PRDM16circle showed significant diagnostic value in 11-13 weeks of gestation (AUC = 0.941, p < 0.001). CONCLUSIONS: Our study first demonstrats that eccDNAs are aberrantly produced in women who develop GDM, including PRDM16circle, which can predict GDM at an early stage of pregnancy, indicating its potential as a biomarker. TRIAL REGISTRATION: ChiCTR2300075971, http://www.chictr.org.cn . Registered 20 September 2023.

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Mild and inexpensive copper-catalyzed aromatization-driven ring-opening amination and oxygenation of spiro dihydroquinazolinones are presented, respectively. These protocols provide facile and atom-economical access to the aminated and the carbonyl-containing quinazolin-4(3H)-ones in good yields with good functional group compatibility, which are difficult to obtain by conventional methods. Remarkably, a telescoped procedure involving the condensation and the ring-opening/functionalization for simple cycloalkanone was found to be accessible. Mechanistic studies suggest a radical pathway for this transformation.

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Hypertension is accompanied by gut microbiota imbalance, but the role of bacteria in the pathogenesis of hypertension requires further study. In this study, we used fecal microbiota transplantation to determine the impact of microbiota composition on blood pressure in spontaneous hypertensive rats (SHRs), using normotensive Wistar Kyoto (WKY) rats as controls. SHRs were randomly divided into two groups (n = 10/group), SHR and SHR-T (SHR plus fecal transplantation) and WKY into WKY and WKY-T (WKY plus fecal transplantation). SHR-T received fecal transplantation from WKY, while WKY-T received fecal transplantation from SHR. Blood pressure was measured from the tail artery in conscious rats. 16S rDNA gene amplicon sequencing was used to analyze bacterial composition. Circulating levels of diamine oxidase, D-lactate, FITC-Dextrans, and lipopolysaccharide were determined. Hematoxylin and eosin (H&E) staining was used to observe structural changes in the intestinal mucosa. Immunofluorescence, Western blot, and RT-PCR were utilized to determine changes in the expression of tight junction proteins. Following cross fecal transplantation, blood pressure decreased in SHR and increased in WKY. Significant differences in gut microbial composition were found between hypertensive and normotensive rats, specifically regarding the relative abundance of lactic and butyric acid-producing bacteria. Changes in gut microbiota composition also impacted the intestinal mucosal barrier integrity. Moreover, fecal transplantation affected the expression of tight junction proteins that may impact intestinal mucosal permeability and structural integrity. Blood pressure may be associated with butyric acid-producing intestinal microbiota and its function in regulating the integrity of intestinal mucosal barrier.

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Wolbachia is an obligate endosymbiont that is maternally inherited and widely distributed in arthropods and nematodes. It remains in the mature eggs of female hosts over generations through multiple strategies and manipulates the reproduction system of the host to enhance its spreading efficiency. However, the transmission of Wolbachia within the host's ovaries and its effects on ovarian cells during oogenesis, have not been extensively studied. We used single-cell RNA sequencing to comparatively analyze cell-typing and gene expression in Drosophila ovaries infected and uninfected with Wolbachia. Our findings indicate that Wolbachia significantly affects the transcription of host genes involved in the extracellular matrix, cytoskeleton organization, and cytomembrane mobility in multiple cell types, which may make host ovarian cells more conducive for the transmission of Wolbachia from extracellular to intracellular. Moreover, the genes nos and orb, which are related to the synthesis of ribonucleoprotein complexes, are specifically upregulated in early germline cells of ovaries infected with Wolbachia, revealing that Wolbachia can increase the possibility of its localization to the host oocytes by enhancing the binding with host ribonucleoprotein-complex processing bodies (P-bodies). All these findings provide novel insights into the maternal transmission of Wolbachia between host ovarian cells.IMPORTANCEWolbachia, an obligate endosymbiont in arthropods, can manipulate the reproduction system of the host to enhance its maternal transmission and reside in the host's eggs for generations. Herein, we performed single-cell RNA sequencing of ovaries from Drosophila melanogaster and observed the effects of Wolbachia (strain wMel) infection on different cell types to discuss the potential mechanism associated with the transmission and retention of Wolbachia within the ovaries of female hosts. It was found that the transcriptions of multiple genes in the ovary samples infected with Wolbachia are significantly altered, which possibly favors the maternal transmission of Wolbachia. Meanwhile, we also discovered that Wolbachia may flexibly regulate the expression level of specific host genes according to their needs rather than rigidly changing the expression level in one direction to achieve a more suitable living environment in the host's ovarian cells. Our findings contribute to a further understanding of the maternal transmission and possible universal effects of Wolbachia within the host.

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The incidence of ulcerative colitis (UC) is rapidly rising worldwide. Oral drug delivery system is a promising approach for treating UC, but it often fails to accumulate to the inflammatory lesions, thus, it is impressive to develop a colon-targeted oral delivery system for preventing systemic toxicity and maintaining UC therapeutics. Here, a negative-charged PLGA nanoparticle system was designed to encapsulate celastrol (Cel), and then chitosan and mannose were coated on the surface of the nanoparticles (MC@Cel-NPs) to endow these nanoparticles with the mucosal adsorption and macrophage targeting abilities. MC@Cel-NPs demonstrate excellent resist decomposition ability against the strong acidic gastrointestinal environment, and accumulates in the specific inflammatory sites through the affinity of electrostatic reaction. After releasing the payload, MC@Cel-NPs could remarkably alleviate the colon inflammation, which was evidenced by the decrease in pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 in both blood and colon sections, and scavenging reactive oxygen species (ROS) in colon cells, including macrophage, neutrophil, T cell, and B cell. This nanoparticle system provided a new approach for treating UC through a Chinese herbal ingredient-related oral delivery manner.

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Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial-to-mesenchymal transition, reduces the production of pro-fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254-388aa interacts with Yes-associated protein (YAP) at WW2 domain (231-263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3',4'-Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4-dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis.

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Yellow fever (YF), caused by the yellow fever virus (YFV), continually spreads and causes epidemics worldwide, posing a great threat to human health. The live-attenuated YF 17D vaccine (YF-17D) has been licensed for preventing YFV infection and administrated via the intramuscular (i.m.) route. In this study, we sought to determine the immunogenicity and protective efficacy of aerosolized YF-17D via the intratracheal (i.t.) route in mice. YF-17D stocks in liquids were successfully aerosolized into particles of 6 µm. Further in vitro phenotype results showed the aerosolization process did not abolish the infectivity of YF-17D. Meanwhile, a single i.t. immunization with aerosolized YF-17D induced robust humoral and cellular immune responses in A129 mice, which is comparable to that received i.p. immunization. Notably, the aerosolized YF-17D also triggered specific secretory IgA (SIgA) production in bronchoalveolar lavage. Additionally, all immunized animals survived a lethal dose of YFV challenge in mice. In conclusion, our results support further development of aerosolized YF-17D in the future.

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BACKGROUND: Bedaquiline, delamanid and fluoroquinolones are associated with increased QTcF. Whether clofazimine is associated with QTcF prolongation is less clear. METHODS: All patients with rifampicin-resistant TB enrolled between May 2017 and Dec 2019 were included. ECGs were performed at baseline, month 1, month 3 and month 6 for patients treated with conventional regimens, and at additional timepoint for patients treated with bedaquiline, delamanid and short regimen. We estimated the maximum increase of QTcF and constructed cox proportional hazards models to assess factors associated with QTcF≥501ms. RESULTS: Among 321 patients, 59 (18.4%) patients had QTcF≥501ms during a mean follow-up of 242 days (median 189, range 4-1091). The median maximum increase of QTcF was 43.4 ms (IQR 31.3-65.9) in patients treated with clofazimine. Treatment with clofazimine was significantly associated with QTcF≥501ms as compared to without clofazimine (adjusted hazards ratio (adjHR) 4.35, 95% confidence interval (CI) 2.01-9.44). Among patients not treated with bedaquiline and delamanid, those treated with clofazimine and a fluoroquinolone (adjHR 3.43, 95% CI 1.61-7.34) and those treated with clofazimine and high dose moxifloxacin (adjHR 6.54, 95% CI 2.43-17.60) had a significantly higher risk of QTcF≥501ms as compared to those treated with a fluoroquinolone without other QTcF prolonging agents. Four (1.6%) patients had documented ventricular tachycardia, in which one was Torsade de pointes. One patient was found to have sudden death during hospitalization. CONCLUSIONS: Clofazimine was significantly associated with an increased risk of QTcF prolongation. QTcF≥501ms was potentially associated with fatal event and needed to be managed cautiously.

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The ability to recognize and differentiate between conspecifics and heterospecifics as well as their signals is critical for the coexistence of closely related species. In the genus Rattus, species are morphologically similar and multiple species often coexist. Here, we investigated the interspecific recognition and signal differentiation of two sympatric rat species, the brown rat (Rattus norvegicus, RN) and the Asian house rat (Rattus tanezumi, RT). In a two-way choice test, both RN and RT females showed a preference for conspecific male rats to heterospecific ones. RT females showed a significant preference for accessible urine of males of same species to those of other species, but not for the inaccessible urine. On the other hand, there were significant differences in the structural characteristics of the ultrasonic vocalization emitted by males of these two rat species. Sodium dodecyl sulphate‒polyacrylamide gel electrophoresis (SDS‒PAGE) and isoelectric focusing electrophoresis unveiled that major urinary proteins (MUPs) in voided urine were more highly expressed in RN males versus RT males. The interspecific differences of urinary volatile compounds were also discussed. In conclusion, female rats had the ability to distinguish between males of either species.