A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

Quantization of Axion-Gauge Couplings and Noninvertible Higher Symmetries.

We derive model-independent quantization conditions on the axion couplings (sometimes known as the anomaly coefficients) to the standard model gauge group [SU(3)×SU(2)×U(1)_{Y}]/Z_{q} with q=1, 2, 3, 6. Using these quantization conditions, we prove that any QCD axion model to the right of the E/N=8/3 line on the |g_{aγγ}|-m_{a} plot must necessarily face the axion domain wall problem in a postinflationary scenario. We further demonstrate the higher-group and noninvertible global symmetries in the standard model coupled to a single axion. These generalized global symmetries lead to universal bounds on the axion string tension and the monopole mass. If the axion were discovered in the future, our quantization conditions could be used to constrain the global form of the standard model gauge group.

Comparison of the recovery time of remimazolam besylate and propofol for gastrointestinal endoscopy sedation in elderly patients.

Background: Recovery time is a crucial factor in ensuring the safety and effectiveness of both patients and endoscopy centers. Propofol is often preferred due to its fast onset and minimal side effects. Remimazolam is a new intravenous sedative agent, characterized by its rapid onset of action, quick recovery and organ-independent metabolism. Importantly, its effect can be specifically antagonized by flumazenil. The primary goal of this study is to compare the recovery time of remimazolam besylate and propofol anesthesia during endoscopic procedures in elderly patients. Methods: 60 patients aged 65-95 years who underwent gastrointestinal endoscopy were randomly and equally assigned to two groups: the remimazolam group (Group R) and the propofol group (Group P). The primary measure was the recovery time, defined as the time from discontinuing remimazolam or propofol until reaching an Observer's Assessment of Alertness and Sedation scale (OAA/S) score of 5 (responds readily to name spoken in normal tone). The time required to achieve an OAA/S score of 3 (responds after name spoken loudly or repeatedly along with glazed marked ptosis) was also recorded and compared. Results: The recovery time for Group R (2.6 ± 1.6 min) was significantly shorter than that for Group P (10.8 ± 3.0 min), with a 95% confidence interval (CI): 6.949-9.431 min, p <0.001. Similarly, the time to attain an OAA/S score of 3 was significantly less in Group R (1.6 ± 0.9 min) compared to Group P (9.6 ± 2.6 min), with a 95% CI: 6.930-8.957 min, p <0.001. Conclusion: Our study demonstrated that remimazolam anesthesia combined with flumazenil antagonism causes a shorter recovery time for elderly patients undergoing gastrointestinal endoscopy compared to propofol. Remimazolam followed by flumazenil antagonism provides a promising alternative to propofol for geriatric patients, particularly during gastrointestinal endoscopy.

The role of confirmatory tests in the diagnosis of primary aldosteronism.

Confirmatory tests for diagnosis of primary aldosteronism (PA) play an important role in sparing patients with a false-positive aldosterone-to-renin ratio (ARR) screening test from undergoing invasive subtyping procedures. We recommend that patients with a positive ARR test should undergo at least one confirmatory test to confirm or exclude the diagnosis of PA before directly proceeding to subtype studies, except for patients with significant PA phenotypes, including spontaneous hypokalemia, plasma aldosterone concentration >20 ng/dL plus plasma renin activity below a detectable level. Although a gold standard confirmatory test has not been identified, we recommend that saline infusion test and captopril challenge test, which were widely used in Taiwan. Patients with PA have been reported to have a higher prevalence of concurrent autonomous cortisol secretion (ACS). ACS is a biochemical condition of mild cortisol overproduction from adrenal lesions, but without the typical clinical features of overt Cushing's syndrome. Concurrent ACS may result in incorrect interpretation of adrenal venous sampling (AVS) and may lead to adrenal insufficiency after adrenalectomy. We recommend screening for ACS in patients with PA scheduled for AVS examinations as well as for adrenalectomy. We recommend the 1-mg overnight dexamethasone suppression test as screening method to detect ACS.

[Chest computed tomography manifestations in neonates with chronic granulomatous disease]. / æ–°ç”Ÿå„¿æ ¢æ€§è‚‰èŠ½è‚¿ç— èƒ¸éƒ¨è®¡ç®—æœºæ–­å±‚æ‰«æçš„ç‰¹å¾åˆ†æž.

OBJECTIVES: To study chest computed tomography (CT) manifestations in neonates with chronic granulomatous disease (CGD) to provide clues for early diagnosis of this disease. METHODS: A retrospective analysis was conducted on the clinical data and chest CT scan results of neonates diagnosed with CGD from January 2015 to December 2022 at Anhui Provincial Children's Hospital. RESULTS: Nine neonates with CGD were included, with eight presenting respiratory symptoms as the initial sign. Chest CT findings included: consolidation in all 9 cases; nodules in all 9 cases, characterized by multiple, variably sized scattered nodules in both lungs; masses in 4 cases; cavities in 3 cases; abscesses in 6 cases; bronchial stenosis in 2 cases; pleural effusion, interstitial changes, and mediastinal lymphadenopathy each in 1 case. CT enhancement scans showed nodules and masses with uneven or ring-shaped enhancement; no signs of pulmonary emphysema, lung calcification, halo signs, crescent signs, bronchiectasis, or scar lesions were observed. There was no evidence of rib or vertebral bone destruction. Fungal infections were present in 8 of the 9 cases, including 6 with Aspergillus infections; three of these involved mixed infections with Aspergillus, with masses most commonly associated with mixed Aspergillus infections (3/4). CONCLUSIONS: The primary manifestations of neonatal CGD on chest CT are consolidation, nodules, and/or masses, with Aspergillus as a common pathogen. These features can serve as early diagnostic clues for neonatal CGD.

The physiology, pathology and potential therapeutic application of serotonylation.

The classical neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), synthesized from tryptophan, can be produced both centrally and peripherally. Through binding to functionally distinct receptors, serotonin is profoundly implicated in a number of fundamental physiological processes and pathogenic conditions. Recently, serotonin has been found covalently incorporated into proteins, a newly identified post-translational modification termed serotonylation. Transglutaminases (TGMs), especially TGM2, are responsible for catalyzing the transamidation reaction by transferring serotonin to the glutamine residues of target proteins. Small GTPases, extracellular matrix protein fibronectin, cytoskeletal proteins and histones are the most reported substrates for serotonylation, and their functions are triggered by this post-translational modification. This Review highlights the roles of serotonylation in physiology and diseases and provides perspectives for pharmacological interventions to ameliorate serotonylation for disease treatment.

Portraying the dark side of endogenous IFN-λ for promoting cancer progression and immunoevasion in pan-cancer.

BACKGROUND: IFN-λ has been shown to have a dual function in cancer, with its tumor-suppressive roles being well-established. However, the potential existence of a negative ''tumor-promoting'' effect of endogenous IFN-λ is still not fully understood. METHODS: We conducted a comprehensive review and analysis of the perturbation of IFN-λ genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-λ expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-λ were obtained by constructing the correlation-based network related to IFN-λ and the gene interaction network in the KEGG pathway and IFN-λ-related genes obtained from the networks were integrated as candidate markers for the prognosis model. We then applied univariate and multivariate COX regression models to select cancer-specific independent prognostic markers associated with IFN-λ and to investigate risk factors for these genes by survival analysis. Additionally, computational methods were used to analyze the transcriptome, copy number variations, genetic mutations, and methylation of IFN-λ-related patient groups. RESULT: Endogenous expression of IFN-λ has been linked to poor prognosis in cancer patients, with the genes IFN-λ2 and IFN-λ3 serving as independent prognostic markers. IFN-λ acts in conjunction with related genes such as STAT1, STAT2, and STAT3 to affect the JAK-STAT signaling pathway, which promotes tumor progression. Abnormalities in IFN-λ genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancer- and immune-related pathways. While there is increased immune cell infiltration in patients with IFN-λ expression, this does not improve survival prognosis, as T-cell dysfunction and an inflammatory environment are also present. The amplification of IFNL2 and IFNL3 copy number variants drives specific endogenous expression of IFN-λ in patients, and those with this specific expression have been found to have more mutations in the TP53 gene and lower levels of DNA methylation. CONCLUSION: Our study integrated multi-omics data to provide a comprehensive insight into the dark side of endogenous IFN-λ, providing a fundamental resource for further discovery and therapeutic exploration in cancer.

Noninvertible Time-Reversal Symmetry.

In gauge theory, it is commonly stated that time-reversal symmetry only exists at θ=0 or π for a 2π-periodic θ angle. In this Letter, we point out that in both the free Maxwell theory and massive QED, there is a noninvertible time-reversal symmetry at every rational θ angle, i.e., θ=πp/N. The noninvertible time-reversal symmetry is implemented by a conserved, antilinear operator without an inverse. It is a composition of the naive time-reversal transformation and a fractional quantum Hall state. We also find similar noninvertible time-reversal symmetries in non-Abelian gauge theories, including the N=4 SU(2) super Yang-Mills theory along the locus |τ|=1 on the conformal manifold.

Effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy: a randomized controlled trial.

AIMS: Dexmedetomidine could be an ideal adjuvant to propofol during gastrointestinal endoscopy because it provides both analgesia and sedation without respiratory depression. This study investigates the effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy. METHODS: Ninety adult patients were randomly assigned to Group Control, Group DEX0.5 (0.5 µg/kg dexmedetomidine) or Group DEX1.0 (1.0 µg/kg dexmedetomidine). Anaesthesia during endoscopy was implemented by plasma target-controlled infusion (TCI) of propofol with different doses of dexmedetomidine. TCI concentration of the first patient for each group was 2.5 µg/mL and the consecutive adjacent concentration gradient was 0.5 µg/mL. Median effective concentration (EC50 ) of propofol by TCI for gastrointestinal endoscopy was determined by using the modified Dixon's up-and-down method. Cardiovascular variables were also measured. RESULTS: EC50 of propofol by TCI and 95% confidence interval (CI) for gastrointestinal endoscopy were 3.77 (3.48-4.09), 2.51 (2.27-2.78) and 2.10 (1.90-2.33) µg/mL in Group Control, Group DEX0.5 and Group DEX1.0, respectively. The average percent change from heart rate (HR) baseline was 2.8 (8.9), -7.4 (7.7) and -10.5 (8.8) (P < .001), and the average percent change from mean arterial pressure (MAP) baseline was -10.6 [-24.7; 3.5], -9.5 [-29.2; 11.4] and -4.0 [-27.3; 15.5] (P = .034) in Group Control, Group DEX0.5 and Group DEX1.0, respectively. CONCLUSIONS: Dexmedetomidine reduced the EC50 of propofol by TCI. A 0.5-1 µg/kg dose of dexmedetomidine caused a decrease in HR without bradycardia. The decrease in dosage of propofol with increasing doses of dexmedetomidine caused more stable MAP. Dexmedetomidine is an ideal adjuvant drug to propofol during gastrointestinal endoscopy.

Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression.

Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by terbinafine, an approved antifungal drug, might inhibit the development of CRC. A population-based study from Sweden identified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio = 0.50) and metastasis (hazard ratio = 0.44) compared with patients without terbinafine administration. In multiple mouse models of CRC, administration of terbinafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation, and cell-cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltration, and restoring antitumor immune response.

Noninvertible Global Symmetries in the Standard Model.

We identify infinitely many noninvertible generalized global symmetries in QED and QCD for the real world in the massless limit. In QED, while there is no conserved Noether current for the U(1)_{A} axial symmetry because of the Adler-Bell-Jackiw anomaly, for every rational angle 2πp/N, we construct a conserved and gauge-invariant topological symmetry operator. Intuitively, it is a composition of the axial rotation and a fractional quantum Hall state coupled to the electromagnetic U(1) gauge field. These conserved symmetry operators do not obey a group multiplication law, but a noninvertible fusion algebra. They act invertibly on all local operators as axial rotations, but noninvertibly on the 't Hooft lines. We further generalize our construction to QCD, and show that the coupling π^{0}F∧F in the effective pion Lagrangian is necessary to match these noninvertible symmetries in the UV. Therefore, the conventional argument for the neutral pion decay using the ABJ anomaly is now rephrased as a matching condition of a generalized global symmetry.

Evaluating the Feasibility and Efficacy of a Pediatric Intensive Care Unit Diary.

As the progress of critical care medicine has improved the survival rate of critically ill patients, comorbidities and long-term health care have attracted people's attention. The terms "post-intensive care syndrome" (PICS) and "PICS-family" (PICS-F) have been used in non-neurocritical care populations, which are characterized by the cognitive, psychiatric, and physical sequelae associated with intensive care hospitalization of survivors and their families. An intensive care unit (ICU) diary authored by the patient's family members may alleviate the psychological distress of the patient and his or her family. This quality improvement project focused on the development and implementation of the pediatric intensive care unit (PICU) diary in the pediatric critical care setting. The project aims to evaluate the feasibility and the potential efficacy of the PICU diary, measured through parental acceptance and satisfaction. Seventeen families of critically ill children admitted to the PICU received the PICU diary during the implementation period. Twenty-four parents completed the weekly follow-up, and 15 subsequently completed the diary entry evaluation. The use of the diary in the PICU setting is feasible and considered beneficial by families of critically ill children.

[Clinical characteristics and genetic analysis of a neonate with Smith-Magenis syndrome].

OBJECTIVE: To explore the clinical features and genetic etiology for a neonate with Smith-Magenis syndrome (SMS). METHODS: Copy number variation sequencing (CNV-seq) was applied to the neonate and his parents, and the genotype-phenotype correlation was analyzed. RESULTS: On the second day after birth, the neonate had presented with pathological jaundice and immunodeficiency. Cranial MRI revealed ventricular enlargement and enlargement of cisterna magna. At 3 months, the infant has presented with square face, prominent forehead, deep-set eyes, hypertelorism, palpebral fissure upward and button noses. Genetic testing showed that he had carried a 2.9 Mb deletion in 17p11.2 region, seq[GRCh37] del(17)(p11.2)(chr17:16 836 379-19 880 992). The same deletion was not found in either parent. CONCLUSION: SMS is mostly diagnosed in child and adulthood, but rarely in neonates. For neonates with SMS, the neurological and behavioral abnormalities have not been shown, but pathological jaundice, CNS abnormalities and immune deficiency may be the characteristics, which require attention of neonatal physicians.

The Cassava Source-Sink project: opportunities and challenges for crop improvement by metabolic engineering.

Cassava (Manihot esculenta Crantz) is one of the important staple foods in Sub-Saharan Africa. It produces starchy storage roots that provide food and income for several hundred million people, mainly in tropical agriculture zones. Increasing cassava storage root and starch yield is one of the major breeding targets with respect to securing the future food supply for the growing population of Sub-Saharan Africa. The Cassava Source-Sink (CASS) project aims to increase cassava storage root and starch yield by strategically integrating approaches from different disciplines. We present our perspective and progress on cassava as an applied research organism and provide insight into the CASS strategy, which can serve as a blueprint for the improvement of other root and tuber crops. Extensive profiling of different field-grown cassava genotypes generates information for leaf, phloem, and root metabolic and physiological processes that are relevant for biotechnological improvements. A multi-national pipeline for genetic engineering of cassava plants covers all steps from gene discovery, cloning, transformation, molecular and biochemical characterization, confined field trials, and phenotyping of the seasonal dynamics of shoot traits under field conditions. Together, the CASS project generates comprehensive data to facilitate conventional breeding strategies for high-yielding cassava genotypes. It also builds the foundation for genome-scale metabolic modelling aiming to predict targets and bottlenecks in metabolic pathways. This information is used to engineer cassava genotypes with improved source-sink relations and increased yield potential.

Ikarugamycin inhibits pancreatic cancer cell glycolysis by targeting hexokinase 2.

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

Assessment of the Clinical Utility of Circulating Tumor Cells at Different Time Points in Predicting Prognosis of Patients With Small Cell Lung Cancer: A Meta-Analysis.

OBJECTIVES: Numerous studies have elucidated that circulating tumor cells (CTCs) have significant prognostic value in various solid tumors. However, the prognostic value of CTCs in small cell lung cancer (SCLC) remains controversial. The current study was performed to investigate the prognostic significance of different time points of CTCs in SCLC. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were retrieved for eligible studies. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to investigate the association between CTCs level and overall survival (OS) and progression-free survival (PFS) in SCLC. Furthermore, subgroup analyses, sensitivity analysis, Begg's and Egger's tests were also conducted. RESULTS: Sixteen cohort studies with 1103 participants were eligible for this meta-analysis. Our results revealed that higher pretreatment CTCs level was significantly correlated with worse OS in SCLC no matter CellSearch (HR, 2.95; 95%CI, 1.56-5.58; P = .001) or other methods (HR, 2.37; 95%CI, 1.13-4.99; P = .023) was used to detect CTCs. Higher pretreatment CTCs status detected by CellSearch was associated with shorter PFS (HR, 3.75; 95%CI, 2.52-5.57; P < .001), while there was no significant association when other methods were adopted to CTC detection (HR, 2.04; 95%CI, .73-5.68; P = .172). Likewise, we observed that higher post-therapy CTCs level detected by both CellSearch (HR, 2.99; 95%CI, 1.51-5.93; P = .002) and other methods (HR, 4.79; 95%CI, 2.03-11.32; P < .001) was significantly correlated with decreased OS in SCLC. However, higher post-therapy CTCs count detected by CellSearch was not correlated with worse PFS (HR, 1.80; 95%CI, .83-3.90; P = .135). Sensitivity analysis demonstrated that the pooled data were still stable after eliminating studies one by one. However, significant publication bias was observed between pretreatment CTCs level detected by CellSearch and OS of SCLC. CONCLUSION: Dynamic monitoring of CTCs level could be a non-invasive and effective tool to predict the disease progression and prognosis in patients with SCLC.

Causes of in-hospital death in patients with type 2 diabetes with microvascular and macrovascular complications in Taiwan.

AIMS: Diabetes mellitus is a major cause of death worldwide, including Taiwan. The mortality data of the subsets of patients who suffered from microvascular or macrovascular complications is limited. The aim of this study was to investigate the causes of in-hospital death of patients with type 2 diabetes, especially the patients with microvascular, macrovascular and both micro-macrovascular complications. METHODS: A total of 12 159 patients with type 2 diabetes were identified from the Taiwan National Health Insurance Research Database (NHIRD) to analyse the causes of death. Type 2 diabetic subjects with microvascular, macrovascular and both micro-macrovascular complications were further classified and compared to patients without microvascular and macrovascular complications in the logistic regression analysis of the risk of death. RESULTS: Pneumonia increased risk of in-hospital death in patients with microvascular, macrovascular and both micro-macrovascular complications, with adjusted odds ratios (AORs) of 2.13 (95% confidence interval [CI] 1.09-4.18), 3.26 (1.71-6.24) and 3.96 (2.17-7.22), respectively. Septicaemia increased risk of in-hospital death in patients with macrovascular (AOR 2.57 [1.31-5.04]) and both micro-macrovascular complications (AOR 4.69 [2.58-8.50]). CONCLUSION: Pneumonia increased risk of in-hospital death among the type 2 diabetic patients with microvascular, macrovascular and both micro-macrovascular complications. Therefore, efforts aim at preventing pneumonia or decreasing its severity may increase survival.

Characterization of Bioactivities and Biosynthesis of Angucycline/Angucyclinone Derivatives Derived from Gephyromycinifex aptenodytis gen. nov., sp. nov.

Strain NJES-13T is the type strain and currently the only species of the newly established actinobacteria genera Aptenodytes in the family Dermatophilaceae isolated from the gut microbiota of the Antarctic emperor penguin. This strain demonstrated excellent bioflocculation activity with bacteria-derived exopolysaccharides (EPSs). Moreover, it produced bioactive angucycline/angucyclinone derivatives (ADs) and contained one type III polyketide synthase (T3PKS), thus demonstrating great potential to produce novel bioactive compounds. However, the low productivity of the potential new AD metabolite was the main obstacle for its chemical structure elucidation. In this study, to increase the concentration of targeted metabolites, the influence of cellular morphology on AD metabolism in strain NJES-13T was determined using glass bead-enhanced fermentation. Based on the cellular ultra-structural observation driven by bacterial EPSs, and quantitative analysis of the targeted metabolites, the successful increasing of the productivity of three AD metabolites was achieved. Afterward, a new frigocyclinone analogue was isolated and then identified as 2-hydroxy-frigocyclinone, as well as two other known ADs named 2-hydroxy-tetrangomycin (2-HT) and gephyromycin (GPM). Three AD metabolites were found to demonstrate different bioactivities. Both C-2 hydroxyl substitutes, 2-hydroxy-tetrangomycin and 2-hydroxy-frigocyclinone, exhibited variable inhibitory activities against Staphylococcus aureus, Bacillus subtilis and Candida albicans. Moreover, the newly identified 2-hydroxy-frigocyclinone also showed significant cytotoxicity against three tested human-derived cancerous cell lines (HL-60, Bel-7402 and A549), with all obtained IC50 values less than 10 µM. Based on the genetic analysis after genomic mining, the plausible biogenetic pathway of the three bioactive ADs in strain NJES-13T was also proposed.

In Vitro Anti-Toxoplasma gondii Activity Evaluation of a New Series of Quinazolin-4(3H)-one Derivatives.

Toxoplasmosis post serious threaten to human health, leading to severely eye and brain disease, especially for immunocompromised patients and pregnant women. The multiple side effects and long dosing period of current main treatment regiments calls for high effective and low toxicity anti-toxoplasmosis drugs. Herein, we report our efforts to synthesize a series of 2-(piperazin-1-yl)quinazolin-4(3H)-one derivatives and investigate their activity against Toxoplasma gondii tachyzoites in vitro based on cell phenotype screening. Among the 26 compounds, 8w and 8x with diaryl ether moiety at the side chain of piperazine exhibited good efficacy to inhibit T. gondii, with IC50 values of 4 µM and 3 µM, respectively. Structure-activity relationship (SAR) studies implies that hydrophobic aryl at the side chain would be preferred for improvement of activity. Molecular docking study reveals these two compounds appeared high affinity to TgCDPK1 by interaction with the hydrophobic pocket of ATP-binding cleft.