Tuning the CO2 Reduction Selectivity of an Immobilized Molecular Ag Complex beyond CO.

The electrochemical reduction of carbon dioxide (CO2) to produce fuels and chemicals has garnered significant attention. However, achieving control over the selectivity of the resulting products remains a challenging task, particularly within molecular systems. In this study, we employed a molecular silver complex immobilized on graphitized mesoporous carbon (GMC) as a catalyst for converting CO2 into CO, achieving an impressive selectivity of over 90% at -1.05 V vs RHE. Notably, the newly formed silver nanoparticles emerged as the active sites responsible for this high CO selectivity rather than the molecular system. Intriguingly, the introduction of copper ions into the restructured Ag-nanoparticle-decorated carbon altered the product selectivity. At -1.1 V vs RHE in 0.1 M KCl, we achieved a high C2 selectivity of 75%. Furthermore, not only the Ag-Cu bimetallic nanoparticle but also the small-sized Ag-Cu nanocluster decorated over GMC was proposed as active sites during catalytic reactions. Our straightforward approach offers valuable insights for fine-tuning the product selectivity of immobilized molecular systems, extending beyond C1 products.

Selection of climate variables in ant species distribution models: case study in South Korea.

The selection of explanatory variables is important in modeling prediction of changes in species distribution in response to climate change. In this study, we evaluated the importance of variable selection in species distribution models. We compared two different types of models for predicting the distribution of ant species: temperature-only and both temperature and precipitation. Ants were collected at 343 forest sites across South Korea from 2006 through 2009. We used a generalized additive model (GAM) to predict the future distribution of 16 species that showed significant responses to changes in climatic factors (temperature and/or precipitation). Four types of GAMs were constructed: temperature, temperature with interaction of precipitation, temperature and precipitation without interaction, and temperature and precipitation with interaction. Most species displayed similar results between the temperatureonly and the temperature and precipitation models. The results for predicted changes in species richness were different from the temperature-only model. This indicates higher uncertainty in the prediction of species richness, which is obtained by combining the prediction results of distribution change for each species, than in the prediction of distribution change. The turnover rate of the ant assemblages was predicted to increase with decreases in temperature and increases in elevation, which was consistent with other studies. Finally, our results showed that the prediction of the distribution or diversity of organisms responding to climate change is uncertain because of the high variability of the model outputs induced by the variables used in the models.

Association between the use of statins and risk of interstitial lung disease/idiopathic pulmonary fibrosis: time-dependent analysis of population-based nationwide data.

BACKGROUND: We aimed to study whether statin use is associated with lowering the development of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). METHODS: The study population was the Korean National Health Insurance Service-Health Screening Cohort. ILD and IPF cases were identified using diagnosis codes (J84.1 for ILD and J84.1A as a special code for IPF) based on the International Classification of Diseases, 10th Revision. The study participants were followed up from 1 January 2004 to 31 December 2015. Statin use was defined by the cumulative defined daily dose (cDDD) per 2-year interval and participants were categorised into never-users, <182.5, 182.5-365.0, 365.0-547.5 and ≥547.5 by cDDD. A Cox regression was used to fit models with time-dependent variables of statin use. RESULTS: Incidence rates for ILD with and without statin use were 20.0 and 44.8 per 100 000 person-years, respectively, and those for IPF were 15.6 and 19.3 per 100 000 person-years, respectively. The use of statins was independently associated with a lower incidence of ILD and IPF in a dose-response manner (p-values for trend <0.001). ILD showed respective adjusted hazard ratios (aHRs) of 1.02 (95% CI 0.87-1.20), 0.60 (95% CI 0.47-0.77), 0.27 (95% CI 0.16-0.45) and 0.24 (95% CI 0.13-0.42) according to the increasing category of statin use compared with never-users. IPF showed respective aHRs of 1.29 (95% CI 1.07-1.57), 0.74 (95% CI 0.57-0.96), 0.40 (95% CI 0.25-0.64) and 0.21 (95% CI 0.11-0.41). CONCLUSION: A population-based cohort analysis found that statin use is independently associated with a decreased risk of ILD and IPF in a dose-response manner.

LRRC6 regulates biogenesis of motile cilia by aiding FOXJ1 translocation into the nucleus.

BACKGROUND: LRRC6 is an assembly factor for dynein arms in the cytoplasm of motile ciliated cells, and when mutated, dynein arm components remained in the cytoplasm. Here, we demonstrate the role of LRRC6 in the active nuclear translocation of FOXJ1, a master regulator for cilia-associated gene transcription. METHODS: We generated Lrrc6 knockout (KO) mice, and we investigated the role of LRRC6 on ciliopathy development by using proteomic, transcriptomic, and immunofluorescence analysis. Experiments on mouse basal cell organoids confirmed the biological relevance of our findings. RESULTS: The absence of LRRC6 in multi-ciliated cells hinders the assembly of ODA and IDA components of cilia; in this study, we showed that the overall expression of proteins related to cilia decreased as well. Expression of cilia-related transcripts, specifically ODA and IDA components, dynein axonemal assembly factors, radial spokes, and central apparatus was lower in Lrrc6 KO mice than in wild-type mice. We demonstrated that FOXJ1 was present in the cytoplasm and translocated into the nucleus when LRRC6 was expressed and that this process was blocked by INI-43, an importin α inhibitor. CONCLUSIONS: Taken together, these results hinted at the LRRC6 transcriptional regulation of cilia-related genes via the nuclear translocation of FOXJ1. Video Abstract.

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease.

Tryptophan hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Properties of Pleural Mesothelial Cells in Idiopathic Pulmonary Fibrosis and Cryptogenic Organizing Pneumonia.

BACKGROUND: Profibrotic properties of pleural mesothelial cells may play an important role in the fibrosis activity in idiopathic pulmonary fibrosis (IPF). The purpose of this study was to compare the expression of pleural mesothelial cell markers in IPF and cryptogenic organizing pneumonia (COP), with an assumption that increased expression implies increase in fibrosis. METHODS: Twenty IPF lung samples were stained by immunohistochemistry for the pleural mesothelial cell markers: leucine rich repeat neuronal 4 (LRRN4), uroplakin 3B, CC-chemokine ligand 18, and laminin-5. Nine COP lung samples were used as controls. A semi-quantitative analysis was performed to compare markers expression in IPF and COP. RESULTS: LRRN4 expression was found in epithelial lining cells along the honeycombing and fibroblastic foci in IPF, but not in the fibrotic interstitial lesion and airspace filling fibrous tufts in COP. We found a significant decrease in baseline forced vital capacity when LRRN4 expression was increased in honeycombing epithelial cells and fibroblastic foci. CONCLUSION: LRRN4 expression patterns in IPF are distinct from those in COP. Our findings suggest that mesothelial cell profibrotic property may be an important player in IPF pathogenesis and may be a clue in the irreversibility of fibrosis in IPF.

COVID-19 Vaccine-Associated Pneumonitis in the Republic of Korea: A Nationwide Multicenter Survey.

BACKGROUND: Recent reports have suggested that pneumonitis is a rare complication following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its clinical features and outcomes are not well known. The aim of this study was to identify the clinical characteristics and outcomes of patients with vaccine-associated pneumonitis following vaccination against SARS-CoV-2. METHODS: In this nationwide multicenter survey study, questionnaires were distributed to pulmonary physicians in referral hospitals. They were asked to report cases of development or exacerbation of interstitial lung disease (ILD) associated with the coronavirus disease 2019 vaccine. Vaccine-associated pneumonitis was defined as new pulmonary infiltrates documented on chest computed tomography within 4 weeks of vaccination and exclusion of other possible etiologies. RESULTS: From the survey, 49 cases of vaccine-associated pneumonitis were identified between February 27 and October 30, 2021. After multidisciplinary discussion, 46 cases were analyzed. The median age was 66 years and 28 (61%) were male. The median interval between vaccination and respiratory symptoms was 5 days. There were 20 (43%), 17 (37%), and nine (19%) patients with newly identified pneumonitis, exacerbation of pre-diagnosed ILD, and undetermined pre-existing ILD, respectively. The administered vaccines were BNT162b2 and ChAdOx1 nCov-19/AZD1222 each in 21 patients followed by mRNA-1273 in three, and Ad26.COV2.S in one patient. Except for five patients with mild disease, 41 (89%) patients were treated with corticosteroid. Significant improvement was observed in 26 (57%) patients including four patients who did not receive treatment. However, ILD aggravated in 9 (20%) patients despite treatment. Mortality was observed in eight (17%) patients. CONCLUSION: These results suggest pneumonitis as a potentially significant safety concern for vaccines against SARS-CoV-2. Clinical awareness and patient education are necessary for early recognition and prompt management. Additional research is warranted to identify the epidemiology and characterize the pathophysiology of vaccine-associated pneumonitis.

Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy.

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs∗60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.

Purification of Therapeutic Antibodies Using the Ca2+-Dependent Phase-Transition Properties of Calsequestrin.

Affinity chromatography utilizing specific interactions between therapeutic proteins and bead-immobilized capturing agents is a standard method for protein purification, but its scalability is limited by long purification times, activity loss by the capturing molecules and/or purified protein, and high costs. Here, we report a platform for purifying therapeutic antibodies via affinity precipitation using the endogenous calcium ion-binding protein, calsequestrin (CSQ), which undergoes a calcium ion-dependent phase transition. In this method, ZZ-CSQ fusion proteins with CSQ and an affinity protein (Z domain of protein A) capture antibodies and undergo multimerization and subsequent aggregation in response to calcium ions, enabling the antibody to be collected by affinity precipitation. After robustly validating and optimizing the performance of the platform, the ZZ-CSQ platform can rapidly purify therapeutic antibodies from industrial harvest feedstock with high purity (>97%) and recovery yield (95% ± 3%). In addition, the ZZ-CSQ platform outperforms protein A-based affinity chromatography (PAC) in removing impurities, yielding ∼20-fold less DNA and ∼4.8-fold less host cell protein (HCP) contamination. Taken together, this platform is rapid, recyclable, scalable, and cost-effective, and it shows antibody-purification performance superior or comparable to that of the standard affinity chromatography method.

All-in-one nanosponge with pluronic shell for synergistic anticancer therapy through effectively overcoming multidrug resistance in cancer.

Overexpression of P-glycoprotein (P-gp) on cancer cells is a major hurdle to effectively treat tumors with multidrug resistance (MDR). The current study aimed to explore anticancer drug and P-gp inhibitor delivery as a promising strategy to efficiently treat colorectal cancer with MDR. To this end, a multidrug-loaded all-in-one nanosponge (ANS) was developed to simultaneously deliver doxorubicin (DOX), paclitaxel (PTX), and the P-gp inhibitor tetrandrine (TET), referred to as DOX/PTX/TET@ANS, without chemical conjugation. ANS with high loading content and efficiency facilitated a pH-dependent and controlled release with different profiles. Compared to free drugs and DOX/PTX@ANS, DOX/PTX/TET@ANS exhibited more effective anticancer effects on P-gp-overexpressing colorectal cancer cells and solid tumor mouse xenografts, without major toxicity. Notably, ANS composed of pluronic shell induced in vitro P-gp inhibition compared to TET, implying a synergistic anticancer effect. These findings suggest that ANS can encapsulate multiple drugs to efficiently deliver chemotherapy, particularly in MDR tumors.

ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms.

Zinc finger MYND-type-containing 10 (ZMYND10), a cytoplasmic protein expressed in ciliated cells, causes primary ciliary dyskinesia (PCD) when mutated; however, its function is poorly understood. Therefore, in this study, we examined the roles of ZMYND10 using Zmynd10-/-mice exhibiting typical PCD phenotypes, including hydrocephalus and laterality defects. In these mutants, morphology, the number of motile cilia, and the 9+2 axoneme structure were normal; however, inner and outer dynein arms (IDA and ODA, respectively) were absent. ZMYND10 interacted with ODA components and proteins, including LRRC6, DYX1C1, and C21ORF59, implicated in the cytoplasmic pre-assembly of DAs, whose levels were significantly reduced in Zmynd10-/-mice. LRRC6 and DNAI1 were more stable when co-expressed with ZYMND10 than when expressed alone. DNAI2, which did not interact with ZMYND10, was not stabilized by co-expression with ZMYND10 alone, but was stabilized by co-expression with DNAI1 and ZMYND10, suggesting that ZMYND10 stabilized DNAI1, which subsequently stabilized DNAI2. Together, these results demonstrated that ZMYND10 regulated the early stage of DA cytoplasmic pre-assembly by stabilizing DNAI1.

ADCK4 Deficiency Destabilizes the Coenzyme Q Complex, Which Is Rescued by 2,4-Dihydroxybenzoic Acid Treatment.

BACKGROUND: Mutations in ADCK4 (aarF domain containing kinase 4) generally manifest as steroid-resistant nephrotic syndrome and induce coenzyme Q10 (CoQ10) deficiency. However, the molecular mechanisms underlying steroid-resistant nephrotic syndrome resulting from ADCK4 mutations are not well understood, largely because the function of ADCK4 remains unknown. METHODS: To elucidate the ADCK4's function in podocytes, we generated a podocyte-specific, Adck4-knockout mouse model and a human podocyte cell line featuring knockout of ADCK4. These knockout mice and podocytes were then treated with 2,4-dihydroxybenzoic acid (2,4-diHB), a CoQ10 precursor analogue, or with a vehicle only. We also performed proteomic mass spectrometry analysis to further elucidate ADCK4's function. RESULTS: Absence of Adck4 in mouse podocytes caused FSGS and albuminuria, recapitulating features of nephrotic syndrome caused by ADCK4 mutations. In vitro studies revealed that ADCK4-knockout podocytes had significantly reduced CoQ10 concentration, respiratory chain activity, and mitochondrial potential, and subsequently displayed an increase in the number of dysmorphic mitochondria. However, treatment of 3-month-old knockout mice or ADCK4-knockout cells with 2,4-diHB prevented the development of renal dysfunction and reversed mitochondrial dysfunction in podocytes. Moreover, ADCK4 interacted with mitochondrial proteins such as COQ5, as well as cytoplasmic proteins such as myosin and heat shock proteins. Thus, ADCK4 knockout decreased the COQ complex level, but overexpression of ADCK4 in ADCK4-knockout podocytes transfected with wild-type ADCK4 rescued the COQ5 level. CONCLUSIONS: Our study shows that ADCK4 is required for CoQ10 biosynthesis and mitochondrial function in podocytes, and suggests that ADCK4 in podocytes stabilizes proteins in complex Q in podocytes. Our study also suggests a potential treatment strategy for nephrotic syndrome resulting from ADCK4 mutations.

Normothermia in Patients With Sepsis Who Present to Emergency Departments Is Associated With Low Compliance With Sepsis Bundles and Increased In-Hospital Mortality Rate.

OBJECTIVES: To investigate the impact of normothermia on compliance with sepsis bundles and in-hospital mortality in patients with sepsis who present to emergency departments. DESIGN: Retrospective multicenter observational study. PATIENTS: Nineteen university-affiliated hospitals of the Korean Sepsis Alliance participated in this study. Data were collected regarding patients who visited emergency departments for sepsis during the 1-month period. The patients were divided into three groups based on their body temperature at the time of triage in the emergency department (i.e., hypothermia [< 36°C] vs normothermia [36-38°C] vs hyperthermia [> 38°C]). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 64,021 patients who visited emergency departments, 689 with community-acquired sepsis were analyzed (182 hyperthermic, 420 normothermic, and 87 hypothermic patients). The rate of compliance with the total hour-1 bundle was lowest in the normothermia group (6.0% vs 9.3% in hyperthermia vs 13.8% in hypothermia group; p = 0.032), the rate for lactate measurement was lowest in the normothermia group (62.1% vs 73.1% vs 75.9%; p = 0.005), and the blood culture rate was significantly lower in the normothermia than in the hyperthermia group (p < 0.001). The in-hospital mortality rates in the hyperthermia, normothermia, and hypothermia groups were 8.5%, 20.6%, and 30.8%, respectively (p < 0.001), but there was no significant association between compliance with sepsis bundles and in-hospital mortality. However, in a multivariate analysis, compared with hyperthermia, normothermia was significantly associated with an increased in-hospital mortality (odds ratio, 2.472; 95% CI, 1.005-6.080). This association remained significant even after stratifying patients by median lactate level. CONCLUSIONS: Normothermia at emergency department triage was significantly associated with an increased risk of in-hospital mortality and a lower rate of compliance with the sepsis bundle. Despite several limitations, our findings suggest a need for new strategies to improve sepsis outcomes in this group of patients.

Lung Cancer development and mortality in interstitial lung disease with and without connective tissue diseases: a five-year Nationwide population-based study.

BACKGROUND: Connective tissue disease associated with interstitial lung disease (CTD-ILD) and interstitial lung disease (ILD) alone have same pathological and imaging backgrounds. However, the differences between lung cancer development and the mortality risk between these two conditions are unclear. Incidence of primary lung cancer and all-cause mortality were studied between interstitial lung disease patients with and without connective tissue disease. METHODS: Data were extracted from the Korean National Health Insurance Research Database in 2009. A total of 12,787 cases of ILD without idiopathic pulmonary fibrosis and 2491 cases of CTD-ILD were diagnosed in 2009. The cohort was followed up until June 30, 2014. Incident lung cancers and all-cause mortality were ascertained. RESULTS: The overall incidence of lung cancer was 165.7 and 161.8 per 10,000 person-years in the CTD-ILD and ILD-only, respectively (rate ratio, 1.08; 95% confidence interval, 0.89-1.30). CTD-ILD patients in the 40-49 and 50-59 years old age groups had lung cancer incidence rates of 92.5 and 139.2, which were 2.0 and 1.7 times higher than those in the ILD-only, respectively. All-cause mortality was significantly higher in the CTD-ILD group compared to ILD-only group in patients aged 50-79 years. All-cause mortality of women in the 50-59, 60-69 and 70-79 age groups was 2.0, 1.8, and 1.4 times higher in the CTD-ILD group than in the ILD-only group, respectively. CONCLUSIONS: CTD-ILD patients aged < 60 years had a higher lung cancer incidence than ILD-only patients in the same age group. Furthermore, CTD-ILD patients aged 50-79 years had higher all-cause mortality than ILD-only patients in the same age group.

Association study of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with venous thromboembolism in a Korean population.

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

Risk factors for interstitial lung disease: a 9-year Nationwide population-based study.

BACKGROUND: Understanding the risk factors that are associated with the development of interstitial lung disease might have an important role in understanding the pathogenetic mechanism of interstitial lung disease as well as prevention. We aimed to determine independent risk factors of interstitial lung disease development. METHODS: This was a retrospective cohort study with nationwide population-based 9-year longitudinal data. We selected subjects who were aged > 40 years at cohort entry and with a self-reported history of cigarette smoking. Cases were selected based on International Classification of Diseases codes. A cohort of 312,519 subjects were followed until December 2013. We used Cox regression analysis to calculate the hazard ratios (HRs) for interstitial lung disease development. RESULTS: Interstitial lung disease developed in 1972 of the 312,519 subjects during the 9-year period. Smoking (HR: 1.2; 95% confidence interval [CI]: 1.1-1.4), hepatitis C (HR: 1.6; 95% CI: 1.1-2.3), history of tuberculosis (HR: 1.5; 95% CI: 1.1-1.9), history of pneumonia (HR: 1.6; 95% CI: 1.3-2.0), and chronic obstructive pulmonary disease (HR: 1.8; 95% CI: 1.6-2.1), men (HR: 1.9; 95% CI: 1.7-2.1) were significantly associated with the development of interstitial lung disease. The risk of interstitial lung disease development increases with age, and the risk was 6.9 times higher (95% CI: 5.9-8.0) in those aged over 70 than in their forties. CONCLUSIONS: Smoking, hepatitis C, history of tuberculosis, history of pneumonia, chronic obstructive pulmonary disease, male sex, and older age were significantly associated with interstitial lung disease development.

Zbtb7c is a molecular 'off' and 'on' switch of Mmp gene transcription.

Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases that play roles in cell proliferation, migration, differentiation, angiogenesis, and apoptosis. The expression of MMP gene is tightly regulated and shows cell- and tissue-specific expression patterns. Despite their differential expression, MMP genes have AP-1 (activator protein-1) binding elements within their promoters. Interestingly, c-JUN phosphorylation by cytokine signaling decreased its interaction with NCoR, but increased its interaction with p300, resulting in activation of MMP gene transcription. Here, we found that Zbtb7c (Kr-pok) is a critical component of a transcriptional repressor complex containing c-Jun and NCoR. c-Jun, bound at AP-1, interacts with Zbtb7c, which in turn recruits an NCoR/Hdac3 complex to repress several Mmp (-8, -10, -13, and -16) genes. The molecular interaction between c-Jun and Zbtb7c also prevents phosphorylation of c-Jun by p-Jnk, However, Zbtb7c phosphorylation by p-Jnk (induced by TNFα), and its (Zbtb7c) subsequent degradation by the ubiquitin-mediated proteasomal pathway, leads to c-Jun phosphorylation by p-Jnk. Promoter-bound p-c-Jun then recruits the coactivator p300 to upregulate Mmp gene. Overall, these findings show that Zbtb7c is a key molecule that recruits an NCoR/Hdac3 complex to inhibit phosphorylation of c-Jun, and thereby repress Mmp gene expression.

Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection constitutes a substantial disease burden in the general population. However, the risk of death for RSV infection has been rarely evaluated with confounders or comorbidities adjusted. We aimed to evaluate whether RSV infection is associated with higher mortality than seasonal influenza after adjusting for confounders and comorbidities and the effect of oseltamivir on the mortality in patients with influenza infection. METHODS: A retrospective cohort study was conducted on adult (≥18 years) patients admitted to the emergency department and ward of a university teaching hospital for suspected viral infection during 2013-2015 (N = 3743). RSV infection was diagnosed by multiplex PCR (N = 87). Adults hospitalized for seasonal influenza during the study period were enrolled as a comparison group (n = 312). The main outcome was 20-day all-cause mortality.We used Cox proportional hazard regression analyses to calculate the relative risk of death. RESULTS: Adult patients were less likely to be diagnosed with RSV than with influenza (2.3 vs 8.3%, respectively), were older and more likely to be diagnosed with pneumonia, chronic obstructive pulmonary disease, hypoxemia, and bacterial co-infection. In patients with RSV infection, the 20-day all-cause mortality was higher than that for influenza, (18.4 vs 6.7%, respectively). RSV infection showed significantly higher risk of death compared to the seasonal influenza group, with hazard ratio, 2.32 (95% CI, 1.17-4.58). Oseltamivir had no significant effect on mortality in patients with influenza. CONCLUSIONS: RSV infection was significantly associated with a higher risk of death than seasonal influenza, adjusted for potential confounders and comorbidities.

ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65.

The NF-κB is found in almost all animal cell types and is involved in a myriad of cellular responses. Aberrant expression of NF-κB has been linked to cancer, inflammatory diseases and improper development. Little is known about transcriptional regulation of the NF-κB family member gene RelA/p65. Sp1 plays a key role in the expression of the RelA/p65 gene. ZBTB2 represses transcription of the gene by inhibiting Sp1 binding to a Sp1-binding GC-box in the RelA/p65 proximal promoter (bp, -31 to -21). Moreover, recent studies revealed that RelA/p65 directly binds to the peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α) to decrease transcriptional activation of the PGC1α target gene PDK4, whose gene product inhibits pyruvate dehydrogenase (PDH), a key regulator of TCA cycle flux. Accordingly, we observed that RelA/p65 repression by ZBTB2 indirectly results in increased PDK4 expression, which inhibits PDH. Consequently, in cells with ectopic ZBTB2, the concentrations of pyruvate and lactate were higher than those in normal cells, indicating changes in glucose metabolism flux favoring glycolysis over the TCA cycle. Knockdown of ZBTB2 in mouse xenografts decreased tumor growth. ZBTB2 may increase cell proliferation by reprogramming glucose metabolic pathways to favor glycolysis by upregulating PDK4 expression via repression of RelA/p65 expression.

KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes.

An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53-p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.