Maternal mRNAs with distinct 3' UTRs define the temporal pattern of Ccnb1 synthesis during mouse oocyte meiotic maturation.

The final stages of female gamete maturation occur in the virtual absence of transcription, with gene expression driven by a program of selective unmasking, translation, and degradation of maternal mRNAs. Here we demonstrate that the timing of Ccnb1 mRNA translation in mouse oocytes is dependent on the presence of transcripts with different 3' untranslated regions (UTRs). This 3' UTR heterogeneity directs distinct temporal patterns of translational activation or repression. Inclusion or exclusion of cis-acting elements is responsible for these divergent regulations. Our findings reveal an additional layer of translation control through alternative polyadenylation usage required to fine-tune the timing of meiosis progression.

Proteomics analysis of an individual formalin-fixed paraffin-embedded tissue section using isobaric-tag amplification.

RATIONALE: The comprehensive analysis of formalin-fixed paraffin-embedded (FFPE) tissues is essential for retrospective clinical studies. However, detecting low-abundance proteins and obtaining proteome-scale data from FFPE samples pose analytical challenges in mass spectrometry-based proteomics. To overcome this challenge, our study focuses on implementing an isobaric labeling approach to improve the detection of low-abundance target proteins in FFPE tissues, thereby enhancing the qualitative and quantitative analysis. METHODS: We employed an isobaric labeling approach utilizing synthetic peptides or proteins to enable the qualitative and quantitative measurement of target proteins in FFPE tissue samples. To achieve this, we incorporated tandem mass tag (TMT)-labeled recombinant proteins or synthetic peptides into TMT-labeled metastatic breast cancer FFPE tissues. Through this strategy, we successfully detect coexisting CD276 (B7-H3) and CD147 proteins while identifying over 6000 proteins using targeted analysis of individual FFPE tissue sections. RESULTS: Our findings provide compelling evidence that the incorporation of isobaric labeling, along with the inclusion of TMT-labeled peptides or proteins, greatly enhances the detection of target proteins in FFPE tissue samples. By employing this approach, we were able to obtain robust qualitative measurements of CD276 and CD147 proteins, showcasing its effectiveness in identifying more than 6000 proteins in FFPE samples. CONCLUSIONS: The integration of an isobaric labeling approach, in conjunction with synthetic peptides or proteins, presents a valuable strategy for enhancing the detection and validation of target proteins in FFPE tissue analysis. This technique holds immense potential in retrospective clinical studies, as it enables comprehensive analysis of low-abundance proteins and facilitating proteome-scale investigations in FFPE samples. By leveraging this methodology, researchers can unlock new insights into disease mechanisms and advance our understanding of complex biological processes.

Motivations to Change Smoking Behaviors Between 2007 and 2019 in Australia: A Repeated Cross-sectional Study.

INTRODUCTION: In 2010, Australian tobacco excise (administered federally) increased by 25%, and by 12.5% annually from 2013 to 2020, with additional increases on roll-your-own (RYO) tobacco between 2017 and 2020. We estimated past year changes in smoking behavior among Australian adults who smoked (daily and non-daily) in the past year, and the association between consumer characteristics and stated motivations to change/attempt to change smoking behavior between 2007 and 2019. METHODS: Logistic regression analysis of combined data from national representative triennial cross-sectional surveys in Australia (N = 22 977). RESULTS: The main motivation cited for changing smoking behavior switched from health-related from 2007 to 2010 to cost-related from 2013 to 2019. Among those who quit between one and 12 months ago, living in a lower socioeconomic area (odds ratio (OR) = 1.61, 95% CI = 1.18% to -2.18%), was associated with reporting the cost of smoking motivated them to quit. Among those who reduced their smoking, smoking daily and >20 cigarettes/day vs. non-daily smoking (OR = 2.11, 95% CI = 1.60% to 2.78%), having high/very high psychological distress (OR = 1.33, 95% CI = 1.12% to 1.59%), and alcohol consumption (ORdaily drinking = 1.38, 95% CI = 1.05% to 1.81%) was associated with cost as a motivation. Exclusive (OR = 0.65, 95% CI = 0.53% to 0.80%) and non-exclusive (OR = 0.77, 95% CI = 0.65% to 0.91%) RYO use was associated with being less likely to report the cost of tobacco as motivation for cutting down. CONCLUSIONS: The cost of smoking became the most cited motivator to change smoking behavior (eg, quitting and cutting down), particularly for those who lived in low socioeconomic areas, smoked more cigarettes per day, drank alcohol, and had high/very high psychological distress. IMPLICATIONS: A change in the main federal tobacco control intervention implemented in Australia from mass-media campaigns to tobacco tax increases has likely led to cost, rather than health, being the main motivation cited for changing smoking behavior in Australia since 2013. Further monitoring is needed to ensure the harmonization in tax rates for RYO and factory-made cigarettes has effectively reduced the price difference between these products because the lower cost of RYO may have reduced the effectiveness of tax increases as a motivator to change smoking behavior.

Tobacco purchasing in Australia during regular tax increases: findings from the International Tobacco Control Policy Evaluation Project.

OBJECTIVE: We examined Australian tobacco purchasing trends, the average self-reported price paid within each purchase type and the association between type of tobacco product purchased and participant characteristics, including quit intentions, between 2007 and 2020. METHODS: We analysed data collected from adults who smoked factory-made and/or roll-your-own (RYO) cigarettes in nine waves (2007-2020) of the International Tobacco Control Policy Evaluation Project Australia Survey (nsample=5452, nobservations=11 534). The main outcome measures were type of tobacco products purchased: RYO, carton, pack or pouch size and brand segment. Logistic regression, fit using generalised estimating equations, was estimated the association between the outcome and participant characteristics. RESULTS: The reported price-minimising purchasing patterns increased from 2007 to 2020: any RYO (23.8-43.9%), large-sized pack (2007: 24.0% to 2016: 34.3%); shifting from large-sized to small-sized packs (2020: 37.7%), and economy brand (2007: 37.2% to 2020: 59.3%); shifting from large (2007: 55.8%) to small economy packs (2014: 15.3% to 2020: 48.1%). Individuals with a lower income, a higher nicotine dependence level and no quit intention were more likely to purchase RYO and large-sized packs. CONCLUSION: RYO, large-sized packs and products with a low upfront cost (eg, small RYO pouches and small-sized economy brand packs) may appeal to people on low incomes. Australia's diverse tobacco pack and pouch sizes allow the tobacco industry to influence tobacco purchases. Standardising pack and pouch sizes may reduce some price-related marketing and especially benefit people who have a low income, are highly addicted and have no quit intention.

Tobacco endgame and priority populations: a scoping review.

AIM: To summarise the research literature on the impacts or perceptions of policies to end tobacco use at a population level (ie, tobacco endgame policies) among people from eight priority population groups (experiencing mental illness, substance use disorders, HIV, homelessness, unemployment or low incomes, who identify as lesbian, gay, bisexual, transgender, queer or intersex (LGBTQI+) or who have experienced incarceration). METHODS: Guided by JBI Scoping Review Methodology, we searched six databases for original research examining the impacts or perceptions of 12 tobacco endgame policies among eight priority populations published since 2000. We report the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. RESULTS: Of the 18 included studies, one described perceptions of five endgame policies among people on low incomes in Aotearoa (New Zealand), and 17 focused on the effectiveness or impacts of a very low nicotine content (VLNC) cigarette standard among people experiencing mental illness (n=14), substance use disorders (n=8), low incomes (n=6), unemployment (n=1) or who identify as LGBTQI+ (n=1) in the USA. These studies provide evidence that VLNC cigarettes can reduce tobacco smoking, cigarette cravings, nicotine withdrawal and nicotine dependence among these populations. CONCLUSIONS: Most of the tobacco endgame literature related to these priority populations focuses on VLNC cigarettes. Identified research gaps include the effectiveness of endgame policies for reducing smoking, impacts (both expected and unexpected) and policy perceptions among these priority populations.

Plasma Circulating Tumor Necrosis Factor Receptors at Multiple Time Points Can Predict the Outcome of Severe Acute Kidney Injury.

INTRODUCTION: This prospective cohort study investigated the clinical role of circulating tumor necrosis factor receptor (cTNFR) levels as prognostic biomarkers in severe acute kidney injury (AKI) patients requiring continuous renal replacement therapy (CRRT). METHODS: We enrolled 136 patients from 7 hospitals participating in the VENUS (VolumE maNagement Under body composition monitoring in critically ill patientS on CRRT) trial from July 2017 to October 2019. The levels of cTNFR1 and cTNFR2 were measured using plasma samples collected on days 0 (D0), 2 (D2), and 7 (D7). Patients were divided into high- and low-cTNFR groups based on their receptor concentrations. RESULTS: D0 concentrations of cTNFR1 and cTNFR2 were positively correlated with one another (R2 = 0.37, p < 0.001). The high-cTNFR1 group displayed a higher in-hospital mortality rate than the low-TNFR1 group (p = 0.002). Moreover, the mortality rate was significantly higher in the high-TNFR1 group than in the low-TNFR1 group after adjusting for age, sex, and acute physiology, and chronic health evaluation II scores (hazard ratio 1.82, 95% confidence interval 1.09-3.03, p = 0.025). D2 and D7 cTNFR1 levels were also associated with in-hospital mortality; contrastingly, cTNFR2 levels were not associated with this outcome. Additionally, patients were divided into three groups according to the change in cTNFR levels from D0 to D2 (ΔcTNFR). Those in the highest ΔcTNFR tertile had a higher mortality rate than the remaining patients (p = 0.033 for ΔcTNFR1; p = 0.025 for ΔcTNFR2). Patients who underwent AKI-to-chronic kidney disease transition had higher concentrations of cTNFR1 (p = 0.014). DISCUSSION/CONCLUSION: Plasma cTNFR1 concentrations at CRRT initiation and changes in cTNFR1 and 2 levels immediately following CRRT initiation are significant biomarkers for predicting the outcomes of patients with severe AKI.

Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

Mode of action, indications and recommendations on extracorporeal photopheresis (ECP).

Extracorporeal photopheresis (ECP) has gained importance in the treatment of several diseases. Initially introduced as a new therapeutic modality for the treatment of patients with cutaneous T-cell lymphoma, the indications for the use of ECP have expanded to include hematology and transplantation immunology. Extracorporeal photopheresis has found its place in the treatment plan of cutaneous T-cell lymphoma, systemic sclerosis, graft-versus-host disease, organ transplantation such as heart and lung, sometimes as first-line therapy and very often in combination with various systemic immunosuppressive therapies. The procedure basically consists of three steps: leukapheresis, photoactivation and reinfusion. The following article presents possible theories about the mechanism of action, which is not yet fully understood, and discusses the five most common indications for ECP treatment with corresponding therapy recommendations.

Tuning Local Coordination Environments of Manganese Single-Atom Nanozymes with Multi-Enzyme Properties for Selective Colorimetric Biosensing.

Single-atom nanozymes (SAzymes) are promising in next-generation nanozymes, nevertheless, how to rationally modulate the microenvironment of SAzymes with controllable multi-enzyme properties is still challenging. Herein, we systematically investigate the relationship between atomic configuration and multi-enzymatic performances. The constructed MnSA -N3 -coordinated SAzymes (MnSA -N3 -C) exhibits much more remarkable oxidase-, peroxidase-, and glutathione oxidase-like activities than that of MnSA -N4 -C. Based on experimental and theoretical results, these multi-enzyme-like behaviors are highly dependent on the coordination number of single atomic Mn sites by local charge polarization. As a consequence, a series of colorimetric biosensing platforms based on MnSA -N3 -C SAzymes is successfully built for specific recognition of biological molecules. These findings provide atomic-level insight into the microenvironment of nanozymes, promoting rational design of other demanding biocatalysts.

An improved Raphanus sativus cv. WK10039 genome localizes centromeres, uncovers variation of DNA methylation and resolves arrangement of the ancestral Brassica genome blocks in radish chromosomes.

KEY MESSAGE: This study presents an improved genome of Raphanus sativus cv. WK10039 uncovering centromeres and differentially methylated regions of radish chromosomes. Comprehensive genome comparison of radish and diploid Brassica species of U's triangle reveals that R. sativus arose from the Brassica B genome lineage and is a sibling species of B. nigra. Radish (Raphanus sativus L.) is a key root vegetable crop closely related to the Brassica crop species of the family Brassicaceae. We reported a draft genome of R. sativus cv. WK10039 (Rs1.0), which had 54.6 Mb gaps. To study the radish genome and explore previously unknown regions, we generated an improved genome assembly (Rs2.0) by long-read sequencing and high-resolution genome-wide mapping of chromatin interactions. Rs2.0 was 434.9 Mb in size with 0.27 Mb gaps, and the N50 scaffold length was 37.3 Mb (40-fold larger assembly compared to Rs1.0). Approximately 38% of Rs2.0 was comprised of repetitive sequences, and 52,768 protein-coding genes and 4845 non-protein-coding genes were predicted and annotated. The improved contiguity and coverage of Rs2.0, along with the detection of highly methylated regions, enabled localization of centromeres where R. sativus-specific centromere-associated repeats, full-length OTA and CRM LTR-Gypsy retrotransposons, hAT-Ac, CMC-EnSpm and Helitron DNA transposons, and sequences highly homologous to B. nigra centromere-specific CENH3-associated CL sequences were enriched. Whole-genome bisulfite sequencing combined with mRNA sequencing identified differential epigenetic marks in the radish genome related to tissue development. Synteny comparison and genomic distance analysis of radish and three diploid Brassica species of U's triangle suggested that the radish genome arose from the Brassica B genome lineage through unique rearrangement of the triplicated ancestral Brassica genome after splitting of the Brassica A/C and B genomes.

The relationship between occupational dust exposure and incidence of diabetes in male workers: A retrospective cohort study.

AIM: Previous studies have focused on the association between ambient particulate matter and diabetes. However, the relationship between subacute exposure to occupational dust and diabetes has not been explored. We aimed to assess this relationship. METHODS: Men who worked in dust-related process factories between January 2013 and December 2017 were recruited from a Korea Health Worker Examination Common Data Model cohort. A history of physician-diagnosed diabetes, use of an anti-diabetic drug, or a fasting blood glucose level of ≥7 mmol/L were considered the criteria to diagnose diabetes. Multivariable time-dependent Cox analysis estimated hazard ratios (HRs) and 95% CIs for incident diabetes associated with exposure to occupational dust exposure; interactions with lifestyle factors were analysed. Sensitivity analyses used propensity score matching and landmark analysis. RESULTS: Among 5141 male participants (median follow-up duration, 3.85 years), 349 participants had diabetes. Occupational dust exposure was related to an increased risk of diabetes in the time-dependent Cox analysis (entire cohort: HR 1.66 [95% CI 1.25-2.19], matched cohort: HR 1.65 [95% CI 1.22-2.24]). The findings showed the same direction in the landmark analysis (HR 1.42 [95% CI 1.01-1.99]). CONCLUSIONS: A significant relationship exists between occupational dust exposure and increased risk of diabetes in male workers. Further studies should be conducted to confirm that occupational dust exposure is a possible risk factor for diabetes.

Effective Screening Route for Highly Active and Selective Metal-Nitrogen-Doped Carbon Catalysts in CO2 Electrochemical Reduction.

To identify high-efficiency metal-nitrogen-doped (M-N-C) electrocatalysts for the electrochemical CO2 -to-CO reduction reaction (CO2 RR), a method that uses density functional theory calculation is presented to evaluate their selectivity, activity, and structural stability. Twenty-three M-N4 -C catalysts are evaluated, and three of them (M = Fe, Co, or Ni) are identified as promising candidates. They are synthesized and tested as proof-of-concept catalysts for CO2 -to-CO conversion. Different key descriptors, including the maximum reaction energy, differences of the *H and *CO binding energy (ΔG*H -ΔG*CO ), and *CO desorption energy (ΔG*CO→CO( g ) ), are used to clarify the reaction mechanism. These computational descriptors effectively predict the experimental observations in the entire range of electrochemical potential. The findings provide a guideline for rational design of heterogeneous CO2 RR electrocatalysts.

cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7.

We aimed to investigate the role of cMet agonistic antibody (cMet Ab) in preventing kidney fibrosis during acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Additionally, we explored the effect of cMet Ab on TGF-ß1/Smad pathway during the pathogenesis of kidney fibrosis. A unilateral ischemia-reperfusion injury (UIRI) mouse model was established to induce AKI-to-CKD transition. Furthermore, we incubated human proximal tubular epithelial cells (hPTECs) under hypoxic conditions as in vitro model of kidney fibrosis. We analyzed the soluble plasma cMet level in patients with AKI requiring dialysis. Patients who did not recover kidney function and progressed to CKD presented a higher increase in the cMet level. The kidneys of mice treated with cMet Ab showed fewer contractions and weighed more than the controls. The mice in the cMet Ab-treated group showed reduced fibrosis and significantly decreased expression of fibronectin and α-smooth muscle actin. cMet Ab treatment decreased inflammatory markers (MCP-1, TNF-α, and IL-1ß) expression, reduced Smurf1 and Smad2/3 level, and increased Smad7 expressions. cMet Ab treatment increased cMet expression and reduced the hypoxia-induced increase in collagen-1 and ICAM-1 expression, thereby reducing apoptosis in the in vitro cell model. After cMet Ab treatment, hypoxia-induced expression of Smurf1, Smad2/3, and TGF-ß1 was reduced, and suppressed Smad7 was activated. Down-regulation of Smurf1 resulted in suppression of hypoxia-induced fibronectin expression, whereas treatment with cMet Ab showed synergistic effects. cMet Ab can successfully prevent fibrosis response in UIRI models of kidney fibrosis by decreasing inflammatory response and inhibiting the TGF-ß1/Smad pathway.

High-Risk Human Papillomavirus Infection and the Risk of Cardiovascular Disease in Korean Women.

RATIONALE: Until now, no cohort studies have evaluated the relationship between high-risk human papillomavirus (HPV) infection and new-onset cardiovascular diseases (CVD). OBJECTIVE: We investigated an association between high-risk HPV infection and the development of CVD. METHODS AND RESULTS: We conducted a cohort study of 63 411 women aged 30 or older without CVD at baseline who underwent a high-risk HPV test and were followed annually or biennially from 2011 to 2016. CVD was ascertained through the linkage to the Health Insurance and Review Agency database. A Cox-proportional hazards regression model was used to estimate adjusted hazard ratios (HRs) with 95% CIs of incident CVD. The prevalence of high-risk HPV infection was 7.6%. During 261 598.9 person-years of follow-up, 1122 cases of new-onset CVD were identified (incidence rate of 4.3 per 103 person-years). High-risk HPV infection was significantly associated with incident CVD. After adjustment for possible confounders, and high sensitivity C-reactive protein, a significant association between high-risk HPV infection and incident CVD was still observed, with a corresponding HR (95% CI) of 1.25 (1.03-1.52). This association was stronger among individuals with obesity and those with metabolic syndrome. Multivariable-adjusted HR (95% CI) for incident CVD comparing high-risk HPV-positive- to high-risk HPV-negative participants was 1.10 (0.87-1.39) in the nonobese, whereas corresponding HR (95% CI) was 1.73 (1.19-2.51) in those with obesity ( P for interaction by obesity=0.02). Similarly, multivariable-adjusted HR (95% CI) for incident CVD comparing high-risk HPV-positive- to high-risk HPV-negative participants was 1.09 (0.87-1.36) in those without metabolic syndrome and 1.99 (1.28-3.08) in those with MetS ( P for interaction=0.05). CONCLUSION: In this large cohort, high-risk HPV infection was significantly associated with an increased risk of developing CVD, especially in obese individuals and those with MetS, indicating that high-risk HPV might affect CVD risk with possible effect modification by obesity and MetS.

Effect of deep learning-based assistive technology use on chest radiograph interpretation by emergency department physicians: a prospective interventional simulation-based study.

BACKGROUND: Interpretation of chest radiographs (CRs) by emergency department (ED) physicians is inferior to that by radiologists. Recent studies have investigated the effect of deep learning-based assistive technology on CR interpretation (DLCR), although its relevance to ED physicians remains unclear. This study aimed to investigate whether DLCR supports CR interpretation and the clinical decision-making of ED physicians. METHODS: We conducted a prospective interventional study using a web-based performance assessment system. Study participants were recruited through the official notice targeting board for certified emergency physicians and residents working at the present ED. Of the eight ED physicians who volunteered to participate in the study, seven ED physicians were included, while one participant declared withdrawal during performance assessment. Seven physicians' CR interpretations and clinical decision-making were assessed based on the clinical data from 388 patients, including detecting the target lesion with DLCR. Participant performance was evaluated by area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, and accuracy analyses; decision-making consistency was measured by kappa statistics. ED physicians with < 24 months of experience were defined as 'inexperienced'. RESULTS: Among the 388 simulated cases, 259 (66.8%) had CR abnormality. Their median value of abnormality score measured by DLCR was 59.3 (31.77, 76.25) compared to a score of 3.35 (1.57, 8.89) for cases of normal CR. There was a difference in performance between ED physicians working with and without DLCR (AUROC: 0.801, P < 0.001). The diagnostic sensitivity and accuracy of CR were higher for all ED physicians working with DLCR than for those working without it. The overall kappa value for decision-making consistency was 0.902 (95% confidence interval [CI] 0.884-0.920); concurrently, the kappa value for the experienced group was 0.956 (95% CI 0.934-0.979), and that for the inexperienced group was 0.862 (95% CI 0.835-0.889). CONCLUSIONS: This study presents preliminary evidence that ED physicians using DLCR in a clinical setting perform better at CR interpretation than their counterparts who do not use this technology. DLCR use influenced the clinical decision-making of inexperienced physicians more strongly than that of experienced physicians. These findings require prospective validation before DLCR can be recommended for use in routine clinical practice.

Alcoholic and Nonalcoholic Fatty Liver Disease and Incident Hospitalization for Liver and Cardiovascular Diseases.

BACKGROUND & AIMS: We compared the associations of nonalcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (AFLD) with risk of incident hospitalization for liver and cardiovascular diseases. METHODS: We collected data from the Kangbuk Samsung Health Study on 218,030 men and women in Korea who underwent a health examination from 2011 through 2016. Fatty liver disease (FLD) was detected by ultrasound during the initial examination. The Fibrosis-4 index was used to identify individuals with liver fibrosis. Participants were followed up for as long as 5.9 years and data on hospitalizations for liver and cardiovascular diseases were collected. RESULTS: The prevalence of NAFLD was 22.0% and the prevalence of AFLD was 6.4%. Over a median follow-up period of 4.2 years, we observed 51 and 1097 incident cases of liver disease- or cardiovascular disease-related hospitalizations, respectively. After adjustment for potential confounders, the multivariable-adjusted hazard ratios for liver disease-related hospitalization, comparing NAFLD and AFLD with the reference category (no excessive alcohol intake and no FLD), were 1.73 (95% CI, 0.76-3.96) and 5.00 (95% CI, 2.12-11.83), respectively. The corresponding hazard ratios for cardiovascular disease hospitalization were 1.20 (95% CI, 1.02-1.40) and 1.08 (95% CI, 0.86-1.34), respectively. Among participants with FLD, the risk of liver disease-related hospitalization increased with high Fibrosis-4 index scores, whereas the risk of incident cardiovascular disease did not. CONCLUSIONS: In a large cohort study, we found an increased risk of liver disease-related hospitalizations for patients with NAFLD or AFLD, especially among those with Fibrosis-4 index scores. An increased risk of cardiovascular disease-associated hospitalization was observed in patients with NAFLD but not AFLD.

A Novel Endogenous Damage Signal, CSF-2, Activates Multiple Beneficial Functions of Adipose Tissue-Derived Mesenchymal Stem Cells.

The major challenges of current mesenchymal stem cell (MSC)-based therapeutics are their low differentiation potential into specialized cell types and their homing ability to sites of injury. Therefore, many researchers have directed their efforts toward finding a novel stimulatory factor that can significantly enhance the therapeutic effects of MSCs. Colony-stimulating factor 2 (CSF-2) is previously known as a hematopoietic growth factor involved in the differentiation of various myeloid cells from hematopoietic progenitor cells. In addition to this canonical hematopoietic function, we identified for the first time that CSF-2 is actively secreted by stem cells, in response to various types of injuries, as an endogenous damage signal that promotes the therapeutic effects of MSCs by enhancing their multi-lineage differentiation and migratory capacities, possibly through its receptor CD116. Our results also revealed that CSF-2 exerts its stimulatory effects on MSCs via PI3K/Akt- and/or FAK/ERK1/2-signaling pathways. More importantly, we also found that MSCs stimulated with CSF-2 show markedly enhanced differentiation and migratory capacities and subsequent in vivo therapeutic effects in an endometrial ablation animal model. Collectively, our findings provide compelling evidence for a novel non-hematopoietic function of CSF-2 in promoting multiple beneficial functions of MSCs via a non-canonical mechanism as an endogenous damage signal.

An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2.

Endometrial stem cells are located in the basal layer of the endometrium, and they are responsible for the cyclic regeneration of the uterus during the menstrual cycle. Recent studies have revealed that recurrent pregnancy loss is associated with an age-related stem cell deficiency in the endometrium. Therefore, intensive study of endometrial stem cell aging may provide new insights for preventing recurrent pregnancy loss. Sonic hedgehog (SHH) signaling has been identified as a morphogen during the embryonic development processes. In addition to this canonical function, we found that the age-associated decline in regenerative potential in the endometrium may be due to decreased SHH-signaling integrity in local stem cells with aging. Importantly, the current study also showed that SHH activity clearly declines with aging both in vitro and in vivo, and exogenous SHH treatment significantly alleviates various aging-associated declines in multiple endometrial stem cell functions, suggesting that SHH may act as an endogenous anti-aging factor in human endometrial stem cells. Moreover, we found that stem cell senescence may enhance SERPINB2 expression, which in turn mediates the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions, suggesting that SERPINB2 is a master regulator of SHH signaling during the aging process.

CONICS integrates scRNA-seq with DNA sequencing to map gene expression to tumor sub-clones.

Motivation: Single-cell RNA-sequencing (scRNA-seq) has enabled studies of tissue composition at unprecedented resolution. However, the application of scRNA-seq to clinical cancer samples has been limited, partly due to a lack of scRNA-seq algorithms that integrate genomic mutation data. Results: To address this, we present. CONICS: COpy-Number analysis In single-Cell RNA-Sequencing. CONICS is a software tool for mapping gene expression from scRNA-seq to tumor clones and phylogenies, with routines enabling: the quantitation of copy-number alterations in scRNA-seq, robust separation of neoplastic cells from tumor-infiltrating stroma, inter-clone differential-expression analysis and intra-clone co-expression analysis. Availability and implementation: CONICS is written in Python and R, and is available from https://github.com/diazlab/CONICS. Supplementary information: Supplementary data are available at Bioinformatics online.

Nevskia lacus sp. nov., a gammaproteobacterium isolated from a eutrophic lake.

A novel Gram-stain negative, rod-shaped and motile bacterial strain, designated strain Seoho-38T, was isolated from a eutrophic lake in South Korea. Polyphasic taxonomic studies were performed to investigate the taxonomic position of the new isolate. The phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain Seoho-38T formed a distinct cluster with Nevskia ramosa Soe1T, Nevskia persephonica G6M-30T, Nevskia soli GR15-1T, Nevskia terrae KIS13-15T and Nevskia aquatilis F2-63T with bootstrap resampling value of 100%. Of those Nevskia strains, the new isolate shows high sequence similarity with N. ramosa Soe1T (98.7%) and N. persephonica G6M-30T (97.2%), and values lower than 96.5% with the other type strains. The new isolate was observed to grow aerobically in 0-1.5% (w/v) NaCl (optimum 0%), at pH 7.0-9.0 (optimum pH 7.0) and temperature 15-36 °C (optimum 20-30 °C) on R2A medium. DNA-DNA relatedness values between strain Seoho-38T and the type strains of reference species in the genus Nevskia were < 24%. The genomic DNA G + C content was determined to be 67.4 mol%. Ubiquinone-8 (Q-8) (95%) and ubiquinone-7 (Q-7) (5%) were identified as the respiratory quinones. The cellular polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, a phosphoaminolipid, two glycolipids, an aminolipid and four unidentified lipids. The major fatty acid components were found to include summed feature 3 (C16:1ω7c and/or C16:1ω6c), summed feature 8 (C18:0ω7c and/or C18:0ω6c), C16:0 and C14:0. Based on the above polyphasic evidence, strain Seoho-38T (= KCTC 52221T = JCM 31888T) represents a new species of the genus Nevskia, for which the name Nevskia lacus sp. nov. is proposed.