Early Acute Kidney Injury Recovery in Elderly Patients Undergoing Valve Replacement Surgery.

OBJECTIVES: This study was designed to determine the incidence, contributing factors, and prognostic implications of acute kidney injury (AKI) recovery patterns in patients who experienced AKI after valve replacement surgery (VRS). DESIGN: A retrospective cohort study was conducted. SETTING: The work took place in a postoperative care center in a single large-volume cardiovascular center. PARTICIPANTS: Patients undergoing VRS between January 2010 and December 2019 were enrolled. INTERVENTION: Patients were categorized into three groups based on their postoperative AKI status: non-AKI, AKI with early recovery (less than 48 hours), and persistent AKI. MEASUREMENT AND MAIN RESULTS: The primary outcome was in-hospital major adverse clinical events. The secondary outcomes included in-hospital and 1-year mortality. A total of 4,161 patients who developed AKI following VRS were included. Of these, 1,513 (36.4%) did not develop postoperative AKI, 1,875 (45.1%) experienced AKI with early recovery, and 773 (18.6%) had persistent AKI. Advanced age, diabetes, New York Heart Association III-IV heart failure, moderate-to-severe renal dysfunction, anemia, and AKI stages 2 and 3 were identified as independent risk factors for persistent AKI. In-hospital major adverse clinical events occurred in 59 (3.9%) patients without AKI, 88 (4.7%) with early AKI recovery, and 159 (20.6%) with persistent AKI (p < 0.001). Persistent AKI was independently associated with an increased risk of in-hospital adverse events and 1-year mortality. In contrast, AKI with early recovery did not pose additional risk compared with non-AKI patients. CONCLUSIONS: In patients who develop AKI following VRS, early AKI recovery does not pose additional risk compared with non-AKI. However, AKI lasting more than 48 hours is associated with an increased risk of in-hospital and long-term adverse outcomes.

Changes of cardiac output and velocity time integral in blood return at the end of renal replacement therapy predict fluid responsiveness in critically Ill patients with acute circulatory failure.

OBJECTIVES: To observe if blood return, also defined as the blood infusion test (BIT) could predict fluid responsiveness in critically ill patients with acute circulatory failure and renal replacement therapy (RRT). METHODS: This was a single-center, prospective, diagnostic accuracy study. Before BIT, the passive leg raise test (PLRT) was performed to record the change of cardiac output (ΔCO) by pulse contour analysis, and ΔCO > = 10% was defined as the fluid responder. Meanwhile, the change in velocity time integral (ΔVTI) was recorded by ultrasound. Later, the ΔCO and ΔVTI during BIT were recorded 5-10 min after PLRT. The receiver-operating characteristic curves of ΔCO and ΔVTI of BIT were performed in predicting the fluid responder defined by PLRT. RESULTS: A total of 43 patients with acute circulatory failure undergoing RRT were enrolled in the present study, and 25 patients (58.1%) were recognized as responders during PLRT. According to the receiver-operating characteristic curves, the cutoff value of ΔCO was 10% and ΔVTI was 9% during BIT with the area under curve of 0.96 and 0.94, respectively. CONCLUSIONS: BIT in RRT could identify fluid responsiveness in critically ill patients with shock. TRIAL REGISTRATION: ChiCTR-DDD-17010534. Registered on 30/01/2017 (retrospective registration).

Red blood cell distribution width: A severity indicator in patients with COVID-19.

Red blood cell distribution width (RDW) was frequently assessed in COVID-19 infection and reported to be associated with adverse outcomes. However, there was no consensus regarding the optimal cutoff value for RDW. Records of 98 patients with COVID-19 from the First People's Hospital of Jingzhou were reviewed. They were divided into two groups according to the cutoff value for RDW on admission by receiver operator characteristic curve analysis: ≤11.5% (n = 50) and >11.5% (n = 48). The association of RDW with the severity and outcomes of COVID-19 was analyzed. The receiver operating characteristic curve indicated that the RDW was a good discrimination factor for identifying COVID-19 severity (area under the curve = 0.728, 95% CI: 0.626-0.830, p < 0.001). Patients with RDW > 11.5% more frequently suffered from critical COVID-19 than those with RDW ≤ 11.5% (62.5% vs. 26.0%, p < 0.001). Multivariate logistic regression analysis showed RDW to be an independent predictor for critical illness due to COVID-19 (OR = 2.40, 95% CI: 1.27-4.55, p = 0.007). A similar result was obtained when we included RDW > 11.5% into another model instead of RDW as a continuous variable (OR = 5.41, 95% CI: 1.53-19.10, p = 0.009). RDW, as an inexpensive and routinely measured parameter, showed promise as a predictor for critical illness in patients with COVID-19 infection. RDW > 11.5% could be the optimal cutoff to discriminate critical COVID-19 infection.

The effect of preoperative statin treatment on acute kidney injury in elderly patients undergoing valve replacement surgery.

PURPOSES: The effects of preoperative statin treatment on acute kidney injury (AKI) remain controversial, and current clinical evidence regarding statin use in the elderly undergoing valve replacement surgery (VRS) is insufficient. The present study aimed to investigate the association between preoperative statin treatment and AKI after VRS in the elderly. METHODS: Three thousand seven hundred ninety-one elderly patients (≥ 60 years) undergoing VRS were included in this study and divided into 2 groups, according to the receipt of statin treatment before the operation: statin users (n = 894) and non-users (n = 2897). We determined the associations between statin use, AKI, and other adverse events using a multivariate model and propensity score-matched analysis. RESULTS: After propensity score-matched analysis, there was no difference between statin users and non-users in regard to postoperative AKI (72.5% vs. 72.4%, p = 0.954), in-hospital death (5.7% vs. 5.1%, p = 0.650) and 1-year mortality (log-rank = 0, p = 0.986). The multivariate analysis showed that statin use was not an independent risk factor for postoperative AKI (OR = 0.97, 95% CI: 0.90-1.17, p = 0.733), in-hospital mortality (OR = 1.12, 95% CI: 0.75-1.68, p = 0.568), or 1-year mortality (HR = 0.95, 95% CI: 0.70-1.28, p = 0.715). CONCLUSION: Preoperative statin treatment did not significantly affect the risk of AKI among elderly patients undergoing VRS.

Osteological development of a small and fast metamorphic frog, Microhyla fissipes (Anura, Neobatrachia, Microhylidae).

Describing osteological development is of great importance for understanding vertebrate phenotypic variations, form-functional transitions and ecological adaptations. Anurans exhibit dramatic changes in their morphology, habitat preferences, diet and behaviour between the tadpole and frog stages. However, the anatomical details of their cranial and postcranial development have not been extensively studied, especially in Microhylidae. In this work, we studied the microhylid Microhyla fissipes, commonly known as the ornamented pygmy frog, a small-sized frog with fast metamorphosis. Its osteological development was comprehensively described based on 120 cleared and stained specimens, including six tadpoles for each stage between 28 and 45, six juveniles and six adults. Additionally, 22 osteological traits of these specimens involved in food acquisition, respiration, audition and locomotion were selected and measured to reflect the changes in tadpole ecological functions during metamorphosis. Our study provides the first detailed qualitative and quantitative developmental information about these structures. Our results have confirmed that skeletal elements (viz., neopalatines, omosternum, clavicles and procoracoids) absent in adults are not detected during development. Our data reveal that morphologically, radical transformations of the cranial structures related to feeding and breathing are completed within stages 42-45 (72 h), but the relative length and width of these skeletons have changed in earlier stages. The postcranial skeletons correlated with locomotion are well developed before stage 42 and approach the adult morphology at stage 45. Indeed, the relative length of the pectoral girdle and forelimb reaches the adult level at stage 42 and stage 45, respectively, whereas that of the vertebral column, pelvic girdle and hind limbs increases from their appearance until reaching adulthood. Based on published accounts of 19 species from Neobatrachia, Mesobatrachia and Archaeobatrachia, cranial elements are among the first ossified skeletons in most studied species, whereas sphenethmoids, neopalatines, quadratojugals, mentomeckelians, carpals and tarsals tend to ossify after metamorphosis. These results will help us to better understand the ecomorphological transformations of anurans from aquatic to terrestrial life. Meanwhile, detailed morphological and quantitative accounts of the osteological development of Microhyla fissipes will provide a foundation for further study.

Association between Prognostic Nutritional Index and Contrast-Associated Acute Kidney Injury in Patients Complicated with Chronic Kidney Disease and Coronary Artery Disease.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) is a major adverse effect of coronary angiography (CAG). Patients with chronic kidney disease (CKD) and coronary artery disease (CAD) are at high risk of CA-AKI. This study aimed to investigate the association between prognostic nutritional index (PNI) and CA-AKI in this high-risk population. METHODS: This study enrolled a total of 4,391 patients. CA-AKI was defined as a serum creatinine increase ≥0.3 mg/dL or 50% from baseline within the first 48 hours following CAG. The PNI was calculated upon hospital admission: serum albumin (g/L) + 5 × total lymphocyte count (109/L). PNI was analysed from the high level to low level as a continuous variable and categorical variable which was divided into four groups by quartile. Restricted cubic splines and logistic regression were applied. RESULTS: Overall, 13.09% (575/4391) of patients developed CA-AKI. PNI score was significantly lower in patients with CA-AKI than that in patients without CA-AKI (P < 0.01). The relationship between PNI score and CA-AKI was linear. A logistic regression model revealed that decreased PNI score was associated with increased risk of CA-AKI [per 1-point decrement; adjusted OR = 1.08, 95% CI, 1.05-1.09; compared with Quartile 1 (PNI ≥ 46.30), Quartile 4 (PNI < 37.90), adjusted OR = 1.88, 95% CI: 1.41-2.51; and Quartile 3 (37.90 ≤ PNI < 42.15), adjusted OR = 1.37, 95% CI: 1.02-1.84]. CONCLUSION: Our study indicated a negative linear relationship between PNI score and CA-AKI in patients undergoing CAG complicated with CKD and CAD. It suggested that malnutrition is associated with increased risk of CA-AKI in this population.

Nutritional screening based on objective indices at admission predicts in-hospital mortality in patients with COVID-19.

BACKGROUND: Could nutritional status serve as prognostic factors for coronavirus disease 2019 (COVID-19)? The present study evaluated the clinical and nutritional characteristics of COVID-19 patients and explored the relationship between risk for malnutrition at admission and in-hospital mortality. METHODS: A retrospective, observational study was conducted in two hospitals in Hubei, China. Confirmed cases of COVID-19 were typed as mild/moderate, severe, or critically ill. Clinical data and in-hospital death were collected. The risk for malnutrition was assessed using the geriatric nutritional risk index (GNRI), the prognostic nutritional index (PNI), and the Controlling Nutritional Status (CONUT) via objective parameters at admission. RESULTS: Two hundred ninety-five patients were enrolled, including 66 severe patients and 41 critically ill patients. Twenty-five deaths were observed, making 8.47% in the whole population and 37.88% in the critically ill subgroup. Patients had significant differences in nutrition-related parameters and inflammatory biomarkers among three types of disease severity. Patients with lower GNRI and PNI, as well as higher CONUT scores, had a higher risk of in-hospital mortality. The receiver operating characteristic curves demonstrated the good prognostic implication of GNRI and CONUT score. The multivariate logistic regression showed that baseline nutritional status, assessed by GNRI, PNI, or CONUT score, was a prognostic indicator for in-hospital mortality. CONCLUSIONS: Despite variant screening tools, poor nutritional status was associated with in-hospital death in patients infected with COVID-19. This study highlighted the importance of nutritional screening at admission and the new insight of nutritional monitoring or therapy.

Prognostic value of central venous-to-arterial carbon dioxide difference in patients with bloodstream infection.

Background: Bloodstream infection (BSI) are prone to circulation disorders, which portend poor outcome. The central venous-to-arterial carbon dioxide difference (Pcv-aCO2) is a biomarker for circulation disorders, but the prognostic value of Pcv-aCO2 in BSI patients remains unclear. This study was to investigate the association of Pcv-aCO2 with adverse events in BSI patients. Methods: The patients with BSI between August 2014 and August 2017 were prospectively enrolled. Clinical characteristic and laboratory results were collected. We analyzed the association of the level of Pcv-aCO2 with clinical variables and 28-day mortality. Results: A total of 152 patients were enrolled. The Pcv-aCO2 was positively correlated with white blood cell count (r=0.241, p=0.003), procalcitonin (r=0.471, p<0.001), C-reactive protein (r=0.192, p=0.018), lactate (r=0.179, p=0.027), Sequential Organ Failure Assessment (r=0.318, p<0.001) and Acute Physiology And Chronic Health Evaluation II score (r=0.377, p<0.001), while that was negatively correlated with central venous oxygen saturation (r=-0.242, p<0.001) and platelet (r=-0.205, p=0.011). Kaplan-Meier curves demonstrated that patients with Pcv-aCO2 >6mmHg had a worse prognosis than those without (log rank=32.10, p<0.001). Multivariate analysis showed Level of Pcv-aCO2 was an independent risk factor for 28-day mortality (HR: 3.10, 95% CI: 1.43-6.74, p=0.004). The area under the receiver operating characteristic curve of Pcv-aCO2 for prediction of 28-day mortality in patients with BSI was 0.794. Pcv-aCO2>6 mmHg had 81.1% sensitivity and 78.8% specificity for predicting 28-day mortality. Conclusion: Pcv-aCO2 may be a simple and valuable biomarker to assessment of 28-day mortality in patients with BSI.

Imminent rupture of abdominal aortic aneurysm complicated by arteriovenous fistulaization and hepatorenal failure: case report and literature review.

Arteriovenous fistula (AVF) is a rare complication of the abdominal aortic aneurysm (AAA) with complex clinical features. However, AVF and AAA usually cause no symptoms except when they rupture. This case study demonstrated that ultrasonography was a rapid and non-invasive method for the initial assessment of AAA and AVF. A 65-year-old man was admitted to the intensive care unit with hepatic and renal dysfunction. Physical examination revealed an abdominal vascular murmur and bilateral toe discoloration. Ultrasonic examination revealed an AAA and right common iliac artery aneurysm with an AVF located between the right common iliac artery and inferior vena cava. A computed tomography scan confirmed the sonographic findings. We propose that ultrasound should be used more commonly as part of the initial evaluation of the potential and established vascular diseases.

Identification and differential regulation of microRNAs during thyroid hormone-dependent metamorphosis in Microhyla fissipes.

BACKGROUND: Anuran metamorphosis, which is obligatorily initiated and sustained by thyroid hormone (TH), is a dramatic example of extensive morphological, biochemical and cellular changes occurring during post-embryonic development. Thus, it provides an ideal model to understand the actions of the hormone and molecular mechanisms underlying these developmental and apoptotic processes. In addition to transcriptional factors, microRNAs (miRNAs) play key roles in diverse biological processes via post-transcriptional repression of mRNAs. However, the possible role of miRNAs in anuran metamorphosis is not well understood. Screening and identification of TH-responding miRNAs are required to reveal the integrated regulatory mechanisms of TH during metamorphosis. Given the specific role of TRs during M. fissipes metamorphosis and the characteristics of M. fissipes as an ideal model, Illumina sequencing technology was employed to get a full scope of miRNA in M. fissipes metamorphosis treated by T3. RESULTS: Morphological and histological analysis revealed that 24 h T3 treatment M. fissipes tadpoles resembled that at the climax of natural metamorphosis. Thus, small RNA libraries were constructed from control and 24 h T3 treatment groups. A total of 164 conserved miRNAs and 36 predicted novel miRNAs were characterized. Furthermore, 5' first and ninth nucleotides of miRNAs were significantly enriched in U in our study. In all, 21 miRNAs were differentially expressed between the T3 and control groups (p < 0.01). A total of 10,206 unigenes were identified as target genes of these differentially expressed miRNAs. KEGG pathway analysis indicated that the most overrepresented miRNA target genes were enriched in the "PI3k-Akt signaling pathway". In addition, a network associated with the TH signaling pathway provides an opportunity to further understand the complex biological processes that occur in metamorphosis. CONCLUSIONS: We identified a large number of miRNAs during M. fissipes metamorphosis, and 21 of them were differentially expressed in the two groups that represented two different metamorphic stages. These miRNAs may play important roles during metamorphosis. The study gives us clues for further studies of the mechanisms of anuran metamorphosis and provides a model to study the mechanism of TH-affected biological processes in humans.

Diagnostic value of cardiopulmonary ultrasound in elderly patients with acute respiratory distress syndrome.

BACKGROUND: Lung ultrasound and echocardiography are mainly applied in critical care and emergency medicine. However, the diagnostic value of cardiopulmonary ultrasound in elderly patients with acute respiratory distress syndrome (ARDS) is still unclear. METHODS: Consecutive patients admitted to ICU with the diagnosis of suspected ARDS based on clinical grounds were enrolled. Cardiopulmonary ultrasound was performed as part of monitoring on day 1, day 2 and day 3. On each day a bedside ultrasound was performed to examine the lungs and calculate the Left Ventricular Ejection Fraction (LVEF). On day 3, a thoracic CT was performed on each patient as gold standard for ARDS imaging diagnosis. According to the results from CT scan, patients were grouped into ARDS group or Non-ARDS group. The relation between the cardiopulmonary ultrasound results on each day and the results of CT scan was analyzed. RESULTS: Fifty one consecutive patients aged from 73 to 97 years old were enrolled. Based on CT criteria, 33 patients were classified into the ARDS group, while 18 patients were included in non-ARDS group. There was no significant difference between the two groups in baseline characteristics, including gender, age, underlying disease, comorbidities, APACHE II score, SOFA score, and PaO2/FiO2 ratio (P > 0.05). Lung ultrasound (LUS) examination results were consistent with the CT scan results in diagnosis of pulmonary lesions. The Kappa values were 0.55, 0.74 and 0.82 on day 1, day 2 and day 3, respectively. The ROC analysis showed that the sensitivity, specificity and area under curve of ROC (AUROC) for lung ultrasound in diagnose ARDS were 0.788,0.778,0.783;0.909,0.833,0.871;0.970,0.833,0.902 on day 1, day 2 and day 3, respectively. However, cardiopulmonary ultrasound performed better in diagnosing ARDS in elderly patients. The sensitivity, specificity and AUROC were 0.879,0.889,0.924;0.939,0.889,0.961;and 0.970,0.833,0.956 on day 1, day 2 and day 3, respectively. The combined performances of cardiopulmonary ultrasound, N-terminal pro-brain natriuretic peptide (NT-proBNP), and PaO2/FiO2 ratio improved the specificity of the diagnosis of ARDS in elderly patients. CONCLUSIONS: LUS examination results were consistent with the CT scan results in diagnosis of pulmonary lesions. Cardiopulmonary ultrasound has a greater diagnostic accuracy in elderly patients with ARDS, compared with LUS alone. The combined performances of cardiopulmonary ultrasound, NT-proBNP, and PaO2/FiO2 increased the specificity of the diagnosis of ARDS in elderly patients.

Urinary Trypsin Inhibitor Attenuates Acute Lung Injury by Improving Endothelial Progenitor Cells Functions.

BACKGROUND: Urinary Trypsin Inhibitor (UTI) is involved in various aspects of tissue repair, regeneration and development. However, the potential role of UTI in protection against acute lung injury (ALI) remains largely unknown. In the present study, we demonstrated that UTI treatment could ameliorate ALI induced by oleic acid (OA) treatment in rabbit model. METHODS: Intravenous application of UTI (10000 U/kg/d) significantly improved the pathologies associated with OA-induced ALI. The lungs were stained with hematoxylin and eosin to scored the lung injury. Peripheral blood mononuclear cells were isolated by density gradient centrifugation with Ficoll-Plaque Plus. The proliferation and ability of tube structure formation of EPCs were observed and the level of phosphorylated Akt protein expression and eNOS protein expression were assayed. RESULTS: Consistent with pathological scores, UTI treatment significantly reduced wet/dry ratio of OA injured lungs. A quantification of capillary density revealed that UTI treatment led to about 2 fold increase over uninjured control and about 1.5 fold increase over PBS treatment. The capacity for tube formation of EPCs on ECM gel was significantly reduced in the ALI group and recovered with UTI treatment. Quantification of western blot bands was summarized and showed that UTI treatment activates Akt/eNOS signaling. NO production could contribute to the improvement of EPCs function by UTI treatment. CONCLUSIONS: UTI-induced phosphorylation/activation of eNOS and Akt, increases the intracellular level of NO, thereby improving tube formation and proliferation function of EPCs. EPCs function is crucial for re-endothelialization after denuding injuries of arteries.

Stromal cell-derived factor-1α attenuates oleate-induced acute lung injury in rabbits.

The stromal cell-derived factor-1α/C-X-C chemokine receptor 4 (SDF-1/CXCR4) axis is involved in various aspects of tissue repair, regeneration and development. However, the role of SDF-1/CXCR4 in acute lung injury (ALI) remains largely unknown. The aim of the present investigation is to examine pathological changes in a rabbit model with ALI induced by oleic acid (OA) and to explore the protective effect of SDF-1α on ALI. Intravenous application (i.v.) of oleic acid (0.1 ml/kg/h for 2h) provoked pulmonary hemorrhage, edema, and protein leakage, resulting in severe ALI. When the rabbit received an infusion of SDF-1α (20 µg/kg/24h) for 30 min before OA treatment, SDF-1α seemed to significantly improve the pathologies associated with OA-induced ALI. While dissecting the molecular mechanisms underlying the beneficial effects of SDF-1α, we found that SDF-1/CXCR4 is expressed in uninjured lung tissues but is greatly reduced after OA treatment. Interestingly, intravenous delivery of SDF-1α could target an injured lung and rescue expression of CXCR4, which in turn activates anti-apoptotic proteins, Bcl-1 and Bcl-xl, but does not affect pro-apoptotic proteins, such as Bad and Bax. These data suggested that SDF-1α could protect rabbit lungs from AIL. The molecular mechanism might be associated with upregulating anti-apoptosis family expression through CXCR4. Thus, SDF-1/CXCR4 signaling pathway may be a promising target for treatment of patients with ALI.

Circular RNAs as potential biomarkers for male severe sepsis.

Circular RNAs (circRNAs) play important roles in many human diseases. However, their role in the development of severe sepsis, a condition that remains one of the main causes of death in intensive care units, has not yet been defined. In this study, we interrogated the molecular mechanisms of circRNAs in severe sepsis. We profiled the expression levels of 5,680 circRNAs in plasma extracted from blood samples of 9 severe sepsis cases or 9 controls (male, age 78 ± 7) using the Human circRNA Array. To enrich protein-coding genes hosting severe sepsis-related circRNAs, we conducted gene ontology and pathways analyses. Out of the identified 760 differentially expressed circRNAs, 404 were upregulated while 356 were downregulated (fold change [FC] ≥2 or ≤-2, and false discovery ratio <0.05). Circ-0008285 (located in exons of CDYL), showed significant upregulation in severe sepsis with an FC of 13.7, and Bonferroni-corrected P < 0.05/5. In silico analysis identified Circ-0008285 interacting microRNAs as well as protein-coding genes. We systematically investigated the differential expression pattern of circRNAs in severe sepsis. The circRNAs we identified might serve as potential biomarkers for diagnosis and prognosis of sepsis.

Simplifying Genotyping of Mutants from Genome Editing with a Parallel qPCR-Based iGenotype Index.

Targeted genome editing is a powerful tool in reverse genetic studies of gene function in many aspects of biological and pathological processes. The CRISPR/Cas system or engineered endonucleases such as ZFNs and TALENs are the most widely used genome editing tools that are introduced into cells or fertilized eggs to generate double-strand DNA breaks within the targeted region, triggering cellular DNA repair through either homologous recombination or non-homologous end joining (NHEJ). DNA repair through the NHEJ mechanism is usually error-prone, leading to point mutations or indels (insertions and deletions) within the targeted region. Some of the mutations in embryos are germline transmissible, thus providing an effective way to generate model organisms with targeted gene mutations. However, point mutations and short indels are difficult to be effectively genotyped, often requiring time-consuming and costly DNA sequencing to obtain reliable results. Here, we developed a parallel qPCR assay in combination with an iGenotype index to allow simple and reliable genotyping. The genotype-associated iGenotype indexes converged to three simple genotype-specific constant values (1, 0, -1) regardless of allele-specific primers used in the parallel qPCR assays or gene mutations at wide ranges of PCR template concentrations, thus resulting in clear genotype-specific cutoffs, established through statistical analysis, for genotype identification. While we established such a genotyping assay in the Xenopus tropicalis model, the approach should be applicable to genotyping of any organism or cells and can be potentially used for large-scale, automated genotyping.

Protein arginine methyltransferase 1 regulates mouse enteroendocrine cell development and homeostasis.

BACKGROUND: The adult intestinal epithelium is a complex, self-renewing tissue composed of specialized cell types with diverse functions. Intestinal stem cells (ISCs) located at the bottom of crypts, where they divide to either self-renew, or move to the transit amplifying zone to divide and differentiate into absorptive and secretory cells as they move along the crypt-villus axis. Enteroendocrine cells (EECs), one type of secretory cells, are the most abundant hormone-producing cells in mammals and involved in the control of energy homeostasis. However, regulation of EEC development and homeostasis is still unclear or controversial. We have previously shown that protein arginine methyltransferase (PRMT) 1, a histone methyltransferase and transcription co-activator, is important for adult intestinal epithelial homeostasis. RESULTS: To investigate how PRMT1 affects adult intestinal epithelial homeostasis, we performed RNA-Seq on small intestinal crypts of tamoxifen-induced intestinal epithelium-specific PRMT1 knockout and PRMT1fl/fl adult mice. We found that PRMT1fl/fl and PRMT1-deficient small intestinal crypts exhibited markedly different mRNA profiles. Surprisingly, GO terms and KEGG pathway analyses showed that the topmost significantly enriched pathways among the genes upregulated in PRMT1 knockout crypts were associated with EECs. In particular, genes encoding enteroendocrine-specific hormones and transcription factors were upregulated in PRMT1-deficient small intestine. Moreover, a marked increase in the number of EECs was found in the PRMT1 knockout small intestine. Concomitantly, Neurogenin 3-positive enteroendocrine progenitor cells was also increased in the small intestinal crypts of the knockout mice, accompanied by the upregulation of the expression levels of downstream targets of Neurogenin 3, including Neuod1, Pax4, Insm1, in PRMT1-deficient crypts. CONCLUSIONS: Our finding for the first time revealed that the epigenetic enzyme PRMT1 controls mouse enteroendocrine cell development, most likely via inhibition of Neurogenin 3-mediated commitment to EEC lineage. It further suggests a potential role of PRMT1 as a critical transcriptional cofactor in EECs specification and homeostasis to affect metabolism and metabolic diseases.

Essential and subtype-dependent function of thyroid hormone receptors during Xenopus metamorphosis.

Thyroid hormone (T3) plays critical roles in organ metabolism and development in vertebrates. Anuran metamorphosis is perhaps the most dramatic and best studied developmental process controlled by T3. Many changes in different organs/tissues during anuran metamorphosis resemble the maturation/remodeling of the corresponding organs/tissues during mammalian postembryonic development. The plasma T3 level peaks during both anuran metamorphosis and mammalian postembryonic development. T3 exerts its developmental function through transcriptional regulation via T3 receptors (TRs). Studies on the metamorphosis of two highly related anurans, pseudo-tetraploid Xenopus laevis and diploid Xenopus tropicalis, have led to a dual function model for TRs during development. This has been supported by strong molecular and genetic evidence. Here we review some of the evidence with a focus on more recent gene knockout studies in Xenopus tropicalis. These studies have not only supported the model but also revealed novel and TR subtype-specific roles during Xenopus development, particularly a critical role of TRα in controlling developmental timing and rate.

Liver development during Xenopus tropicalis metamorphosis is controlled by T3-activation of WNT signaling.

Thyroid hormone (T3) regulates vertebrate organ development, growth, and metabolism through the T3 receptor (TR). Due to maternal influence in mammals, it has been difficult to study if and how T3 regulates liver development. Liver remodeling during anuran metamorphosis resembles liver maturation in mammals and is controlled by T3. We generated Xenopus tropicalis animals with both TRα and TRß genes knocked out and found that TR double knockout liver had developmental defects such as reduced cell proliferation and failure to undergo hepatocyte hypertrophy or activate urea cycle gene expression. RNA-seq analysis showed that T3 activated canonical Wnt pathway in the liver. Particularly, Wnt11 was activated in both fibroblasts and hepatic cells, and in turn, likely promoted the proliferation and maturation of hepatocytes. Our study offers new insights into not only how T3 regulates liver development but also on potential means to improve liver regeneration.

Comparative Analysis of Transcriptome Profiles Reveals Distinct and Organ-Dependent Genomic and Nongenomic Actions of Thyroid Hormone in Xenopus tropicalis Tadpoles.

Background: Thyroid hormone (triiodothyronine [T3]) is essential for development and organ metabolism in all vertebrates. T3 has both genomic and nongenomic effects on target cells. While much has been learnt on its genomic effects via T3 receptors (TRs) in vertebrate development, mostly through TR-knockout and TR-knockin studies, little is known about the effects of T3 on gene expression in animals in the absence of TR. We have been studying Xenopus metamorphosis as a model for mammalian postembryonic development, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult forms. We have recently generated TR double knockout (TRDKO) Xenopus tropicalis animals. This offers an opportunity to compare the effects of T3 on global gene expression in tadpole tissues in the presence or absence of TR. Methods: We analyzed the effects of T3 on gene expression in tadpole tail and intestine by using RNA-seq analysis on wild-type and TRDKO tadpoles with or without T3 treatment. Results: We observed that removing TRs reduced the number of genes regulated by T3 in both organs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that T3 affected distinct biological processes and pathways in wild-type and TRDKO tadpoles. Many GO terms and KEGG pathways that were enriched among genes regulated in wild-type tissues are likely involved in mediating the effects of T3 on metamorphosis, for example, those related to development, stem cells, apoptosis, and cell cycle/cell proliferation. However, such GO terms and pathways were not enriched among T3-regulated genes in TRDKO tadpoles. Instead, in TRDKO tadpoles, GO terms and pathways related to "metabolism" and "immune response" were highly enriched among T3-regulated genes. We further observed strong divergence in the TR-independent nongenomic effects of T3 in the intestine and tail. Conclusions: Our data suggest that T3 has distinct and organ-dependent effects on gene expression in developing tadpoles. The TR-mediated effects are consistent with the metamorphic changes, in agreement with the fact that TR is necessary and sufficient to mediate the effects of T3 on metamorphosis. T3 appears to have a major effect on metabolism and immune response via TR-independent nongenomic processes.