Background and objectives We undertook a systematic review and meta-analysis of published cohort studies and case-control studies to estimate (1) the risk of pregnancy complications among patients with CKD versus those without CKD and (2) the risk of CKD progression among pregnant patients versus nonpregnant controls with CKD.Design, setting, participants, & measurements We searched electronic databases for studies published between 1946 and 2014, and we reviewed articles using validity criteria. Random-effects analytical methods were used.Results Twenty-three studies (14 with data for adverse pregnancy outcomes and 9 for renal outcomes) with 506,340 pregnancies were included. Pregnancy with CKD had greater odds of preeclampsia (odds ratio [OR], 10.36; 95% confidence interval [95% CI], 6.28 to 17.09), premature delivery (OR, 5.72; 95% CI, 3.26 to 10.03), small for gestational age/low birth weight (OR, 4.85; 95% CI, 3.03 to 7.76), cesarean section (OR, 2.67; 95% CI, 2.01 to 3.54), and failure of pregnancy (OR, 1.80; 95% CI, 1.03 to 3.13). Subgroup analysis showed that odds of preeclampsia (P,0.01) and premature delivery (P,0.01) were higher in women with nondiabetic nephropathy compared with diabetic nephropathy, and the odds of preeclampsia (P=0.01) and premature delivery (P,0.01) were higher in women with macroproteinuria compared with microproteinuria. The median for follow-up time for renal events was 5 years (interquartile range, 5-14.7 years). There were no significant differences in the occurrence of renal events between CKD pregnant women and those without pregnancy (OR, 0.96; 95% CI, 0.69 to 1.35). Subgroup analysis showed that publication year, sample size, follow-up years, type of primary disease, CKD classification, level of serum creatinine at baseline, proteinuria, and level of systolic BP did not modify the renal outcomes.Conclusions The risks of adverse maternal and fetal outcomes in pregnancy are higher for women with CKD versus pregnant women without CKD. However, pregnancy was not a risk factor for progression of renal disease in women with CKD before pregnancy.

Cyclins, cyclin-dependent kinases and other components of the core cell cycle machinery drive cell division. Growing evidence indicates that this machinery operates in a distinct fashion in some mammalian stem cell types, such as pluripotent embryonic stem cells. In this review, we discuss our current knowledge of how cell cycle proteins mechanistically link cell proliferation, pluripotency and cell fate specification. We focus on embryonic stem cells, induced pluripotent stem cells, and embryonic neural stem/progenitor cells. The core cell cycle machinery operating in the cell nucleus orchestrates cell division. The key components of this machinery are proteins called cyclins that bind, activate and provide substrate specificity to their associated catalytic partners, the cyclin-dependent kinases (CDKs) 1-4. Cell cycle progression can be divided into four phases: gap 1 (G1), DNA synthesis (S), gap 2 (G2) and mitosis (M). Depending on the mitogenic environment, cells traversing G1 phase either activate a program that will result in cell division, or they enter a quiescent G0 state 1-4 (Fig. 1a). At the molecular level, stimulation of cells with growthpromoting factors results in upregulation of the D-type cyclins (D1, D2 and D3), which activate the cyclin-dependent kinase 4 (CDK4) and CDK6 1-5. In a classical cell cycle model, cyclin D-CDK4/6 complexes, together with E-type cyclins (E1 and E2) and their associated kinases (primarily CDK2, but also CDK1 and CDK3) phosphorylate and functionally inactivate the retinoblastoma protein RB1, and pRB1-related RBL1 and RBL2 proteins 1-4. This leads to the activation or de-repression of E2F transcription factors, which then transactivate genes required for the entry and progression of cells into S phase 1-4,6,7. This model has been questioned by the demonstration that throughout most of G1 phase, RB1 exists in a mono-phosphosphorylated state, and becomes fully phosphorylated by cyclin E-CDK2 at the end of G1 phase 8. In addition to RB1 phosphorylation, inactivation of Cdh1, a substrate recognition subunit of the anaphase promoting complex (APC/C), contributes to an Correspondence should be addressed to: P.S. Competing interests PS has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals and Exo Therapeutics; his laboratory receives research funding from Novartis. WM is currently an employee of Cedilla Therapeutics.

Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumor suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an “orphan” CDK19 kinase, as well as CDK8 and CDK3. These cyclin C-CDK complexes phosphorylate Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin C-knockout mice. Cyclin C ablation or heterozygosity collaborate with other oncogenic lesions and accelerate development of T-cell-acute lymphoblastic leukemia (T-ALL). Furthermore, the cyclin C gene is heterozygously deleted in a significant fraction of human T-ALL, and these tumors express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin C-CDK unable to phosphorylate ICN1. Hence, tumor cells may develop different strategies to evade cyclin C inhibitory function.

Progression of mammalian cells through the G1 and S phases of the cell cycle is driven by D-type and E-type cyclins. According to the current models, at least one of these cyclin families must be present to allow cell proliferation. Here, we show that several cell types can proliferate in the absence of all G1 cyclins. However, upon ablation of G1 cyclins, embryonic stem (ES) cells attenuated their pluripotent characteristics, with majority of cells acquiring the trophectodermal cell fate. We established that G1 cyclins, together with their associated cyclin-dependent kinases (CDKs) phosphorylate and stabilize core pluripotency factors Nanog, Sox2 and Oct4. Treatment of murine ES cells, patient-derived glioblastoma tumor-initiating cells, or triple-negative breast cancer cells with a CDK-inhibitor strongly decreased Sox2 and Oct4 levels. Our findings suggest that CDK-inhibition might represent an attractive therapeutic strategy by targeting glioblastoma tumor-initiating cells, which depend on Sox2 to maintain their tumorigenic potential.

Berberine (BBR) exerts potential protective effect against myocardial ischemia/reperfusion (MI/R) injury. Activation of silent information regulator 1 (SIRT1) signaling attenuates MI/R injury by reducing oxidative damage and inflammation response. This study investigated the antioxidative and anti-inflammatory effects of BBR treatment in MI/R condition and elucidated its potential mechanisms. Sprague-Dawley rats were treated with BBR in the absence or presence of the SIRT1 inhibitor sirtinol (Stnl) and then subjected to MI/R injury. BBR conferred cardioprotective effects by improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, diminishing serum creatine kinase and lactate dehydrogenase levels, upregulating SIRT1, Bcl-2 expressions, and downregulating Bax and caspase-3 expressions. Stnl attenuated these effects by inhibiting SIRT1 signaling. BBR treatment also reduced myocardium superoxide generation, gp91phox expression, malondialdehyde (MDA) level, and cardiac inflammatory markers and increased myocardium superoxide dismutase (SOD) level. However, these effects were also inhibited by Stnl. Consistently, BBR conferred similar antioxidative and anti-inflammatory effects against simulated ischemia reperfusion injury in cultured H9C2 cardiomyocytes. SIRT1 siRNA administration also abolished these effects. In summary, our results demonstrate that BBR significantly improves post-MI/R cardiac function recovery and reduces infarct size against MI/R injury possibly due to its strong antioxidative and anti-inflammatory activity. Additionally, SIRT1 signaling plays a key role in this process.

Since 2019, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causing coronavirus disease 2019 (COVID‐19) has infected 10 millions of people across the globe, and massive mutations in virus genome have occurred during the rapid spread of this novel coronavirus. Variance in protein sequence might lead to a change in protein structure and interaction, then further affect the viral physiological characteristics, which could bring tremendous influence on the pandemic. In this study, we investigated 20 nonsynonymous mutations in the SARS‐CoV‐2 genome in which incidence rates were all ≥ 1% as of September 1st, 2020, and then modeled and analyzed the mutant protein structures. The results showed that four types of mutations caused dramatic changes in protein structures (RMSD ≥ 5.0 Å), which were Q57H and G251V in open‐reading frames 3a (ORF3a), S194L, and R203K/G204R in nucleocapsid (N). Next, we found that these mutations also affected the binding affinity of intraviral protein interactions. In addition, the hot spots within these docking mutant complexes were altered, among which the mutation Q57H was involved in both Orf3a–S and Orf3a–Orf8 protein interactions. Besides, these mutations were widely distributed all over the world, and their occurrences fluctuated as time went on. Notably, the incidences of R203K/G204R in N and Q57H in Orf3a were both over 50% in some countries. Overall, our findings suggest that SARS‐CoV‐2 mutations could change viral protein structure, binding affinity, and hot spots of the interface, thereby might have impacts on SARS‐CoV‐2 transmission, diagnosis, and treatment of COVID‐19.

Crescentic IgA nephropathy (IgAN), defined as .50% crescentic glomeruli on kidney biopsy, is one of the most common causes of rapidly progressive GN. However, few studies have characterized this condition. To identify risk factors and develop a prediction model, we assessed data from patients$14 years old with crescentic IgAN who were followed $12 months. The discovery cohort comprised 52 patients from one kidney center, and the validation cohort comprised 61 patients from multiple centers. At biopsy, the mean serum creatinine (SCr) level 6 SD was 4.363.4 mg/dl, and the mean percentage of crescents was 66.4%615.8%. The kidney survival rates at years 1, 3, and 5 after biopsy were 57.4%64.7%, 45.8%65.1%, and 30.4%66.6%, respectively. Multivariate Cox regression revealed initial SCr as the only independent risk factor for ESRD (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.10 to 1.57; P=0.002). Notably, the percentage of crescents did not associate independently with ESRD. Logistic regression showed that the risk of ESRD at 1 year after biopsy increased rapidly at SCr.2.7 mg/dl and reached 90% at SCr.6.8 mg/dl (specificity=98.5%, sensitivity=64.6% for combined cohorts). In both cohorts, patients with SCr.6.8 mg/dl were less likely to recover from dialysis. Analyses in additional cohorts revealed a similar association between initial SCr and ESRD in patients with antiglomerular basement membrane disease but not ANCA-associated systemic vasculitis. In conclusion, crescentic IgAN has a poor prognosis, and initial SCr concentration may predict kidney failure in patients with this disease.

No abstract