Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27.

The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe-/- and Ldlr-/- mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3+ follicular helper T cells (TFH cells). TFH cells isolated from Apoe-/- mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3+ TFH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased TFH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune TFH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner.

Publisher Correction: Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27.

In the version of this article initially published, the third label along the horizontal axis of Fig. 4b (Il13a) and the middle label above each plot in Fig. 6k (Stat-/-) were incorrect, and the hash marks along the horizontal axis for Fig. 6i were spaced incorrectly. Also, the statistical results in the citation for Supplementary Fig. 5a (*P < 0.05, **P < 0.01 and ***P < 0.001 (unpaired Student's t-test)) in the fifth subsection of Results were incorrect. The correct label for Fig. 4b is Il23a and for Fig. 6k is Stat1-/-, and the right hash mark along the horizontal axis for Fig. 6i should be beneath the data points at right. The correct citation of the statistical results is as follows: "(P < 0.05 and P < 0.01 (unpaired Student's t-test); Supplementary Fig. 5a)." The errors have been corrected in the HTML and PDF version of the article.

Postoperative Decrease in Bone Marrow Lesion Associated With Better Clinical Outcomes Following Medial Open-Wedge High Tibial Osteotomy.

PURPOSE: To assess serial changes of preoperative bone marrow lesion (BML) following medial open-wedge high tibial osteotomy (MOWHTO) up to 2 years and evaluate whether postoperative change of BML affected patient-reported outcome measures (PROMs) at 2 years' follow-up. Factors related to the postoperative changes in BML also were evaluated. METHODS: The current study retrospectively assessed prospectively collected data of consecutive patients between December 2016 and March 2018 who underwent MOWHTO for symptomatic knee osteoarthritis with varus malalignment (≥5°) and a minimum 2-year follow-up. Serial magnetic resonance imaging scans at preoperative and postoperative 3, 6, 18, and 24 months were performed, and the extent of BML was evaluated consecutively using 2 validated methods. Clinically, preoperative and postoperative PROMs and their achievement of minimal clinically important difference values were evaluated. The associations of the extent of BMLs with PROMs at each follow-up period over time were analyzed using a linear mixed model. Furthermore, factors related to the postoperative changes of BML were assessed. RESULTS: Of 26 patients, 21 (80.8%) had preoperative BML at medial femoral and tibial condyles. The postoperative decrease in BML was noted in 17 (81.0%) and 18 (85.7%) at medial femoral and tibial condyles. The BML decreased at postoperative 3 months and, thereafter, the extent of BML gradually reduced until postoperative 24 months. The proportion of patients achieved minimal clinically important difference was 84.6% for total Western Ontario and McMaster Universities Osteoarthritis Index scores and 80.8%, 76.9%, and 84.6% for KOOS symptom, pain, and activity of daily living subscales. Postoperative decrease in BML was significantly associated with better PROMs over postoperative 24 months. Furthermore, normo-correction (2°-5° valgus) was a significant factor for decreased BML following MOWHTO. CONCLUSIONS: Preoperative BML gradually decreased with time following MOWHTO, and the postoperative decrease in BML related with better PROMs over postoperative 24 months. Moreover, postoperative valgus alignment was a significant factor relating the postoperative decrease of BML. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Correction: Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules.

Correction for 'Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules' by Minchae Kang et al., Soft Matter, 2022, 18, 3313-3317, https://doi.org/10.1039/D2SM00384H.

Radiologic findings associated with mucoid degeneration of the anterior cruciate ligament.

INTRODUCTION: Mucoid degeneration (MD) of the anterior cruciate ligament (ACL) is a well-recognized pathology characterized by the degradation of collagen fibers and infiltration of a mucoid-like substance. This study is to determine the anatomical associated factors for MD-ACL using radiographic and magnetic resonance imaging (MRI). MATERIALS AND METHODS: This was a retrospective study on patients who had undergone knee arthroscopy between 2011 and 2020. The patients with MD-ACL were defined and enrolled by the MRI and arthroscopy. Eventually, 52 patients in the MD-ACL group (group 1) and 52 patients in the control group (group 2) were enrolled, following sex and age matching. Radiologic evaluation included the assessment of Kellgren-Lawrence (K-L) grade, mechanical hip-knee-ankle (HKA) angle, posterior tibial slope (PTS) angle, and Insall-Salvati ratio. The notch width index and transverse notch angle were measured on MRI, and the grade of trochlear dysplasia was defined. Logistic regression analysis, receiver operating characteristic (ROC) curves, and area under curve (AUC) were performed. RESULTS: The ROM was significantly decreased in group 1, whereas the PTS angle was significantly larger in group 1. Combined ganglion cysts of ACL were found in 42/52 patients (80.7%) in group 1. The risk of MD-ACL was associated with a steeper PTS angle, increased Insall-Salvati ratio, male sex, higher K-L grade, and decreased transverse notch angle and notch width index. The cutoff values in ROC analysis were found to be ≤ 28.27% for the notch width index (AUC, 0.849; p < 0.001), > 12.2° for the PTS angle (AUC, 0.765; p < 0.001), and ≤ 47.4° for the transverse notch angle (AUC, 0.711; p < 0.001), but not significant for Insall-salvati ratio. CONCLUSION: A steeper PTS angle, decreased notch width index, and transverse notch angle are significantly associated with the presence of MD-ACL. These factors should be considered during diagnosis or when determining the treatment strategy for symptomatic MD-ACL patients. LEVEL OF EVIDENCE: Level IIIb.

Aggregation or phase separation can be induced in highly charged proteins by small charged biomolecules.

Protein phase separation in biological systems has captured the attention of scientists in the last decade; however, the main mechanism underlying protein phase separation in cells remains unclear. Biologists, physicists, and chemists have all tried to understand this important biological phenomenon, each using their own unique techniques and language. Each subject has its advantages in explaining protein phase separation; however, in this study, we find that the chemical language of molecular structure is the key to explaining the mechanism underlying protein phase separation. Using fluroescence microscopy and molecular dynamics, this study identifies small multivalently charged biomolecules, such as nucleoside triphosphate (negatively charged) and polyamine (positively charged), as important drivers of phase separation of highly charged proteins in cells.

Serial Improvement of Medial Meniscus Extrusion Following Medial Open-Wedge High Tibial Osteotomy Does Not Correlate With Clinical Outcomes and Arthroscopic Articular Cartilage Improvement.

PURPOSE: To assess serial change up to 2 years in medial meniscus extrusion (MME) following medial open-wedge high tibial osteotomy (MOWHTO) and to determine whether postoperative changes in MME correlated with clinical outcomes and arthroscopic articular cartilage status. METHODS: This study included 26 patients from December 2016 to March 2018 who underwent MOWHTO for primary medial osteoarthritis with varus malalignment. Second-look arthroscopy with plate removal was performed at postoperative 2 years. MME was consecutively measured using coronal magnetic resonance imaging at preoperative and postoperative 3 months, 6 months, 1.5 years, and 2 years. We also assessed which preoperative parameters could reflect the postoperative changes in MME and evaluated whether postoperative clinical outcomes and arthroscopic articular cartilage improvement would be influenced by the MME changes. RESULTS: Regarding the postoperative serial changes in MME values, significant improvement in MME was noted from postoperative 6 months (P = .003), and thereafter, mean MME was further improved with time until postoperative 2 years (P < .001). Regarding the correlation between preoperative parameters and MME changes, preoperative medial proximal tibial angle (MPTA) showed significant correlations in univariate and multivariate analysis (P = .004 and P = .004, respectively). Meanwhile, changes in MME were not correlated with postoperative clinical outcomes or arthroscopic articular cartilage improvement. CONCLUSION: After MOWHTO, MME improved with time and was significantly correlated with preoperative MPTA. However, the changes in MME after MOWHTO did not reflect postoperative clinical and arthroscopic articular cartilage improvement. LEVEL OF EVIDENCE: IV, case series.

Steep posterior lateral tibial slope, bone contusion on lateral compartments and combined medial collateral ligament injury are associated with the increased risk of lateral meniscal tear.

PURPOSE: To determine the risk factors for lateral meniscus and root tears in patients with acute anterior cruciate ligament (ACL) injuries. METHODS: A total of 226 patients undergoing acute ACL reconstruction were included in the study sample. Exclusion criteria were revisions, fractures, chronic cases, and multiple ligament injuries, with the exception of medial collateral ligament (MCL) injuries. The patients were divided into groups based on the presence of lateral meniscus and root tears by arthroscopy. Binary logistic regression was used to analyze risk factors including age, sex, body mass index (BMI), injury mechanism (contact/non-contact), Segond fracture, side-to-side laxity, location of bone contusion, medial and lateral tibial and meniscal slope, mechanical axis angle, and grade of pivot shift. RESULTS: Overall lateral meniscus (LM) tears were identified in 97 patients (42.9%), and LM root tears were found in 22 patients (9.7%). The risk of an LM tear in ACL-injured knees increased with bone contusion on LTP (odds ratio [OR], 3.5; 95% confidence interval [CI] 1.419-8.634; P = 0.007), steeper lateral tibial slope (OR, 1.133; 95% CI 1.003-1.28; P = 0.045), MCL injury (OR, 2.618; 95% CI 1.444-4.746; P = 0.002), and non-contact injury mechanism (OR, 3.132; 95% CI 1.446-6.785; P = 0.004) in logistic regression analysis. The risk of LM root tear in ACL-injured knees increased with high-grade pivot shift (OR, 9.127; 95% CI 2.821-29.525; P = 0.000) and steeper lateral tibial slope (OR, 1.293; 95% CI 1.061-1.576; P = 0.011). CONCLUSION: The increased risk of LM lesions in acute ACL-injured knees should be considered if significant risk factors including bone contusion on lateral compartments, MCL injury, and a steeper lateral tibial slope are present. Moreover, high-grade rotational injury with steeper lateral tibial slope are also significant risk factors for LM root tears, and therefore care should be taken by clinicians not to miss such lesions. LEVEL OF EVIDENCE: III.

Photoelectron Spectroscopy of OH--Anion-Water Clusters Generated by Ultrasonic Nebulizer.

Investigating molecules in the gas phase is the only way to discover their intrinsic molecular properties; however, it is challenging to produce the gaseous phase of large-molecule chemicals. Thermal evaporation is typically used to convert molecules into gases, but it is still challenging to study ionic molecules in solutions in the gas phase. Electrospray ionization is one of the best methods to generate molecules in the gas phase, and it is uniquely capable of studying large biomolecules, including proteins. However, the molecular temperature required to study the spectroscopic properties of the molecules is very high. In this study, we developed a new, simple evaporation method using an ultrasonic nebulizer to obtain gas-phase molecules. Using this new equipment, we observed OH- anions and their water clusters in the gas phase and obtained their photoelectron spectra. We observed that the vertical electron-detachment energy (VDE) of OH- was 1.90 ± 0.05 eV and the VDEs of its water clusters and OH- (H2O)n (n = 1-2) decreased to 1.50 ± 0.05 eV (n = 1) and 1.30 ± 0.05 eV (n = 2), respectively.

Clinical and radiographic results after arthroscopic repair of lateral meniscus tear in lateral-depression tibial plateau fracture.

INTRODUCTION: To evaluate the clinical and radiographic results of AR/IF and meniscus repair for treating lateral meniscus (LM) tears associated with lateral tibial plateau fractures and to identify the factors associated with LM tear. MATERIALS AND METHODS: Forty-two patients with lateral plateau fractures (Schatzker types II and III) treated by AR/IF were included retrospectively. Radiographic evaluations using the Rasmussen system and computerized tomography (CT) were performed. Clinical evaluations were also conducted at final follow-up. Second-look arthroscopy was applied during metal removal. RESULTS: All fractures were healed after 46.3 months of follow-up. The mean Tegner activity level was not decreased significantly, going from 7.1 ± 2.1 pre-injury to 6.6 ± 2.3 at final follow-up (p = 0.301). However, the amount of depression noted on CT imaging was significantly decreased from 8.9 mm ± 4.4 to 1.2 mm ± 1.3 (p = 0.000). The mean Rasmussen radiologic score at final follow-up was 14.5 ± 5.3 points. Osteoarthritis was progressed in six patients (14.3%). Twenty-five patients had concomitant LM tear, with 18 cases treated by repair and the remaining ones treated by partial meniscectomy. Preoperative joint depression (> 11 mm) was significantly associated with the risk of LM tear (p = 0.024; odds ratio (OR): 9.0, 95% confidence interval (CI): 1.018-79.545) and most of those lesions could be repaired (p = 0.001). Postoperatively, 16 repaired patients were evaluated by second-look arthroscopy; 15 had healed completely and one had healed partially. CONCLUSION: LM tears are frequently combined with lateral tibial plateau fracture, especially in correlation with more than 11 mm of joint depression, though most of those lesions can be repaired at the time of fracture fixation. AR/IF with arthroscopic meniscus repair could achieve good clinical and radiographic outcomes when treating Schatzker types II and III tibial plateau fractures. STUDY DESIGN: Level IV retrospective cohort study.

Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis.

BACKGROUND: Macrophages produce many inflammation-associated molecules, released by matrix metalloproteinases, such as adhesion molecules, and cytokines, as well, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (Ninj1 [nerve injury-induced protein]), a novel matrix metalloproteinase 9 substrate, expression, and atherosclerosis progression. METHODS: Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from patients with coronary artery disease and healthy controls, and atheroprone apolipoprotein e-deficient (Apoe-/-) and wild-type mice, as well. Apoe-/- mice lacking systemic Ninj1 expression (Ninj1-/-Apoe-/-) were generated to assess the functional effects of Ninj1. Bone marrow transplantation was also used to generate low-density lipoprotein receptor-deficient (Ldlr-/-) mice that lack Ninj1 specifically in bone marrow-derived cells. Mice were fed a Western diet for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj11-56 (ML56) and Ninj126-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1). RESULTS: Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted proinflammatory gene expression by activating mitogen-activated protein kinase and inhibiting the phosphoinositide 3-kinase/Akt signaling pathway. Whole-body and bone marrow-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by matrix metalloproteinase 9 to generate a soluble form that exhibited antiatherosclerotic effects, as assessed in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1. CONCLUSIONS: Ninj1 is a novel matrix metalloproteinase 9 substrate in macrophages, and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.

Anionic Activation of CO2 via (Mn-CO2)- Complex on Magic-Numbered Anionic Coinage Metal Clusters Mn- (M = Cu, Ag, Au).

Given the immense challenge of excessive accumulation of carbon dioxide (CO2) in the earth's atmosphere, an extensive search is under way to convert atmospheric CO2 to compounds of more utility. With CO2 being thermodynamically extremely stable, activation of CO2 is the first and most important step toward its chemical conversion. Building upon our earlier model for the anionic activation of CO2 with azabenzene and inspired by the work of others on metal atom-CO2 complexes, we investigated the possibility of anionic activation of CO2 on small anionic metal clusters, which would have implications for catalytic conversion of CO2 on metal surfaces with atomic-scale structural irregularities. We carried out theoretical calculations using density functional theory to examine small anionic metal clusters of Cu, Ag, and Au to check whether they form a complex with CO2, with the sign of CO2 being chemically activated. We found that a class of anionic metal clusters Mn- with 1, 2, and 6 atoms consistently produced the activated complex (Mn-CO2)- for all three metals. There exists a strong interaction between the CO2 moiety and Mn- via a partially covalent M-C bond with a full delocalization of the electronic charge, as a result of electron transfer from the HOMO of Mn- to the LUMO of CO2 as in metal-CO2 π-backbonding. We examined the interaction of frontier orbitals from the viewpoints of the orbital geometry and orbital energetics and found that the above magic numbers are consistent with both aspects.

Electron Attachment to the (O2···CO2) van der Waals Complex Results in a Monomeric Anion (O2-CO2)-, a Possible Form of CO4.

We found that electron attachment to the van der Waals complex (O2···CO2) turns the weak intermolecular bond into a pseudochemical bond of significant strength. The resulting monomeric molecular anion (O2-CO2)- may be a form of CO4-, the gaseous anionic species suspected to be present in Earth's ionosphere whose chemical characteristics have not been comprehensively identified since its existence was first predicted by Conway in 1962. The measured vertical detachment energy of CO4- is very large (4.56 ± 0.05 eV), while the known electron affinity of its component species is much smaller (0.448 eV, O2) or even negative (-0.6 eV, CO2). These characteristics are correctly borne out by theoretical calculations that show that electron attachment transforms the van der Waals complex to a single contiguous molecular anion, with the formation of a pseudochemical bond between O2 and CO2 through an extended π-orbital system.

Tranexamic acid in a periarticular multimodal cocktail injection for blood management in total knee arthroplasty: a prospective randomized study.

BACKGROUND: This study aimed to assess the efficacy of tranexamic acid (TXA) mixed in a periarticular multimodal cocktail (PAMC) as a topical administration and to determine whether combined use of intravenous and topical administration is more effective than a single administration of TXA. METHODS: A total of 240 patients who underwent primary total knee arthroplasty (TKA) was enrolled for this prospective randomized controlled study. Patients were divided into three groups of 80 patients each. Baseline data were comparable for all groups. Average follow-up was 18.7 months. Group 1 consisted of patients who received intravenous (IV) TXA, Group 2 patients were those who received TXA in a PAMC injection for topical administration, and Group 3 consisted of patients who received a combination of both intravenous and topical administration of TXA. Primary outcomes were postoperative hemoglobin drop and amount of suction drainage. Secondary outcomes were estimated blood loss (EBL), postoperative transfusion rate, and complications. RESULTS: The mean postoperative hemoglobin drop was significantly lower in Group 3 (2.13 ± 0.77 g/dL, p=0.004), and there was no difference between Group 1 and Group 2 (2.56 ± 1.07 g/dL vs 2.55 ± 0.86 g/dL, p=0.999). The mean drainage amount was significantly lower in Group 3 (326.58 ± 57.55 ml, p<0.001), and there was no difference between Group 1 and Group 2 (367.93 ± 87.26 ml vs 397.66 ± 104.10 ml, p=0.072). Similarly, the mean EBL was significantly lower in Group 3 (p=0.003), and there was no significant difference between Group 1 and Group 2 (p=0.992). There were no significant differences in requirement for postoperative transfusion rate or incidence of complications among the three groups. CONCLUSION: TXA mixed in a PAMC injection showed a similar effect to IV administration of TXA following TKA. Furthermore, combined use of both IV and PAMC injection provided better perioperative bleeding control with similar safety in patients without relevant comorbidities. TRIAL REGISTRATION: WHO ICTRP identifier KCT0005703 . Retrospectively registered: 12/24/2020.

Editorial Commentary: Saucerization Is Superior to Total Meniscectomy in Patients With Symptomatic Discoid Lateral Meniscus.

Current treatment recommendations favor meniscal rim preservation through partial meniscectomy with repair when indicated in patients with symptomatic discoid lateral menisci. Although many studies have shown the importance of meniscal rim preservation, some have shown that suture repair does not yield improved outcomes over partial meniscectomy without repair, considering the cost of repair and lack of available data. However, partial meniscectomy with repair is essential when peripheral instability is seen in patients with symptomatic discoid lateral menisci. Arthroscopic reshaping in young patients can be challenging for an inexperienced surgeon because visualization within the lateral joint space may be limited by a thickened meniscus and the small size of the pediatric knee. To preserve a stable peripheral rim, various meniscal repair methods should be used for stabilizing the reshaped meniscus on the capsule based on repair location, tear type, and surgeon preference.

Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9.

AIMS: Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. METHODS AND RESULTS: The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. CONCLUSION: We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.

Atorvastatin protects cardiomyocyte from doxorubicin toxicity by modulating survivin expression through FOXO1 inhibition.

BACKGROUND: Survivin has an anti-apoptotic effect against anthracycline-induced cardiotoxicity. Clinically, statin use is associated with a lower risk for heart failure in breast cancer patients with anthracycline chemotherapy. So, the purpose of our study was to investigate whether survivin mediates the protective effect of statin against anthracycline-induced cardiotoxicity. METHODS: Mice were treated once a week with 5 mg/kg doxorubicin for 4 weeks with or without atorvastatin 20 mg/kg every day then heart tissues were analyzed. Molecular and cellular biology analyses were performed with H9c2 cell lysates. RESULTS: Doxorubicin suppressed survivin expression via activation of FOXO1 in H9c2 cardiomyocytes. Whereas, atorvastatin inhibited FOXO1 by increasing phosphorylation and inhibiting nuclear localization. Doxorubicin induced FOXO1 binding to STAT3 and prevented STAT3 from interacting with Sp1. However, atorvastatin inhibited these interactions and stabilized STAT3/Sp1 transcription complex. Chromatin immunoprecipitation analysis demonstrated that doxorubicin decreased STAT3/Sp1 complex binding to survivin promoter, whereas atorvastatin stabilized this binding. In mouse model, atorvastatin rescued doxorubicin-induced reduction of survivin expression and of heart function measured by cardiac magnetic resonance imaging. CONCLUSIONS: Our study suggested a new pathophysiologic mechanism that survivin mediated protective effect of atorvastatin against doxorubicin-induced cardiotoxicity via FOXO1/STAT3/Sp1 transcriptional network.

C1q/TNF-α-Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions.

RATIONALE: Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation. OBJECTIVE: To investigate the physiological/pathophysiological role of CTRP1 in BP regulation. METHODS AND RESULTS: CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice. CONCLUSIONS: For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.

Chiral Pd6L8 Nanocube Pairs: Recognition of Chiral Amino Acids via Electrochemistry.

The self-assembly of PdX2 (X- = ClO4- and PF6-) with C3-symmetric l- and d-L [L = (2S,2'S,2″S)- and (2R,2'R,2″R)-[benzenetricarbonyltris(azanediyl)]tris(3-phenylpropane-2,1-diyl)triisonicotinate] produces the chiral nanocube pair [Pd6(l-L)8](X)12 and [Pd6(d-L)8](X)12 (X- = ClO4- and PF6-, respectively) with an inner cavity of 12.3 × 12.3 × 12.3 Å3. These chiral nanocubes are effective for the enantiorecognition of various chiral amino acids via the square-wave-voltammetry technique. In the present study, the site of enantiorecognition was confirmed by density functional theory calculated interactions between each nanocube and the chiral amino acids, and the calculated interactions were coincident with the shifts of the electrochemical oxidation potentials.

Editorial Commentary: Why Should the Contralateral Side Be Examined in Patients With Symptomatic Discoid Lateral Meniscus?

Recent reports have found the rate of bilateral discoid lateral meniscus (DLM) to be high (79%-97%) in patients with unilaterally symptomatic DLM; the associated torn meniscus incidence is also high at 33%. The present study results indicated that older, symptomatic DLM patients with more degenerative changes may be at risk for a similar condition in the contralateral knee. Long-term follow-up with magnetic resonance imaging screening for asymptomatic contralateral knees is necessary to determine the fate of the contralateral knee.