Description: Mutations in FUS cause amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to neurodegeneration remain obscure. We previously found that U1 snRNP is the most abundant FUS interactor. Here, we report that components of the U1 snRNP core particle (Sm proteins and U1 snRNA), but not the mature U1 snRNP-specific proteins (U1-70K, U1A and U1C), co-mislocalize with FUS to the cytoplasm in ALS patient fibroblasts harboring mutations in the FUS nuclear localization signal (NLS). Similar results were obtained in HeLa cells expressing the ALS-causing FUS R495X NLS mutation, and mislocalization of Sm proteins is RRM-dependent. Moreover, as observed with FUS, knockdown of any of the U1 snRNP-specific proteins results in a dramatic loss of SMN-containing Gems. Significantly, knockdown of U1 snRNP in zebrafish results in motor axon truncations, a phenotype also observed with FUS, SMN and TDP-43 knockdowns. Our observations linking U1 snRNP to ALS patient cells with FUS mutations, SMN-containing Gems, and motor neurons indicate that U1 snRNP is a component of a molecular pathway associated with motor neuron disease. Linking an essential canonical splicing factor (U1 snRNP) to this pathway provides strong new evidence that splicing defects may be involved in pathogenesis and that this pathway is a potential therapeutic target.

Description: We compute the Suslin homology of relative curves with modulus. This result may be regarded as a modulus version of the computation of motives for curves, due to Suslin and Voevodsky.

Description: Palaeomagnetic and rock magnetic measurements on sediment cores from Integrated Ocean Drilling Program (IODP) Sites U1331 and U1332 in the equatorial Pacific are used to examine changes in the relative palaeointensity (RPI) of the geomagnetic field during the Oligocene and Eocene. The main magnetic carrier of these sediments is interpreted to be partially oxidized magnetite, which varies in concentration by less than about a factor of six along the stratigraphic section. In some cases, these variations occur as abrupt changes or fluctuations. The largest change in lithology and rock magnetic properties occurs across the Eocene/Oligocene (E/O) boundary, with the radiolarian-rich late Eocene sediments having higher magnetic concentration than the nannofossil-rich early Oligocene sediments. RPI estimates computed from ratios of the natural remanent magnetization to anhysteretic remanent magnetization and isothermal remanent magnetization appear to be insignificantly influenced by the lithologic differences within either the Oligocene or Eocene but are significantly influenced by the differences between the Eocene and Oligocene sediments. We thus estimate the RPI separately for the Oligocene and Eocene intervals. For both sites, the RPI records always have minima at chron boundaries. The records also show large fluctuations between highs and lows even during stable polarity periods. These features are similar to what has been observed for RPI records spanning the past 3 Myr, suggesting persistent geomagnetic field behaviour since the Eocene. The two new records show consistent variation with the RPI reported from Site U1333, which is in the vicinity of Sites U1331 and U1332. The RPI variations during the Oligocene at Site U1332 are also generally consistent with those reported from the South Atlantic. One interesting feature is that the RPI is consistently high throughout most of Chron C12r (31.021–33.232 Ma). In addition, Cryptochron C18n.1n-1, which is characterized by common marked intensity lows in the RPI records, is observed at the age of 39.094–39.114 Ma for Site U1331 and 38.958–38.983 Ma for Site U1332.

Description: Mammalian Musashi1 (Msi1) is an RNA-binding protein that regulates the translation of target mRNAs, and participates in the maintenance of cell ‘stemness’ and tumorigenesis. Msi1 reportedly binds to the 3'-untranslated region of mRNA of Numb , which encodes Notch inhibitor, and impedes initiation of its translation by competing with eIF4G for PABP binding, resulting in triggering of Notch signaling. Here, the mechanism by which Msi1 recognizes the target RNA sequence using its Ribonucleoprotein (RNP)-type RNA-binding domains (RBDs), RBD1 and RBD2 has been revealed on identification of the minimal binding RNA for each RBD and determination of the three-dimensional structure of the RBD1:RNA complex. Unique interactions were found for the recognition of the target sequence by Msi1 RBD1: adenine is sandwiched by two phenylalanines and guanine is stacked on the tryptophan in the loop between β1 and α1. The minimal recognition sequences that we have defined for Msi1 RBD1 and RBD2 have actually been found in many Msi1 target mRNAs reported to date. The present study provides molecular clues for understanding the biology involving Musashi family proteins.

Description: Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex under primary regulation by the renin-angiotensin system. Angiotensin II (A-II) acts through the angiotensin types 1 and 2 receptors (AT1R and AT2R). A-II is metabolized in different tissues by various enzymes to generate two heptapeptides A-III and angiotensin 1-7, which can then be catabolized into smaller peptides. A-II was more potent than A-III in stimulating aldosterone secretion in the adrenocortical cell line HAC15, and A-II, but not A-III, stimulated cortisol secretion. A-II stimulated mRNA expression of steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2, whereas A-III stimulated 3β-hydroxysteroid dehydrogenase, CYP11B1, and CYP11B2 but decreased the expression of CYP17A1 required for cortisol synthesis. The stimulation of aldosterone secretion by A-II and A-III was blocked by the AT1R receptor blocker, losartan, but not by an AT2R blocker. A-II was rapidly metabolized by the HAC15 cells to mainly to angiotensin 1-7, but not to A-III, and disappeared from the supernatant within 6 h. A-III was metabolized rapidly and disappeared within 1 h. In conclusion, A-II was not converted to A-III in the HAC15 cell and is the more potent stimulator of aldosterone secretion and cortisol of the two. A-III stimulated aldosterone secretion but not cortisol secretion.

Description: Aims Previous studies have reported that insulin resistance plays an important role in the progression of atherosclerosis. However, the relationship between insulin resistance and coronary plaque instability is not well established. The purpose of this study was to assess the relationship between insulin resistance and coronary plaque characteristics identified by optical coherence tomography (OCT). Methods and results This study enrolled 155 consecutive patients undergoing percutaneous coronary intervention. OCT image acquisitions were performed in the culprit lesions. Insulin resistance was identified using the homeostasis model assessment of insulin resistance (HOMA-IR). Subjects were divided into three tertiles according to the HOMA-IR values. Patients in the higher HOMA tertile had more frequent prevalence of lipid-rich plaques than those in the middle and lower tertiles (83 vs. 62 vs. 57%; P = 0.01). The thin-cap fibroatheroma (TCFA) prevalence rates among the higher (〉2.5), middle (1.4–2.5), and lower HOMA-IR (〈1.4) tertiles were 50, 29, and 26% ( P = 0.02). The microvessel prevalence rates of the three tertiles were 54, 39, and 28% ( P = 0.02). Furthermore, in the higher HOMA-IR group, the fibrous cap was significantly thinner compared with the other two tertiles (vs. lower HOMA-IR, P = 0.009; vs. middle HOMA-IR, P = 0.008). On multivariate analysis, acute coronary syndrome [odds ratio (OR): 17.98; 95% confidence interval (CI): 7.12–52.02; P 〈 0.0001] and HOMA-IR 〉2.50 (OR: 3.57; 95% CI: 1.42–9.55; P = 0.007) were independent predictors for the presence of TCFA. Conclusion This study suggests that insulin resistance might be associated with coronary plaque vulnerability.

Description: Radioprotective 105 (RP105) is a type I transmembrane protein, which associates with a glycoprotein, MD-1. Monoclonal antibody (mAb)-mediated ligation of RP105/MD-1 robustly activates B cells. RP105/MD-1 is structurally similar to Toll-like receptor 4 (TLR4)/MD-2. B-cell responses to TLR2 and TLR4/MD-2 ligands are impaired in the absence of RP105 or MD-1. In addition to RP105/MD-1, MD-1 alone is secreted. The structure of MD-1 shows that MD-1 has a hydrophobic cavity that directly binds to phospholipids. Little is known, however, about a ligand for MD-1 and the role of MD-1 in vivo . To study the role of RP105/MD-1 and MD-1 alone, specific mAbs against MD-1 are needed. Here, we report the establishment and characterization of two anti-MD-1 mAbs (JR2G9, JR7G1). JR2G9 detects soluble MD-1, whereas JR7G1 binds both soluble MD-1 and the cell surface RP105/MD-1 complex. With these mAbs, soluble MD-1 was detected in the serum and urine. The MD-1 concentration was altered by infection, diet and reperfusion injury. Serum MD-1 was rapidly elevated by TLR ligand injection in mice. The quantitative PCR and supernatant-precipitated data indicate that macrophages are one of the sources of serum soluble MD-1. These results suggest that soluble MD-1 is a valuable biomarker for inflammatory diseases.