Small interfering RNAs (siRNAs) have been used extensively in reverse genetic research, and many have made their way into clinical trials. The most widely used siRNA structure consists of ...double-stranded RNA with 19 base pairs and 2-nucleotide overhangs at the 3'-end of both strands (19+2). Although widely used, this symmetric structure bears inherent disadvantages in both research and clinical applications. One of the most common caveats is the off-target effect leading to adverse effects in clinical application. In the current study, using C-C chemokine receptor (CCR5) as a target, we have shown that 19+2 siRNA could still cause considerable global off-target effects regardless of rational design based on its thermodynamic asymmetry. However, we demonstrated that structurally asymmetric siRNA targeting CCR5 could be adopted to improve the strand specificity and greatly reduce the off-target effects without significantly compromising its on-target effects. Data from microarray analysis suggest that an unidentified mechanism resulting in global gene down-regulation might be avoided through strand shortening. Taken together, our work suggested a promising and simple way to improve strand specificity and overcome the off-target gene-expression effects without introducing more complications while retaining the efficacy of siRNA.
We report the first observation of the double strange baryon Ξ(1620)0 in its decay to Ξ−π+ via Ξ+c → Ξ−π+π+ decays based on a 980 fb−1 data sample collected with the Belle detector at the KEKB ...asymmetric-energy e+e− collider. The mass and width are measured to be 1610.4 ± 6.0(stat)+6.1−4.2(syst) MeV /c2 and 59.9 ± 4.8(stat)+2.8−7.1(syst) MeV, respectively. We obtain 4.0σ evidence of the Ξ(1690)0 with the same data sample. These results shed light on the structure of hyperon resonances with strangeness S = −2
To evaluate the diagnostic performance of multi-modality functional imaging in differentiating malignant and benign thyroid
F-fluorodeoxyglucose (
F-FDG) incidentaloma.
This study included 87 ...patients with thyroid
F-FDG incidentalomas detected by
F-FDG- positron emission tomography/computed tomography (
F-FDG-PET/CT) and diagnosed at surgery or biopsy, who received
F-FDG-PET/CT, diffusion-weighted MR imaging (DWI) and ultrasound elastography (USE). The metabolic tumor volume (MTV), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC) values and ultrasound elasticity scores of thyroid
F-FDG incidentalomas were measured and compared in benign and malignant thyroid incidentalomas. The differences of malignant and benign thyroid incidentalomas were tested by χ
test, Fisher's exact test, t test, or Mann-Whitney U test. The diagnostic performance was evaluated and optimal cut-off values were determined in distinguishing malignant from benign thyroid incidentalomas by receiver operating characteristic curve analysis.
MTV, TLG and USE scores of malignant thyroid incidentalomas were significantly higher than benign; but ADC value was significantly lower. We defined the functional imaging parameters TLG < 2.48, ADC > 1.80 × 10
mm
/s, and USE score of 1 as markers of benign thyroid incidentalomas and each scored -1 point; TLG ≥ 2.48, ADC ≤ 1.80 × 10
mm
/s, and USE score of 4 as markers of malignancy and each scored 1 point. Combined multi-functional imaging parameters achieved the highest performance (84.6% sensitivity and 97.1% specificity) for distinguish malignant from benign thyroid incidentaloma with AUC 0.957 (95% CI 0.917, 0.997).
Functional imaging might help to distinguishing malignant from benign thyroid
F-FDG incidentalomas, and combined multi-functional imaging parameters could improve it.
We present the first measurements of the electric and magnetic form factors of the neutron in the timelike (positive q^{2}) region as function of four-momentum transfer. We explored the differential ...cross sections of the reaction e^{+}e^{-}→nover ¯n with data collected with the BESIII detector at the BEPCII accelerator, corresponding to an integrated luminosity of 354.6 pb^{-1} in total at twelve center-of-mass energies between sqrts=2.0-2.95 GeV. A relative uncertainty of 18% and 12% for the electric and magnetic form factors, respectively, is achieved at sqrts=2.3935 GeV. Our results are comparable in accuracy to those from electron scattering in the comparable spacelike region of four-momentum transfer. The electromagnetic form factor ratio R_{em}≡|G_{E}|/|G_{M}| is within the uncertainties close to unity. We compare our result on |G_{E}| and |G_{M}| to recent model predictions, and the measurements in the spacelike region to test the analyticity of electromagnetic form factors.
To assess the role of human and rat cytochrome P450s in the metabolism of aza-polynuclear aromatic hydrocarbons (aza-PAHs) and to examine the influence of heterocyclic nitrogen on the metabolism of ...these chemicals, we have investigated the biotransformation of dibenza,hacridine (DBa,hACR), an aza-PAH with two nonidentical bay regions, by recombinant human cytochromes P450 1A1, 1B1, and 3A4 and rat P450 1A1. Among the three P450s, 1A1 was the most effective in metabolizing DBa,hACR followed by 1B1 and 3A4. The major DBa,hACR metabolites produced by human P450 1A1 and 1B1 were the dihydrodiols with a bay region double bond, namely, DBa,hACR-3,4-diol and DBa,hACR-10,11-diol (putative proximate carcinogen). P450 1A1 produced a higher proportion of DBa,hACR-10,11-diol (derived from the benzo ring adjacent to the nitrogen) (44.7%) than of DBa,hACR-3,4-diol (derived from benzo ring away from the nitrogen) (23.8%). In contrast, 1B1 produced a much greater proportion of 3,4-diol (54.7%) than of 10,11-diol (6.4%). These data indicate that (i) human P450 1A1 and 1B1 differ dramatically with respect to the regiospecific metabolism of DBa,hACR, (ii) human P450 1A1 is substantially more active than human P450 1B1 in the metabolic activation of the aza-PAH to its 10,11-diol, and (iii) the presence of nitrogen influences the relative extent to which the two benzo ring diols with a bay region double bond are formed by human P450s 1A1 and 1B1. In contrast to human P450s 1A1 and 1B1, rat P450 1A1 showed no regioselectivity in the metabolism of DBa,hACR producing nearly equal proportions of 10,11-diol and 3,4-diol. Despite significant differences in their regioselectivity, human P450 1A1 and 1B1 and rat P450 1A1 showed similar stereoselectivity in the metabolism of DBa,hACR to its diols having a bay region double bond, producing primarily the R,R enantiomers (>94%). The data of these studies indicte that human and rat P450 1A1 differ in their regioselectivity in the metabolism of DBa,hACR to its two benzo ring diols with a bay region double bond and consequently in their ability to metabolically activate the parent aza-PAH. However, human and rat P450 1A1 do not differ with respect to their stereoselectivity in the metabolism of DBa,hACR to the diols.
Previous reports showed that bone mass and architecture only partially recovered by remobilization (RM) after immobilization (IM)‐induced osteopenia, and that parathyroid hormone (PTH) had an ...anabolic effect on the skeleton. The aim of this study was to determine whether low doses of PTH could restore IM‐induced cortical bone loss and whether a combination of PTH plus loading (RM) treatment would be more effective than the PTH in unloaded (IM) limbs. One hundred and sixty 6‐month‐old rats were divided into aging and IM groups. The right hindlimb of the rat was immobilized by elastic bandage for 18 weeks, and then groups of rats were either kept IM or RM and treated with 30 μg or 80 μg of hPTH(1–38)/kg/day for 2, 10, and 20 weeks. Fluorescent‐labeled, undecalcified cross‐sections of right tibial shafts were studied. We found that RM for 20 weeks after 18 weeks of IM only partially recovered IM‐induced muscle weight loss and PTH had no effect on muscle weight in either IM or RM limbs; that RM for 20 weeks after 18 weeks of IM partially restored some minimal cortical width by stimulating periosteal and endocortical bone formation and decreasing endocortical resorption; that PTH treatment of IM limbs completely restored IM‐induced cortical bone loss and added extra bone by stimulating bone formation indices on all bone surfaces and depressing bone resorption on endocortical surface; that PTH treatment of RM limbs produced similar anabolic effects as in IM limbs with 30 μg/kg/day dose but the 80 μg/kg/day dose‐treated limbs had a higher periosteal bone formation rate, which created a larger cross‐sectional area, more cortical bone area, and a thicker cortex than the same dose treated IM limbs; and that PTH 80 μg/kg/day treatment produced more anabolic effect than the 30 μg/kg/day in both IM and RM limbs. We concluded that reloading the hindlimb by RM after long‐term IM could not recover the cortical bone mass. PTH at employed doses was able to completely restore IM‐induced cortical bone loss, and this effect was independent of mechanical stimulation. However, when PTH was combined with mechanical loading (RM), a synergistic anabolic effect on periosteal bone formation occurred which increased the cross sectional area that can increase bone strength.
A study of lesion development in stems of Eucalyptus nitens following artificial inoculations with canker fungi was carried out on 16‐year‐old plantation trees. In a first trial cambium bark wounds ...on smooth‐ and rough‐barked trees were inoculated with the mycelium of nine species of canker fungi, including Endothia gyrosa. In a second trial spores or mycelium of E. gyrosa were applied directly onto undamaged or superficially wounded bark surfaces. Infection subsequent to artificial inoculation via wounding (whatever the wounding technique or type of inoculum) resulted in significantly larger external lesions (mean lesion area up to 35.6 cm2 20 months after inoculation) on smooth bark compared with those on rough bark (up to 19.0 cm2). Microscopic studies of infected rough and smooth bark suggest that, once smooth bark is compromised by wounding and artificial inoculation, the particular anatomical structure of smooth bark may offer less mechanical resistance to post‐penetration hyphal spread in comparison with rough bark. It is suggested that at a pre‐penetration stage under natural conditions spores of E. gyrosa more easily infect rough bark via cracks associated with this type of bark but not present in smooth bark.
Développement des lésions sur les troncs d’Eucalyptus nitens àécorce lisse ou rugueuse, après inoculation par des champignons agents de chancre
L’étude a été conduite en plantation sur des arbres de 16 ans. Dans un premier essai, des blessures de l’écorce jusqu’au cambium sur des arbres àécorce lisse ou rugueuse, ont été inoculées avec le mycélium de 9 espèces de champignons agents de chancre, dont Endothia gyrosa. Dans un deuxième essai, des spores ou du mycélium de E. gyrosa ont été appliqués directement sur l’écorce intacte ou blessée seulement superficiellement. Quel que soit la technique d’inoculation ou le type d’inoculum, l’infection a été plus importante extérieurement (surface moyenne jusqu’à 35,6 cm2 après 20 mois) chez les écorces lisses que chez les rugueuses (jusqu’à 19,0 cm2). L’étude microscopique des écorces infectées suggérait qu’à condition que l’écorce lisse soit impliquée dans la blessure, sa structure anatomique particulière offre moins de résistance mécanique à la post‐pénétration mycélienne que l’écorce rugueuse. Il est suggéré qu’au stade de la pré‐pénétration en conditions naturelles, les spores de E. gyrosa infectent plus facilement l’écorce rugueuse à la faveur des fissures qui sont présentes chez ce type d’écorce mais absentes chez les écorces lisses.
Entwicklung von Läsionen am Stamm von rauh‐ und glattrindigen Individuen von Eucalyptus nitens nach künstlicher Inokulation mit krebserregenden Pilzen
Es wurde die Entwicklung von Läsionen an Stämmen 16jähriger Eucalyptus nitens‐Pflanzungen nach künstlicher Inokulation mit Krebserregern untersucht. In einem ersten Versuch wurden an rauh‐ und glattrindigen Bäumen Rindenwunden, die bis zum Kambium reichten, mit Myzel von neun Arten krebserregender Pilze, einschliesslich Endothia gyrosa, beimpft. In einem zweiten Versuch wurden Sporen oder Myzel von E. gyrosa direkt auf unverletzte oder nur oberflächlich verletzte Rinde aufgebracht. Künstliche Inokulation von Wunden (unabhängig von der Methode der künstlichen Verwundung oder der Art des Inokulums) führte zu signifikant grösseren, äusseren Wunden auf glatter (durchschnittliche Läsionsfläche 35.6 cm2 20 Monate nach Inokulation) als auf rauher Rinde (bis 19.0 cm2). Mikroskopische Untersuchungen zeigten, dass glatte Rinde gegen die Ausbreitung von Pilzhyphen mechanisch weniger resistent ist als rauhe Rinde. Unter natürlichen Bedingungen dürften dagegen Sporen von E. gyrosa Bäume mit rauher Rinde leichter durch vorhandene Rindenrisse infizieren, die bei glatter Rinde fehlen.
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