In order to solve the problems of flow field divergence, short circuit, and poor forming precision in electrochemical machining (ECM) large-diameter special-shaped inner spiral tube with pull reverse ...flow-cathode structure, a pull downstream cathode structure is proposed which has the function of changing working teeth and converging electrolyte flow field. The gap flow field simulation model was established, and then comparing and analyzing the gap flow field between pull downstream cathode model and the pull reverse flow cathode model. The simulation results show that pull downstream cathode structure is better than pull reverse flow-cathode structure in the gap electrolyte velocity, pressure, and streamline under the condition of 15 m/s electrolyte inlet velocity and electrolyte outlet pressure with atmospheric pressure. We also analyzed the stress and displacement of these two different cathode structures. The simulation results show that the maximum stress is 0.350 MPa and the maximum displacement is 4.275 × 10
−5
mm with pull downstream cathode. However, the maximum stress of traditional pull reverse flow cathode is 0.428 MPa and the maximum displacement is 5.6355 × 10
−5
mm. Finally, under the conditions of 12 V, 20 mm/min cathode feed speed, 15 wt% NaCl electrolyte with temperature 30 °C, and inlet pressure 1.5 MPa, the 2000 mm qualified sample was machined stably and reliably by pull downstream cathode. It indicates that it is feasible to machining large-diameter special-shaped inner spiral tube with the new pull downstream cathode structure.
Research suggests that expert understanding is characterized by coherent mental representations featuring a high level of connectedness. This paper advances the idea that educators can facilitate ...this level of understanding in students through the
practicing connections
framework: a practical framework to guide instructional design for developing deep understanding and transferable knowledge in complex academic domains. We start by reviewing what we know from learning sciences about the nature and development of transferable knowledge, arguing that
connectedness
is key to the coherent mental schemas that underlie deep understanding and transferable skills. We then propose features of instruction that might uniquely facilitate deep understanding and suggest that the connections between a domain’s
core concepts
,
key representations
, and
contexts and practices of the world
must be made explicit and practiced, over time, in order for students to develop coherent understanding. We illustrate the practicing connections approach to instructional design in the context of a new online interactive introductory statistics textbook developed by the authors.
Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor ...receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months).
This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2− ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling).
Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug–drug interaction between ribociclib and fulvestrant or new safety signals were observed.
This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2− ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.
•We report an extended OS follow-up to the MONALEESA-3 trial (median, 56.3 months).•mOS was longer for the ribociclib arm versus the placebo arm: 53.7 versus 41.5 months (HR, 0.73; 95% CI 0.59-0.90).•OS benefit was observed with ribociclib in the first- and second-line settings.•No apparent drug–drug interaction between ribociclib and fulvestrant or new safety signals were observed.
The precipitate morphology in Mg–rare earth (RE) element binary alloys is predicted using a multi-scale modeling approach combining a three-dimensional (3-D) phase-field model and first-principles ...density functional theory calculations. First-principles calculations provide all the required input parameters for the phase-field model, including lattice parameters, elastic constants, formation energies and interfacial energies. This integrated model is applied to a Mg–Nd alloy as a model system. Quantitative 3-D phase-field simulations are performed to study the metastable β′ precipitate morphologies, habit plane formation and spatial distribution of the precipitates during isothermal aging. The predicted morphologies of β′ precipitates are in excellent agreement with existing experimental observations. The influence of the precipitate morphology on the mechanical properties is also evaluated using the Orowan equation. The results are expected to provide guidance for achieving desirable precipitate morphologies and thus mechanical properties in Mg alloys.
Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors ...(SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Asthenozoospermia (AZS) is a common cause of male infertility, characterized by abnormal reduction in the motility of ejaculated spermatozoa. Here, in a patient from a consanguineous family, we ...identified a homozygous mutation (c.G4343A, p.R1448Q) in SPAG17 by whole‐exome sequencing. The encoded protein, SPAG17, localizes to the axonemal central apparatus and is considered essential for flagellar waveform. In silico analysis revealed that R1448Q is a potential pathogenic mutation. Immunostaining and western blot assays showed that the R1448Q mutation may exert a negative effect on the steady‐state of the SPAG17 protein. Therefore, SPAG17 may be a new pathogenic gene causing AZS.
A longstanding debate concerns the use of concrete versus abstract instructional materials, particularly in domains such as mathematics and science. Although decades of research have focused on the ...advantages and disadvantages of concrete and abstract materials considered independently, we argue for an approach that moves beyond this dichotomy and combines their advantages. Specifically, we recommend beginning with concrete materials and then explicitly and gradually fading to the more abstract. Theoretical benefits of this "concreteness fading" technique for mathematics and science instruction include (1) helping learners interpret ambiguous or opaque abstract symbols in terms of well-understood concrete objects, (2) providing embodied perceptual and physical experiences that can ground abstract thinking, (3) enabling learners to build up a store of memorable images that can be used when abstract symbols lose meaning, and (4) guiding learners to strip away extraneous concrete properties and distill the generic, generalizable properties. In these ways, concreteness fading provides advantages that go beyond the sum of the benefits of concrete and abstract materials.
Aircraft carbon fiber/epoxy composite material is sensitive to lightning strike. Its damage assessment and protection design suffered from lightning strike is becoming increasingly important. Four ...different types of carbon fiber/epoxy composite laminates are selected, which are without protection, with full spraying aluminum coating, with local spraying aluminum coating and with spraying aluminum coating on glass cloth pasted to fastener head, respectively. Impulse electrical current tests were performed by implementing electrical current waveforms with different peak values with regard to different lightning zonings. Three-dimensional finite element models of composite laminate and its protection structures are accurately built to assess lightning ablation characteristics based on the coupled thermal/electrical/structural analysis and element deletion method, in which different electrical and thermal physical properties of the elements are defined depending on different temperature conditions. The results show that simulation results are good agreement with experimental results. Fiber damaged area, the damaged area and the maximum damaged thickness increases with the increase of electrical current peak. Aluminum coating has a good effect on anti-lightning strike. The thicker aluminum layer and the better to anti-lightning strike.
The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, ...however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by
-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.
During May-June 2021 and 2022, leaf blight symptoms were observed on loquat leaves (Eriobotrya japonica cv. 'Mogi') in Jiangsu Province (Xuzhou municipality, 117.17° E, 34.13° N) in China. ...Approximately 10% of the leaves on the two hundred trees studied in a six-year-old loquat orchard exhibited round lesions that changed from light yellow to reddish-brown in 8-10 days. Approximately 3% of the infected leaves exhibited numerous lesions that coalesced, leading to expansive blighted areas. Twenty-five samples of symptomatic tissue, approximately 0.2 cm2 in size, were collected in May 2022 from five different trees (five samples per tree), sterilized in 2% NaOCl for 1 min, washed twice with sterilized ddH2O, and incubated at 26°C for 5 days on PDA medium containing 50 µg/mL chloramphenicol. Six isolates were obtained via single spore isolation. ITS (OQ954852-OQ954857), TUB2 (OQ968488-OQ968493), EF1-α (OQ971890-OQ971895), RPB1 (OQ971896-OQ971901), and RPB2 (OR037266-OR037271) genes were amplified using the ITS1/ITS4, T1/T22, EF1-728F/EF1-986R, RPB1-R8/RPB1-F5, and fRPB2-7CF/fRPB2-11aR primers, respectively (O'Donnell et al. 2010). The species was identified using the Fusarioid ID database (Crous et al. 2021), revealing that all obtained isolates showed high homology to representative F. luffae strains. Upon combining the ITS, TUB2, EF1-α, RPB1, and RPB2 sequences, the isolates showed 99.42%-97.85% and 99.59%-98.10% identity to F. luffae CGMCC 3.19497 (ex-type strain) and NRRL 32522, respectively. A molecular phylogenetic tree was constructed using MEGA X, with a selection of representative Fusarium strains. Microscope observations showed septate mycelium, microconidia (6.86 ± 0.91 µm length, 1.67 ± 0.24 µm width, containing 1 septum; number of observations = 21), fusiform macroconidia (15.88 ± 1.43 µm length, 1.66 ± 0.24 µm width, containing 1 septum; number of observations = 45), and linear chlamydospores (79.36 ± 28.36 µm length, 12.03 ± 3.37 µm width; number of observations = 152). These observations are consistent with the morphology of F. luffae (Wang et al. 2019). All isolates exhibited identical morphological characteristics. All isolates were evaluated for pathogenicity in vivo using healthy non-detached loquat leaves. A total of 15 leaves from 5 different three-month-old 'Mogi' loquat trees were used for each isolate. Experiments were performed three times. A suspension of 1 × 106 spores/mL obtained from a seven-day-old colony (10 mL per 15 leaves), was sprayed on non-wounded leaves for inoculation. Sterilized ddH2O was used in the control experiment. Inoculated trees were stored at 26°C and 70% relative humidity for four days. Leaf blight symptoms were observed in all inoculated leaves, and the symptoms were observed in all repeated trials. The pathogen was recovered, and its identity was confirmed by ITS sequencing and morphological analysis, fulfilling Koch's postulates. In recent years, F. luffae has been reported to cause fruit rot on muskmelon, flower rot on kiwifruit, soybean pod rot, and leaf spot on cherry in China (Yu et al. 2022; Zhang et al. 2022; Zhao et al. 2022; Zhou et al. 2022), demonstrating the host promiscuity of this pathogen. Although F. solani has been identified as the causal agent of root rot and fruit rot on loquat (Abbas et al. 2017; Wu et al. 2021), this is the first report of F. luffae causing leaf blight on loquat worldwide. This report will help to understand the pathogens affecting loquat orchards in China.
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