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Abstract Cardiovascular disease (CVD) remains the predominant cause of mortality and disability worldwide. Against this backdrop, finding effective drugs for the pharmacological treatment of CVD has become one of the most urgent and challenging issues in medical research. Garlic (Allium sativum L.) is one of the oldest plants and is world-renowned for its dietary and medicinal values. Allicin (diallyl thiosulfinate) is one of the primary natural active ingredients in garlic, which has been proven to have powerful cardioprotective effects and mediate various pathological processes related to CVD, such as inflammatory factor secretion, myocardial cell apoptosis, oxidative stress, and more. Therefore, allicin holds a promising application prospect in the treatment of CVD. This review summarized the biological functions of allicin and its potential mechanisms in CVD, including antioxidation, anti-inflammation, and anti-apoptosis effects. Reckoning with these, we delved into recent studies on allicin’s cardioprotective effects concerning various CVDs, such as atherosclerosis, hypertension, myocardial infarction, arrhythmia, cardiac hypertrophy, heart failure, and cardiotoxicity. Further, considering the tremendous advancement in nanomedicine, nanotechnology-based drug delivery systems show promise in addressing limitations of allicin’s clinical applications, including improving its solubility, stability, and bioavailability. Through this review, we hope to provide a reference for further research on allicin in cardioprotection and drug development. Graphical Abstract

Reactive oxidative species (ROS) generation triggers pyroptosis and induces development of inflammatory osteolysis. Hecogenin (HG) has anti-inflammatory and antioxidative property, but its effects on inflammatory osteolysis remains unclear. In our study, we investigated the mechanism of HG on pyroptosis and its effect on inflammatory osteolysis in vitro and in vivo. The impact of HG on osteoclastogenesis was evaluated using cytotoxicity, TRAcP staining and bone resorption assays. The RNA-sequencing was employed to identify potential signaling pathways, and then RT-qPCR, western blot, immunofluorescence, and ELISA were used to verify. To determine the protective effect of HG in vivo, Lipopolysaccharide (LPS)-induced animal models were utilized, along with micro-CT and histological examination. HG suppressed RANKL-induced osteoclast differentiation, bone resorption, NFATc1 activity and downstream factors. RNA-sequencing results showed that HG inhibited osteoclastogenesis by modulating the inflammatory response and macrophage polarization. Furthermore, HG inhibited the NF-κB pathway, and deactivated the NLRP3 inflammasome. HG activated the expression of nuclear factor E2-related factor 2 (Nrf2) to eliminate ROS generation. Importantly, the inhibitory effect of HG on NLRP3 inflammasome could be reversed by treatment with the Nrf2 inhibitor ML385. In vivo, HG prevented the mice against LPS-induced osteolysis by suppressing osteoclastogenesis and inflammatory factors. In conclusion, HG could activate Nrf2 to eliminate ROS generation, inactivate NLRP3 inflammasome and inhibit pyroptosis, thereby suppressing osteoclastogenesis in vitro and alleviating inflammatory osteolysis in vivo, which indicating that HG might be a promising candidate to treat inflammatory osteolysis.

Abstract High penetrations of renewable energy are crucial for low‐carbon power systems. However, the higher volatility of renewable power generation pushes real‐time operations closer to equipment limits. It is thus important to utilize flexibilities in the system through corrective security‐constrained economic dispatch (SCED) that allows generators to take corrective adjustments after contingencies. The corrective SCED problem, containing a large number of contingencies, and corresponding post‐contingency decisions and constraints, is very large in scale and difficult to solve using purely model‐based methods within the strict time limits of real‐time markets. To accelerate the solution process, this paper develops a novel interpretable data‐driven contingency classification method. Historical data and their potentially useful patterns are utilized in interpretable data‐driven decision tree classifiers. To directly consider continuous features, such as net load values, and to consider imbalanced datasets without much additional complexity, Improved Strong Optimal Classification Trees (ISOCTs) are developed with new branching threshold constraints and category weights in the objective function. ISOCTs are then embedded into a hybrid model‐based and data‐driven framework to guarantee the accuracy of the real‐time active contingency set and the resulting security of dispatch decisions. Numerical testing results demonstrate the classification accuracy, computational efficiency, and interpretability of the proposed approach.

Abstract Energy Storage Resources (ESRs) can help promote high penetrations of renewable generation and shift the peak load. However, the increasing number of ESRs and their features different from conventional generators bring computational challenges to operations of wholesale electricity markets. In order to improve the computational efficiency, this paper tightens the generic ESR formulation for unit commitment. To avoid the complexity caused by ESR operations in both discharge and charge directions, a novel “decoupled analysis” is conducted to analyze one direction at a time. For each direction, ESRs over two and three time periods are categorized into several types based on their parameters. For each type, our recent four‐step systematic formulation tightening approach is used to construct the corresponding tight formulation. In order to consider more periods without analyzing all the drastically increased number of types, a series of major types are selected based on how many periods an ESR is able to discharge (charge) consecutively at the upper power limit. A related generic form of tight constraints over multiple periods is established. Moreover, validity and facet‐defining proofs of our tight constraints have been provided. Numerical testing results illustrate the tightening process and demonstrate computational benefits of the tightened formulations.

Although a growing number of studies have suggested the relevance of greenspace exposure to respiratory health, most have explored single greenfield indicators or selected disease outcomes. This systematic review aimed to comprehensively assess the evidence that greenspace exposure is associated with chronic obstructive pulmonary disease (COPD) incidence, prevalence, mortality, and related lung function indicators and to explore the impact of greenspace exposure on COPD-related disease outcomes. We searched the literature published before 28 September 2023, using six electronic databases and snowball searches. After screening 3689 studies, 16 eligible studies were included. These studies examined various greenspace indicators such as the Normalized Difference Vegetation Index (NDVI), canopy coverage, greenspace coverage, and land cover conditions. Most studies have reported the positive effects of greenspace exposure. However, the findings had significant heterogeneity, with large differences in the greenness assessment, COPD identification methods, and population characteristics. The mechanisms of this impact have not been conclusively determined, but we propose several hypotheses to explain the pathways by which greenspace exposure affects COPD. Overall, our findings contribute valuable knowledge for understanding the relationship between greenspace exposure and COPD, informing future research in this field.

Abstract Background The widely accepted explanation of preeclampsia (PE) pathogenesis is insufficient trophoblast invasion and impaired uterine spiral artery remodeling. However, the underlying molecular mechanism remains unclear. Methods We performed transcriptome sequencing on placentas of normal and PE patients and identified 976 differentially expressed long noncoding RNAs (lncRNAs). TCF21 antisense RNA inducing demethylation (TARID) was one of the most significantly differentially expressed lncRNAs and was negatively correlated with the systolic and diastolic blood pressure in PE patients. Furthermore, we verified the effect of TARID on the biological behavior of trophoblasts and performed UID mRNA-seq to identify the effectors downstream of TARID. Then, co-transfection experiments were used to better illustrate the interaction between TARID and its downstream effector. Results We concluded that the downregulation of TARID expression may inhibit trophoblast infiltration and spiral artery remodeling through inhibition of cell migration, invasion, and tube formation mediated through the CXCL3/ERK/MAPK pathway. Conclusions Overall, these findings suggested that TARID may be a therapeutic target for PE through the CXCL3/ERK/MAPK pathway.

Background MicroRNAs (miRNAs) are endogenous noncoding single-stranded small RNAs. Numerous studies have shown that miRNAs have pivotal roles in the occurrence and development of myocardial fibrosis (MF). However, miRNA expression profile in rats with MF after myocardial infarction (MI) is not well understood. The present study aimed to find the potential miRNA for MF post MI. Methods SPF male Sprague-Dawley (SD) rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. Hematoxylin-eosin and Masson trichrome staining were used to detect myocardial histopathological changes for model evaluation. The differentially expressed miRNAs were detected by using the Agilent Rat miRNA gene chip in the myocardial tissue of the infarct marginal zone. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by DAVID. The expression of miR-199a-5p was verified by real-time fluorescence quantitative PCR (qRT-PCR). Transfected miR-199a-5p mimics into cardiac fibroblasts (CFs) to construct cell models of miR-199a-5p overexpression. Dual-luciferase reporter assay was employed to validate the target gene of miR-199a-5p. The protein expression of the target gene in CFs transfected with miR-199a-5p mimics were detected by Western blot. Results Myocardial fibrosis was exacerbated in the model group compared with the control group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3β. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3β was decreased in CFs transfected with miR-199a-5p mimics. Conclusion Our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3β, which provides novel targets for diagnosis and treatment of MF.

Electromigration is one of the most important research issues affecting the reliability of solder joints. Current-induced Joule heating affects the electromigration behavior of solder joints. Solder joints with different cross-sectional areas were designed to obtain different Joule heating properties. The effects of the interfacial intermetallic compound (IMC) and mechanical properties of Sn58Bi/Cu solder joints were studied for different Joule heating properties. The results showed that as the cross-sectional area of the Sn58Bi/Cu solder joints increased, the Joule heating of the joint increased. The anode IMC thickness of the joint thickened and transformed into a planar shape. The Bi migrated to the anode region to form a Bi-rich layer and gradually increased in thickness. The cathode IMC thickness first increased, then decreased, and gradually dissolved. The Sn-rich layer formed near the solder side and gradually increased in thickness, with microcracks occurring when the cross-sectional area of the joint increased to 0.75 mm2. The joint shear fracture path moved from the soldering zone near the cathode IMC layer to the interfacial IMC layer. The fracture mechanism of the joint changed from a mixed brittle/tough fracture, dominated by deconstruction and secondary cracking, to a brittle fracture dominated by deconstruction. The joint shear strength was reduced by 60.9% compared to that in the absence of electromigration.

Cancer continues to pose a severe threat to global health, making pursuing effective treatments more critical than ever. Traditional therapies, although pivotal in managing cancer, encounter considerable challenges, including drug resistance, poor drug solubility, and difficulties targeting tumors, specifically limiting their overall efficacy. Nanomedicine’s application in cancer therapy signals a new epoch, distinguished by the improvement of the specificity, efficacy, and tolerability of cancer treatments. This review explores the mechanisms and advantages of nanoparticle-mediated drug delivery, highlighting passive and active targeting strategies. Furthermore, it explores the transformative potential of nanomedicine in tumor therapeutics, delving into its applications across various treatment modalities, including surgery, chemotherapy, immunotherapy, radiotherapy, photodynamic and photothermal therapy, gene therapy, as well as tumor diagnosis and imaging. Meanwhile, the outlook of nanomedicine in tumor therapeutics is discussed, emphasizing the need for addressing toxicity concerns, improving drug delivery strategies, enhancing carrier stability and controlled release, simplifying nano-design, and exploring novel manufacturing technologies. Overall, integrating nanomedicine in cancer treatment holds immense potential for revolutionizing cancer therapeutics and improving patient outcomes.

Abstract Purpose Amyand’s hernia is a rare hernia defined as an inguinal hernia that contains the appendix within the hernia sac. Current treatment of Amyand’s hernia remains controversial. Our study retrospectively reviewed 6 cases of Amyand’s hernia, aiming to provide a reference for the surgical treatment of Amyand's hernia. Methods Six patients diagnosed with Amyand’s hernia from September 2010 to May 2020 were retrospectively enrolled in our study. We summarized clinical data of six patients including the chief complaint, physical examinations, laboratory examinations, imaging examinations, surgical methods, and postoperative treatments and outcomes. Results The diagnosis of six cases with Amyand’s hernia was made during surgery. Two patients had normal appendixes whereas the remaining four patients had appendicitis. Two patients with normal appendix received tension-free mesh repair through the inguinal incision. Among those with inflamed or perforated appendixes, two received mesh repair and the other two did not. The discharge time after surgery of six patients was 9.8 ± 6.1 days. One patient suffered from a wound infection. No additional postoperative complications were detected. Conclusions Computed tomography and ultrasonography are helpful but limited in the definite diagnosis of Amyand’s hernia. The presence of a normal appendix does not require to be resected, but appendicectomy is necessary if the appendix is inflamed. The treatment of Amyand's hernia should be tailored based on the patient's condition and the type of Amyand's hernia.

To solve the electromigration problem of micro−electronic connection solder joints, an ideal electromigration tester was designed, and the thickness of the intermetallic compounds (IMCs), average void diameter, grain orientation, failure, shear strength, and fracture path of Sn2.5Ag0.7Cu0.1RE0.05Ni−GNSs/Cu solder joints under constant−temperature electromigration were studied. The results indicate that the solder joints show evidence of typical electromigration polarity in the asymmetric growth of interfacial IMCs on the anode and cathode sides under the conditions of a current density ≥7 × 103 A/cm2 and an included angle between the c−axis of the β−Sn grains and the current direction θ ≤ 53.2°. The anode−side interfacial IMC is dominated by a Cu6Sn5 phase with a gradually increasing thickness, forming a Cu3Sn phase and showing evidence of microcracks. The Cu6Sn5 phase of the cathode−side interfacial IMC is gradually completely dissolved, and the growth of the Cu3Sn phase is accompanied by the formation of Kirkendall voids. The anisotropic diffusion of Cu atoms in the β−Sn of the micro−solder joints causes increased solder joint resistance and reduced shear strength. The shear fracture path of the solder joints moves from the cathode side near the IMC solder seam to the Cu3Sn interface. The shear fracture mechanism changes from ductile transgranular fracture dominated by β−Sn dimples to brittle fracture dominated by interfacial IMC cleavage and slip steps.

Summary: Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.

Tomato leaf mold disease caused by Cladosporium fulvum (C. fulvum) is one of the most common diseases affecting greenhouse tomato production. Cf proteins can recognize corresponding AVR proteins produced by C. fulvum, and Cf genes are associated with leaf mold resistance. Given that there are many physiological races of C. fulvum and that these races rapidly mutate, resistance to common Cf genes (such as Cf-2, Cf-4, Cf-5, and Cf-9) has decreased. In the field, Ont7813 plants (carrying the Cf-13 gene) show effective resistance to C. fulvum; thus, these plants could be used as new, disease-resistant materials. To explore the mechanism of the Cf-13-mediated resistance response, transcriptome sequencing was performed on three replicates each of Ont7813 (Cf-13) and Moneymaker (MM; carrying the Cf-0 gene) at 0, 9, and 15 days after inoculation (dai) for a total of 18 samples. In total, 943 genes were differentially expressed, specifically in the Ont7813 response process as compared to the Moneymaker response process. Gene ontology (GO) classification of these 943 differentially expressed genes (DEGs) showed that GO terms, including “hydrogen peroxide metabolic process (GO_Process)”, “secondary active transmembrane transporter activity (GO_Function)”, and “mismatch repair complex (GO_Component)”, which were the same as 11 other GO terms, were significantly enriched. An analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that many key regulatory genes of the Cf-13-mediated resistance response processes were involved in the “plant hormone signal transduction” pathway, the “plant–pathogen interaction” pathway, and the “MAPK signaling pathway–plant” pathway. Moreover, during C. fulvum infection, jasmonic acid (JA) and salicylic acid (SA) contents significantly increased in Ont7813 at the early stage. These results lay a vital foundation for further understanding the molecular mechanism of the Cf-13 gene in response to C. fulvum infection.

There are a growing number of people entering underground spaces. However, underground spaces have unique environmental characteristics, and little is known about their effects on human health. It is crucial to elucidate the effects of the underground space environment on the health of humans and other organisms. This paper reviews the effects of hypoxia, toxic atmospheric particles, and low background radiation in the underground space environment on living organisms from the perspective of oxidative stress. Most studies have revealed that living organisms maintained in underground space environments exhibit obvious oxidative stress, which manifests as changes in oxidants, antioxidant enzyme activity, genetic damage, and even disease status. However, there are few relevant studies, and the pathophysiological mechanisms have not been fully elucidated. There remains an urgent need to focus on the biological effects of other underground environmental factors on humans and other organisms as well as the underlying mechanisms. In addition, based on biological research, exploring means to protect humans and living organisms in underground environments is also essential.

This paper describes a zero-dimensional model for evaluating the mass flow rate history of a solid rocket motor igniter. Based on the results of an igniter-firing experiment, in which the igniter is the only source of combustion gas and no propellant is ignited, the proposed model can be used to compute the mass flow rate of the igniter. Different species and temperature-dependent properties, such as the specific heat for each species, are considered. The coupling between the flow field variables in the combustion chamber and the heat transfer at the gas-solid interface is computed in a segment way. Calculations are performed for different species and properties, and the errors are discussed. Using the computed igniter mass flow rate as a boundary condition, a two-dimensional calculation is performed for validation purposes. The results are in good agreement with experimental data. The proposed model can be used to provide reasonable boundary conditions for solid rocket motor simulations and to evaluate the performance of igniters. Although derived on the basis of a small-scale solid rocket motor, the model has the potential to be used in large-scale systems.

Extensive crustal anatexis is common during the decompressional exhumation of deeply subducted continental crust and the delamination of a collision‐thickened orogenic lithosphere, indicating that determining the timing of partial melting can provide insights into the possible tectonic evolution during orogenic processes. An integrated study of petrology, zirconology and whole-rock geochemical compositions from migmatites and pegmatites in the Nageng, Langmuri and Wulonggou area of the East Kunlun Orogenic Belt, is presented in this study. The protoliths of these migmatites include Tonian sedimentary rocks and ca. 440 Ma arc-related dioritic rock. Together with previous studies, an extensive crustal anatexis event recorded by anatectic zircons occurred after ca. 410 Ma. In addition, hafnium isotope analyses indicate that the anatectic zircons may or may not inherit their Hf isotope compositions from protolith zircons during partial melting, depending on whether or not the garnet Hf contributes to the Hf budget of anatectic melt. Thus, the most reasonable method to trace the source of granite is to compare the Hf isotope composition of anatectic zircon in migmatite and magmatic zircon in contemporaneous granite. By such method, anatectic melt produced by migmatites in this study could account for both penecontemporaneous A- and I-type granites with high magmatic zircon εHf(t) values and S-type granites with low magmatic zircon εHf(t) values. As the extensive crustal anatexis is later than both metamorphic peak and amphibole-facies retrogression of high-pressure and ultrahigh-pressure (HP-UHP) metamorphic rocks, it is reasonable that post-collision orogenic collapse of the collision‐thickened orogenic lithosphere as a result of delamination and asthenospheric upwelling occurred after ca. 410 Ma, which is also supported by contemporaneous granulite-facies metamorphism, molasse deposition, and magmatic events including Xiarihamu mafic-ultramafic intrusions, A-type granites, and mafic dykes formed in the continental rifting setting. [ABSTRACT FROM AUTHOR]

The replacement of rutile by Fe-Ti oxides is a common phenomenon during the retrogression of eclogites. Here, we report an unusual case regarding the replacement of Fe-Ti oxides by rutile during greenschist-facies metamorphic overprinting of veins in amphibolites (retrograded eclogites) from the Dabie ultrahigh-pressure (UHP) terrane, eastern China. The veins mainly consist of plagioclase, Fe-Ti oxides, and quartz, which crystallized from a Ti-rich amphibolite-facies fluid that formed during exhumation of the eclogites. Two types of textures involving the replacement of Fe-Ti oxides by rutile are recognized in the veins: (1) the first type is characterized by the development of rutile coronas (Rt-C) and other silicates (high-Fe epidote, muscovite, and chlorite) around the external boundaries of the Fe-Ti oxide grains, and (2) the second type is characterized by the formation of symplectitic intergrowths of rutile (Rt-S) and magnetite after exsolved hemo-ilmenite (H-Ilm) lamellae in the Fe-Ti oxides. The micro-textures, mineral assemblages, and Zr-in-rutile thermometry indicate that both replacement reactions involved mineral re-equilibration processes in the presence of an infiltrating fluid phase at ~476-515 °C, taking place by an interface-coupled dissolution-precipitation mechanism. Thermodynamic modeling reveals that both replacement reactions occurred during oxidation processes under relatively high-oxygen fugacity (fO2) conditions, approximately 2.5-4.5 logfO2 units higher than the fayalite-magnetite-quartz (FMQ) reference buffer. In situ Sr isotopic analyses of epidote (Ep-C) coexisting with the Rt-C suggest that the infiltrating fluid involved in the greenschist-facies replace- ment reactions was externally derived from the surrounding granitic gneisses (the wall rocks of the amphibolites). Compared with the rutile in the UHP eclogites (Rt-E) and amphibolites (Rt-A), the Rt-C is characterized by distinctly lower contents of Nb (<10 ppm) and Ta (<2 ppm) and Nb/Ta ratios (<10) and higher contents of Cr (>340 ppm) and V (>1580 ppm). These results provide a geochemical fingerprint for distinguishing the low-pressure (LP) rutile from relic high-grade phases in retrograded HP-UHP rocks. Our results reveal that rutile can form during LP retrograde stage in UHP rocks by high-fO2 fluid-induced replacement reactions. The unusual replacements of Fe-Ti oxides by rutile-bearing assemblages during retrogression provide important constraints on fluid-mineral reactions and fO2 variations in exhumed UHP slabs. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro- BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N- and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both crossarmed and open-armed conformations.We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations. [ABSTRACT FROM AUTHOR]

Abstract: Continuous powder mixing has attracted a lot of interest within the pharmaceutical industry. Much work has been done recently that targets the characterization of continuous powder mixing. In this paper, a quantitative scaling up strategy is introduced that allows the transition from lab to industrial scale. The proposed methodology is based on the variance spectrum analysis, and the residence time distribution, which are key indexes in capturing scale-up of the batch-like mixing, and scale-up of the axial mixing and motion, respectively. Our simulation results are used as preliminary guidance for scaling up different powder mixing cases. [Copyright &y& Elsevier]

Variance reduction ratio (VRR) is generally considered as an important index in characterizing the continuous powder mixing. Although the capacity of the mixer to smooth out feeder fluctuations can be expressed by the VRR, few studies are performed quantitatively in this area. The feeder effects are investigated on the solid mixer through the Fourier series analysis. The VRR is deduced quantitatively using the Fourier series of the feed rate variability and the residence time distribution (RTD), which facilitate the explicit decomposition of VRR into intensities of different frequency components. It provides a novel model to determine whether the integrated feeder-mixer system satisfies specific solid mixing performance criteria, and provides guidelines of system improvement. © 2010 American Institute of Chemical Engineers AIChE J, 2011 [ABSTRACT FROM AUTHOR]

Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations. [ABSTRACT FROM AUTHOR]

Discusses the significance of the interplay of the tumor suppressor gene p53 and a DNA-repair protein called XRCC4 for tumorigenesis, genomic stability and development. Use of mice; Mortality of XRCC4-deficient mice; Importance of non-homologous end-joining pathway for the mammalian genome.

XRCC4 is a generally expressed protein of 334 amino acids that is involved in the repair of DNA double-strand breaks and in V(D)J recombination, but its function is unknown. In this study, we have used a mutational approach and the yeast two-hybrid method to perform an initial characterization of this protein. We show that the XRCC4 protein is located in the nucleus. We also demonstrate that several potential phosphorylation sites are not required for XRCC4 function in a transient V(D)J recombination assay. In addition, we show that XRCC4 forms a homodimer in vivo with the homodimerization domain being located within amino acids 115–204. Finally, we define a core domain of XRCC4 that functions in V(D)J recombination and comprises amino acids 18–204. Potential functions of XRCC4 are discussed. [ABSTRACT FROM AUTHOR]