Nonproportional Correlative Reduction Finite Element Method for Slope Strength Parameters

To solve the problems presented by the rational determination of the reduction mode in the traditional strength reduction method and to overcome the difficulty in determining double safety factors from the existing double reduction factors method, a nonproportional relationship between the cohesion reduction factor and the internal friction angle reduction factor is established for a case in which the strength parameter distribution obeys the linear attenuation assumption. By introducing this correlation into the traditional strength reduction finite element method, the nonproportional correlative reduction finite element method for slope strength parameters is proposed. To verify the reliability of the proposed method, the nonproportional correlation is introduced into Bishop’s slice method, yielding the nonproportional double safety factors of Bishop’s slice method. For the whole safety storage of the slope based on the double safety factors, a comprehensive safety factor with the contribution of the shear strength parameter to the sliding resistance force as weight is proposed. Finally, in combination with an example and a comparative analysis of the slope sliding surface positions and the comprehensive safety factors for three different types of reduction modes with two types of methods, the rationality and reliability of this method were validated

Synthesis, Structures, and Norbornene Polymerization Behavior of <i>o</i>‑Aryloxide-Substituted NHC-Ligated σ, π‑Cycloalkenyl Palladium Complexes

Treatment of the pro-ligand (2-OH-3,5-^<i>t</i>Bu₂C₆H₂)­(Mes)­(C₃H₃N₂)⁺Br^– (<b>2a</b>) with di­[μ-chloro-2η²,5η¹-(6-methoxy-<i>endo</i>-bicyclo­[2.2.1]-hept-2-enyl)­palladium­(II)] (<b>1a)</b> and K₂CO₃ in dioxane, or reaction of the pro-ligand <b>2a</b> subsequently with ^<i>n</i>BuLi and <b>1a</b> in THF afforded the <i>o</i>-aryloxide-substituted NHC-ligated σ, π-cycloalkenyl palladium complex <b>3</b>. Similarly, treatment of the pro-ligands (2-OH-3,5-^<i>t</i>Bu₂C₆H₂)­(R)­(C₃H₃N₂)⁺Br^– [R = Mes (<b>2a</b>), Me (<b>2b</b>), ^<i>i</i>Pr (<b>2c</b>), Ph (<b>2d</b>)] with bis­[μ-chloro-1η²,5η¹-(6-ethoxy-<i>exo</i>-5,6-dihydrodicyclopentadienyl)­palladium­(II)] (<b>1b</b>) and K₂CO₃ in dioxane afforded the desired products <b>4</b>–<b>9</b>. All these complexes were fully characterized by ¹H and ¹³C NMR, high-resolution mass spectrometry (HRMS), and elemental analysis. Single-crystal X-ray diffraction analysis results further confirmed the molecular structures of <b>3</b>–<b>6</b>. With methylaluminoxane (MAO) as cocatalyst, these complexes showed excellent catalytic activities up to 10⁷ g of PNB (mol of Pd) ^–1 h^–1 in the addition polymerization of norbornene

Evaluation of allelic alterations in short tandem repeats in papillary thyroid cancer

Abstract Background Malignant tissue samples may be the only source of biological material for forensic investigations, including individual identification or paternity testing; however, such samples may lead to uncertainties due to frequent genomic aberrations associated with tumors, including alterations of the short tandem repeat (STR) loci used for forensic casework. Methods Short tandem repeat loci routinely used in forensic analysis (n = 23) were analyzed in 68 surgically removed papillary thyroid cancer specimens. Tumor cells and normal stromal cells were separated by laser capture microdissection. Results Four kinds of changes were detected between normal and tumor tissues: partial loss of heterozygosity (pLOH), complete loss of heterozygosity, an additional allele, and a new allele not found in normal tissue. These changes were distributed across 20 of the tested STRs, with no mutations in VWA, D16S539, or Penta D. The most frequently affected locus was D2S1338, and the most frequent type of alteration was pLOH. Samples from patients aged 40–59 years exhibited the highest frequencies of STR variation. Conclusion Our results suggest that great care should be taken in the evaluation of DNA typing results obtained from malignant tissues, particularly when no normal tissue reference samples are available

The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β₂-microglobulin

The ΔN6 truncation is the main posttranslational modification of β2-microglobulin (β2M) found in dialysis-related amyloid. Investigation of the interaction of wild-type (WT) β2M with N-terminally truncated variants is therefore of medical relevance. However, it is unclear which residues among the six residues at the N-terminus are crucial to the interactions and the modulation of amyloid fibril propagation of β2M. We herein analyzed homo- and heterotypic seeding of amyloid fibrils of WT human β2M and its N-terminally-truncated variants ΔN1 to ΔN6, lacking up to six residues at the N-terminus. At acidic pH 2.5, we produced amyloid fibrils in vitro from recombinant, WT β2M and its six truncated variants, and found that ΔN6 β2M fibrils exhibit a significantly lower conformational stability than WT β2M fibrils. Importantly, under more physiological conditions (pH 6.2), we assembled amyloid fibrils in vitro only from recombinant, ΔN4, ΔN5, and ΔN6 β2M but not from WT β2M and its three truncated variants ΔN1 to ΔN3. Notably, the removal of the six, five or four residues at the N-terminus leads to enhanced fibril formation, and homo- and heterotypic seeding of ΔN6 fibrils strongly promotes amyloid fibril formation of WT β2M and its six truncated variants, including at more physiological pH 6.2. Collectively, these results demonstrated that the residues 4 to 6 at the N-terminus particularly modulate amyloid fibril propagation of β2M and the interactions of WT β2M with N-terminally truncated variants, potentially indicating the direct relevance to the involvement of the protein’s aggregation in dialysis-related amyloidosis

REGγ Mediated Regulation of p21Waf/Cip1, p16INK4a and p14ARF/p19ARF in Vivo

peer reviewedp21Waf/Cip1, p16INK4a and p14ARF (p19ARF in mice) have been demonstrated to be degraded by REGγ-proteasome pathway in an ATP- and ubiquitin-independent manner in vitro. However, the in vivo roles of REGγ mediated-degradation of p21Waf/Cip1, p16INK4a and p14ARF remain unclear. In this study, we showed enhanced expression of p21Waf/Cip1, p16INK4a and p19ARF in multiple tissues from REG–/– mice compared to REG+/+ mice. Furthermore, we examined the expression of p21Waf/Cip1, p16INK4a and p14ARF in different cancer tissues and observed that the REGγ protein levels were highly expressed in different human cancers while the level of p21Waf/Cip1, p16INK4a and p14ARF appears to be inversely corre- lated. These results demonstrate that REGγ may exert its function in physiological and pathological conditions through degradation of p21Waf/Cip1, p16INK4a and p14ARF in vivo

REGγ deficiency promotes premature aging via the casein kinase 1 pathway

Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ−/− tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ−/− MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the “antiaging” and “proaging” effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders