Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Based on 30 high-resolution U-Th dating controls, we reconstruct stalagmite δ18O records from 45 to 15 thousand years ago (ka B.P., before AD 1950) from the Shizhu Cave, which is located in southwestern China under the influence of both the Indian Summer Monsoon (ISM) and the East Asian Summer Monsoon (EASM). By integrating with the other stalagmite δ18O records in Asia during the middle to late last glacial, our results reveal two main moisture trajectories: one from the Indian Ocean, through the Shizhu Cave towards central China, and the other from the Pacific Ocean to central and northern China. The systematic decrease of the average values of stalagmite δ18O records from oceans to inland China reveals a spatial pattern of water vapour fractionation and moisture trajectory during the middle to late last glacial. In contrast, the variation amplitude, which is defined as the departures apart from the background δ18O records during Heinrich stadials 1 to 4 (HS1–HS4), show an increasing trend from the coastal oceans to mid-latitude inland China, presenting a ‘coastal-inland’ pattern, which can be interpreted by the enhanced East Asian Winter Monsoon (EAWM) and the weakened EASM. More specifically, the enriched stalagmite δ18O records in the EASM region during HS1 to HS4 are caused by the decreased summer rainfall amount or/and the increased proportion of summer moisture resources from the Pacific Ocean. These new observations deepen our understanding of the complicated stalagmite δ18O records in the EASM region.

Adsorption of uranyl (UO22+) ions to mineral surfaces is a potentially effective method for removing this hazardous metal from water, but other toxic trace metal ions (Xn+: Rb+, Sr2+, Cr3+, Mn2+, Ni2+, Zn2+, Cd2+) in uraniferous wastewaters compete with UO22+ for adsorption sites and thus may diminish the capacity of adsorbents to sequester UO22+. A better understanding of competitive adsorption among these metal ions and the development of better adsorbents are, therefore, of critical importance. The purpose of the present study was to synthesize and characterize magnetic adsorbents, consisting of MFe2O4 (M = Mn, Fe, Zn, Co, or Ni) nanoparticles synthesized on montmorillonite (Mnt) edge sites, and to investigate their use as adsorbents for UO22+, including competitive adsorption with trace metal ions. Selective adsorption was studied using Langmuir, Freundlich, and Dubinin-Radushkevich isotherms, and the results showed that Xn+ ions were adsorbed primarily on MFe2O4-montmorillonite surfaces, and the UO22+ ions were adsorbed on the interfaces between montmorillonite edge surfaces and MFe2O4 nanoparticles. Using the Freundlich model, the interface adsorption capacity of UO22+ reached 25.1 mg·g–1 in mixed solution. Further, the UO22+ and Cr3+ ions had a redox reaction on the interfaces with synergistic adsorption. Herein, the adsorption capacity of Cr3+ was 60.2 mg·g–1 using the Freundlich isotherm. The results demonstrated that the MFe2O4-montmorillonite with highly selective adsorption of UO22+ ions is applicable to UO22+ treatment in the presence of toxic trace metal ions.

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In this paper, several linear two-dimensional consecutive k-type systems are studied, which include the linear connected-(k, r)-out-of-$(m,n)\colon\! F$ system and the linear l-connected-(k, r)-out-of-$(m,n)\colon\! F$ system without/with overlapping. Reliabilities of these systems are studied via the finite Markov chain imbedding approach (FMCIA) in a novel way. Some numerical examples are provided to illustrate the theoretical results established here and also to demonstrate the efficiency of the developed method. Finally, some possible applications and generalizations of the developed results are pointed out.

Pyrophyllite is an important layered phyllosilicate material that is used in many fields due to its beneficial physicochemical and mechanical properties. Due to the presence of multiple defects in pyrophyllite, an in-depth investigation was conducted using density functional theory to explore the effects of Na(I), K(I), Mg(II), Ca(II) and Fe(II) doping on the atomic structure, electronic properties and mechanical characteristics of pyrophyllite. The results demonstrated that, among the studied defects, K(I) doping had the most pronounced effects on the lattice constants and bonding lengths of pyrophyllite, while the least significant effects were observed in the case of Fe(II) doping. Moreover, the partial and total densities of states and band structures of the five kinds of doped pyrophyllite also changed significantly due to the redistribution of electrons. Finally, the elastic constants of the doped pyrophyllite were lower than that of the undoped pyrophyllite. Doping with Na(I), K(I), Mg(II), Ca(II) and Fe(II) reduced the deformation resistance, stiffness and elastic wave velocity but increased the degree of anisotropy in pyrophyllite. The observed effects on the mechanical properties of pyrophyllite followed the order: Mg(II) > Fe(II) > Ca(II) >K(I) > Na(I).

Finite state Markov processes and their aggregated Markov processes have been extensively studied, especially in ion channel modeling and reliability modeling. In reliability field, the asymptotic behaviors of repairable systems modeled by both processes have been paid much attention to. For a Markov process, it is well-known that limiting measures such as availability and transition probability do not depend on the initial state of the process. However, for an aggregated Markov process, it is difficult to directly know whether this conclusion holds true or not from the limiting measure formulas expressed by the Laplace transforms. In this paper, four limiting measures expressed by Laplace transforms are proved to be independent of the initial state through Tauber’s theorem. The proof is presented under the assumption that the rank of transition rate matrix is one less than the dimension of state space for the Markov process, which includes the case that all states communicate with each other. Some numerical examples and discussions based on these are presented to illustrate the results directly and to show future related research topics. Finally, the conclusion of the paper is given.

We study the diffusive instability subject to a solid–liquid interface and a Kolmogorov flow using modal, non-modal analyses and energy analysis. It is found that the phase boundary has different effects on the threshold of diffusive convection for weak and strong salinity stratification. In the context of oceanography where the salinity Rayleigh number RS is very high, the ice–water interface has negligible influence on the onset of diffusive convection. In the presence of shear, the diffusive convection for RS < 106 tends to be inhibited and with the increase of shear intensity, the oscillatory, steady convective and Kelvin–Helmholtz instabilities will be successively dominant. For RS > 106, the shear has a destabilizing effect on the diffusive convection, due to the generation of thermohaline-sheared instability found by Radko (J. Fluid Mech., vol. 805, 2016, pp. 147–170). Non-modal analysis indicates that for realistic parameters of high-latitude oceans, with the transition of the ultimate energy source of instability from the density gradient to background current, the thermohaline-shear instability is expected to transition from oscillatory to steady instability. The initial transient amplification due to double diffusion has also been studied, which is due to the generation of overstable instability at the initial phase. For RS < 106, the optimal initial condition to achieve the maximum transient growth favours longitudinal rolls. For thermohaline-shear instability, however, it favours transverse rolls and specifically, in oscillatory thermohaline-shear instability, the transient amplification can be enhanced by the shear by one order of magnitude, thus having important influence on the stability of the system.

OBJECTIVES/GOALS: Glioblastoma (GBM) patients face a poor prognosis. Glioma stem cells (GSCs), a chemo resistant GBM subpopulation, possess enhanced DNA repair and elevated levels of epigenetic modifier KDM1A. This study aims to establish the significance of KDM1A in DNA repair and determine the potential of novel KDM1A inhibitor NCD38 to enhance TMZ efficacy in GSCs. METHODS/STUDY POPULATION: Patient derived GSCs were obtained via IRB-approved protocol from patient samples at UT Health San Antonio. KDM1A knockdown and knockout cells were generated by transduction of validated KDM1A-specific shRNA or gRNA, respectively. Brain bioavailability of KDM1A inhibitor NCD38 was established using LS-MS/MS. Effect of combination of KDM1A knockdown, knockout, or inhibition with TMZ was studied using cell viability, neurosphere, and self-renewal assays. Mechanistic studies were conducted using CUT&Tag-seq, RNA-seq, immunofluorescence, comet, Western blotting, RT-qPCR, homologous recombination (HR) or non-homologous end-joining (NHEJ) DNA repair reporter assays. In vivo efficacy of KDM1A knockdown or inhibitor alongside TMZ treatment was determined using orthotopic murine GBM models. RESULTS/ANTICIPATED RESULTS: KDM1A knockdown, knockout, or inhibition increased efficacy of TMZ in reducing cell viability and self-renewal of GSCs. Pharmacokinetic studies demonstrated KDM1A inhibitor NCD38 is readily brain penetrable. CUT&Tag-seq studies revealed KDM1A is enriched at DNA repair gene promoters. RNA-seq studies suggest KDM1A inhibition reduces DNA double strand break repair gene expression, with these findings validated using RT-qPCR and Western blotting. Knockdown, knockout, or inhibition of KDM1A attenuated HR and NHEJ-mediated DNA repair capacity. Immunofluorescence and comet assay support findings of increased DNA damage in NCD38/TMZ combination treated GSCs. Importantly, KDM1A knockdown or inhibition enhanced efficacy of TMZ and significantly improved survival of orthotopic GBM tumor-bearing mice. DISCUSSION/SIGNIFICANCE: Our results show compelling evidence that KDM1A is essential for DNA repair in GSCs and that KDM1A inhibition sensitizes GBM to TMZ via attenuation of DNA repair pathways. These findings suggest combination of KDM1A inhibitor NCD38 with TMZ could serve as a promising novel therapeutic strategy that can be translated to improve GBM patient outcomes.

The notion of ordered system signature, originally defined for independent and identical coherent systems, is first extended to the case of independent and non-identical coherent systems, and then some key properties that help simplify its computation are established. Through its use, a dynamic ordered system signature is defined next, which facilitates a systematic study of dynamic properties of several coherent systems under a life test. The theoretical results established here are then illustrated through some specific examples. Finally, the usefulness in the evaluation of aging used systems of the concepts introduced is demonstrated.

The Lochkovian, Pragian, and basal part of the Emsian, which represent the post-Kwangsian Orogeny strata in the South China Block, are mainly composed of siliciclastic rocks. This lithological composition impedes investigation of Pragian and Lochkovian conodont biostratigraphy in the South China Block, which results in a persistent controversy on the age of relevant lithological units. The present study provides new evidence by reporting for the first time Lochkovian conodonts obtained from the South China Block, specifically the Gaoling Member of the Nahkaoling Formation at the Lingli section, central Guangxi. The conodont fauna, consisting of Pandorinellina exigua lingliensis Lu n. subsp., Pandorinellina exigua exigua, Zieglerodina? tuojiangensis Lu n. sp., Amydrotaxis praejohnsoni, and Eognathodus cf. E. irregularis, places the studied interval of the Gaoling Member in the lower or middle Lochkovian (contingent upon varying definitions for the base of the middle Lochkovian) to lower Pragian. Moreover, Amydrotaxis praejohnsoni, which was reported previously only in North America and eastern Australia, is herein also recorded in the South China Block, and thus may play an important role in intercontinental biostratigraphical correlation. By shedding light on the age of the upper limit of the underlying Lianhuashan Formation at the Lingli section, the present study indicates that the Kwangsian Orogeny ended before the late Lochkovian. This date is slightly earlier than the previously estimated late Lochkovian based on studies of fossil plants from the siliciclastic rocks deposited after the Kwangsian Orogeny.

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This paper presents systematic molecular dynamics modelling of Na-montmorillonite subjected to uniaxial compression and unidirectional shearing. An initial 3D model of a single-cell Na-montmorillonite structure is established using the Build Crystal module. The space group is C2/m, and COMPASS force fields are applied. Hydration analysis of Na-montmorillonite has been performed to validate the simulation procedures, where the number of absorbed water molecules varied with respect to the various lattice parameters. A series of uniaxial compression stress σzz and unidirectional shear stress τxy values are applied to the Na-montmorillonite structure. It is shown that the lattice parameter and hydration degree exhibit significant influence on the stress–strain relationship of Na-montmorillonite. The ultimate strain increases with increases in the lattice parameter but decreases in the number of water molecules. For saturated Na-montmorillonite, more water molecules result in a stiffer clay mineral under uniaxial compression and unidirectional shearing.

High-molecular-weight glutenin subunits (HMW-GS) contribute to dough elasticity and bread baking quality in wheat. In this study, wheat varieties were classified based on their HMW-GS composition into three groups: 1Dx5 (5 + 10, Gaoyou 8901, Xinmai 28, Xinmai 19, Xinmai 26 and Jinbaoyin), 1Dx2 (2 + 12, Zhoumai 24, Xinmai 9 and Yumai) and 1Dx4 (4 + 12, Aikang 58). Sequence analysis showed that 1Dx-GY8901, 1Dx-XM28, 1Dx-XM19 and 1Dx-XM26 were similar to the 1Dx5 gene and clustered on the same branch, while 1Dx-AK58, 1Dx-ZM24, 1Dx-JBY, 1Dx-YM, 1Dx-XM9 and 1Dx-JBY were more similar to the 1Dx2 gene and clustered on the same branch with 1Dx.2.2. There was a mutation of Ser to Cys at position S2, for an extra Cys in the repeat regions of 1Dx-XM19, 1Dx-XM26, 1Dx-XM28 and 1Dx-GY8901. The wheat HMW-GS genes exhibited similar percentages of α-helix, extended strand, β-turn and random coil structure, with ranges of 13.33–13.59, 4.77–5.78, 7.08–9.18 and 72.3–73.94%, respectively. Sequence conservation and the composition of HMW-GS subunits were also analysed for a series of strong gluten wheat varieties, Xinmai 9 (1, 7 + 8, 2 + 12), Xinmai 19 (1, 7 + 9, 5 + 10), Xinmai 26 (1, 7 + 8, 5 + 10) and Xinmai 28 (1, 7 + 9, 5 + 10). The results of this work should facilitate future breeding efforts and provide the theoretical basis for wheat quality improvement.

Immune cells play a key role in maintaining renal dynamic balance and dealing with renal injury. The physiological and pathological functions of immune cells are intricately connected to their metabolic characteristics. However, immunometabolism in chronic kidney disease (CKD) is not fully understood. Pathophysiologically, disruption of kidney immune cells homeostasis causes inflammation and tissue damage via triggering metabolic reprogramming. The diverse metabolic characteristics of immune cells at different stages of CKD are strongly associated with their different pathological effect. In this work, we reviewed the metabolic characteristics of immune cells (macrophages, natural killer cells, T cells, natural killer T cells and B cells) and several non-immune cells, as well as potential treatments targeting immunometabolism in CKD. We attempt to elaborate on the metabolic signatures of immune cells and their intimate correlation with non-immune cells in CKD.

According to Hamilton's rule, matrilineal-biased investment restrains men in matrilineal societies from maximising their inclusive fitness (the ‘matrilineal puzzle'). A recent hypothesis argues that when women breed communally and share household resources, a man should help his sisters' household, rather than his wife's household, as investment to the later but not the former would be diluted by other unrelated members (Wu et al., 2013). According to this hypothesis, a man is less likely to help on his wife's farm when there are more women reproducing in the wife's household, because on average he would be less related to his wife's household. We used a farm-work observational dataset, that we collected in the matrilineal Mosuo in southwest China, to test this hypothesis. As predicted, high levels of communal breeding by women in his wife's households do predict less effort spent by men on their wife's farm, and communal breeding in men's natal households do not affect whether men help on their natal farms. Thus, communal breeding by women dilutes the inclusive fitness benefits men receive from investment to their wife and children, and may drive the evolution of matrilineal-biased investment by men. These results can help solve the ‘matrilineal puzzle'.