Systemic and cytosolic delivery represents a grand challenge preventing many therapeutic proteins from clinical applications. Despite tremendous progresses in the past decade, most approaches ...generally lack the ability of triggered traceless protein release, require complicated formulation, and/or yield low protein loading. By using the protein as a crosslinker, here, a simple and general formulation affording protein nanogels (NG) with uniformed sizes and exceptionally high protein loading (>50%) is reported. By using the fine‐tuned bis‐ and monosubstituted maleamic anhydride‐amine chemistry for the crosslinking of the protein and a 4‐armed PEG‐MA4, the NG is implemented with a tandem pH‐programmed and traceless release character. The final NG, CDM‐MA‐NG, is stable under normal physiological conditions and effectively protects the crosslinked cargo cytochrome C from serum fouling, proteolytic and thermal degradation. In vitro, CDM‐MA‐NG exhibits a high level of cellular uptake and potent cancer cell killing only when incubated at pH 6.5, but not 7.4. Systemic administration of CDM‐MA‐NG leads to significantly inhibited tumor growth and extended survival rate. Given the abundance of the amine groups on protein surface, this work describes a universal platform for therapeutic protein formulation, and opens up enormous opportunities for the systemic, cytosolic, and traceless delivery of protein‐based nanomedicines.
A tandem dual‐pH‐sensitive charge‐reversal nanogel is developed for the cytosolic delivery and traceless release of functional proteins. The high protein loading nanogel is obtained via the in situ reaction of lysines with bis‐ and monosubstituted maleic anhydride. The nanogel can lead to rapid cell apoptosis and remarkable inhibition of tumor growth without detectable side efforts.
Objectives
This study aimed to review the results of oral leucoplakia (OL) using ablative fractional laser‐assisted photodynamic therapy (AFL‐PDT) and to further evaluate the risk factors for ...recurrence and malignant transformation.
Materials and Methods
Forty‐eight patients diagnosed with OL using histopathology were enrolled in this study. All patients received one session of AFL‐PDT. Therapeutic efficacy was evaluated 1 month posttreatment. Follow‐up was scheduled every 3 months in the first year and every 6 months thereafter.
Results
An overall positive response rate of 87.5% (42/48) was achieved, including 62.5% (30/48) complete responses and 25.0% (12/48) partial responses. During the 3‐year follow‐up period, the recurrence and malignant transformation rates were 37.5% (18/48) and 8.3% (4/48), respectively. Lesions on gingiva/palate seemed to be associated with recurrence (p < 0.001; odds ratio OR: 1.64, 95% confidence interval CI: 1.13–2.37). The severity of epithelial dysplasia (p = 0.02; OR: 2.93, 95% CI: 1.96–4.42) and recurrence (p = 0.016; OR: 3.14, 95% CI: 2.04–4.84) were associated with a predisposition to malignant transformation.
Conclusions
AFL‐PDT is an effective management of OL, but requires close follow‐up. OL lesions on the gingiva/palate are predisposed to recurrence. OLs that recur with moderate/severe epithelial dysplasia have a higher risk of transforming into oral squamous cell carcinoma.
Charging infrastructure deployment is to seek the proper plan of settling charging stations and charging piles under multiple constraints, such as recharging demand, cruising range, etc., and it has ...been asserted as an NP-Complete problem. In this paper, we propose a multicriteria-oriented approach of efficiently deploying charging infrastructure to cope with the problem. We firstly formulate five realistic charging objective functions that exhibit a significant diminishing returns effect, i.e., submodularity, and then exploit the submodularity of these objectives to design the acceleration algorithms for Charging Station PLacement (CSPL) with the provable performance guarantees. The corresponding algorithms are respectively named Lazy Greedy with Direct Gain (LGDG) and Lazy Greedy with Effective Gain (LGEG), and they scale well to the road networks of arbitrary size. Relying on the inference that the linear combination of submodular functions is still a submodular function, we treat CSPL as a multicriteria optimization problem that can be efficiently solved by the proposed algorithms. Moreover, we employ Erlang-Loss system to gain an optimal Charging Pile ASsignment (CPAS), which is capable of reducing the gap between the growing complexity of charging demands and the constrained supply of charging resources in considering the correlation between the primary human activities and the charging process. The experimental evaluation with real data sets shows that, compared with the state-of-the-art methods, the proposed approach reveals better effectiveness and efficiency, and it offers a potent solution to the planning of charging infrastructure for electric vehicles with large-scale datasets in reality.
Exosomes are cell-derived vesicles and are abundant in biological fluids; they contain RNA molecules which may serve as potential diagnostic biomarkers in 'precision medicine'. To promote the ...clinical application of exosomal RNA (exoRNA), many isolation methods must be compared and validated. Exosomes in cell culture medium (CCM) and serum may be isolated using ultracentrifugation (UC), ExoQuick or Total Exosome Isolation Reagent (TEI), and exoRNA may be extracted using TRIzol-LS, SeraMir, Total Exosome RNA Isolation (TER), HiPure Liquid RNA/miRNA kit (HLR), miRNeasy or exoRNeasy. ExoRNA was assessed using NanoDrop, Bioanalyzer 2100, quantitative polymerase chain reaction and high-throughput sequencing. UC showed the lowest recovery of particles, but the highest protein purity for exosome isolation. For isolation of exoRNA, we found that combinations of the TEI and TER methods resulted in high extraction efficiency and purity of small RNA obtained using CCM. High yield and a narrow size distribution pattern of small RNA were shown in exoRNA isolated by exoRNeasy from serum. In RNA profile analysis, the small RNA constituent ratio, miRNA content and amount varied as a result of methodological differences. This study showed that different methods may introduce variations in the concentration, purity and size of exosomes and exoRNA. Herein we discuss the advantages and disadvantages of each method and their application to different materials, therefore providing a reference according to research design.
Ling-zhi, a widely cultivated fungus in China, has a long history in traditional Chinese medicine. Although the name 'Ganoderma lucidum', a species originally described from England, has been applied ...to the fungus, their identities are not the same. This study aims to clarify the identity of this medicinally and economically important fungus. Specimens of Ling-zhi from China (field collections and cultivated basidiomata of the Chinese 'G. lucidum'), G. lucidum from UK and other related Ganoderma species, were examined both morphologically and molecularly. High variability of basidioma morphology was found in the cultivated specimens of the Chinese 'G. lucidum', while some microscopic characters were more or less consistent, i.e. short clavate cutis elements, Bovista-type ligative hyphae and strongly echinulate basidiospores. These characters were also found in the holotype of G. sichuanense, a species originally described from Sichuan, China, and in recent collections made in the type locality of the species, which matched the diagnostic characters in the prologue. For comparison, specimens of closely related species, G. lucidum, G. multipileum, G. resinaceum, G. tropicum and G. weberianum, were also examined. DNA sequences were obtained from field collections, cultivated basidiomata and living strains of the Chinese 'G. lucidum', specimens from the type locality of G. sichuanense, and specimens of the closely related species studied. Three-gene combined analyses (ITS+IGS+rpb2) were performed and the results indicated that the Chinese 'G. lucidum' shared almost identical sequences with G. sichuanense. Based on both morphological and molecular data, the identity of the Chinese 'G. lucidum' (Ling-zhi) is considered conspecific with G. sichuanense. Detailed morphological descriptions and illustrations are provided in addition to discussion of nomenclature implications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Superconducting topological crystalline insulators are expected to form a new type of topological superconductors to host Majorana zero modes under the protection of lattice symmetries. The bulk ...superconductivity of topological crystalline insulators can be induced through chemical doping and the proximity effect. However, only conventional full gaps are observed, so the existence of topological superconductivity in topological crystalline insulators is still controversial. Here, the successful fabrication of atomically flat lateral and vertical Sn1−xPbxTe–Pb heterostructures by molecular beam epitaxy is reported. The superconductivity of the Sn1−xPbxTe–Pb heterostructures can be directly investigated by scanning tunneling spectroscopy. Unconventional peak–dip–hump gap features and fourfold symmetric quasiparticle interference patterns taken at the zero energy in the superconducting gap support the presence of the topological superconductivity in superconducting Sn1−xPbxTe. Strong superconducting proximity effect and easy preparation of various constructions between Sn1−xPbxTe and Pb make the heterostructures to be a promising candidate for topological superconducting devices to detect and manipulate Majorana zero modes in the future.
Superconducting topological crystalline insulators are expected to form a new type of topological superconductors protected by lattice symmetries. Unconventional peak–dip–hump gap features and fourfold symmetric quasiparticle interference patterns taken at the zero energy in the superconducting gap support the presence of the topological superconductivity in Sn1−xPbxTe–Pb heterostructures. Moreover, the superconducting proximity effect is found to be unexpectedly strong even at 4.2 K.
Recently, theory has predicted a Majorana zero mode (MZM) to induce spin selective Andreev reflection (SSAR), a novel magnetic property which can be used to detect the MZM. Here, spin-polarized ...scanning tunneling microscopy or spectroscopy has been applied to probe SSAR of MZMs in a topological superconductor of the Bi_{2}Te_{3}/NbSe_{2} heterostructure. The zero-bias peak of the tunneling differential conductance at the vortex center is observed substantially higher when the tip polarization and the external magnetic field are parallel rather than antiparallel to each other. This spin dependent tunneling effect provides direct evidence of MZM and reveals its magnetic property in addition to the zero energy modes. Our work will stimulate MZM research on these novel physical properties and, hence, is a step towards experimental study of their statistics and application in quantum computing.
Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully ...understood. To mimic increased expression of Nrg1, a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gtoNrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gtoNrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Na
1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Na
currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gtoNrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders.
A frequency-domain finite element method (FEM) with the low-storage matrix-free feature is proposed for efficient analysis of electromagnetic fields. As opposed to conventional frequency-domain FEM ...which requires the matrix assembly before solving, the proposed matrix-free algorithm avoids the assembly and storage of the global matrix. In this approach, the global sparse matrix-vector (SpMV) multiplication is decomposed into element-wise matrix-vector (MV) multiplications. Additionally, the sum factorization technique is applied on tensorial basis functions to reduce the complexities of local MV multiplications. The numerical results demonstrate the superiority of our algorithm over traditional FEM in terms of both memory and time consumption. Besides, the improvement is more profound when higher-order basis functions are considered. A speedup of more than 10 against matrix-assembled solvers is observed. Given that memory transfer is bounded more than computation resources in modern supercomputer architectures, our algorithm is more friendly to high-performance computing platforms.
This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with ...recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).
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Regorafenib plus toripalimab improves response and overall survivalPatients with liver metastasis have lower response rate than those withoutIncreased Fusobacterium is found in non-responders compared with responders
Wang et al. demonstrate the safety, efficacy, and survival of regorafenib plus toripalimab in colorectal cancer patients. They show the gut microbiome results that Fusobacterium is negatively correlated with response and survival. This provides a combination regimen for unselected refractory metastatic colorectal cancer patients.
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