The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of ...tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.
Mechanotransduction couples mechanical stimulation with ion flux, which is critical for normal biological processes involved in neuronal cell development, pain sensation, and red blood cell volume ...regulation. Although they are key mechanotransducers, mechanosensitive ion channels in mammals have remained difficult to identify. In 2010, Coste and colleagues revealed a novel family of mechanically activated cation channels in eukaryotes, consisting of Piezo1 and Piezo2 channels. These have been proposed as the long-sought-after mechanosensitive cation channels in mammals. Piezo1 and Piezo2 exhibit a unique propeller-shaped architecture and have been implicated in mechanotransduction in various critical processes, including touch sensation, balance, and cardiovascular regulation. Furthermore, several mutations in Piezo channels have been shown to cause multiple hereditary human disorders, such as autosomal recessive congenital lymphatic dysplasia. Notably, mutations that cause dehydrated hereditary xerocytosis alter the rate of Piezo channel inactivation, indicating the critical role of their kinetics in normal physiology. Given the importance of Piezo channels in understanding the mechanotransduction process, this review focuses on their structural details, kinetic properties and potential function as mechanosensors. We also briefly review the hereditary diseases caused by mutations in Piezo genes, which is key for understanding the function of these proteins.
With the development of proteomics and epigenetics, a large number of RNA‐binding proteins (RBPs) have been discovered in recent years, and the interaction between long non‐coding RNAs (lncRNAs) and ...RBPs has also received increasing attention. It is extremely important to conduct in‐depth research on the lncRNA‐RBP interaction network, especially in the context of its role in the occurrence and development of cancer. Increasing evidence has demonstrated that lncRNA‐RBP interactions play a vital role in cancer progression; therefore, targeting these interactions could provide new insights for cancer drug discovery. In this review, we discussed how lncRNAs can interact with RBPs to regulate their localization, modification, stability, and activity and discussed the effects of RBPs on the stability, transport, transcription, and localization of lncRNAs. Moreover, we explored the regulation and influence of these interactions on lncRNAs, RBPs, and downstream pathways that are related to cancer development, such as N6‐methyladenosine (m6A) modification of lncRNAs. In addition, we discussed how the lncRNA‐RBP interaction network regulates cancer cell phenotypes, such as proliferation, apoptosis, metastasis, drug resistance, immunity, tumor environment, and metabolism. Furthermore, we summarized the therapeutic strategies that target the lncRNA‐RBP interaction network. Although these treatments are still in the experimental stage and various theories and processes are still being studied, we believe that these strategies may provide new ideas for cancer treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: As the human lifespan increases, the number of people affected by agerelated
dementia is growing at an epidemic pace. Vascular pathology dramatically affects cognitive
profiles, resulting ...in dementia and cognitive impairment. While vascular dementia itself constitutes
a medical challenge, hypo-perfusion/vascular risk factors enhance amyloid toxicity and other memory-
damaging factors and hasten Alzheimer’s disease (AD) and other memory disorders’ progression,
as well as negatively affect treatment outcome.
Methods: Research and online content related to vascular cognitive impairment and dementia is
reviewed, specifically focusing on the potential treatment of the disorder.
Results: Few therapeutic options are currently available to improve the prognosis of patients with
vascular dementia and cognitive impairment, mixed AD dementia with vascular pathology, or other
memory disorders. Emerging evidence, however, indicates that, like AD and other memory disorders,
synaptic impairment underlies much of the memory impairment in the cognitive decline of
vascular cognitive impairment and vascular dementia.
Conclusion: Effective rescues of the memory functions might be achieved through synaptic and
memory therapeutics, targeting distinct molecular signaling pathways that support the formation of
new synapses and maintaining their connections. Potential therapeutic agents include: 1) memory
therapeutic agents that rescue synaptic and memory functions after the brain insults; 2) antipathologic
therapeutics and an effective management of vascular risk factors; and 3) preventative
therapeutic agents that achieve memory therapy through functional enhancement. These therapeutic
agents are also likely to benefit patients with AD and/or other types of memory disorders.
Human gnathostomiasis is a food-borne zoonosis. Its etiological agents are the third-stage larvae of Gnathostoma spp. Human gnathostomiasis is often reported in developing countries, but it is also ...an emerging disease in developed countries in non-endemic areas. The recent surge in cases of human gnathostomiasis is mainly due to the increasing consumption of raw freshwater fish, amphibians, and reptiles.
This article reviews the literature on Gnathostoma spp. and the disease that these parasites cause in humans. We review the literature on the life cycle and pathogenesis of these parasites, the clinical features, epidemiology, diagnosis, treatment, control, and new molecular findings on human gnathostomiasis, and social-ecological factors related to the transmission of this disease.
The information presented provides an impetus for studying the parasite biology and host immunity. It is urgently needed to develop a quick and sensitive diagnosis and to develop an effective regimen for the management and control of human gnathostomiasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Polycyclic aromatic compounds with strong conjugated effect, possess the advantage of improving electronic polarizability, thus accelerating the electron transportation. Here, a facile ...copolymerization between urea and polycyclic aromatic compounds (benzoic acid, naphthoic acid and anthroic acid) has been applied to constructing aromatic rings-grafted graphitic carbon nitride (GCN) photocatalysts. Incorporation of aromatic rings in the GCN network is an effective protocol to extend its π-conjugated system for visible light harvesting and improves the charge transfer efficiency for prolonging lifetime of photogenerated charge carriers in photocatalytic reactions. The corresponding characterization methods demonstrate that the aromatic rings-modified GCN can effectively narrow the bandgap to favor broad band visible light absorption and suppress recombination of electrons and holes. Remarkably, the moderate conjugated effect of aromatic rings (naphthalene) is crucial to promote charge separation. The developed naphthalene-grafted GCN achieves the highest water splitting performance with hydrogen evolution rate up to 102.1 μmol h−1, nearly 3.5 times of that of the GCN, and apparent quantum efficiency reaches 5.6% at 450 nm. This finding reveals that the conjugated effect of aromatic rings is significant to control photocatalytic property and brings new ideas for designing aromatic system-modified GCN as highly active photocatalysts towards solar-to-chemical energy conversion.
This study reports the preparation, characterization and photocatalytic activity of aromatic rings-grafted graphitic carbon nitride (GCN) photocatalysts, which display enhanced visible light absorption and improved separation of charge carriers due to the extended π-conjugated system, and thus the high hydrogen evolution rate. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The World Health Organization has declared the outbreak of a novel coronavirus (SARS-CoV-2 or 2019-nCoV) as a global pandemic. However, the mechanisms behind the coronavirus infection are not yet ...fully understood, nor are there any targeted treatments or vaccines. In this study, we identified high-binding-affinity aptamers targeting SARS-CoV-2 RBD, using an ACE2 competition-based aptamer selection strategy and a machine learning screening algorithm. The K d values of the optimized CoV2-RBD-1C and CoV2-RBD-4C aptamers against RBD were 5.8 nM and 19.9 nM, respectively. Simulated interaction modeling, along with competitive experiments, suggests that two aptamers may have partially identical binding sites at ACE2 on SARS-CoV-2 RBD. These aptamers present an opportunity for generating new probes for recognition of SARS-CoV-2 and could provide assistance in the diagnosis and treatment of SARS-CoV-2 while providing a new tool for in-depth study of the mechanisms behind the coronavirus infection.
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IJS, KILJ, NUK, PNG, UL, UM
•Dependence of long-term cyclic behaviors and non-coaxiality under heart-shaped traffic loads on the ζ and ηd is revealed.•An increase in ζ and ηd results in ε1acc and M, along with increased ...susceptibility to volumetric contraction.•The overall deformation accumulation direction and stress-dilatancy relationship within individual cycle are assessed.•A systematic interpretation on the non-coaxiality behaviors under anisotropic heart-shaped stress path is conducted.
Subgrades composed of siliceous sand are often subjected to traffic-induced cyclic loads. However, there is a knowledge gap regarding the long-term deformation behaviour and non-coaxiality of siliceous sand under high-cyclic traffic loading. This study addresses this issue by conducting a series of drained high-cyclic tests using a hollow cylinder apparatus to simulate an anisotropic heart-shaped stress path. The effects of cyclic stress ratio (ζ) and torsion-shear stress ratio (ηd) were carefully evaluated and interpreted. The results showed that an increase in ζ and ηd results in a higher axial cumulative strain and resilient modulus, along with increased susceptibility to volumetric contraction. The dilatancy d (dεvacc/dεqacc) characterizing overall deformation accumulation experienced a transformation of first stabilizing then declining. By contrast, the individual stress-dilatancy relations within loading and unloading stages exhibited an inward movement trend. Moreover, the development and influencing factors of non-coaxiality were meticulously analysed, revealing that while the number of loading cycles had a negligible effect on non-coaxiality behaviour, it was considerably influenced by stress levels. A significant increase in the range of non-coaxiality angle variation was observed at larger ζ and ηd values. This study provides insights for the construction and design of tunnel foundations and pavement engineering.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, ...formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.
With the development of next generation sequencing techniques, it is fast and cheap to determine protein sequences but relatively slow and expensive to extract useful information from protein ...sequences because of limitations of traditional biological experimental techniques. Protein function prediction has been a long standing challenge to fill the gap between the huge amount of protein sequences and the known function. In this paper, we propose a novel method to convert the protein function problem into a language translation problem by the new proposed protein sequence language "ProLan" to the protein function language "GOLan", and build a neural machine translation model based on recurrent neural networks to translate "ProLan" language to "GOLan" language. We blindly tested our method by attending the latest third Critical Assessment of Function Annotation (CAFA 3) in 2016, and also evaluate the performance of our methods on selected proteins whose function was released after CAFA competition. The good performance on the training and testing datasets demonstrates that our new proposed method is a promising direction for protein function prediction. In summary, we first time propose a method which converts the protein function prediction problem to a language translation problem and applies a neural machine translation model for protein function prediction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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