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Limbal stem cells are essential for continuous corneal regeneration and injury repair. METTL3-catalyzed N6-methyladenosine (m6A) mRNA modifications are involved in many biological processes and play a specific role in stem cell regeneration, while the role of m6A modifications in corneal injury repair remains unknown. In this study, we generated a limbal stem cell-specific METTL3 knockout mouse model and studied the role of m6A in repairing corneal injury caused by alkali burn. The results showed that METTL3 knockout in the limbal stem cells promotes the in vivo cell proliferation and migration, leading to the fast repair of corneal injury. In addition, m6A modification profiling identified stem cell regulatory factors AHNAK and DDIT4 as m6A targets. Our study reveals the essential functions of m6A RNA modification in regulating injury repair and provides novel insights for clinical therapy of corneal diseases. [ABSTRACT FROM AUTHOR]

The identification of new genes involved in regulating cold tolerance in rice is urgent because low temperatures repress plant growth and reduce yields. Cold tolerance is controlled by multiple loci and involves a complex regulatory network. Here, we show that rice jacalin‐related lectin (OsJRL) modulates cold tolerance in rice. The loss of OsJRL gene functions increased phenylalanine metabolism and flavonoid biosynthesis under cold stress. The OsJRL knock‐out (KO) lines had higher phenylalanine ammonia‐lyase (PAL) activity and greater flavonoid accumulation than the wild‐type rice, Nipponbare (NIP), under cold stress. The leaves had lower levels of reactive oxygen species (ROS) and showed significantly enhanced cold tolerance compared to NIP. In contrast, the OsJRL overexpression (OE) lines had higher levels of ROS accumulation and showed lower cold tolerance than NIP. Additionally, the OsJRL KO lines accumulated more abscisic acid (ABA) and jasmonic acid (JA) under cold stress than NIP. The OsJRL OE lines showed increased sensitivity to ABA compared to NIP. We conclude that OsJRL negatively regulates the cold tolerance of rice via modulation of phenylalanine metabolism and flavonoid biosynthesis. [ABSTRACT FROM AUTHOR]

Accurately evaluating tumor neoangiogenesis and conducting precise interventions toward an immune-favorable microenvironment are of significant clinical importance. In this study, a novel nanodroplet termed as the nanodroplet-based ultrasound contrast agent and therapeutic (NDs UCA/Tx ) is designed for ultrasound imaging and precise interventions of tumor neoangiogenesis. Briefly, the NDs UCA/Tx shell is constructed from an engineered CMs containing the tumor antigen, vascular endothelial growth factor receptor 1 (VEGFR1) extracellular domain 2-3, and CD93 ligand multimerin 2. The core is composed of perfluorohexane and the immune adjuvant R848. After injection, NDs UCA/Tx is found to be enriched in the tumor vasculature with high expression of CD93. When triggered by ultrasound, the perfluorohexane in NDs UCA/Tx underwent acoustic droplet vaporization and generated an enhanced ultrasound signal. Some microbubbles exploded and the resultant debris (with tumor antigen and R848) together with the adsorbed VEGF are taken up by nearby cells. This cleared the local VEGF for vascular normalization, and also served as a vaccine to activate the immune response. Using a syngeneic mouse model, the satisfactory performance of NDs UCA/Tx in tumor vasculature imaging and immune activation is confirmed. Thus, a multifunctional NDs UCA/Tx is successfully developed for molecular imaging of tumor neoangiogenesis and precise remodeling of the tumor microenvironment., (© 2024 Wiley‐VCH GmbH.)

The three-terminal ballistic junction (TBJ) has promising applications in nanoelectronics. We investigate the transport properties of a α - T 3 -based TBJ, where two typical configurations are considered, i.e. the A- and Z-TBJ. It is found that both A- and Z-TBJ exhibit transmission anisotropy, and the transmission of the A-TBJ has stronger anisotropy than that of the Z-TBJ. The amplitude of the rectification coefficient is smaller than that of phosphorene TBJ, but larger than that of graphene TBJ. When the symmetrical input is applied, the output voltage curve exhibits symmetric behavior. While in the case of asymmetric input, the symmetric behavior is broken, and the maximum value of the output voltage can reach a positive value. Interestingly, the voltage output shows a dramatic nonlinear response which may be useful for the voltage diode application with a push-pull input voltage. In addition, the heat fluxes of the asymmetric input are much smaller than those of the symmetric input. The maximum value of the heat flux under the symmetric input exceeds twice of that under the asymmetric input. Our results are useful to design nanoelectronic devices based on α - T 3 TBJ., (© 2024 IOP Publishing Ltd.)

Regular exercise maintains a healthy metabolic profile, while the underlying mechanisms have not been fully elucidated. Extracellular vesicles serve as an important mediator in intercellular communication. In this study, we aimed to explore whether exercise-induced extracellular vesicles (EVs) of skeletal muscle origins contribute to exercise-related protective effects on metabolism. We found that the twelve weeks of swimming training improved glucose tolerance, reduced visceral lipid accumulation, alleviated liver damage, and inhibited atherosclerosis progression in both obese WT mice and ApoE -/- mice, which could be partially blocked by EV biogenesis repression. Injection of skeletal muscle-derived EVs from exercised C57BL/6J mice (twice a week for 12 weeks) had similar protective effects on both obese WT mice and ApoE -/- mice as exercise itself. Mechanistically, these exe-EVs could be endocytosed by major metabolic organs, especially the liver and adipose tissue. With the protein cargos rich in mitochondrial and fatty acid oxidation-related components, exe-EVs remodeled metabolism towards beneficial cardiovascular outcomes. Our study here has shown that exercise remodels metabolism towards beneficial cardiovascular outcomes at least partially via the skeletal muscle secreted EVs. Therapeutic delivery of exe-EVs or the analogues could be promising for prevention of certain cardiovascular and metabolic diseases.

Limbal stem cells are essential for continuous corneal regeneration and injury repair. METTL3-catalyzed N6-methyladenosine (m 6 A) mRNA modifications are involved in many biological processes and play a specific role in stem cell regeneration, while the role of m 6 A modifications in corneal injury repair remains unknown. In this study, we generated a limbal stem cell-specific METTL3 knockout mouse model and studied the role of m 6 A in repairing corneal injury caused by alkali burn. The results showed that METTL3 knockout in the limbal stem cells promotes the in vivo cell proliferation and migration, leading to the fast repair of corneal injury. In addition, m 6 A modification profiling identified stem cell regulatory factors AHNAK and DDIT4 as m 6 A targets. Our study reveals the essential functions of m 6 A RNA modification in regulating injury repair and provides novel insights for clinical therapy of corneal diseases., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Yarong Dai et al.)

The coronavirus disease 2019 (COVID-19) is a new type of pneumonia caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. COVID-19 is affecting millions of patients, and the infected number keeps increasing. SARS-CoV-2 is highly infectious, has a long incubation period, and causes a relatively high death rate, resulting in severe health problems all over the world. Currently there is no effective proven drug for the treatment of COVID-19; therefore, development of effective therapeutic drugs to suppress SARS-CoV-2 infection is urgently needed. In this review, we first summarize the structure and genome features of SARS-CoV-2 and introduce its infection and replication process. Then, we review the clinical symptoms, diagnosis, and treatment options of COVID-19 patients. We further discuss the potential molecular targets and drug development strategies for treatment of the emerging COVID-19. Finally, we summarize clinical trials of some potential therapeutic drugs and the results of vaccine development. This review provides some insights for the treatment of COVID-19., (© 2020 The Author(s).)

The Bcl-2 family of proteins regulates apoptosis at the level of mitochondrial permeabilization. Pro-death members of the family, including Bak and Bax, initiate apoptosis, whereas pro-survival members such as Bcl-x(L) and Mcl-1 antagonize the function of Bak and Bax via heterodimeric interactions. These heterodimeric interactions are primarily mediated by the binding of the helical amphipathic BH3 domain from a pro-death protein to a hydrophobic cleft on the surface of the pro-survival protein. Since high levels of pro-survival Bcl-2 proteins are present in many cancers, peptides corresponding to pro-death BH3 domains hold promise as therapeutics. Here we apply a high-throughput flow cytometry assay to engineer the Bak BH3 domain for improved affinity toward the pro-survival proteins Bcl-x(L) and Mcl-1. Two strategies, engineering the hydrophobic face of the Bak BH3 peptide and increasing its overall helicity, are successful in identifying Bak BH3 variants with improved affinity to Bcl-x(L) and Mcl-1. Hydrophobic face engineering of the Bak BH3 peptide led to variants with up to a 15-fold increase in affinity for Bcl-x(L) and increased specificity toward Bcl-x(L). Engineering of the helicity of Bak BH3 led to modest (3- to 4-fold) improvements in affinity with retention of promiscuous binding to all pro-survival proteins. HeLa cell killing studies demonstrate that the affinity matured Bak BH3 variants retain their expected biological function.