KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m6A reader YTHDC1 protein degradation.

BACKGROUND: Neuroblastoma (NB) patients with amplified MYCN often face a grim prognosis and are resistant to existing therapies, yet MYCN protein is considered undruggable. KAP1 (also named TRIM28) plays a crucial role in multiple biological activities. This study aimed to investigate the relationship between KAP1 and MYCN in NB. METHODS: Transcriptome analyses and luciferase reporter assay identified that KAP1 was a downstream target of MYCN. The effects of KAP1 on cancer cell proliferation and colony formation were explored using the loss-of-function assays in vitro and in vivo. RNA stability detection was used to examine the influence of KAP1 on MYCN expression. The mechanisms of KAP1 to maintain MYCN mRNA stabilization were mainly investigated by mass spectrum, immunoprecipitation, RIP-qPCR, and western blotting. In addition, a xenograft mouse model was used to reveal the antitumor effect of STM2457 on NB. RESULTS: Here we identified KAP1 as a critical regulator of MYCN mRNA stability by protecting the RNA N6-methyladenosine (m6A) reader YTHDC1 protein degradation. KAP1 was highly expressed in clinical MYCN-amplified NB and was upregulated by MYCN. Reciprocally, KAP1 knockdown reduced MYCN mRNA stability and inhibited MYCN-amplified NB progression. Mechanistically, KAP1 regulated the stability of MYCN mRNA in an m6A-dependent manner. KAP1 formed a complex with YTHDC1 and RNA m6A writer METTL3 to regulate m6A-modified MYCN mRNA stability. KAP1 depletion decreased YTHDC1 protein stability and promoted MYCN mRNA degradation. Inhibiting MYCN mRNA m6A modification synergized with chemotherapy to restrain tumor progression in MYCN-amplified NB. CONCLUSIONS: Our research demonstrates that KAP1, transcriptionally activated by MYCN, forms a complex with YTHDC1 and METTL3, which in turn maintain the stabilization of MYCN mRNA in an m6A-dependent manner. Targeting m6A modification by STM2457, a small-molecule inhibitor of METTL3, could downregulate MYCN expression and attenuate tumor proliferation. This finding provides a new alternative putative therapeutic strategy for MYCN-amplified NB.

Oxygen evolution and its drivers in a stratified reservoir: A supply-side perspective for informing hypoxia alleviation strategies.

Hypoxia in stratified waters greatly threatens aquatic ecology and societal development owing to enhanced nutrient discharge and increasing global temperature. Current research predominantly alleviates hypoxia by reducing dissolved oxygen (DO) consumption or conducting hypolimnetic oxygenation, yet their implementation has encountered bottlenecks. Therefore, this study explores the potential of increasing the inherent DO supplies in stratified reservoirs to mitigate hypoxia. High-frequency in situ observations and massive modeling experiments are integrated to discern the DO supply mode and the dominant driver of DO evolution. Results indicate that periodic thermodynamic conditions determine the DO supply relationships between oxygen sources (inflow carriage, reaeration, and photosynthesis) for different water layers. Thermal stratification causes the hypolimnion to rely mostly on the inflow for DO supply, leading to a fragile budget prone to hypoxia. However, episodic hydrodynamic events (turnover, wind stir, density current, and flood) can promote DO supply and inhibit hypoxia. Temperature and DO regimes are primarily driven by outflow conditions, followed by inflow and meteorology conditions. Furthermore, hypolimnetic hypoxia can be regulated by altering inflow volume, outflow volume, and outlet elevation. These findings highlight the importance of longitudinal solute exchange in DO evolution in stratified reservoirs, providing a basis for alleviating hypoxia through cascade reservoir operations.

Wireless sequential dual light delivery for programmed PDT in vivo.

Using photodynamic therapy (PDT) to treat deep-seated cancers is limited due to inefficient delivery of photosensitizers and low tissue penetration of light. Polymeric nanocarriers are widely used for photosensitizer delivery, while the self-quenching of the encapsulated photosensitizers would impair the PDT efficacy. Furthermore, the generated short-lived reactive oxygen spieces (ROS) can hardly diffuse out of nanocarriers, resulting in low PDT efficacy. Therefore, a smart nanocarrier system which can be degraded by light, followed by photosensitizer activation can potentially overcome these limitations and enhance the PDT efficacy. A light-sensitive polymer nanocarrier encapsulating photosensitizer (RB-M) was synthesized. An implantable wireless dual wavelength microLED device which delivers the two light wavelengths sequentially was developed to programmatically control the release and activation of the loaded photosensitizer. Two transmitter coils with matching resonant frequencies allow activation of the connected LEDs to emit different wavelengths independently. Optimal irradiation time, dose, and RB-M concentration were determined using an agent-based digital simulation method. In vitro and in vivo validation experiments in an orthotopic rat liver hepatocellular carcinoma disease model confirmed that the nanocarrier rupture and sequential low dose light irradiation strategy resulted in successful PDT at reduced photosensitizer and irradiation dose, which is a clinically significant event that enhances treatment safety.

Role of miRNAs in neurovascular injury and repair.

MicroRNAs (miRNA) are endogenously produced small, non-coded, single-stranded RNAs. Due to their involvement in various cellular processes and cross-communication with extracellular components, miRNAs are often coined the "grand managers" of the cell. miRNAs are frequently involved in upregulation as well as downregulation of specific gene expression and thus, are often found to play a vital role in the pathogenesis of multiple diseases. Central nervous system (CNS) diseases prove fatal due to the intricate nature of both their development and the methods used for treatment. A considerable amount of ongoing research aims to delineate the complex relationships between miRNAs and different diseases, including each of the neurological disorders discussed in the present review. Ongoing research suggests that specific miRNAs can play either a pathologic or restorative and/or protective role in various CNS diseases. Understanding how these miRNAs are involved in various regulatory processes of CNS such as neuroinflammation, neurovasculature, immune response, blood-brain barrier (BBB) integrity and angiogenesis is of empirical importance for developing effective therapies. Here in this review, we summarized the current state of knowledge of miRNAs and their roles in CNS diseases along with a focus on their association with neuroinflammation, innate immunity, neurovascular function and BBB.

Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition.

Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.

Effect of glabridin combined with bakuchiol on UVB-induced skin damage and its underlying mechanism: An experimental study.

BACKGROUND: Research has demonstrated the anti-photoaging properties of glabridin and bakuchiol. METHODS: The impact of glabridin, glabridin + bakuchiol, and bakuchiol on the levels of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) in mice skin fibroblasts was observed. Furthermore, we investigated the potential roles of fibronectin (FN), interferon-γ (IFN-γ), interleukin-22 (IL-22), and transforming growth factor-ß (TGF-ß) in the tissues, and evaluated their impact on the enzymatic levels in the skin. In conjunction with transcriptomic analysis, metabolomic profiling, and network pharmacology, all samples underwent comprehensive metabolomic and principal component analysis. The Venny2.1 method was utilized to identify variances in shared metabolites between the treatment group and the UVB group, as well as between the UVB group and the control group. Subsequently, a cluster heat map was generated to forecast and analyze metabolic pathways and targets. RESULTS: The outcomes from the hematoxylin and eosin and toluidine blue staining revealed that glabridin and bakuchiol markedly decreased dermal thickness and suppressed mast cell infiltration in photoaged mice. Immunohistochemistry and Elisa analysis revealed that glabridin and bakuchiol effectively attenuated the levels of pro-inflammatory factors, including IL-1ß, tumor necrosis factor-α, IL-22, and IFN-γ. Furthermore, an increase in the levels of anti-inflammatory factors such as FN and TGF-ß was also observed. The determination of the contents of superoxide dismutase, hydroxypropyltransferase and malondialdehyde in mice dorsal skin revealed that glabridin and bakuchiol not only elevated the levels of superoxide dismutase and hydroxyproline, but also reduced malondialdehyde content. Due to the limited number of shared differential metabolites exclusively within Kyoto Encyclopedia of Genes and Genomes, comprehensive pathway enrichment analysis was not feasible. CONCLUSION: This study demonstrates that glabridin and bakuchiol effectively impede photoaging and alleviate skin inflammation in mice.

Multifield-Modulated Spintronic Terahertz Emitter Based on a Vanadium Dioxide Phase Transition.

The efficient generation and active modulation of terahertz (THz) waves are strongly required for the development of various THz applications such as THz imaging/spectroscopy and THz communication. In addition, due to the increasing degree of integration for the THz optoelectronic devices, miniaturizing the complex THz system into a compact unit is also important and necessary. Today, integrating the THz source with the modulator to develop a powerful, easy-to-adjust, and scalable or on-chip THz emitter is still a challenge. As a new type of THz emitter, a spintronic THz emitter has attracted a great deal of attention due to its advantages of high efficiency, ultrawide band, low cost, and easy integration. In this study, we have proposed a multifield-modulated spintronic THz emitter based on the VO2/Ni/Pt multilayer film structure with a wide band region of 0-3 THz. Because of the pronounced phase transition of the integrated VO2 layer, the fabricated THz emitter can be efficiently modulated via thermal or electric stimuli with a modulation depth of about one order of magnitude; the modulation depths under thermal stimulation and electrical stimulation were 91.8% and 97.3%, respectively. It is believed that this multifield modulated spintronic THz emitter will provide various possibilities for the integration of next-generation on-chip THz sources and THz modulators.

LINC00115 promotes chemoresistant breast cancer stem-like cell stemness and metastasis through SETDB1/PLK3/HIF1α signaling.

BACKGROUND: Cancer stem-like cell is a key barrier for therapeutic resistance and metastasis in various cancers, including breast cancer, yet the underlying mechanisms are still elusive. Through a genome-wide lncRNA expression profiling, we identified that LINC00115 is robustly upregulated in chemoresistant breast cancer stem-like cells (BCSCs). METHODS: LncRNA microarray assay was performed to document abundance changes of lncRNAs in paclitaxel (PTX)-resistant MDA-MB-231 BCSC (ALDH+) and non-BCSC (ALDH-). RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to determine the binding proteins of LINC00115. The clinical significance of the LINC00115 pathway was examined in TNBC metastatic lymph node tissues. The biological function of LINC00115 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA sequencing, mass spectrometry, and the CRISPR/Cas9-knockout system. The therapeutic potential of LINC00115 was examined through xenograft animal models. RESULTS: LINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3, leading to enhanced SETDB1 methylation of PLK3 at both K106 and K200 in drug-resistant BCSC. PLK3 methylation decreases PLK3 phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α, in turn, upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1α are prognostic for clinical triple-negative breast cancers. CONCLUSIONS: Our findings uncover LINC00115 as a critical regulator of BCSC and highlight targeting LINC00115 and SETDB1 as a potential therapeutic strategy for chemotherapeutic resistant breast cancer.

Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRASG12D-mutant pancreatic ductal adenocarcinoma.

Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.

Prevention and Potential Treatment Strategies for Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is a significant viral pathogen that causes respiratory infections in infants, the elderly, and immunocompromised individuals. RSV-related illnesses impose a substantial economic burden worldwide annually. The molecular structure, function, and in vivo interaction mechanisms of RSV have received more comprehensive attention in recent times, and significant progress has been made in developing inhibitors targeting various stages of the RSV replication cycle. These include fusion inhibitors, RSV polymerase inhibitors, and nucleoprotein inhibitors, as well as FDA-approved RSV prophylactic drugs palivizumab and nirsevimab. The research community is hopeful that these developments might provide easier access to knowledge and might spark new ideas for research programs.

Risk assessment of SARS-CoV-2 replicating and evolving in animals.

The retransmissions of SARS-CoV-2 from several mammals - primarily mink and white-tailed deer - to humans have raised concerns for the emergence of a new animal-derived SARS-CoV-2 variant to worsen the pandemic. Here, we discuss animal species that are susceptible to natural or experimental infection with SARS-CoV-2 and can transmit the virus to mates or humans. We describe cutting-edge techniques to assess the impact of a mutation in the viral spike (S) protein on its receptor and on antibody binding. Our review of spike sequences of animal-derived viruses identified nine unique amino acid exchanges in the receptor-binding domain (RBD) that are not present in any variant of concern (VOC). These mutations are present in SARS-CoV-2 found in companion animals such as dogs and cats, and they exhibit a higher frequency in SARS-CoV-2 found in mink and white-tailed deer, suggesting that sustained transmissions may contribute to maintaining novel mutations. Four of these exchanges, such as Leu452Met, could undermine acquired immune protection in humans while maintaining high affinity for the human angiotensin-converting enzyme 2 (ACE2) receptor. Finally, we discuss important avenues of future research into animal-derived viruses with public health risks.

Craniofacial Fibrous Dysplasia in Fronto-Orbital Region: A Single-Center Retrospective Study of 38 Cases.

OBJECTIVE: This study presents the clinical characteristics, imaging manifestations, and surgical experience in 38 patients diagnosed with craniofacial fibrous dysplasia in fronto-orbital region (foFD). METHODS: We retrospectively analyzed the clinical data from 38 patients who had surgery for foFD. The surgical procedure typically involved extensive tumor removal, followed by immediate reconstruction of the frontal bone and orbit using synthetic materials. Additionally, 9 patients underwent simultaneous microscopic decompression of the optic canal. RESULTS: Common clinical manifestations included progressive fronto-orbital bone deformity (35), proptosis (28), orbital dystopia (21), and visual impairment (9). The disease primarily affecting the frontal bone (38), the sphenoid bone (28), and the ethmoid bone (24). The optic canal was involved in 9 patients with functional impairment. Computed tomography scans in all 38 cases revealed satisfactory repair material positioning and complete resolution of frontal deformities. Among the 9 patients who underwent optic canal decompression, 7 experienced partial recovery of visual acuity after surgery. CONCLUSIONS: In the surgical treatment of foFD, it is crucial to achieve maximal bone resection and repair skull defects, while decompressing the optic canal can provide significant benefits for patients with decreased visual function preoperatively. The use of preformed artificial materials offers advantages in aesthetic restoration after lesion excision.

Covalent Organic Frameworks: Their Composites and Derivatives for Rechargeable Metal-Ion Batteries.

Covalent organic frameworks (COFs) have attracted considerable interest in the field of rechargeable batteries owing to their three-dimensional (3D) varied pore sizes, inerratic porous structures, abundant redox-active sites, and customizable structure-adjustable frameworks. In the context of metal-ion batteries, these materials play a vital role in electrode materials, effectively addressing critical issues such as low ionic conductivity, limited specific capacity, and unstable structural integrity. However, the electrochemical characteristics of the developed COFs still fall short of practical battery requirements due to inherent issues such as low electronic conductivity, the tradeoff between capacity and redox potential, and unfavorable micromorphology. This review provides a comprehensive overview of the recent advancements in the application of COFs, COF-based composites, and their derivatives in rechargeable metal-ion batteries, including lithium-ion, lithium-sulfur, sodium-ion, sodium-sulfur, potassium-ion, zinc-ion, and other multivalent metal-ion batteries. The operational mechanisms of COFs, COF-based composites, and their derivatives in rechargeable batteries are elucidated, along with the strategies implemented to enhance the electrochemical properties and broaden the range of their applications.

Hypoxia-inducible factor-1: Regulatory mechanisms and drug therapy in myocardial infarction.

Myocardial infarction (MI), an acute cardiovascular disease characterized by coronary artery blockage, inadequate blood supply, and subsequent ischemic necrosis of the myocardium, is one of the leading causes of death. The cellular, physiological, and pathological responses following MI are complex, involving multiple intertwined pathological mechanisms. Hypoxia-inducible factor-1 (HIF-1), a crucial regulator of hypoxia, plays a significant role in of the development of MI by modulating the behavior of various cells such as cardiomyocytes, endothelial cells, macrophages, and fibroblasts under hypoxic conditions. HIF-1 regulates various post-MI adaptive reactions to acute ischemia and hypoxia through various mechanisms. These mechanisms include angiogenesis, energy metabolism, oxidative stress, inflammatory response, and ventricular remodeling. With its crucial role in MI, HIF-1 is expected to significantly influence the treatment of MI. However, the drugs available for the treatment of MI targeting HIF-1 are currently limited, and most contain natural compounds. The development of precision-targeted drugs modulating HIF-1 has therapeutic potential for advancing MI treatment research and development. This study aimed to summarize the regulatory role of HIF-1 in the pathological responses of various cells following MI, the diverse mechanisms of action of HIF-1 in MI, and the potential drugs targeting HIF-1 for treating MI, thus providing the theoretical foundations for potential clinical therapeutic targets.

Poly (ADP-Ribose) polymerase 1 and parthanatos in neurological diseases: From pathogenesis to therapeutic opportunities.

Poly (ADP-ribose) polymerase-1 (PARP-1) is the most extensively studied member of the PARP superfamily, with its primary function being the facilitation of DNA damage repair processes. Parthanatos is a type of regulated cell death cascade initiated by PARP-1 hyperactivation, which involves multiple subroutines, including the accumulation of ADP-ribose polymers (PAR), binding of PAR and apoptosis-inducing factor (AIF), release of AIF from the mitochondria, the translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and massive MIF-mediated DNA fragmentation. Over the past few decades, the role of PARP-1 in central nervous system health and disease has received increasing attention. In this review, we discuss the biological functions of PARP-1 in neural cell proliferation and differentiation, memory formation, brain ageing, and epigenetic regulation. We then elaborate on the involvement of PARP-1 and PARP-1-dependant parthanatos in various neuropathological processes, such as oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, autophagy damage, and endoplasmic reticulum (ER) stress. Additional highlight contains PARP-1's implications in the initiation, progression, and therapeutic opportunities for different neurological illnesses, including neurodegenerative diseases, stroke, autism spectrum disorder (ASD), multiple sclerosis (MS), epilepsy, and neuropathic pain (NP). Finally, emerging insights into the repurposing of PARP inhibitors for the management of neurological diseases are provided. This review aims to summarize the exciting advancements in the critical role of PARP-1 in neurological disorders, which may open new avenues for therapeutic options targeting PARP-1 or parthanatos.

A systematic review and meta-analysis of Comaneci/Cascade temporary neck bridging devices for the treatment of intracranial aneurysms.

Background: The temporary neck bridging devices represented by Comaneci and Cascade are a type of promising endovascular device for the treatment of intracranial bifurcation or wide-necked aneurysms. This systematic review and meta-analysis aim to assess the efficacy and safety of Comaneci/Cascade devices for the treatment of intracranial aneurysms. Methods: We performed a systematic literature search on articles in PubMed, Embase, and Web of Science that evaluated the efficacy and safety of Comaneci/Cascade devices for endovascular treatment of intracranial aneurysms, based on the Preferred Reporting Items for Systematic Reviews and Meta Analytics (PRISMA) guideline. We extracted the characteristics and treatment related information of patients included in the study, recorded the rate of technical success, procedural related complications, and angiographic outcomes. The angiographic outcome was evaluated based on Raymond Roy classification, and adequate occlusion was defined as Raymond Ray I + II. Results: Nine studies comprising 253 patients with 255 aneurysms were included. Among them, eight studies were conducted in Europe, one study was conducted in the USA. All these studies were retrospective. 206 aneurysms (80.78%) were ruptured. The vast majority of patients with ruptured aneurysms did not receive antiplatelet therapy. The rate of technical success was 97.1% (95% CI, 94.9 to 99.3%, I2 = 0%). The rate of periprocedural clinical complications was 10.9% (95% CI, 5.4 to 22.1%, I2 = 54%). The rate of complete occlusion (RR1) and adequate occlusion (RR1 + RR2) on immediate angiography after the procedure were 77.7% (95% CI, 72.7 to 83.2%, I2 = 35%) and 98% (95% CI, 95.9 to 100%, I2 = 0%) respectively. The rate of complete occlusion (RR1) and adequate occlusion (RR1 + RR2) on the last follow-up angiography were 81.2% (95% CI, 69.2 to 95.2%, I2 = 81%) and 93.7% (95% CI, 85.6 to 100%, I2 = 69%) respectively, with follow-up range from 3 to 18 months. 22/187 (11.76%) cases of aneurysms progressed during the follow-up period. 39/187 (20.86%) cases of aneurysms received additional treatment during the follow-up period. No fatal complications occurred during the treatment. Conclusion: The Comaneci/Cascade device can be used as an auxiliary treatment for intracranial aneurysms, with a good occlusion effect, but the incidence of complications still needs to be monitored.

Codon usage bias analysis of the spike protein of human coronavirus 229E and its host adaptability.

Human coronavirus 229E (HCoV-229E) represents one of the known coronaviruses capable of infecting humans and causes mild respiratory symptoms. It is also considered to have a zoonotic source, originating from animals and being transmitted the humans. In this study, a comprehensive phylogenetic and codon usage analysis of the spike (S) gene of HCoV-229E was conducted. Utilizing phylogenetic analysis and principal component analysis, HCoV-229E was categorized into four distinct clusters, each demonstrating unique host affiliations. Furthermore, it was observed that the codon usage bias within the S gene of HCoV-229E is relatively low, primarily influenced by natural selection patterns, with contributions from mutation pressure and dinucleotide abundance. Comparative analysis involving Codon Adaptation Index (CAI) and Relative Codon Deoptimization Index (RCDI) revealed that the codon usage pattern of HCoV-229E mirrors more closely that of camels, as opposed to alpacas and humans. The elucidation of the codon usage pattern within HCoV-229E, which we have meticulously examined, offers valuable insights for a more comprehensive comprehension of viral features, history, and evolutionary trajectory.

Light-responsive smart nanocarriers for wirelessly controlled photodynamic therapy for prostate cancers.

Photodynamic therapy (PDT) is an effective non-invasive or minimally invasive treatment method against different tumors. Loading photosensitizers in nanocarriers can potentially increase their accumulation in tumor sites. However, the PDT efficacy may be hindered because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Herein, light responsive nano assemblies composed of (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) were designed and loaded with the photosensitizer, Rose Bengal lactone (RB), to act as a smart nanocarrier (RB-M) for the delivery of the photosensitizer. A wirelessly activated light-emitting diode (LED) implant was designed to programmatically induce the release of the loaded RB first, followed by activating PDT after diffusion of RB into the cytoplasm. The results showed that sequential '405-580 nm' irradiation of the RB-M treated 22RV1 cells resulted in the highest PDT outcome among different irradiation protocols. The combination of this smart nanocarrier and sequential '405-580 nm' irradiation strategy exhibited good PDT efficacy against 2D 22RV1 prostate cancer cells as well as 3D cancer cell spheroids. This platform overcomes the light penetration limitations in PDT, and can potentially be applied in cancer bearing patients who are unfit for chemotherapy. STATEMENT OF SIGNIFICANCE: Nanocarriers for the delivery of photosensitizer in photodynamic therapy may result in relatively low therapeutic efficacy because of self-quenching of the encapsulated photosensitizer and the small diffusion radii of the generated reactive oxygen species (ROS). Light responsive smart nanocarriers can potentially overcome this challenge. In this study, a light responsive polymer (Polyethylene glycol)-block-poly(4,5-dimethoxy-2-nitrobenzylmethacrylate) (PEG-b-PNBMA) was synthesized and utilized to fabricate the smart nanocarrier. A wirelessly activated light-emitting diode (LED) implant was designed for light delivery in deep tissue. This new approach permits wirelessly and programmatically control of photosensitizer release and PDT activation under deep tissue, thus significantly enhancing PDT efficacy against prostate cancer cells as well as 3D cancer cell spheroids. This design should have a significant impact on controllable PDT under deep tissue.

SEPSIS LEADS TO IMPAIRED MITOCHONDRIAL CALCIUM UPTAKE AND SKELETAL MUSCLE WEAKNESS BY REDUCING THE MICU1:MCU PROTEIN RATIO.

ABSTRACT: Purpose: Intensive care unit-acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio-mediated mitochondrial calcium ([Ca 2+ ] m ) uptake dysfunction. Methods: Cecal ligation and perforation (CLP) was performed on C57BL/6J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 µg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca 2+ ] c ) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings: The results suggest that sepsis induces [Ca 2+ ] m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions: ICUAW is associated with impaired [Ca 2+ ] m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca 2+ ] m uptake disorder.

Emerging therapeutic role of gut microbial extracellular vesicles in neurological disorders.

Extracellular vesicles (EVs) serve as cell-to-cell and inter-organ communicators by conveying proteins and nucleic acids with regulatory functions. Emerging evidence shows that gut microbial-released EVs play a pivotal role in the gut-brain axis, bidirectional communication, and crosstalk between the gut and the brain. Increasing pre-clinical and clinical evidence suggests that gut bacteria-released EVs are capable of eliciting distinct signaling to the brain with the ability to cross the blood-brain barrier, exerting regulatory function on brain cells such as neurons, astrocytes, and microglia, via their abundant and diversified protein and nucleic acid cargo. Conversely, EVs derived from certain species of bacteria, particularly from gut commensals with probiotic properties, have recently been shown to confer distinct therapeutic effects on various neurological disorders. Thus, gut bacterial EVs may be both a cause of and therapy for neuropathological complications. This review marshals the basic, clinical, and translational studies that significantly contributed to our up-to-date knowledge of the therapeutic potential of gut microbial-derived EVs in treating neurological disorders, including strokes, Alzheimer's and Parkinson's disease, and dementia. The review also discusses the newer insights in recent studies focused on developing superior therapeutic microbial EVs via genetic manipulation and/or dietary intervention.