Hyperglycemia induced cathepsin L maturation linked to diabetic comorbidities and COVID-19 mortality.

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.

People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.

Enhancing CO2 dissolution and inorganic carbon conversion by metal-organic frameworks improves microalgal growth and carbon fixation efficiency.

Carbon supplementation strategies still have certain practical application constraints. Zn/Fe-based metal-organic frameworks (MOFs) nanoparticles that which are not toxic to Scenedesmus obliquus were successfully introduced into microalgal solutions to overcome low CO2 solubility. The maximum specific surface area of MOFs reached 342.94 m2·g-1 at a Zn/Fe molar ratio of 10/1. Under the optimal MOFs concentrations of 2.5 mg·L-1, the conversion of inorganic carbon increased by 2.6-fold. When S. obliquuswas cultured in a MOFs-modified medium with 1.50 % CO2 at 25 °C, the CO2 mass transfer coefficient and mixing time reached 9.01 × 10-3 min-1 and 55 s, respectively. The maximum chlorophyll-a content, biomass productivity, and CO2 fixation efficiency reached 32.57 mg·L-1, 0.240 g·L-1·d-1 and 21.6 %, respectively. Enriching CO2 for ribulose-1,5-bisphosphate carboxylase/oxygenase carboxylation by MOFs may be the key to improving the photosynthetic efficiency of microalgae. This strategy could serve as a reference for improving the microalgal CO2 fixation efficiency.

Commercializable Naphthalene Diimide Anolytes for Neutral Aqueous Organic Redox Flow Batteries.

Neutral aqueous organic redox flow batteries (AORFBs) hold the potential to facilitate the transition of renewable energy sources from auxiliary to primary energy, the commercial production of anolyte materials still suffers from insufficient performance of high-concentration and the high cost of the preparation problem. To overcome these challenges, this study provides a hydrothermal synthesis methodology and introduces the charged functional groups into hydrophobic naphthalene diimide cores, and prepares a series of high-performance naphthalene diimide anolytes. Under the synergistic effect of π-π stacking and H-bonding networks, the naphthalene diimide exhibits excellent structural stability and the highest water solubility (1.85 M for dex-NDI) reported to date. By employing the hydrothermal method, low-cost naphthalene diimides are successfully synthesized on a hundred-gram scale of $0.16 g-1 ($2.43 Ah-1), which is also the lowest price reported to date. The constructed full battery achieves a high electron concentration of 2.4 M, a high capacity of 54.4 Ah L-1, and a power density of 318 mW cm-2 with no significant capacity decay observed during long-duration cycling. These findings provide crucial support for the commercialization of AORFBs and pave the way for revolutionary developments in neutral AORFBs.

Robust Chalcogenophene Viologens as Anolytes for Long-Life Aqueous Organic Redox Flow Batteries with High Battery Voltage.

A series of chalcogenophene viologens ([(NPr)2FV]Cl4, [(NPr)2TV]Cl4, and [(NPr)2SeV]Cl4) as anolytes for neutral aqueous organic redox flow batteries (AORFBs) via a combination of chalcogenophenes (furan, thiophene, and selenophene) and viologens are reported. The chalcogenophene viologens showed narrow HOMO-LUMO energy gap, high solubility, and stable electrochemical properties. Compared with the parent [(NPr)2V]Cl4, the introduction of π-conjugated chalcogenophene groups reduced the redox potential and enhanced the stability of their free radical state, which endowed the chalcogenophene viologens/FcNCl-based AORFBs with a higher theoretical battery voltage of 1.20 V and enhanced stability for one-electron storage. In particular, the [(NPr)2FV]Cl4/FcNCl-based AORFB exhibited excellent long-cycle stability for 3000 cycles with 0.0006% capacity decay per cycle for one-electron storage and 300 cycles with 0.06% capacity decay per cycle for two-electron storage at a charge voltage of 1.9 V (1.42 V theoretical battery voltage). This work provided a new strategy for regulating the voltage and improving the performance of neutral AORFBs.

Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.

Advanced carbon sequestration by the hybrid system of photobioreactor and microbial fuel cell with novel photocatalytic porous framework.

A new hybrid system is proposed to capture CO2 as well as generate electricity with the low CO2 inlet condition of confined space. Within the system, a novel photocatalytic porous framework coated by g-C3N4/TiO2 is prepared to avoid the inhibition of microalgae growth caused by the direct addition of photocatalyst. Under 0.8% v/v CO2 inlet condition, chemical oxygen demand (COD) yields from the photocatalytic framework immersed in the phosphate buffer and the algae suspension are 1.63 mg L-1 h-1 and 1.90 mg L-1 h-1, respectively. CO2 sequestration rate of a 60L cylindrical photobioreactor increases from 12% to 22%. The combination modes between photobioreactor and photocatalytic framework can be selected flexibly depends on the demands of application. This hybrid system not only benefits to enhance the CO2 sequestration rate of photobioreactor but also has the potential to be served as the power source in a confined space.

Chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala.

Exacerbation of pain by chronic stress and comorbidity of pain with stress-related psychiatric disorders, including anxiety and depression, represent significant clinical challenges. However, the underlying mechanisms still remain unclear. Here, we investigated whether chronic forced swim stress (CFSS)-induced exacerbation of neuropathic pain is mediated by the integration of stress-affect-related information with nociceptive information in the central nucleus of the amygdala (CeA). We first demonstrated that CFSS indeed produces both depressive-like behaviors and exacerbation of spared nerve injury (SNI)-induced mechanical allodynia in rats. Moreover, we revealed that CFSS induces both sensitization of basolateral amygdala (BLA) neurons and augmentation of long-term potentiation (LTP) at the BLA-CeA synapse and meanwhile, exaggerates both SNI-induced sensitization of CeA neurons and LTP at the parabrachial (PB)-CeA synapse. In addition, we discovered that CFSS elevates SNI-induced functional up-regulation of GluN2B-containing NMDA (GluN2B-NMDA) receptors in the CeA, which is proved to be necessary for CFSS-induced augmentation of LTP at the PB-CeA synapse and exacerbation of pain hypersensitivity in SNI rats. Suppression of CFSS-elicited depressive-like behaviors by antidepressants imipramine or ifenprodil inhibits the CFSS-induced exacerbation of neuropathic pain. Collectively, our findings suggest that CFSS potentiates synaptic efficiency of the BLA-CeA pathway, leading to the activation of GluN2B-NMDA receptors and sensitization of CeA neurons, which subsequently facilitate pain-related synaptic plasticity of the PB-CeA pathway, thereby exacerbating SNI-induced neuropathic pain. We conclude that chronic stress exacerbates neuropathic pain via the integration of stress-affect-related information with nociceptive information in the CeA.

Influence of Environmental Factors on the Adsorption Capacity and Thermal Conductivity of Silica Nano-Porous Materials.

In this work, the influence of temperature and humidity environment on the water vapor adsorption capacity and effective thermal conductivity of silica nano-porous material is conducted within a relative humidity range from 15% to 90% at 25 °C, 40 °C and 55 °C, respectively. The experiment results show that both the temperature and relative humidity have significant influence on the adsorption capacity and effective thermal conductivity of silica nano-porous materials. The adsorption capacity and effective thermal conductivity increase with humidity because of the increases of water vapor concentration. The effective thermal conductivity increases linearly with adsorption saturation capacity at constant temperature. Because adsorption process is exothermic reaction, the increasing temperature is not conducive to the adsorption. But the effective thermal conductivity increases with the increment of temperature at the same water uptake because of the increment of water thermal conductivity with temperature Geometric models and unit cell structure are adopted to predict the effective thermal conductivity and comparisons with the experimental result are made, and for the case of moist silica nano-porous materials with high porosity no quantitative agreement is found. It is believed that the adsorbed water will fill in the nano-pores and gap and form lots of short cuts, leading to a significant reduction of the thermal resistance.

Structural design for birefringent holey fiber with a beat length insensitive to wavelength.

By combination of two defect structures with positive and negative birefringence, we design a holey fiber with a beat length that is less sensitive to wavelength. The influence of different structural parameters on birefringence of holey fiber is calculated by the finite-difference beam propagation method. A stable beat length can be achieved at some given wavelength window by adjusting the parameters. An almost uniform beat length with a greater than 180 nm bandwidth at 1310 and 1550 nm wavelength windows is obtained, which is useful for the design and fabrication of fiber-optic wave plates with a wide band.

Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain.

Activation of N-methyl-d-aspartate (NMDA) receptors in the spinal dorsal horn has been shown to be essential for the initiation of central sensitization and the hyperexcitability of dorsal horn neurons in chronic pain. However, whether the spinal NR2B-containing NMDA (NMDA-2B) receptors are involved still remains largely unclear. Using behavioral test and in vivo extracellular electrophysiological recording in L5 spinal nerve-ligated (SNL) neuropathic rats, we investigate the roles of spinal cord NMDA-2B receptors in the development of neuropathic pain. Our study showed that intrathecal (i.t.) injection of Ro 25-6981, a selective NMDA-2B receptor antagonist, had a dose-dependent anti-allodynic effect without causing motor dysfunction. Furthermore, i.t. application of another NMDA-2B receptor antagonist ifenprodil prior to SNL also significantly inhibited the mechanical allodynia but not the thermal hyperalgesia. These data suggest that NMDA-2B receptors at the spinal cord level play an important role in the development of neuropathic pain, especially at the early stage following nerve injury. In addition, spinal administration of Ro 25-6981 not only had a dose-dependent inhibitory effect on the C-fiber responses of dorsal horn wide dynamic range (WDR) neurons in both normal and SNL rats, but also significantly inhibited the long-term potentiation (LTP) in the C-fiber responses of WDR neurons induced by high-frequency stimulation (HFS) applied to the sciatic nerve. These results indicate that activation of the dorsal horn NMDA-2B receptors may be crucial for the spinal nociceptive synaptic transmission and for the development of long-lasting spinal hyperexcitability following nerve injury. In conclusion, the spinal cord NMDA-2B receptors play a role in the development of central sensitization and neuropathic pain via the induction of LTP in dorsal horn nociceptive synaptic transmission. Therefore, the spinal cord NMDA-2B receptor is likely to be a target for clinical pain therapy.