Male-pronuclei-specific granulin facilitates somatic cells reprogramming via mitigating excessive cell proliferation and enhancing lysosomal function.

Critical reprogramming factors resided predominantly in the oocyte or male pronucleus can enhance the efficiency or the quality of induced pluripotent stem cells (iPSCs) induction. However, few reprogramming factors exist in the male pronucleus had been verified. Here, we demonstrated that granulin (Grn), a factor enriched specifically in male pronucleus, can significantly improve the generation of iPSCs from mouse fibroblasts. Grn is highly expressed on Day 1, Day 3, Day 14 of reprogramming induced by four Yamanaka factors and functions at the initial stage of reprogramming. Transcriptome analysis indicates that Grn can promote the expression of lysosome-related genes, while inhibit the expression of genes involved in DNA replication and cell cycle at the early reprogramming stage. Further verification determined that Grn suppressed cell proliferation due to the arrest of cell cycle at G2/M phase. Moreover, ectopic Grn can enhance the lysosomes abundance and rescue the efficiency reduction of reprogramming resulted from lysosomal protease inhibition. Taken together, we conclude that Grn serves as an activator for somatic cell reprogramming through mitigating cell hyperproliferation and promoting the function of lysosomes.

Omicron wave during December 2022 - January 2023: access to pharmaceuticals and healthcare resources and impacts on health outcomes in Shenzhen, China.

Purpose: This study described pharmaceutical and medical resource accessibility of COVID-19 treatment in Shenzhen, China during the peak of COVID-19 infection from December 2022 to January 2023, and examined its influence on clinical outcomes. Methods: We surveyed Shenzhen residents on COVID-19-related topics using electronic questionnaires. We conducted descriptive statistical analyses and multiple regressions including logistic and Tobit models to explore the impacts of resource constraints on patient outcomes. Resource utilisation and attempts to seek medical care were also described for severity-stratified subgroups. Results: 76.8% of respondents reported experiencing COVID-19 symptoms between December 7, 2022 and January 29, 2023. Of those who attempted to purchase medication, 72.8% reported drug shortage. 49% of those seeking medical treatment experienced difficulties. Compared with those who did not experience drug shortages, those who did had an odds ratio of 1.959 (95% CI: 1.159 ∼3.313) of presenting with moderate to severe symptoms. Compared with those without difficulties in seeking medical treatment, those who did had an average of 0.39 (95% CI: 0.110 ∼0.670) more days absent from work. Conclusion: Shenzhen residents with COVID-19 symptoms from December 2022 to January 2023 experienced a certain degree of pharmaceutical and medical resource constraints, which might have compromised their prognosis.

Evaluating the Public Health and Health Economic Impacts of Baloxavir Marboxil and Oseltamivir for Influenza Pandemic Control in China: A Cost-Effectiveness Analysis Using a Linked Dynamic Transmission-Economic Evaluation Model.

BACKGROUND: Pandemic influenza poses a recurring threat to public health. Antiviral drugs are vital in combating influenza pandemics. Baloxavir marboxil (BXM) is a novel agent that provides clinical and public health benefits in influenza treatment. METHODS: We constructed a linked dynamic transmission-economic evaluation model combining a modified susceptible-exposed-infected-recovered (SEIR) model and a decision tree model to evaluate the cost-effectiveness of adding BXM to oseltamivir in China's influenza pandemic scenario. The cost-effectiveness was evaluated for the general population from the Chinese healthcare system perspective, although the users of BXM and oseltamivir were influenza-infected persons. The SEIR model simulated the transmission dynamics, dividing the population into four compartments: susceptible, exposed, infected, and recovered, while the decision tree model assessed disease severity and costs. We utilized data from clinical trials and observational studies in the literature to parameterize the models. Costs were based on 2021 CN¥ and not discounted due to a short time-frame of one year in the model. One-way, two-way, and probabilistic sensitivity analyses were also conducted. RESULTS: The integrated model demonstrated that adding BXM to treatment choices reduced the cumulative incidence of infection from 49.49% to 43.26% and increased quality-adjusted life years (QALYs) by 0.00021 per person compared with oseltamivir alone in the base-case scenario. The intervention also amounted to a positive net monetary benefit of CN¥77.85 per person at the willingness to pay of CN¥80,976 per QALY. Sensitivity analysis confirmed the robustness of these findings, with consistent results across varied key parameters and assumptions. CONCLUSIONS: Adding BXM to treatment choices instead of only treating with oseltamivir for influenza pandemic control in China appears to be cost-effective compared with oseltamivir alone. The dual-agent strategy not only enhances population health outcomes and conserves resources, but also mitigates influenza transmission and alleviates healthcare burden.

Impacts of COVID-19 vaccine boosters on clinical outcomes associated with the Omicron variant in China: A cross-sectional survey.

Objective: To investigate the real-world effectiveness of COVID-19 vaccine boosters during China's Omicron wave. Methods: In January 2023, we surveyed Shenzhen, China residents via online questionnaires to investigate their COVID-19 symptoms and vaccination history. The outcomes of interest included fever, other COVID-19-related symptoms, severity of symptoms, whether early onset (before December 23, 2022) and duration. Respondents were categorized as no booster, one booster 6mo ago, one booster within 6mo, or two boosters based on dose count and vaccination timing. We used multivariable logistic regressions and Tobit models to assess COVID-19 vaccine booster impacts. Results: Compared to the no booster group, two booster recipients had a lower fever risk (OR = 0.35, 95 %CI = 0.16-0.76) but not lower risks of COVID-19-related symptoms (OR = 0.74, 95 %CI = 0.26-2.06) and self-reported severe symptoms (OR = 0.47, 95 %CI = 0.19-1.15). Nor did the two booster recipients had a shorter illness duration (marginal effect = -0.79 days, 95 %CI = -1.65-0.07) and a lower risk of symptom onset delay (OR = 0.48, 95 %CI = 0.19-1.23). Compared to the no booster group, both one booster within six months (OR = 2.17, 95 %CI = 1.34-3.52) and one booster six months ago (OR = 1.30, 95 %CI = 0.92-1.82) did not reduce the risks of fever and symptoms (one booster within six months: OR = 1.57, 95 %CI = 0.84-2.90; one booster six months ago: OR = 1.23, 95 %CI = 0.79-1.93). Regardless of timing, one booster did not reduce illness duration (within six months: marginal effect = 0.25 days, 95 %CI = -0.20-0.70; six months ago: marginal effect = 0.27 days, 95 %CI = -0.08-0.62). However, receiving one booster within six months delayed symptom onset (OR = 0.54, 95 %CI = 0.34-0.86), while one booster six months ago did not (OR = 1.03, 95 %CI = 0.74-1.44). Conclusions: Receiving two booster doses reduced the onset of fever during the Omicron outbreak in mainland China.

Effects of atrazine and curcumin exposure on TCMK-1 cells: Oxidative damage, pyroptosis and cell cycle arrest.

Atrazine (ATR), a commonly used herbicide, is highly bioaccumulative and toxic, posing a threat to a wide range of organisms. Curcumin has strong antioxidant properties. However, it is unclear whether curcumin counteracts cellular pyroptosis as well as cell cycle arrest induced by ATR exposure. Therefore, we conducted a study using TCMK-1 cells and established cell models by adding 139 µmol/L ATR and 20 µmol/L curcumin. The results showed that ATR exposure produced excessive reactive oxygen species (ROS), reduced activities of enzymes such as GSH-PX, SOD and Total Antioxidant Capacity, markedly increased the content of H2O2, disrupted the antioxidant system, activated Caspase-1, and the expression levels of the pyroptosis-related genes NLRP3, GSDMD, ASC, Caspase-1, IL-1ß and IL-18 were increased. The simultaneous excess of ROS led to DNA damage, activation of P53 led to elevated expression levels of P53 and P21, as a consequence, the expression levels of cyclinE, CDK2 and CDK4 were reduced. These results suggest that Cur can modulate ATR exposure-induced pyroptosis as well as cell cycle arrest in TCMK-1 cells by governing oxidative stress.

Quercetin antagonizes apoptosis, autophagy and immune dysfunction induced by di(2-ethylhexyl) phthalate via ROS/ASK1/JNK pathway.

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that can damage various organizations and physiques through oxidative stress. Quercetin (Que) is a rich polyphenol flavonoid with good anti-inflammatory and antioxidant effects. However, the protection mechanism of Que against DEHP exposure-induced IPEC-J2 cell injury and the implication of autophagy, apoptosis and immunity are still unclear. In this experiment, we looked into the toxicity regime of DEHP exposure on IPEC-J2 cells and the antagonistic function of Que on DEHP. In the experiment, 135 µM DEHP and/or 80 µM Que were used to treat the IPEC-J2 cells for 24 h. Experiments indicated that DEHP exposure can cause increased reactive oxygen species (ROS) levels leading to oxidative stress, decreased CAT, T-AOC and GSH-Px activities, increased MDA and H2O2 accumulation, activated the ASK1/JNK signalling pathway, and further increases in the levels of apoptosis markers Bax, Caspase3, Caspase9, and Cyt-c, while reduced the Bcl-2 expression. DEHP also increased the expression of genes linked to autophagy (ATG5, Beclin1, LC3), while decreasing the expression of P62. Additionally, DEHP exposure led to elevated levels of IL1-ß, IL-6, MCP-1, and TNF expression. When exposed to Que alone, there were no significant changes in cellular oxidative stress level, ASK1/JNK signalling pathway expression level, apoptosis, autophagy and cellular immune function. The combination of DEHP and Que treatment remarkably decreased the proportion of autophagy and apoptosis, and recovered cellular immunity. In summary, Que can attenuate DEHP-induced apoptosis and autophagy in IPEC-J2 cells by regulating the ROS/ASK1/JNK signalling pathway and improving the immune dysfunction of IPEC-J2 cells.

Hydraulic resistance of three-dimensional pial perivascular spaces in the brain.

BACKGROUND: Perivascular spaces (PVSs) carry cerebrospinal fluid (CSF) around the brain, facilitating healthy waste clearance. Measuring those flows in vivo is difficult, and often impossible, because PVSs are small, so accurate modeling is essential for understanding brain clearance. The most important parameter for modeling flow in a PVS is its hydraulic resistance, defined as the ratio of pressure drop to volume flow rate, which depends on its size and shape. In particular, the local resistance per unit length varies along a PVS and depends on variations in the local cross section. METHODS: Using segmented, three-dimensional images of pial PVSs in mice, we performed fluid dynamical simulations to calculate the resistance per unit length. We applied extended lubrication theory to elucidate the difference between the calculated resistance and the expected resistance assuming a uniform flow. We tested four different approximation methods, and a novel correction factor to determine how to accurately estimate resistance per unit length with low computational cost. To assess the impact of assuming unidirectional flow, we also considered a circular duct whose cross-sectional area varied sinusoidally along its length. RESULTS: We found that modeling a PVS as a series of short ducts with uniform flow, and numerically solving for the flow in each, yields good resistance estimates at low cost. If the second derivative of area with respect to axial location is less than 2, error is typically less than 15%, and can be reduced further with our correction factor. To make estimates with even lower cost, we found that instead of solving for the resistance numerically, the well-known resistance of a circular duct could be scaled by a shape factor. As long as the aspect ratio of the cross section was less than 0.7, the additional error was less than 10%. CONCLUSIONS: Neglecting off-axis velocity components underestimates the average resistance, but the error can be reduced with a simple correction factor. These results could increase the accuracy of future models of brain-wide and local CSF flow, enabling better prediction of clearance, for example, as it varies with age, brain state, and pathological conditions.

RNA m6A modification regulates cell fate transition between pluripotent stem cells and 2-cell-like cells.

N6-methyladenosine (m6A) exerts essential roles in early embryos, especially in the maternal-to-zygotic transition stage. However, the landscape and roles of RNA m6A modification during the transition between pluripotent stem cells and 2-cell-like (2C-like) cells remain elusive. Here, we utilised ultralow-input RNA m6A immunoprecipitation to depict the dynamic picture of transcriptome-wide m6A modifications during 2C-like transitions. We found that RNA m6A modification was preferentially enriched in zygotic genome activation (ZGA) transcripts and MERVL with high expression levels in 2C-like cells. During the exit of the 2C-like state, m6A facilitated the silencing of ZGA genes and MERVL. Notably, inhibition of m6A methyltransferase METTL3 and m6A reader protein IGF2BP2 is capable of significantly delaying 2C-like state exit and expanding 2C-like cells population. Together, our study reveals the critical roles of RNA m6A modification in the transition between 2C-like and pluripotent states, facilitating the study of totipotency and cell fate decision in the future.