Brain tissue oxygen partial pressure monitoring and prognosis of patients with traumatic brain injury: a meta-analysis.

To assess whether monitoring brain tissue oxygen partial pressure (PbtO2) or employing intracranial pressure (ICP)/cerebral perfusion pressure (CCP)-guided management improves patient outcomes, including mortality, hospital length of stay (LOS), mean daily ICP and mean daily CCP during the intensive care unit(ICU)stay. We searched the Web of Science, EMBASE, PubMed, Cochrane Library, and MEDLINE databases until December 12, 2023. Prospective randomized controlled and cohort studies were included. A meta-analysis was performed for the primary outcome measure, mortality, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eleven studies with a total of 37,492 patients were included. The mortality in the group with PbtO2 was 29.0% (odds ratio: 0.73;95% confidence interval [CI]:0.56-0.96; P = 0.03; I = 55%), demonstrating a significant benefit. The overall hospital LOS was longer in the PbtO2 group than that in the ICP/CPP group (mean difference:2.03; 95% CI:1.03-3.02; P<0.0001; I = 39%). The mean daily ICP in the PbtO2 monitoring group was lower than that in the ICP/CPP group (mean difference:-1.93; 95% CI: -3.61 to -0.24; P = 0.03; I = 41%). Moreover, PbtO2 monitoring did not improve the mean daily CPP (mean difference:2.43; 95%CI: -1.39 to 6.25;P = 0.21; I = 56%).Compared with ICP/CPP monitoring, PbtO2 monitoring reduced the mortality and the mean daily ICP in patients with severe traumatic brain injury; however, no significant effect was noted on the mean daily CPP. In contrast, ICP/CPP monitoring alone was associated with a short hospital stay.

VPg-based bidirectional synthetic mRNA circuits enable orthogonal protein regulation for high-resolution cell separation.

Synthetic mRNA circuits commonly sense input to produce binary output signals for cell separation. Based on virus-origin cap-independent translation initiation machinery and RBP-aptamer interaction, we designed smart synthetic mRNA-based circuits that sense single input molecules to bidirectionally tune output signals in an orthogonal manner, enabling high-resolution separation of cell populations.

Self-feedback loop-containing synthetic mRNA switches for controlled microRNA sensing.

Synthetic mRNA switches are powerful cell fate manipulation tools that sense cellular input molecules to directly control protein expression at the translational level. The lack of available switch designs that can mimic the natural sophisticated protein regulation is a fundamental issue that limits the application of synthetic mRNA switches. Here we report a new set of synthetic mRNA switches by incorporating self-feedback loop machineries to dynamically control protein expression levels upon sensing cellular microRNAs. We redesigned the coding region of the switch to express output protein along with mRNA regulatory proteins. RNA-binding proteins (RBPs) and RBP-binding RNA motifs (aptamers) guide the regulatory proteins to act on their own mRNAs, enhancing or flattening the effect of microRNA sensing. Importantly, we demonstrated that the switches with the positive feedback feature can enlarge a high-or-low microRNA effect into a nearly all-or-none pattern, substantially boosting the use of synthetic mRNA switches as high-performance microRNA sensors or binary cell regulation tools. We believe these novel mRNA switch designs provide new strategies to construct complex mRNA-based genetic circuits for future molecular sensing and cell engineering.

Effect of awake prone positioning on tracheal intubation rates in patients with COVID-19: A meta-analysis.

Purpose: We investigated the effect of awake prone positioning on endotracheal intubation rates in spontaneously breathing patients with COVID-19 not undergoing endotracheal intubation. Methods: We searched the CINAHL, Cochrane Library, PUBMED, MEDLINE, and Web of Science databases until December 31, 2022. Prospective randomized controlled, cohort, and case-control studies were included. A meta-analysis was performed on the primary outcome measure, tracheal intubation rates, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Ten studies with a total of 2641 patients were included. The tracheal intubation rate in the awake prone position was 34% (95%CI: 0.59-1.10; P = 0.18; I2 = 55%), showing a non-significant benefit. Mortality was lower in prone-positioned than in supine-positioned patients (odds ratio: 0.75; 95% CI: 0.61-0.93; P = 0.007; I2 = 46%), prone positioning significantly improved the PaO2/FiO2 ratio (mean difference -29.17; 95%CI: -50.91 to -7.43; P = 0.009; I2 = 44%). Conclusions: Prone positioning can improve the PaO2/FIO2 ratio in patients with COVID-19 but we found no significant effect on tracheal intubation rates. Awake prone positioning seems to be associated with lower mortality, however, and may thus be a beneficial and effective intervention for patients with COVID-19. The optimal timing, duration, and target population need to be determined in future studies.

Dual Input-Controlled Synthetic mRNA Circuit for Bidirectional Protein Expression Regulation.

Synthetic mRNA circuits manipulate cell fate by controlling output protein expression via cell-specific input molecule detection. Most current circuits either repress or enhance output production upon input binding. Such binary input-output mechanisms restrict the fine-tuning of protein expression to control complex cellular events. Here we designed mRNA circuits using enhancer/repressor modules that were independently controlled by different input molecules, resulting in bidirectional output regulation; the maximal enhancement over maximal repression was 57 fold. The circuit either enhances or represses protein production in different cells based on the difference in the expression of two microRNAs. This study examined novel bidirectional circuit designs capable of fine-tuning protein production by sensing multiple input molecules. It also broadened the scope of cell manipulation by synthetic mRNA circuits, facilitating the development of mRNA circuits for precise cell manipulation and providing cell-based solutions to biomedical problems.

Intracellular Molecules Induced Extracellular Peptide Self-Assembly for Efficient and Effective In Situ Cell Purification.

Synthetic messenger RNA (mRNA) switches are powerful tools for in situ cell purification, especially for cells derived from stem cells. However, the retention effectiveness of the target cells is limited by the leaky expression of toxic protein. The elimination efficiency of non-target cells is also constrained due to the lack of signal amplification. In this study, we designed a novel approach that uses synthetic mRNA switch to convey intracellular marker molecule information into spatially controlled extracellular toxic assembly formation. The approach bypasses the use of toxic protein to ensure high target cell recovery effectiveness. Meanwhile, the marker molecule information is amplified at multiple levels to ensure high non-target cell elimination effectiveness. Our approach can be tailored to meet various in situ cell purification needs, promising high-quality in situ cell purification for a wide range of biomedical applications.

Cytidine-containing tails robustly enhance and prolong protein production of synthetic mRNA in cell and in vivo.

Synthetic mRNAs are rising rapidly as alternative therapeutic agents for delivery of proteins. However, the practical use of synthetic mRNAs has been restricted by their low cellular stability as well as poor protein production efficiency. The key roles of poly(A) tail on mRNA biology inspire us to explore the optimization of tail sequence to overcome the aforementioned limitations. Here, the systematic substitution of non-A nucleotides in the tails revealed that cytidine-containing tails can substantially enhance the protein production rate and duration of synthetic mRNAs both in vitro and in vivo. Such C-containing tails shield synthetic mRNAs from deadenylase CCR4-NOT transcription complex, as the catalytic CNOT proteins, especially CNOT6L and CNOT7, have lower efficiency in trimming of cytidine. Consistently, these enhancement effects of C-containing tails were observed on all synthetic mRNAs tested and were independent of transfection reagents and cell types. As the C-containing tails can be used along with other mRNA enhancement technologies to synergically boost protein production, we believe that these tails can be broadly used on synthetic mRNAs to directly promote their clinical applications.