A non-image-forming visual circuit mediates the innate fear of heights in male mice.

The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in male mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to height threats through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG.

Unveiling the link between lactate metabolism and rheumatoid arthritis through integration of bioinformatics and machine learning.

Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by synovitis and joint damage. Recent findings suggest a potential link to abnormal lactate metabolism. This study aims to identify lactate metabolism-related genes (LMRGs) in RA and investigate their correlation with the molecular mechanisms of RA immunity. Data on the gene expression profiles of RA synovial tissue samples were acquired from the gene expression omnibus (GEO) database. The RA database was acquired by obtaining the common LMRDEGs, and selecting the gene collection through an SVM model. Conducting the functional enrichment analysis, followed by immuno-infiltration analysis and protein-protein interaction networks. The results revealed that as possible markers associated with lactate metabolism in RA, KCNN4 and SLC25A4 may be involved in regulating macrophage function in the immune response to RA, whereas GATA2 is involved in the immune mechanism of DC cells. In conclusion, this study utilized bioinformatics analysis and machine learning to identify biomarkers associated with lactate metabolism in RA and examined their relationship with immune cell infiltration. These findings offer novel perspectives on potential diagnostic and therapeutic targets for RA.

Poor condyle position after mandibular reconstruction and a classification system for patients with "VSCU" based on computed tomography: a cross-sectional study with retrospective data collection.

Background: Although the application of vascularized free bone muscle flap to reconstruct the mandible has become a standardized approach for mandible reconstruction, the results of its reconstruction are not always satisfactory. The purpose of this study was to identify the types of mandibular and condylar defects by analyzing the unsatisfactory cases of mandibular reconstruction in clinical practice, and to provide some clinical experience of reconstruction. Methods: Our study retrospectively analyzed 364 patients who underwent mandibular resection and vascularized free bone flap reconstruction of the mandible and temporomandibular joint (TMJ). We innovatively proposed a "VSCU" classification system (V: vertical position, S: sagittal position, C: coronal position, U: condylar resection is not required) by analyzing computed tomography (CT) scans of mandibular branches and TMJs. Results: In all, 221 cases of free iliac muscle flap and 143 cases of fibula muscle flap were included in this study, of which 23 cases had unsatisfactory results after TMJ reconstruction. We classified 23 patients with unsatisfactory mandibular reconstruction according to the "VSCU" classification system. The most common type was U + V + SfC (n=8), followed by V - SfC + U + (n=4), V - s + C + U + (n=3), V - sbcou - (n=3), V - SBC + U + (n=2), V - s + C + U - (n=1). The most common classification was insufficient mandibular rami length, followed by condylar sagittal anteriorization. There was no significant change in the position of condyle on the healthy side during mandibular reconstruction involving condyle. P1 on the affected side was 52.28±4.17 mm before operation and 58.94±5.65 mm after operation, P<0.01; P2 was 12.83±3.49 mm before operation and 24.90±7.15 mm after operation. S2 was 4.54±2.84 mm before operation and 19.10±8.54 mm after operation. A2 was 11.46±3.35 mm before operation and 24.15±8.29 mm after operation. The P values were all less than 0.01, and the differences were statistically significant. Conclusions: We propose to use the "VSCU" classification system for accurate 3-dimensional (3D) analysis and positioning, and then obtain accurate models through computer-aided design and manufacturing (CAD/CAM), which can reduce the occurrence of poor reconstruction effect and unreasonable joint position, and is worthy of clinical promotion.

Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma.

The main challenge in treating stomach adenocarcinoma (STAD) is chemotherapy resistance, which is characterized by changes in the immune microenvironment. Disulfidptosis, a novel form of programmed cell death, is involved in STAD but its mechanism is not fully understood. Long non-coding RNAs (LncRNAs) may play a role in regulating disulfidptosis and influencing the immune microenvironment and chemotherapy resistance in STAD. This study aims to establish disulfidptosis-related lncRNA (DRL) features and explore their significance in the immune microenvironment and chemotherapy resistance in STAD patients. By analyzing RNA sequencing and clinical data from STAD patients and extracting disulfidptosis-related genes, we identified DRLs through co-expression, single-factor and multi-factor Cox regression, and Lasso regression analyses. We also investigated differences in the immune microenvironment, immune function, immune checkpoint gene expression, and chemotherapy resistance between different risk groups using various algorithms. A prognostic risk model consisting of 2 DRLs was constructed, with a strong predictive value for patient survival, outperforming other clinical-pathological factors in predicting 3-year and 5-year survival. Immune-related analysis revealed a strong positive correlation between T cell CD4+ cells and risk score across all algorithms, and higher expression of immune checkpoint genes in the high-risk group. In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.

Combinatorial metabolic engineering of Bacillus subtilis for de novo production of polymyxin B.

Polymyxin is a lipopeptide antibiotic that is effective against multidrug-resistant Gram-negative bacteria. However, its clinical development is limited due to low titer and the presence of homologs. To address this, the polymyxin gene cluster was integrated into Bacillus subtilis, and sfp from Paenibacillus polymyxa was expressed heterologously, enabling recombinant B. subtilis to synthesize polymyxin B. Regulating NRPS domain inhibited formation of polymyxin B2 and B3. The production of polymyxin B increased to 329.7 mg/L by replacing the native promoters of pmxA, pmxB, and pmxE with PfusA, C2up, and PfusA, respectively. Further enhancement in this production, up to 616.1 mg/L, was achieved by improving the synthesis ability of 6-methyloctanoic acid compared to the original strain expressing polymyxin heterologously. Additionally, incorporating an anikasin-derived domain into the hybrid nonribosomal peptide synthase of polymyxin increased the B1 ratio in polymyxin B from 57.5% to 62.2%. Through optimization of peptone supply in the fermentation medium and fermentation in a 5.0-L bioreactor, the final polymyxin B titer reached 962.1 mg/L, with a yield of 19.24 mg/g maltodextrin and a productivity of 10.02 mg/(L·h). This study demonstrates a successful approach for enhancing polymyxin B production and increasing the B1 ratio through combinatorial metabolic engineering.

Improving salt-tolerant artificial consortium of Bacillus amyloliquefaciens for bioconverting food waste to lipopeptides.

High-salt content in food waste (FW) affects its resource utilization during biotransformation. In this study, adaptive laboratory evolution (ALE), gene editing, and artificial consortia were performed out to improve the salt-tolerance of Bacillus amyloliquefaciens for producing lipopeptide under FW and seawater. High-salt stress significantly decreased lipopeptide production in the B. amyloliquefaciens HM618 and ALE strains. The total lipopeptide production in the recombinant B. amyloliquefaciens HM-4KSMSO after overexpressing the ion transportor gene ktrA and proline transporter gene opuE and replacing the promoter of gene mrp was 1.34 times higher than that in the strain HM618 in medium containing 30 g/L NaCl. Lipopeptide production under salt-tolerant consortia containing two strains (HM-4KSMSO and Corynebacterium glutamicum) and three-strains (HM-4KSMSO, salt-tolerant C. glutamicum, and Yarrowia lipolytica) was 1.81- and 2.28-fold higher than that under pure culture in a medium containing FW or both FW and seawater, respectively. These findings provide a new strategy for using high-salt FW and seawater to produce value-added chemicals.

Northward shift of Indian summer monsoon and intensifying winter westerlies cause stronger precipitation seasonality over Pamirs and its downstream basins in the 21st century.

Hydroclimate will change over Pamirs and its downstream basins (PDB), including Indus River, Tarim River, Amu Darya and Syr Darya Basins, in response to the variation of Indian summer monsoon (ISM) and mid-latitude westerlies. However, the precipitation variation and its mechanism over PDB in the 21st century are yet not fully understood. Here, the best models ensemble selected from 25 CMIP6 models under SSP2-4.5 and SSP5-8.5 scenarios is applied to detect the precipitation variations over PDB in the 21st century. A remarkable dipolar pattern is found in both summer and winter precipitation over PDB, particularly in the central Indus River Basin and upper Amu and Syr Darya Basins. The central Indus River Basin (upper Amu and Syr Darya Basins) will experience an increasingly wet (dry) summer in response to northward ISM and a dry (wet) winter driven by mid-latitude westerlies. The amplifying dipolar pattern of seasonal precipitation thus increases the water resource vulnerability over PDB and emphasizes the role of Pamirs in modulating the water resources over surrounding basins, especially the Amu Darya and Syr Darya Basins in the future. The findings underscore the need for prioritizing policies by considering the impacts of precipitation seasonality on social planning.

N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.

Assessing risk of recurrent small bowel obstruction after non-operative management in patients with history of intra-abdominal surgery: a population-based comprehensive analysis in Taiwan.

BACKGROUND: Despite a significant 30% ten-year readmission rate for SBO patients, investigations into recurrent risk factors after non-operative management are scarce. The study aims to generate a risk factor scoring system, the 'Small Bowel Obstruction Recurrence Score' (SBORS), predicting 6-month recurrence of small bowel obstruction (SBO) after successful non-surgical management in patients who have history of intra-abdominal surgery. METHODS: We analyzed data from patients aged ≥ 18 with a history of intra-abdominal surgery and diagnosed with SBO (ICD-9 code: 560, 568) and were successful treated non-surgically between 2004 and 2008. Participants were divided into model-derivation (80%) and validation (20%) group. RESULTS: We analyzed 23,901 patients and developed the SBORS based on factors including the length of hospital stay > 4 days, previous operations > once, hemiplegia, extra-abdominal and intra-abdominal malignancy, esophagogastric surgery and intestino-colonic surgery. Scores > 2 indicated higher rates and risks of recurrence within 6 months (12.96% vs. 7.27%, OR 1.898, p < 0.001 in model-derivation group, 12.60% vs. 7.05%, OR 1.901, p < 0.001 in validation group) with a significantly increased risk of mortality and operative events for recurrent episodes. The SBORS model demonstrated good calibration and acceptable discrimination, with an area under curve values of 0.607 and 0.599 for the score generation and validation group, respectively. CONCLUSIONS: We established the effective 'SBORS' to predict 6-month SBO recurrence risk in patients who have history of intra-abdominal surgery and have been successfully managed non-surgically for the initial obstruction event. Those with scores > 2 face higher recurrence rates and operative risks after successful non-surgical management.

GB12-09, a bispecific antibody targeting IL4Rα and IL31Rα for atopic dermatitis therapy.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by dysregulated immune responses. The key mediators of AD pathogenesis are T helper 2 (TH2) cells and TH2 cytokines. Targeting interleukin 4 (IL4), IL13 or IL31 has become a pivotal focus in both research and clinical treatments for AD. However, the need remains pressing for the development of a more effective and safer therapy, as the current approaches often yield low response rates and adverse effects. In response to this challenge, we have engineered a immunoglobulin G-single-chain fragment variable (scFv) format bispecific antibody (Ab) designed to concurrently target IL4R and IL31R. Our innovative design involved sequence optimization of VL-VH and the introduction of disulfide bond (VH44-VL100) within the IL31Rα Ab scFv region to stabilize the scFv structure. Our bispecific Ab efficiently inhibited the IL4/IL13/IL31 signaling pathways in vitro and reduced serum immunoglobulin E and IL31 levels in vivo. Consequently, this intervention led to improved inflammation profiles and notable amelioration of AD symptoms. This research highlighted a novel approach to AD therapy by employing bispecific Ab targeting IL4Rα and IL31Rα with potent efficacy.

Perinatal prevalence of birth defects in the Mainland of China, 2000-2021: a systematic review and meta-analysis.

BACKGROUND: Although birth defects are of great concern globally, the latest national prevalence has not yet been quantified in China. We conducted a systematic review and meta-analysis to estimate the perinatal prevalence of birth defects in the Mainland of China between 2000 and 2021. METHODS: We performed a systematic literature search of six databases for relevant articles published between January 1, 2000, and March 1, 2023. We included published studies that reported data on the perinatal prevalence of birth defects in the Mainland of China. The DerSimonian and Laird random-effects models were used to estimate the pooled prevalence and its 95% confidence interval (CI). We also conducted subgroup analyses and univariable meta-regressions to explore differences in prevalence by time period, geographic region, and other characteristics. RESULTS: We included 254 studies reporting the perinatal prevalence of birth defects and 86 studies reporting only the prevalence of specific types of birth defects. Based on 254 studies covering 74,307,037 perinatal births and 985,115 cases with birth defects, the pooled perinatal prevalence of birth defects was 122.54 (95% CI 116.20-128.89) per 10,000 perinatal births in the Mainland of China during 2000-2021. Overall, the perinatal prevalence of birth defects increased from 95.60 (86.51-104.69) per 10,000 in 2000-2004 to 208.94 (175.67-242.22) per 10,000 in 2020-2021. There were also significant disparities among different geographical regions. Congenital heart defects (33.35 per 10,000), clefts of the lip and/or palate (13.52 per 10,000), polydactyly (12.82 per 10,000), neural tube defects (12.82 per 10,000), and inborn errors of metabolism (11.41 per 10,000) were the five most common types of birth defects. The perinatal prevalence among males was significantly higher than that among females (ß = 2.44 × 10-3, P = 0.003); a higher perinatal prevalence of birth defects was observed among perinatal births whose mothers were ≥ 35 years (ß = 4.34 × 10-3, P < 0.001). CONCLUSION: Comprehensive and sustained efforts are needed to strengthen surveillance and detection of birth defects, improve prenatal and postnatal healthcare, and promote rehabilitation, especially in underdeveloped areas.

Electroacupuncture of scalp acupoint alleviates cerebral ischemic inflammatory injury by down-regulating RORγt and promoting balance of IL-17A+Th17/FOXP3+Treg in MCAO rats. / 电头针调控RORγt促进IL-17A+Th17/FOXP3+Treg细胞平衡缓解MCAOå¤§é¼ è„‘ç¼ºè¡€ç‚Žæ€§æŸä¼¤çš„ç ”ç©¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) of scalp acupoint (Dingnieqian-xiexian, MS6) on expression of retinoid-related orphan receptor γT (ROR γ t), interleukin (IL)-17A, IL-10, transfor-ming growth factor-ß1 (TGF-ß1), IL-6, IL-21, and IL-17A+ Thelper cells(Th) 17 and forkhead transcription factor P3 (FOXP3)+ regulatory T cells (Treg) differentiation of ischemic cortex in ischemic stroke rats, so as to explore its molecular mechanisms underlying relief of inflammatory injury of ischemic stroke. METHODS: A total of 120 male SD rats were randomly assigned to sham operation, model, EA, inhibitor, agonist and EA+agonist groups, with 15 rats in each group. The ischemic stroke model was established by occlusion of the left middle cerebral artery according to Longa's methods. For rats of the EA group and EA+agonist group, EA (2 Hz/100 Hz, 1 mA) was applied to bilateral MS6 for 30 min, once daily for 7 days. Rats of the inhibitor group received intraperitoneal injection of solution of SR1001 (RORγt inhibitor) (2.5 mg/mL, 10 mg/kg), once daily for 7 days. Rats of the agonist and EA+agonist groups received intraperitoneal injection of solution of SR1078 (RORγt agonist) (5 mg/mL, 5 mg/kg) before EA, once daily for 7 days. Rats of the sham operation and model groups were grabbed and fixed in the same way with the other groups. The Zea-longa's score, modified neurological severity score (mNSS) and the neurobehavioral score were assessed before and after the intervention. At the end of experiments, the ischemic cortex tissue was collected. The 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining was used to detect the volume of cerebral infarction. The expression of RORγt mRNA was detected by real-time quantitative PCR；the protein expression levels of RORγt, IL-17A, IL-10 and TGF-ß1 were detected by Western blot；the immunoactivity of IL-6 and IL-21 were detected by immunohistochemistry；the fluorescence areas of IL-17A+Th17 and FOXP3+Treg cells were measured by immunofluorescence and their ratio was calculated in the tissue of ischemic cortex. RESULTS: Relevant to the sham operation group, the model group had a significant increase in the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg (P<0.01), and an obvious decrease in the expression levels of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity (P<0.01). In contrast to the model group, both EA and inhibitor groups had a significant decrease in the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg (P<0.01, P<0.05), and a marked increase in the expression levels of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity (P<0.05, P<0.01), while the above indicators of the agonist group were all reversed (P<0.01, P<0.05). Comparison between the agonist and EA+agonist groups showed that the Zea-Longa's score, mNSS score, neurobehavioral score, cerebral infarct volume, expression levels of RORγt mRNA and protein, IL-17A protein, IL-6 and IL-21 immunoactivity, IL-17A+Th17 immunofluorescence intensity, and the ratio of IL-17A+Th17/FOXP3+Treg were significantly lower (P<0.01, P<0.05), and the expression of TGF-ß1 and IL-10 proteins and FOXP3+Treg immunofluorescence intensity were obviously higher (P<0.01, P<0.05) in the EA+agonist group than in the agonist group, suggesting that EA intervention can effectively weaken the effects of RORγt agonist. CONCLUSIONS: EA of scalp acupoint MS6 can effectively improve the neurological function, behavior reaction and reduce cerebral infarct volume in ischemic stroke rats, which may be associated with its functions in down-regulating the expression of RORγt and promoting the balance of IL-17A+Th17/FOXP3+Treg to alleviate inflammatory injury after ischemic stroke.

Enhancement of polymyxin B1 production by an artificial microbial consortium of Paenibacillus polymyxa and recombinant Corynebacterium glutamicum producing precursor amino acids.

Polymyxin B, produced by Paenibacillus polymyxa, is used as the last line of defense clinically. In this study, exogenous mixture of precursor amino acids increased the level and proportion of polymyxin B1 in the total of polymyxin B analogs of P. polymyxa CJX518-AC (PPAC) from 0.15 g/L and 61.8 % to 0.33 g/L and 79.9 %, respectively. The co-culture of strain PPAC and recombinant Corynebacterium glutamicum-leu01, which produces high levels of threonine, leucine, and isoleucine, increased polymyxin B1 production to 0.64 g/L. When strains PPAC and C. glu-leu01 simultaneously inoculated into an optimized medium with 20 g/L peptone, polymyxin B1 production was increased to 0.97 g/L. Furthermore, the polymyxin B1 production in the co-culture of strains PPAC and C. glu-leu01 increased to 2.21 g/L after optimized inoculation ratios and fermentation medium with 60 g/L peptone. This study provides a new strategy to improve polymyxin B1 production.

Atlantoaxial rotatory subluxation following surgical treatment of a cervical teratoma in a child: a case report.

Atlantoaxial rotatory subluxation (AARS), which is characterised by an abnormal alignment of the atlantoaxial joint, is rarely reported after oral and maxillofacial surgery. A four-year-old girl developed AARS after neck surgery. The child initially had treatment for one month in a timely manner. Follow ups revealed reduced symptoms of neck pain and the previous tilt disappeared after serial treatment. This case aimed to increase awareness of AARS and provide a reference for oral and maxillofacialsurgeons.

Combination of XEOL, TR-XEOL and HB-T interferometer at the TPS 23A X-ray nanoprobe for exploring quantum materials.

In this study, a combination of X-ray excited optical luminescence (XEOL), time-resolved XEOL (TR-XEOL) and the Hanbury-Brown and Twiss (HB-T) interferometer at the Taiwan Photon Source (TPS) 23A X-ray nanoprobe beamline for exploring quantum materials is demonstrated. On the basis of the excellent spatial resolution rendered using a nano-focused beam, emission distributions of artificial micro-diamonds can be obtained by XEOL maps, and featured emission peaks of a selected local area can be obtained by XEOL spectra. The hybrid bunch mode of the TPS not only provides a sufficiently high peak power density for experiments at each beamline but also permits high-quality temporal domain (∼200 ns) measurements for investigating luminescence dynamics. From TR-XEOL measurements, the decay lifetime of micro-diamonds is determined to be approximately 16 ns. Furthermore, the XEOL spectra of artificial micro-diamonds can be investigated by the HB-T interferometer to identify properties of single-photon sources. The unprecedented strategy of combining XEOL, TR-XEOL and the HB-T interferometer at the X-ray nanoprobe beamline will open new avenues with significant characterization abilities for unraveling the emission mechanisms of single-photon sources for quantum materials.

Epileptic Seizure Detection with an End-to-End Temporal Convolutional Network and Bidirectional Long Short-Term Memory Model.

Automatic seizure detection plays a key role in assisting clinicians for rapid diagnosis and treatment of epilepsy. In view of the parallelism of temporal convolutional network (TCN) and the capability of bidirectional long short-term memory (BiLSTM) in mining the long-range dependency of multi-channel time-series, we propose an automatic seizure detection method with a novel end-to-end TCN-BiLSTM model in this work. First, raw EEG is filtered with a 0.5-45 Hz band-pass filter, and the filtered data are input into the proposed TCN-BiLSTM network for feature extraction and classification. Post-processing process including moving average filtering, thresholding and collar technique is then employed to further improve the detection performance. The method was evaluated on two EEG database. On the CHB-MIT scalp EEG database, our method achieved a segment-based sensitivity of 94.31%, specificity of 97.13%, and accuracy of 97.09%. Meanwhile, an event-based sensitivity of 96.48% and an average false detection rate (FDR) of 0.38/h were obtained. On the SH-SDU database we collected, the segment-based sensitivity of 94.99%, specificity of 93.25%, and accuracy of 93.27% were achieved. In addition, an event-based sensitivity of 99.35% and a false detection rate of 0.54/h were yielded. The total detection time consumed for 1[Formula: see text]h EEG data was 5.65[Formula: see text]s. These results demonstrate the superiority and promising potential of the proposed method in real-time monitoring of epileptic seizures.

Ionizable Polymeric Micelles with Phenylalanine Moieties Enhance Intracellular Delivery of Self-Replicating RNA for Long-Lasting Protein Expression In Vivo.

mRNA-based therapeutics are revolutionizing the landscape of medical interventions. However, the short half-life of mRNA and transient protein expression often limits its therapeutic potential, demanding high treatment doses or repeated administrations. Self-replicating RNA (RepRNA)-based treatments could offer enhanced protein production and reduce the required dosage. Here, we developed polymeric micelles based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) block copolymers modified with phenylalanine (Phe) moieties via biodegradable ester bonds for the efficient delivery of RepRNA. These polymers successfully encapsulated RepRNA into sub-100 nm micelles assisted by the hydrophobicity of the Phe moieties and their ability to π-π stack with the bases in RepRNA. The micelles made from Phe-modified PEG-PG (PEG-PG(Phe)) effectively maintained the integrity of the loaded RepRNA in RNase-rich serum conditions. Once taken up by cells, the micelles triggered a pH-responsive membrane disruption, promoted by the strong protonation of the amino groups at endosomal pH, thereby delivering the RepRNA to the cytosol. The system induced strong protein expression in vitro and outperformed commercial transfecting reagents in vivo, where it resulted in enhanced and long-lasting protein expression.

Effect of early hemostasis strategy on secondary post-traumatic sepsis in trauma hemorrhagic patients.

INTRODUCTION: Fibrinogen and platelet, as the two main components of hemostatic resuscitation, are frequently administered in traumatic massive hemorrhage patients. It is reasonable to infer that they may have an impact on post-traumatic sepsis as more and more recognition of their roles in inflammation and immunity. This study aims to determine the association between the fibrinogen/platelet transfusion ratio during the first 24 h after trauma and the risk of the post- traumatic sepsis. METHODS: We analyzed the data from the National Trauma Data Bank (NTDB). Subjects included the critically injured adult patients admitted to Level I/II trauma center from 2013 to 2017 who received fibrinogen and platelet supplementation and more than 10 units (about 4000 ml) packed red blood cells (pRBCs) during the first 24 h after trauma. Two parts of analyses were performed: (1) multivariable stepwise regression was used to determine the variables that influence the risk of post-traumatic sepsis; (2) propensity score matching (PSM), to compare the influences of different transfusion ratio between fibrinogen and platelet on the risk of sepsis and other outcomes after trauma. RESULTS: 8 features were screened out by bi-directional multivariable stepwise logistic regression to predict the post-traumatic sepsis. They are age, sex, BMI, ISSabdomen, current smoker, COPD, Fib4h/24h and Fib/PLT24h. Fib/PLT24h was negatively related to sepsis (p < 0.05). A total of 1601 patients were included in the PSM cohort and grouped by Fib/PLT24h = 0.025 according to the fitting generalized additive model (GAM) model curve. The incidence of sepsis was significantly decreased in the high Fib/PLT group [3.3 % vs 9.4 %, OR = 0.33, 95 %CI (0.17-0.60)]; the length of stay in ICU and mechanical ventilation were both shortened as well [8 (IQR 2.00,17.00) vs 9 (IQR 3.00,19.25), p = 0.006 and 4 (IQR 2.00,10.00) vs 5 (IQR 2.00,14.00), p = 0.003, respectively. CONCLUSIONS: Early and sufficient supplementation of fibrinogen was a convenient way contribute to reduce the risk of sepsis after trauma.