Inhibiting the CB1 receptor in CIH-induced animal model alleviates colon injury.

Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1ß, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.

Effect of acupuncture and moxibustion on artery elasticity for early carotid atherosclerosis. / é’ˆç¸å¯¹é¢ˆåŠ¨è„‰ç²¥æ ·ç¡¬åŒ–æ—©æœŸæ‚£è€ è¡€ç®¡å¼¹æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of acupuncture and moxibustion on arterial elasticity in patients with early carotid atherosclerosis. METHODS: A total of 62 patients with early carotid atherosclerosis were randomly divided into a blank group (12 cases, 1 cases dropped-off), a sham-acupuncture group (25 cases, 5 cases dropped-off) and an acupuncture group (25 cases, 3 cases dropped-off). Patients in the acupuncture group received acupuncture treatment, including ①acupuncture：Baihui (GV20), Yintang (GV24+), Renying (ST9), Neiguan (PC6), Yanglingquan (GB34)；②moxibustion：Yinqiguiyuan (Zhongwan ［CV12］, Xiawan ［CV10］, Qihai ［CV6］, Guanyuan ［CV4］), Sihua (Geshu ［BL17］, Danshu ［BL19］)；③Intradermal needle：Xinshu (BL15), Danshu (BL19). Patients in the sham acupuncture group received placebo acupuncture, moxibustion, an intradermal needle, and the acupoints were the same as the acupuncture group. The above treatments were performed twice a week for 12 weeks. No intervention was given to the patients in the blank group. Diet and lifestyle education was given to the three groups. The ultrafast pulse wave velocity, including beginning-systolic pulse wave velocity (BS) and end-systolic pulse wave velocity (ES), was observed before treatment and 1, 2, 3 months after treatment in the three groups. The blood lipid level and platelet count (PLT) at each time point were observed. The safety of the treatments was also evaluated. RESULTS: Compared with those before treatment, the BS and ES values of both sides in the acupuncture group decreased at 2 and 3 months after treatment (P<0.05). Compared with the blank group, the bilateral ES of the acupuncture group were decreased at 2 months after treatment (P<0.05), and the bilateral BS and ES were decreased at 3 months (P<0.05). Compared with the sham-acupuncture group, the acupuncture group showed a decrease in left BS and left ES after 3 months of treatment (P<0.05), and the overall decrease on the left side of the acupuncture group was better than that on the right side. There were no significant differences between three groups in the levels of blood lipid and PLT at each time point. No serious adverse safety events occurred in the three groups during the treatment. CONCLUSIONS: Acupuncture and moxibustion therapy can improve arterial elasticity in patients with early carotid atherosclerosis, and it is safe and effective.

[Establishment and Effective Evaluation of Haikou Ozone Concentration Statistical Prediction Model].

This study selected 15 key predictors of the maximum of 8-hour averaged ozone (O3) concentration (O3-8h), using the O3 concentration of Haikou and ERA5 reanalysis data from 2015 to 2020, and constructed a multiple linear regression (MLR) model, support vector machine (SVM) model, and BP neural network (BPNN) model, to predict and test the O3-8h concentration of Haikou in 2021. The results showed that the absolute value of correlation coefficients between the O3-8h and related key prediction factors was mainly among 0.2 and 0.507. The 1 000 hPa relative humidity (RH1000), wind direction (WD1000), and 875 hPa meridional wind (v875) showed a good indicative effect on the O3-8h, with the absolute correlation value exceeding 0.4. The three prediction models could predict the seasonal variation in the O3-8h in Haikou, which was larger in the winter half year and smaller in the summer half year. The root mean square error(RMSE) was the smallest (22.29 µg·m-3) in the BPNN model. The correlation coefficients between the predicted values of three statistical models and observations were ranked as 0.733 (BPNN) > 0.724 (SVM) > 0.591 (MLR), all passing the 99.9% significance test. For the prediction of the O3-8h level, we found that TS scores of these three prediction models decreased with the increase in O3-8h concentration level. Relatively, the point over rate and not hit rate increased with the rise in O3-8h concentration level. TS scores of the SVM and BPNN model were relatively larger than those of MLR, especially in the light pollution level with TS scores remaining above 70%, indicating a better prediction capability.

Negative pressure pulmonary edema after laparoscopic cholecystectomy: A case report and literature review.

RATIONALE: Negative pressure pulmonary edema (NPPE) is an acute onset of non-cardiogenic interstitial pulmonary edema, commonly seen among surgical patients after extubation from general aneasthesia. It is mainly caused by rapid inspiration with acute upper airway obstruction resulting in significant negative thoracic pressure. PATIENT CONCERNS: A 24-year-old female patient who underwent laparoscopic cholecystectomy under general anesthesia and developed NPPE postoperatively. DIAGNOSES: Her main clinical manifestation was coughing up pink foamy sputum; postoperative CT showed increased texture in both lungs and bilateral ground glass opacities. INTERVENTIONS: Diuretics and steroids were used, and symptomatic supportive treatments such as oxygen were given. OUTCOMES: After treatment, on the fourth post-operative day, her symptoms were relieved and her vital signs were stable enough for her to be discharged. LESSONS: Although this is a rare and severe complication, the prognosis of NPPE is good when it is managed with proper diagnosis and treatment.

Role of human Kallistatin in glucose and energy homeostasis in mice.

OBJECTIVE: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. METHODS: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. RESULTS: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. CONCLUSIONS: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.

Generation of Ultrabrilliant Polarized Attosecond Electron Bunches via Dual-Wake Injection.

Laser wakefield acceleration is paving the way for the next generation of electron accelerators, for their own sake and as radiation sources. A controllable dual-wake injection scheme is put forward here to generate an ultrashort triplet electron bunch with high brightness and high polarization, employing a radially polarized laser as a driver. We find that the dual wakes can be driven by both transverse and longitudinal components of the laser field in the quasiblowout regime, sustaining the laser-modulated wakefield which facilitates the subcycle and transversely split injection of the triplet bunch. Polarization of the triplet bunch can be highly preserved due to the laser-assisted collective spin precession and the noncanceled transverse spins. In our three-dimensional particle-in-cell simulations, the triplet electron bunch, with duration about 500 as, six-dimensional brightness exceeding 10^{14} A/m^{2}/0.1% and polarization over 80%, can be generated using a few-terawatt laser. Such an electron bunch could play an essential role in many applications, such as ultrafast imaging, nuclear structure and high-energy physics studies, and the operation of coherent radiation sources.

A global perspective: characteristics of infertility-related randomized clinical trials.

BACKGROUND: Infertility is a prevalent global condition, and emerging reproductive technologies may enhance its evaluation and treatment. Understanding the current features of randomized clinical trials in infertility is crucial for improving study design and ensuring the translation of results for patient benefits. OBJECTIVES: To investigate the primary characteristics of randomized clinical trials related to infertility and areas where require improvement. MATERIALS AND METHODS: We conducted a search on the International Clinical Trials Registry platform for eligible infertility trials between 2003 and 2022. The distribution ratio of various characteristics uploaded by infertility-related studies on the platform was analyzed and compared according to sex and registration year. RESULTS: Out of the total trials, 85.3% (1,906) included only women, 8.6% (192) included only men, and 6.1% (136) included couples. The majority of retrieved trials followed a parallel arm design (91.0%) and were non-industry-funded (92.2%), with a median planned sample size of 131 patients (interquartile range 75-270). Among these trials, 54.5% (1,217) were conducted in Asia. The most common primary purpose of infertility-related trials was treatment (88.8%), with over half of the investigated interventions focusing on medication (57.9%). DISCUSSION: Asia is the leading region for research, and the drug therapy is still widely used and updated. However, support care for infertile couples has also received some preference. Areas that require improvement and promotion include addressing male infertility and focusing on underserved regions like Africa. The results also highlight deficiencies in trial registration and masking methods, emphasizing the need for better regulation and facilitation of infertility trials in the post-COVID-19 era. CONCLUSION: Based on the current status of infertility RCT studies, greater attention should be paid to infertile men and populations in underdeveloped regions like Africa in future studies, together with a standardized registration and implementation procedures.

Interferon therapy improves survival in patients with hepatitis B virus-related hepatocellular carcinoma after curative surgery: a meta-analysis.

BACKGROUND AND AIM: A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. METHODS: MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. RESULTS: 10 trials with a total of 2062 subjects were screened. Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. CONCLUSIONS: Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.

Effects of hypoxia in the diabetic corneal stroma microenvironment.

Corneal dysfunctions associated with Diabetes Mellitus (DM), termed diabetic keratopathy (DK), can cause impaired vision and/or blindness. Hypoxia affects both Type 1 (T1DM) and Type 2 (T2DM) surprisingly, the role of hypoxia in DK is unexplored. The aim of this study was to examine the impact of hypoxia in vitro on primary human corneal stromal cells derived from Healthy (HCFs), and diabetic (T1DMs and T2DMs) subjects, by exposing them to normoxic (21% O2) or hypoxic (2% O2) conditions through 2D and 3D in vitro models. Our data revealed that hypoxia affected T2DMs by slowing their wound healing capacity, leading to significant alterations in oxidative stress-related markers, mitochondrial health, cellular homeostasis, and endoplasmic reticulum health (ER) along with fibrotic development. In T1DMs, hypoxia significantly modulated markers related to membrane permeabilization, oxidative stress via apoptotic marker (BAX), and protein degradation. Hypoxic environment induced oxidative stress (NOQ1 mediated reduction of superoxide in T1DMs and Nrf2 mediated oxidative stress in T2DMs), modulation in mitochondrial health (Heat shock protein 27 (HSP27), and dysregulation of cellular homeostasis (HSP90) in both T1DMs and T2DMs. This data underscores the significant impact of hypoxia on the diabetic cornea. Further studies are warranted to delineate the complex interactions.

Neutrophil-to-lymphocyte ratio associated with symptomatic saccular unruptured intracranial aneurysm.

BACKGROUND AND PURPOSE: Whether symptomatic unruptured intracranial aneurysms (UIAs) lead to change in circulating inflammation remains unclear. This study aims to evaluate the role of hematological inflammatory indicators in predicting symptomatic UIA. METHODS: Adult patients diagnosed with saccular intracranial aneurysm from March 2019 to September 2023 were recruited retrospectively. Clinical and laboratory data, including the white blood cells (WBC), neutral counts (NEUT), lymphocyte counts (LYM), and monocyte counts (MONO) of each patient, were collected. The neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were calculated as NLR = NEUT/LYM, LMR = LYM/MONO, SII = PLT*NEUT/LYM. The hematological inflammatory indicators were compared in symptomatic saccular and asymptomatic UIA patients. Multivariable logistic regression analyses were performed to explore the factors predicting symptomatic UIA. RESULTS: One hundred and fifty UIA patients with a mean age of 58.5 ± 12.4 were included, of which 68% were females. The NLR and LMR were significantly associated with symptomatic UIA, and the association remained in small UIAs (< 7 mm). The multiple logistic regression analysis showed that NLR was independently associated with symptomatic UIA. On ROC curve analysis, the optimal cutoff value of NLR to differentiate symptomatic from asymptomatic was 2.38. In addition, LMR was significantly associated with symptomatic UIA smaller than 7 mm. CONCLUSION: There was a significant correlation between NLR and symptomatic UIA. The NLR was independently associated with symptomatic UIA.

Development of uniform fenofibrate-loaded biodegradable microparticle by membrane emulsification.

Fenofibrate has shown therapeutic effects on diabetic retinopathy. However, fenofibrate can be rapidly cleared from the eye after a single intravitreal injection. Here, we aim to develop fenofibrate loaded PLGA microparticles (Feno-MP) with high drug loading and sustained in vitro release up to 6 months suitable for intravitreal injection. First, orthogonal array experimental design was applied for formulation optimization. The selected formulation parameters were used to formulate Feno-MP using homogenization method and direct membrane emulsification method. Both methods generated Feno-MP with high drug loading and sustained in vitro drug release more than 140 days. Unlike the polydisperse Feno-MP prepared using homogenization method, membrane emulsification method generated Feno-MP with uniform size distribution. By controlling the membrane pore size, 1.5 µm, 8 µm and 16 µm Feno-MP were formulated and we found that larger Feno-MP demonstrated higher drug loading, more sustained drug release in vitro with less burst drug release than the smaller Feno-MP. In conclusion, we developed Feno-MP with high drug loading and sustained release profile, and elucidated that changing the particle size could have notable impacts on drug loading and release kinetics. Formulating Feno-MP with uniform size distribution by membrane emulsification method would benefit the batch-to-batch repeatability.

Integration of Multiparameter MRI into Conventional Pretreatment Risk Factors to Predict Positive Surgical Margins After Radical Prostatectomy.

INTRODUCTION/BACKGROUND: Positive surgical margins (PSMs) after radical prostatectomy (RP) can increase the risk of biochemical recurrence in prostate cancer (PCa) patients. However, the prediction of the likelihood of PSMs in patients undergoing similar surgical procedures remains a challenge. We aim to develop a predictive model for PSMs in patients undergoing non-nerve-sparing RP. PATIENTS AND METHODS: In this retrospective study, we analyzed data from PCa patients who underwent minimally invasive non-nerve-sparing RP at our hospital between June 2017 and June 2021. We identified independent risk factors associated with PSMs using clinical and MRI-based parameters in univariate and multivariate logistic regression analyzes. These factors were then used to develop a nomogram for predicting the probability of PSMs. The predictive performance was validated using calibration and receiver operating characteristic curve, area under the curve ,and decision curve analysis. RESULTS: Multivariate analyzes revealed prostate-specific antigen density, tumor size, tumor location at the apex, tumor contact length, extracapsular extension (ECE) level, and apparent diffusion coefficient value as independent risk factors. A nomogram was developed and validated with high accuracy (C-index = 0.78). Furthermore, we found that 44.2% of patients diagnosed with organ-confined disease had ECE after surgery, and 29.1% of patients with Gleason scores ≤7 had higher pathological scores. Interestingly, the tumor burden calculated from PCa biopsy cores was overestimated when compared to postoperative PCa specimens. CONCLUSION: We developed a reliable nomogram for predicting the risk of PSMs in PCa patients undergoing non-nerve-sparing RP. The study highlights the importance of incorporating these parameters in personalized surgical management.

Interleukin-17-mediated protective cytokine signaling against degeneration of the retinal pigment epithelium.

Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal γδ T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to characterize the profiles of immune cells in mouse choroid. We found that γδ T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6. This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal γδ T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia.

Manipulation of Giant Multipole Resonances via Vortex γ Photons.

Traditional photonuclear reactions primarily excite giant dipole resonances, making the measurement of isovector giant resonances with higher multipolarities a great challenge. In this Letter, the manipulation of collective excitations of different multipole transitions in even-even nuclei via vortex γ photons is investigated. We develop the calculation method for photonuclear cross sections induced by the vortex γ photon beam using the fully self-consistent random-phase approximation plus particle-vibration coupling (RPA+PVC) model based on Skyrme density functional. We find that the electromagnetic transitions with multipolarity J<|m_{γ}| are forbidden for vortex γ photons due to the angular momentum conservation, with m_{γ} being the projection of total angular momentum of γ photon on its propagation direction. For instance, this allows for probing the isovector giant quadrupole resonance without interference from dipole transitions using vortex γ photons with m_{γ}=2. Furthermore, the electromagnetic transition with J=|m_{γ}|+1 vanishes at a specific polar angle. Therefore, the giant resonances with specific multipolarity can be extracted via vortex γ photons. Moreover, the vortex properties of γ photons can be meticulously diagnosed by measuring the nuclear photon-absorption cross section. Our method opens new avenues for photonuclear excitations, generation of coherent γ photon laser and precise detection of vortex particles, and consequently, has significant impact on nuclear physics, nuclear astrophysics and strong laser physics.

Generation of High-Density High-Polarization Positrons via Single-Shot Strong Laser-Foil Interaction.

We put forward a novel method for producing ultrarelativistic high-density high-polarization positrons through a single-shot interaction of a strong laser with a tilted solid foil. In our method, the driving laser ionizes the target, and the emitted electrons are accelerated and subsequently generate abundant γ photons via the nonlinear Compton scattering, dominated by the laser. These γ photons then generate polarized positrons via the nonlinear Breit-Wheeler process, dominated by a strong self-generated quasistatic magnetic field B^{S}. We find that placing the foil at an appropriate angle can result in a directional orientation of B^{S}, thereby polarizing positrons. Manipulating the laser polarization direction can control the angle between the γ photon polarization and B^{S}, significantly enhancing the positron polarization degree. Our spin-resolved quantum electrodynamics particle-in-cell simulations demonstrate that employing a laser with a peak intensity of about 10^{23} W/cm^{2} can obtain dense (≳10^{18} cm^{-3}) polarized positrons with an average polarization degree of about 70% and a yield of above 0.1 nC per shot. Moreover, our method is feasible using currently available or upcoming laser facilities and robust with respect to the laser and target parameters. Such high-density high-polarization positrons hold great significance in laboratory astrophysics, high-energy physics, and new physics beyond the standard model.

Cell sheet-based approach to study the diabetic corneal stroma.

Prolonged hyperglycemia during diabetes mellitus (DM) is associated with severe complications that may affect both the anterior and posterior ocular segments, leading to impaired vision or blindness. The cornea is a vital part of the eye that has a dual role as a protective transparent barrier and as a major refractive structure and is likewise negatively affected by hyperglycemia in DM. Understanding the cellular and molecular mechanisms underlying the phenotypic changes associated with DM is critical to developing targeted therapies to promote tissue integrity. In this proof-of-concept study, we applied a cell sheet-based approach to generate stacked constructs of physiological corneal thickness using primary human corneal fibroblasts isolated from cadaveric control (healthy), Type 1 DM and Type 2 DM corneal tissues. Self-assembled corneal stromal sheets were generated after 2 weeks in culture, isolated, and subsequently assembled to create stacked constructs, which were evaluated using transmission electron microscopy. Analysis of gene expression patterns revealed significant downregulation of fibrotic markers, α-smooth muscle actin, and collagen type 3, with stacking in Type 2 DM constructs when compared to controls. IGF1 expression was significantly upregulated in Type 2 DM constructs compared to controls with a significant reduction induced by stacking. This study describes the development of a thicker, self-assembled corneal stromal construct as a platform to evaluate phenotypic differences associated with DM-derived corneal fibroblasts and enable the development of targeted therapeutics to promote corneal integrity.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Increased intracellular miR-142 in adults with Type 1 diabetes.

microRNAs (miRs), including miR-142, modulate gene expression and processes implicated in vascular damage and may serve as therapeutic targets and agents, including in Type 1 diabetes (T1D). The project aimed to assess whether miR-142 levels differ between people with and without T1D, and to analyse miR-142 associations with cardiovascular (CVD) risk factors. Intracellular miRs were isolated from whole blood cell pellets using TRIzol-based methodology. In a cross-sectional study in 102 adults cellular miR-142 levels were significantly higher (on unadjusted and adjusted analyses) in 69 adults with T1D relative to 33 non-diabetic subjects: mean ± SD, 3.53 ± 3.66 vs. 1.25 ± 0.78, p < 0.0002, but were not related to HbA1c levels. Further miR-142 research, including longitudinal and intervention studies and basic science are of interest. miR-142 may be valuable in clinical practice for predicting health and as a treatment target.

Site-specific crosslinking and assembly of tetrameric ß-glucuronidase improve glycyrrhizin hydrolysis.

In this study, eight nonconserved residues with exposed surfaces and flexible conformations of the homotetrameric PGUS (ß-glucuronidase from Aspergillus oryzae Li-3) were identified. Single-point mutation into cysteine enabled the thiol-maleimide reaction and site-specific protein assembly using a two-arm polyethylene glycol (PEG)-maleimide crosslinker (Mal2 ). The Mal2 (1k) (with 1 kDa PEG spacer)-crosslinked PGUS assemblies showed low crosslinking efficiency and unimproved thermostability except for G194C-Mal2 (1k). To improve the crosslinking efficiency, a lengthened crosslinker Mal2 (2k) (with 2 kDa PEG spacer) was used to produce PGUS assembly and a highly improved thermostability was achieved with a half-life of 47.2-169.2 min at 70°C, which is 1.04-3.74 times that of wild type PGUS. It is found that the thermostability of PGUS assembly was closely associated with the formation of inter-tetramer assembly and intratetramer crosslinking, rather than the PEGylation of the enzyme. Therefore, the four-arm PEG-maleimide crosslinker Mal4 (2k) (with 2 kDa PEG spacer) was employed to simultaneously increase the inter-tetramer assembly and intratetramer crosslinking, and the resulting PGUS assemblies showed further improved thermostabilities compared with Mal2 (2k)-crosslinked assemblies. Finally, the application of PGUS assemblies with significantly improved thermostability to the bioconversion of GL proved that the PGUS assembly is a strong catalyst for glycyrrhizin (GL) hydrolysis in industrial applications.

Jackstone in the renal calyx: A rare case report.

BACKGROUND: Jackstone is a rare entity of calculi in urinary tracts and has the characteristic appearance resembling toy jacks. They are nearly always reported to occur in the urinary bladder, we first report a rare case of jackstone located in the obstructed renal calyx. CASE SUMMARY: We report a 46-year-old man presenting with intermittent, painless gross hematuria and left flank pain. Urinary computed tomography revealed staghorn stones and secondary hydronephrosis. A jackstone with radiating branches was found in one of the dilated renal calyx. Percutaneous nephrolithotomy was performed and endoscopic images were recorded during the operation. Postoperative stone composition analysis revealed it as calcium oxalate monohydrate stones. CONCLUSION: Jackstones can occur in the renal collecting system besides the bladder. The unique appearance and imaging manifestations are the most important factors in the diagnosis of jackstones, and further exploration of the formation mechanism is required.