A Novel Inhalable Nanobody Targeting IL-4Rα for the Treatment of Asthma.

BACKGROUND: Inhalable biologics represent a promising approach to improve the efficacy and safety of asthma treatment. Although several monoclonal antibodies (mAbs) targeting IL-4Rα have been approved or are undergoing clinical trials, the development of inhalable mAbs targeting IL-4Rα presents significant challenges. OBJECTIVE: Capitalizing on the distinctive advantages of nanobodies (Nbs) in maintaining efficacy during storage and administration, we sought to develop a novel inhalable IL-4Rα Nb for effectively treating asthma. METHODS: Three IL-4Rα immunized Nb libraries were utilized to generate specific and functional IL-4Rα Nbs. LQ036, a bivalent Nb comprising two HuNb103 units, was constructed with a high affinity and specificity for hIL-4Rα. The efficacy, pharmacokinetic and safety of inhaled LQ036 were evaluated in B-hIL4/hIL4Ra humanized mice. RESULTS: LQ036 inhibited secreted embryonic alkaline phosphatase (SEAP) reporter activity, TF-1 cell proliferation, and suppressed pSTAT6 in T cells from asthma patients. Crystal structure analysis revealed a binding region similar to Dupilumab but with higher affinity, leading to better efficacy in blocking the signaling pathway. HuNb103 competed with IL-4 and IL-13 for IL-4Rα binding. Additionally, LQ036 significantly inhibited OVA-specific IgE levels in serum, CCL17 levels in BALF, bronchial mucous cell hyperplasia, and airway goblet cell hyperplasia in B-hIL4/hIL4Ra humanized mice. Inhaled LQ036 exhibited favorable pharmacokinetics, safety and tissue distribution, with higher concentrations observed in the lungs and bronchi. CONCLUSION: These findings from preclinical studies establish the safety and efficacy of inhaled LQ036, underscoring its potential as a pioneering inhalable biologic therapy for asthma.

Node-adaptive graph Transformer with structural encoding for accurate and robust lncRNA-disease association prediction.

BACKGROUND: Long noncoding RNAs (lncRNAs) are integral to a plethora of critical cellular biological processes, including the regulation of gene expression, cell differentiation, and the development of tumors and cancers. Predicting the relationships between lncRNAs and diseases can contribute to a better understanding of the pathogenic mechanisms of disease and provide strong support for the development of advanced treatment methods. RESULTS: Therefore, we present an innovative Node-Adaptive Graph Transformer model for predicting unknown LncRNA-Disease Associations, named NAGTLDA. First, we utilize the node-adaptive feature smoothing (NAFS) method to learn the local feature information of nodes and encode the structural information of the fusion similarity network of diseases and lncRNAs using Structural Deep Network Embedding (SDNE). Next, the Transformer module is used to capture potential association information between the network nodes. Finally, we employ a Transformer module with two multi-headed attention layers for learning global-level embedding fusion. Network structure coding is added as the structural inductive bias of the network to compensate for the missing message-passing mechanism in Transformer. NAGTLDA achieved an average AUC of 0.9531 and AUPR of 0.9537 significantly higher than state-of-the-art methods in 5-fold cross validation. We perform case studies on 4 diseases; 55 out of 60 associations between lncRNAs and diseases have been validated in the literatures. The results demonstrate the enormous potential of the graph Transformer structure to incorporate graph structural information for uncovering lncRNA-disease unknown correlations. CONCLUSIONS: Our proposed NAGTLDA model can serve as a highly efficient computational method for predicting biological information associations.

Nitrogen application in pod zone improves yield and quality of two peanut cultivars by modulating nitrogen accumulation and metabolism.

Cultivated peanut (Arachis hypogaea L.) represents one of the most important oil and cash crops world-widely. Unlike many other legumes, peanuts absorb nitrogen through their underground pods. Despite this unique feature, the relationship between yield and nitrogen uptake within the pod zone remains poorly understood. In our pot experiment, we divided the underground peanut part into two zones-pod and root-and investigated the physiological and agronomic traits of two peanut cultivars, SH11 (large seeds, LS) and HY23 (small seeds, SS), at 10 (S1), 20 (S2), and 30 (S3) days after gynophores penetrated the soil, with nitrogen application in the pod zone. Results indicated that nitrogen application increased pod yield, kernel protein content, and nitrogen accumulation in plants. For both LS and SS peanut cultivars, optimal nitrogen content was 60 kg·hm- 2, leading to maximum yield. LS cultivar exhibited higher yield and nitrogen accumulation increases than SS cultivar. Nitrogen application up-regulated the expression of nitrogen metabolism-related genes in the pod, including nitrate reductase (NR), nitrite reductase (NIR), glutamine synthetase (GS), glutamate synthase (NADH-GOGAT), ATP binding cassette (ABC), and nitrate transporter (NRT2). Additionally, nitrogen application increased enzyme activity in the pod, including NR, GS, and GOGAT, consistent with gene expression levels. These nitrogen metabolism traits exhibited higher up-regulations in the large-seeded cultivar than in the small-seeded one and showed a significant correlation with yield in the large-seeded cultivar at S2 and S3. Our findings offer a scientific basis for the judicious application and efficient utilization of nitrogen fertilization in peanuts, laying the groundwork for further elucidating the molecular mechanisms of peanut nitrogen utilization.

Higher risk of osteoporosis in adult-onset asthma than childhood-onset asthma: from genetic and prospective evidence.

Both COA and AOA have a genetically causal effect on osteoporosis. COA and AOA were independently associated with incident osteoporosis, and the risk was greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications. PURPOSE/INTRODUCTION: Childhood-onset asthma (COA) differs with adult-onset asthma (AOA) on genetic susceptibility, severity, and co-morbidities. Whether COA or AOA is independently associated with osteoporosis is unexplored. We aimed to determine the effects of COA and AOA on osteoporosis at genetic and individual level. METHODS: We used two-sample Mendelian randomization analysis to explore the causal effects of COA and AOA on osteoporosis. In the UK Biobank cohort, we included 478,289 osteoporosis-free participants at baseline (2006-2010). Participants were classified as non-asthma, COA, and AOA at recruitment. Multivariate Cox regression analysis was used to evaluate the effects of COA, AOA, and multiple asthma medications on incident osteoporosis risk. RESULTS: COA and AOA were causally related to osteoporosis, with odds ratio of 1.007 (95% confidence interval (CI), 1.0003-1.0132) and 1.012 (95% CI, 1.002-1.023), respectively. Multivariate Cox regression analysis suggested that COA (hazard ratio (HR), 1.46; 95% CI, 1.32-1.61) and AOA (HR, 1.70; 95% CI, 1.61-1.80) were independently associated with incident osteoporosis, and the risk was greatly higher in AOA (HR, 1.51; 95% CI, 1.34-1.70). In addition to corticosteroids, monotherapy with leukotriene modifiers (HR, 1.70; 95% CI, 1.20-2.42), long-acting beta agonists (HR, 1.49; 95% CI, 1.18-1.87), and short-acting beta agonists (HR, 1.72; 95% CI1.01-2.93) were independently associated with a higher risk of osteoporosis. CONCLUSIONS: Both COA and AOA have a genetically causal effect on osteoporosis, and the risk of osteoporosis is greatly higher in AOA. Besides corticosteroids, the increased risk of osteoporosis among asthma patients should be attributed to genetic susceptibility and other asthma medications.

Gestational diabetes mellitus is associated with distinct folate-related metabolites in early and mid-pregnancy: A prospective cohort study.

AIMS: This study aimed to evaluate the association between gestational diabetes mellitus (GDM) and circulating folate metabolites, folic acid (FA) intake, and the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genotype. MATERIALS AND METHODS: A prospective pregnancy cohort study was conducted in Beijing, China, from 2022 to 2023. Circulating folate metabolites, including red blood cell (RBC) 5-methyltetrahydrofolate (5-MTHF), 5, 10-methylene-tetrahydrofolate (5,10-CH2-THF), 5- formyltetrahydrofolate (5-CHO-THF), and unmetabolised folic acid (UMFA), and plasma homocysteine (HCY), 5-MTHF, and methylmalonic acid (MMA), were determined at 6-17 weeks and 20-26 weeks of gestation. FA intake and the MTHFR and MTRR genotype were also examined. GDM was diagnosed between 24 and 28 weeks of pregnancy by a 75-g oral glucose tolerance test (OGTT). The association between the folate status and GDM was ascertained using multivariate generalised linear models, logistic regression models, and restricted cubic spline regression, adjusting for potential confounders. RESULTS: The study included 2032 pregnant women, of whom 392 (19.29%) developed GDM. UMFA above the 75th percentile (≥P75) [adjusted OR (aOR) (95% confidence interval [CI]) = 1.36 (1.01-1.84)], UMFA ≥ P90 [aOR (95% CI) = 1.82 (1.23-2.69)], and HCY ≥ P75 [aOR (95% CI) = 1.40 (1.04-1.88)] in early pregnancy, and RBC 5-MTHF [aOR (95% CI) = 1.48 (1.10-2.00)], RBC 5,10-CH2-THF [aOR (95% CI) = 1.55 (1.15-2.10)], and plasma 5-MTHF [aOR (95% CI) = 1.36 (1.00-1.86)] in mid-pregnancy ≥ P75 are associated with GDM. Higher UMFA levels in early pregnancy show positive associations with the 1-h and 2-h glucose levels during the OGTT, and higher HCY levels are associated with increased fasting glucose levels during the OGTT. In comparison, RBC 5- MTHF and 5,10-CH2-THF, and plasma 5- MTHF in mid-pregnancy are positively associated with the 1-h glucose level (p < 0.05). The MTHFR and MTRR genotype and FA intake are not associated with GDM. CONCLUSIONS: Elevated levels of UMFA and HCY during early pregnancy, along with elevated RBC 5-MTHF and 5,10-CH2-THF and plasma 5-MTHF during mid-pregnancy, are associated with GDM. These findings indicate distinct connections between different folate metabolites and the occurrence of GDM.

Phospholipid Type Regulates Protein Corona Composition and In Vivo Performance of Lipid Nanodiscs.

Over the years, there has been significant interest in PEGylated lipid-based nanocarriers within the drug delivery field. The inevitable interplay between the nanocarriers and plasma protein plays a pivotal role in their in vivo biological fate. Understanding the factors influencing lipid-based nanocarrier and protein corona interactions is of paramount importance in the design and clinical translation of these nanocarriers. Herein, discoid-shaped lipid nanodiscs (sNDs) composed of different phospholipids with varied lipid tails and head groups were fabricated. We investigated the impact of phospholipid components on the interaction between sNDs and serum proteins, particle stability, and biodistribution. The results showed that all of these lipid nanodiscs remained stable over a 15 day storage period, while their stability in the blood serum demonstrated significant differences. The sND composed of POPG exhibited the least stability due to its potent complement activation capability, resulting in rapid blood clearance. Furthermore, a negative correlation between the complement activation capability and serum stability was identified. Pharmacokinetic and biodistribution experiments indicated that phospholipid composition did not influence the capability of sNDs to evade the accelerated blood clearance phenomenon. Complement deposition on the sND was inversely associated with the area under the curve. Additionally, all lipid nanodiscs exhibited dominant adsorption of apolipoprotein. Remarkably, the POPC-based lipid nanodisc displayed a significantly higher deposition of apolipoprotein E, contributing to an obvious brain distribution, which provides a promising tool for brain-targeted drug delivery.

Low-dose aspirin for the prevention of preterm birth in nulliparous women: systematic review and meta-analysis.

OBJECTIVE: The objective was to assess the efficacy and safety of low-dose aspirin for the prevention of preterm birth in nulliparous women. DATA SOURCES: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to June 2022. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared aspirin to placebo in nulliparous women were eligible. METHODS: This study was reported in accordance with the PRISMA 2020 checklist. The primary outcomes of this study were the rates of preterm birth at less than 37 weeks and less than 34 weeks of gestation. The secondary outcomes included postpartum hemorrhage, placental abruption, cesarean section, any hypertensive disorder of pregnancy and small for gestational age. Relative risks with their 95% confidence intervals were calculated for analysis. Heterogeneity was assessed by Cochran's Q test and Higgins's I2. A random-effects model was used when I2 was > 50% to generate the RR and 95% CI; otherwise, a fixed-effects model was used. The risk of publication bias was assessed by funnel plots. We performed sensitivity analysis by sequentially omitting each included study to confirm the robustness of the analysis. RESULTS: Seven studies with a total of 29,029 participants were included in this review. Six studies were assessed as having a low risk of bias or an unclear risk of bias, and one study was judged as having a high risk of bias. In nulliparous women, low-dose aspirin was associated with a significant reduction in the rate of preterm birth at less than 34 weeks of gestational age (RR 0.84,95% CI: 0.71-0.99; I2 = 0%; P = 0.04), but we did not observe a significant difference in the rate of preterm birth at less than 37 weeks of gestation (RR 0.96,95% CI: 0.90-1.02; I2 = 31%; P = 0.18). Low-dose aspirin was associated with a significant increase in the rates of postpartum hemorrhage (RR 1.32,95% CI: 1.14-1.54; I2 = 0%; P = 0.0003), placental abruption (RR 2.18,95% CI: 1.10-4.32; I2 = 16%; P = 0.02) and cesarean section (RR 1.053, 95% CI: 1.001-1.108; I2 = 0%; P = 0.05) in nulliparous women. We also did not observe a significant effect of low-dose aspirin on the rates of any hypertensive disorder of pregnancy (RR 1.05, 95% CI: 0.96-1.14; I2 = 9%; P = 0.28) or small for gestational age (RR 0.96, 95% CI: 0.91-1.02; I2 = 0%; P = 0.16) in nulliparous women. Funnel plots indicated that no significant publication bias existed in this meta-analysis. Except for preterm birth at less than 34 weeks of gestation, placental abruption and cesarean section, the sensitivity analysis showed similar results, which confirmed the robustness of this meta-analysis. CONCLUSIONS: Low-dose aspirin might reduce the risk of preterm birth at less than 34 weeks of gestation in nulliparous women. The use of low-dose aspirin in nulliparous women increased the risk of postpartum hemorrhage and might increase the risk of placental abruption and cesarean section.

The influence of maternal prepregnancy weight and gestational weight gain on the umbilical cord blood metabolome: a case-control study.

BACKGROUND: Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles. METHODS: A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS. RESULTS: Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P < 0.01). CONCLUSIONS: Prepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.

A humanized trivalent Nectin-4-targeting nanobody drug conjugate displays potent antitumor activity in gastric cancer.

BACKGROUND: Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. RESULTS: An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. CONCLUSION: We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer.

Comparative study of percutaneous endoscopic lumbar decompression and traditional revision surgery in the treatment of symptomatic adjacent segment degeneration.

OBJECTIVE: The objective of this study is to evaluate and compare the surgical outcomes and complications of Percutaneous Endoscopic Lumbar Decompression (PELD) and traditional revision surgery in treating symptomatic Adjacent Segment Degeneration (ASD). This comparison aims to delineate the advantages and disadvantages of these methods, assisting spine surgeons in making informed surgical decisions. METHODS: 66 patients with symptomatic ASD who failed conservative treatment for more than 1 month and received repeated lumbar surgery were retrospectively collected in the study from January 2015 to November 2018, with the average age of 65.86 ± 11.04 years old. According to the type of surgery they received, all the patients were divided in 2 groups, including 32 patients replaced the prior rod in Group A and 34 patients received PELD at the adjacent level in Group B. Patients were followed up routinely and received clinical and radiological evaluation at 3, 6, 12 months and yearly postoperatively. Complications and hospital costs were recorded through chart reviews. RESULTS: The majority of patients experienced positive surgical outcomes. However, three cases encountered complications. Notably, Group B patients demonstrated superior pain relief and improved postoperative functional scores throughout the follow-up period, alongside reduced hospital costs (P < 0.05). Additionally, significant reductions in average operative time, blood loss, and hospital stay were observed in Group B (P < 0.05). Notwithstanding these benefits, three patients in Group B experienced disc re-herniation and underwent subsequent revision surgeries. CONCLUSIONS: While PELD offers several advantages over traditional revision surgery, such as reduced operative time, blood loss, and hospital stay, it also presents a higher likelihood of requiring subsequent revision surgeries. Future studies involving a larger cohort and extended follow-up periods are essential to fully assess the relative benefits and drawbacks of these surgical approaches for ASD.

Depletion of tilmicosin residue in Gushi chickens following oral administration via drinking water.

This study aimed to examine the depletion of tilmicosin residues in Gushi chickens following the administration at a concentration of 75 mg/L in their drinking water for three consecutive days. Plasma, liver, kidney, lung, muscle, and skin + fat samples were collected from 6 chickens at 6 h, 1, 3, 5, and 7 days after the treatment. Tilmicosin concentrations in the samples were determined using a high-performance liquid chromatography (HPLC) method. The findings revealed that the highest tilmicosin residues were detected in the liver, followed by the kidney, lung, skin + fat, muscle, and plasma. Notably, at 7 days post-treatment, no drug residue was detected in all samples except for the liver and kidney. The non-compartmental model was employed to calculate relevant pharmacokinetic parameters. The elimination half-lives (t1/2λz ) of tilmicosin were as follows, ranked from long to short: skin + fat (45.42 h), liver (44.17 h), kidney (40.06 h), plasma (37.64 h), lung (31.39 h), and muscle (30.05 h). Considering the current residue depletion and the maximum residue limits (MRLs) set by Chinese regulatory authorities, the withdrawal times for tilmicosin were estimated as 18.91, 10.81, and 8.58 days in the kidney, liver, and skin + fat, respectively. A rounded-up value of 19 days was selected as the conclusive withdrawal time. Furthermore, based on the observed tilmicosin concentrations in plasma and lung, combined with previously reported minimum inhibitory concentration (MIC) values against Mycoplasma gallisepticum, the current dosing regimen was deemed adequate for treating Mycoplasma gallisepticum infections in Gushi chickens.

Efficacy and safety of PLDR-IMRT for the re-irradiation of recurrent NPC: A prospective, single-arm, multicenter trial.

Salvage treatment of locoregionally recurrent nasopharyngeal carcinoma (NPC) requires weighing the benefits of re-irradiation against increased risks of toxicity. Here, we evaluated the outcomes of patients treated with intensity-modulated-based pulsed low-dose-rate radiotherapy (PLDR-IMRT) to enhance the curative effect of salvage treatment and reduce RT-related SAEs. A prospective clinical trial was conducted from March 2018 to March 2020 at multiple institutions. NPC patients who experienced relapse after radical therapy were re-irradiated with a median dose of 60 Gy (50.4-70 Gy)/30 f (28-35 f) using PLDR-IMRT. Thirty-six NPC patients who underwent PLDR-IMRT for locoregional recurrence were identified. With a median follow-up of 26.2 months, the objective response rate (ORR) of the entire cohort was 91.6%. The estimated mPFS duration was 28 months (95% CI: 24.9-31.1), and the estimated mLRFS duration was 30.4 months (95% CI: 25.2-35.5). The overall survival (OS) rate for all patients was 80.6%, the progression-free survival (PFS) rate was 75% and the cancer-specific survival (CSS) rate was 88.9% at 1 year. The LRFS and DMFS rates were 88.9% and 91.7%, respectively, at 1 year. A combination of systematic therapies could provide survival benefits to patients who experience NPC relapse (p < 0.05), and a Karnofsky performance status (KPS) score of ≥90 was a favorable factor for local control (p < 0.05). The incidence of acute SAEs (grade 3+) from PLDR was 22.2%, and the incidence of chronic SAEs was 19.4% among all patients. PLDR-IMRT combined with systematic therapy can effectively treat patients with locoregionally recurrent nasopharyngeal carcinoma and causes fewer adverse events than the rates expected with IMRT.

Redeveloping antigen detection kits for the diagnosis of rat hepatitis E virus.

The emergence of Rocahepevirus ratti [species HEV ratti (r HEV)] as a causative agent of hepatitis E in humans presents a new potential threat to global public health. The R. ratti genotype 1 (r-1 HEV) variant only shares 50%-60% genomic identity with Paslahepevirus balayani [species HEV balayani (b HEV)] variants, which are the main causes of hepatitis E infection in humans. Here, we report antigen diagnoses for r-1 HEV and b HEV using an enzymatic immunoassay (EIA) method. We detected recombinant virus-like particles protein (HEV 239) of r HEV and b HEV using a collection of hepatitis E virus (HEV)-specific monoclonal antibodies. Two optimal candidates, the capture antibody P#1-H4 and the detection antibodies C145 (P#1-H4*/C145#) and C158 (P#1-H4*/C158#), were selected to detect antigen in infected rat samples and r-1 HEV- or b HEV-infected human clinical samples. The two candidates showed similar diagnostic efficacy to the Wantai HEV antigen kit in b HEV-infected clinical samples. Genomic divergence resulted in low diagnostic efficacy of the Wantai HEV antigen kit (0%, 0 of 10) for detecting r-1 HEV infection. Compared with the P#1-H4*/C145# candidate (80%, 8 of 10), the P#1-H4*/C158# candidate had excellent diagnostic efficacy in r-1 HEV-infected clinical samples (100%, 10 of 10). The two candidates bind to a discrete antigenic site that is highly conserved across r HEV and b HEV. P#1-H4*/C145# and P#1-H4*/C158# are efficacious candidate antibody combinations for rat HEV antigen detection.

In vivo brain temperature mapping using polymer optical fiber Bragg grating sensors.

Variation of the brain temperature is strongly affected by blood flow, oxygen supply, and neural cell metabolism. Localized monitoring of the brain temperature is one of the most effective ways to correlate brain functions and diseases such as stroke, epilepsy, and mood disorders. While polymer optical fibers (POFs) are considered ideal candidates for temperature sensing in the brain, they have never been used so far in vivo. Here, we developed for the first, to the best of our knowledge, time an implantable probe based on a microstructured polymer optical fiber Bragg grating (FBG) sensor for intracranial brain temperature mapping. The temperature at different depths of the brain (starting from the cerebral cortex) and the correlation between the brain and body core temperature of a rat were recorded with a sensitivity of 33 pm/°C and accuracy <0.2°C. Our in vivo experimental results suggest that the proposed device can achieve real-time and high-resolution local temperature measurement in the brain, as well as being integrated with existing neural interfaces.

In Situ Construction of Manganese Oxide Photothermocatalysts for the Deep Removal of Toluene by Highly Utilizing Sunlight Energy.

The alternative use of electric energy by renewable energy to supply power for catalytic oxidation of pollutants is a sustainable technology, requiring a competent catalyst to realize efficient utilization of light and drive the catalytic reaction. Herein, in situ-synthesized manganese oxide heterostructure composites are developed through solvothermal reduction and subsequent calcination of amorphous manganese oxide (AMO). 95% of toluene conversion and 80% of CO2 mineralization were achieved over amorphous manganese oxide calcined at 250 °C (AMO-250) under light irradiation, and catalyst stability was maintained for at least 40 h. Highly utilization of light energy, uniformly dispersed nanoparticles, large specific surface area, improved metal reducibility, and oxygen desorption and migration ability at low temperature contribute to the good catalytic oxidation activity of AMO-250. Light activated more lattice oxygen to participate in the reaction via the Mars-van Krevelen (MvK) mechanism, and traditional e--h+ photocatalytic behavior exists over the AMO-250 heterostructure composite as an auxiliary degradation path. The reaction pathways of photothermocatalysis and thermocatalysis are close, except for the emergence of different copolymers, where light enhances the deep conversion of intermediates. A proof-of-concept study under natural sunlight has confirmed the feasibility of practical application in the photothermocatalytic degradation of pollutants.

Association between light rare earth elements in maternal plasma and the risk of spontaneous preterm birth: a nested case-control study from the Beijing birth cohort study.

BACKGROUND: Parental exposure to rare earth elements (REEs) could increase the risk of premature rupture of membranes, a major cause of spontaneous preterm birth (SPB). In addition, different subtypes of SPB, such as spontaneous preterm labor (SPL) and preterm premature rupture of membranes (PPROM), may have different susceptibility to environmental exposure. Therefore, we investigated the potential associations between REE exposure in different trimesters and SPB and its subtypes. METHODS: A nested case-control study was performed. We included 244 women with SPB as cases and 244 women with full-term delivery as controls. The plasma concentrations of light REEs were measured in the first and third trimesters. Logistic regression was used to analyze the associations between single REE levels and SPB, and Bayesian kernel machine regression (BKMR) was used to analyze the mixed-exposure effect. RESULTS: Exposure to light REEs was associated with SPB and its subtypes only in the third trimester. Specifically, the intermediate- and highest-tertile concentration groups of La and the highest-tertile concentration group of Sm were associated with an increased risk of SPL, with adjusted odds ratios (AORs) of 2.00 (95% CIs: 1.07-3.75), 1.87 (95% CIs: 1.01-3.44), and 1.82 (95% CIs: 1.00-3.30), respectively. The highest-tertile concentration group of Pr was associated with an increased risk of PPROM, with an AOR of 1.69 (95% CIs: 1.00-2.85). Similar results were also found in BKMR models. CONCLUSIONS: La and Sm levels in plasma may be associated with the risk of SPL, and Pr levels in plasma may be associated with the risk of PPROM.

Pregnancy outcomes and neonatal thyroid function in women with thyroid cancer: a retrospective study.

BACKGROUND: Evidence regarding adverse pregnancy outcomes in patients with thyroid cancer has been conflicting, and the effect of thyroid dysfunction caused by thyroid hormone suppression therapy in terms of neonatal thyroid stimulating hormone (TSH) is unclear. This study aimed to investigate whether thyroid cancer was associated with adverse pregnancy outcomes and had an adverse effect on neonatal thyroid function. METHODS: This was a retrospective study of 212 singleton pregnancies with thyroid cancer and 35,641 controls without thyroid cancer. Data on maternal pregnancy outcomes and neonatal outcomes were analyzed. RESULTS: The median TSH level in the thyroid cancer group was significantly lower than that in the control group (0.87 µIU/mL vs. 1.17 µIU/mL; P < 0.001), while the FT4 level was higher than that in the control group (17.16 pmol/L vs. 16.33 pmol/L; P < 0.001). The percentage of thyroid peroxidase antibodies (TPOAb) positive in the thyroid cancer group was significantly higher than that in the control group (25.0% vs. 11.8%; P < 0.001). Pregnancies with thyroid cancer had a higher risk of late miscarriage (OR 7.166, 95% CI: 1.521, 33.775, P = 0.013), after adjusting maternal TPOAb positive, there was no statistical significance (OR 3.480, 95% CI: 0.423, 28.614, P = 0.246). Pregnancies with thyroid cancer had higher gestational weight gain (GWG) (14.0 kg vs. 13.0 kg, P < 0.001). Although there was no significant difference in the prevalence of gestational diabetes mellitus (GDM) (20.8% vs. 17.4%, P = 0.194), the oral glucose tolerance test (OGTT) showed that fasting plasma glucose and 2-hour value in the thyroid cancer group were higher than those in the control group (P = 0.020 and 0.004, respectively). There was no statistically significant difference in TSH between the thyroid cancer group and the control group, regardless of full-term newborns or preterm newborns. CONCLUSIONS: Thyroid cancer might not have substantial adverse effects on pregnancy outcomes except for excessive GWG. No adverse effect on neonatal TSH was found, but the effect on long-term thyroid function and neuropsychological function in offspring need further study. TRIAL REGISTRATION: Beijing Birth Cohort Study (ChiCTR220058395).

TROP2-directed nanobody-drug conjugate elicited potent antitumor effect in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a highly aggressive malignancy with limited treatment options and a poor prognosis. Trophoblast cell surface antigen 2 (TROP2), a cell surface antigen overexpressed in the tumors of more than half of pancreatic cancer patients, has been identified as a potential target for antibody-drug conjugates (ADCs). Almost all reported TROP2-targeted ADCs are of the IgG type and have been poorly studied in pancreatic cancer. Here, we aimed to develop a novel nanobody-drug conjugate (NDC) targeting TROP2 for the treatment of pancreatic cancer. RESULTS: In this study, we developed a novel TROP2-targeted NDC, HuNbTROP2-HSA-MMAE, for the treatment of TROP2-positive pancreatic cancer. HuNbTROP2-HSA-MMAE is characterized by the use of nanobodies against TROP2 and human serum albumin (HSA) and has a drug-antibody ratio of 1. HuNbTROP2-HSA-MMAE exhibited specific binding to TROP2 and was internalized into tumor cells with high endocytosis efficiency within 5 h, followed by intracellular translocation to lysosomes and release of MMAE to induce cell apoptosis in TROP2-positive pancreatic cancer cells through the caspase-3/9 pathway. In a xenograft model of pancreatic cancer, doses of 0.2 mg/kg and 1 mg/kg HuNbTROP2-HSA-MMAE demonstrated significant antitumor effects, and a dose of 5 mg/kg even eradicated the tumor. CONCLUSION: HuNbTROP2-HSA-MMAE has desirable affinity, internalization efficiency and antitumor activity. It holds significant promise as a potential therapeutic option for the treatment of TROP2-positive pancreatic cancer.

A Novel Screw Modeling Approach to Study the Effects of Screw Parameters on Pullout Strength.

Screw loosening remains a prominent problem for osteoporotic patients undergoing pedicle screw fixation surgeries and is affected by screw parameters (e.g., diameter, pitch, and thread angle). However, the individual and interactive effects of these parameters on screw fixation are not fully understood. Furthermore, the current finite element modeling of a threaded screw is less computationally efficient. To address these issues, we (1) explored a novel "simulated threaded screw" approach (virtual threads assigned to the contact elements of a simplified screw) and compared its performance with threaded and simplified screws, and (2) examined this approach the individual and interactive effects of altering screw diameter (5.5-6.5 mm), pitch (1-2 mm) and half-thread angle (20-30 deg) on pullout strength of normal vertebrae. Results demonstrated that the "simulated threaded screw" approach equivalently predicted pullout strength compared to the "threaded screw" approach (R2 = 0.99, slope = 1). We further found that the pullout strength was most sensitive to the change in screw diameter, followed by thread angle, pitch, and interactions of diameter*pitch or diameter*angle. In conclusion, the "simulated threaded screw" approach can achieve the same predictive capability compared to threaded modeling of the screw. The current findings may serve as useful references for planning of screw parameters, so as to improve the complication of screw loosening.

Response of methylmercury in paddy soil and paddy rice to pristine biochar: A meta-analysis and environmental implications.

Biochar has received increased research attention due to its effectiveness in mitigating the potential risks of mercury (Hg) in agricultural soils. However, there is a lack of consensus on the effect of pristine biochar on the net production, availability, and accumulation of methylmercury (MeHg) in the paddy rice-soil system. As such, a meta-analysis with 189 observations was performed to quantitatively assess the effects of biochar on Hg methylation, MeHg availability in paddy soil, and the accumulation of MeHg in paddy rice. Results suggested that biochar application could significantly increase the production of MeHg in paddy soil by 19.01%; biochar could also decrease the dissolved and available MeHg in paddy soil by 88.64% and 75.69%, respectively. More importantly, biochar application significantly inhibited the MeHg accumulation in paddy rice by 61.10%. These results highlight that biochar could decrease the availability of MeHg in paddy soil and thus inhibit MeHg accumulation in paddy rice, although it might facilitate the net production of MeHg in paddy soil. Additionally, results also indicated that the biochar feedstock and its elementary composition significantly impacted the net MeHg production in paddy soil. Generally, biochar with a low carbon content, high sulfur content, and low application rate might be beneficial for inhibiting Hg methylation in paddy soil, meaning that Hg methylation depends on biochar feedstock. These findings suggested that biochar has great potential to inhibit MeHg accumulation in paddy rice, and further research should focus on selecting biochar feedstock to control Hg methylation potential and determine its long-term effects.