Megahertz multi-parametric ophthalmic OCT system for whole eye imaging.

An ultrahigh-speed, wide-field OCT system for the imaging of anterior, posterior, and ocular biometers is crucial for obtaining comprehensive ocular parameters and quantifying ocular pathology size. Here, we demonstrate a multi-parametric ophthalmic OCT system with a speed of up to 1 MHz for wide-field imaging of the retina and 50 kHz for anterior chamber and ocular biometric measurement. A spectrum correction algorithm is proposed to ensure the accurate pairing of adjacent A-lines and elevate the A-scan speed from 500 kHz to 1 MHz for retinal imaging. A registration method employing position feedback signals was introduced, reducing pixel offsets between forward and reverse galvanometer scanning by 2.3 times. Experimental validation on glass sheets and the human eye confirms feasibility and efficacy. Meanwhile, we propose a revised formula to determine the "true" fundus size using all-axial length parameters from different fields of view. The efficient algorithms and compact design enhance system compatibility with clinical requirements, showing promise for widespread commercialization.

CI:Mor interactions in the lysogeny switches of Lactococcus lactis TP901-1 and Staphylococcus aureus φ13 bacteriophages.

Aim: To structurally characterize in detail the interactions between the phage repressor (CI) and the antirepressor (Mor) in the lysis-lysogeny switches of two Gram-positive bacteriophages, the lactococcal TP901-1 and staphylococcal φ13. Methods: We use crystallographic structure determination, computational structural modeling, and analysis, as well as biochemical methods, to elucidate similarities and differences in the CI:Mor interactions for the two genetic switches. Results: By comparing a newly determined and other available crystal structures for the N-terminal domain of CI (CI-NTD), we show that the CI interface involved in Mor binding undergoes structural changes upon binding in TP901-1. Most importantly, we show experimentally for the first time the direct interaction between CI and Mor for φ13, and model computationally the interaction interface. The computational modeling supports similar side chain rearrangements in TP901-1 and φ13. Conclusion: This study ascertains experimentally that, like in the TP901-1 lysogeny switch, staphylococcal φ13 CI and Mor interact with each other. The structural basis of the interaction of φ13 CI and Mor was computationally modeled and is similar to the interaction demonstrated experimentally between TP901-1 CI-NTD and Mor, likely involving similar rearrangement of residue side chains during the formation of the complex. The study identifies one CI residue, Glu69, which unusually interacts primarily through its aliphatic chain with an aromatic residue on Mor after changing its conformation compared to the un-complexed structure. This and other residues at the interface are suggested for investigation in future studies.

Advances in regenerated cellulosic aerogel from waste cotton textile for emerging multidimensional applications.

Rapid development of society and the improvement of people's living standards have stimulated people's keen interest in fashion clothing. This trend has led to the acceleration of new product innovation and the shortening of the lifespan for cotton fabrics, which has resulting in the accumulation of waste cotton textiles. Although cotton fibers can be degraded naturally, direct disposal not only causes a serious resource waste, but also brings serious environmental problems. Hence, it is significant to explore a cleaner and greener waste textile treatment method in the context of green and sustainable development. To realize the high-value utilization of cellulose II aerogel derived from waste cotton products, great efforts have been made and considerable progress has been achieved in the past few decades. However, few reviews systematically summarize the research progress and future challenges of preparing high-value-added regenerated cellulose aerogels via dissolving cotton and other cellulose wastes. Therefore, this article reviews the regenerated cellulose aerogels obtained through solvent methods, summarizes their structure, preparation strategies and application, aimed to promote the development of the waste textile industry and contributed to the realization of carbon neutrality.

Actively tunable and switchable terahertz metamaterials with multi-band perfect absorption and polarization conversion.

In this paper, we theoretically present and numerically demonstrate an actively tunable and switchable multi-functional metamaterial based on vanadium dioxide (VO2) and graphene in the terahertz region. When VO2 is in the metallic phase, the proposed metamaterial serves as a multi-band perfect absorber, which exhibits the characteristics of insensitive polarization and robust tolerance for variations of the incidence angle. When VO2 is in the insulator phase, the proposed metamaterial acts as a polarization converter, which can simultaneously achieve perfect linear-to-linear and linear-to-circular polarization conversions. The simulation results show the cross-polarization conversion rate can reach ∼100% at the frequency region from 6.09 to 6.43 THz as well as 8.15 THz. Moreover, the ellipticity of linear-to-circular polarization conversion reaches ±1 at frequencies of 5.75 and 8.34 THz, respectively, which means the linear polarization waves can be completely converted into circular polarization waves. The proposed metamaterial provides new insight for the design of optoelectronic devices with multi-functionality in the terahertz region.

Identification of a multidrug resistance genomic island harboring a nonfunctional optrA gene in Campylobacter coli of chicken origin.

Campylobacter spp., such as Campylobacter jejuni and Campylobacter coli, are important zoonotic Gram-negative pathogens that cause acute intestinal diseases in humans. In this study, a retrospective analysis was conducted on previously collected Campylobacter isolates from antimicrobial resistance surveillance. A total of 29 optrA-positive C. coli strains were identified and subjected to second-generation sequencing. Multilocus sequence typing and single nucleotide polymorphism analyses demonstrated that the 29 optrA-positive isolates were genetically homogeneous. Notably, among the 29 isolated strains, the ΔoptrA variants exhibit a nonsense mutation at position 979 where the base C is substituted by T, leading to the formation of a premature termination codon. The alignment of sequences and genetic environmental characteristics suggested that ΔoptrA located on a chromosomally carried multidrug-resistant genomic island. There are other resistant genes on the multidrug resistance genomic island, such as aph(2'')-If, aph(3')-III, aadE, tet(O), tet(L), cat, erm(A), optrA and blaOXA-61. As a result, the 29 ΔoptrA-positive strains displayed susceptibility to both florfenicol and linezolid. The ΔoptrA gene is linked to the erm(A) gene, resulting in the formation of translocatable unit (TU) that are encompassed by two copies of IS1216 mobile elements. Multiple occurrences of similar TUs have been documented in numerous C. coli and provided evidence for the significance of TUs in facilitating the transfer of drug resistance genes in C. coli.

A triple-crosslinking strategy for high-performance regenerated cellulose fibers derived from waste cotton textiles.

Regenerated cellulose fibers has attracted increasing attention for high-grade textile raw materials and industrial textiles, but the low mechanical property caused by differences in regenerated raw materials and production levels limits its commercial application in the product diversity. Herein, we proposed a novel triple-crosslinking strategy by coupling with hydrogen bonds, chemical crosslinking, and internal mineralization from multiple pulsed vapor phase infiltration (MPI) to improve the mechanical performance of regenerated cellulose fibers. A binary solvent composed of ionic liquid (IL) and dimethyl sulfoxide (DMSO) is used to dissolve waste cotton textile and then wet spinning. Dual-crosslinking is firstly achieved by coupling glutaraldehyde (GA) and cellulose reaction. Subsequently, a metal oxide is intentionally infiltrated into inner cellulosic through MPI technology to form a third form of crosslinking, accompanied by the ultra-thin metal oxide nano-layer onto the surface of regenerated cellulose fibers. Results showed that the triple-crosslinking strategy has increased the tensile stress of the fiber by 43.57 % to 287.03 MPa. In all, triple-crosslinking strategy provides a theoretical basis and technical approach for the reinforcement of weak fibers in waste cotton recycling, which is expected to accelerate the development of the waste textile recycling industry and promote of the added-value of regenerated products.

Isoform-selective TGF-ß3 inhibition for systemic sclerosis.

BACKGROUND: Transforming growth factor ß (TGF-ß) is implicated as a key mediator of pathological fibrosis, but its pleiotropic activity in a range of homeostatic functions presents challenges to its safe and effective therapeutic targeting. There are three isoforms of TGF-ß, TGF-ß1, TGF-ß2, and TGF-ß3, which bind to a common receptor complex composed of TGF-ßR1 and TGF-ßR2 to induce similar intracellular signals in vitro. We have recently shown that the cellular expression patterns and activation thresholds of TGF-ß2 and TGF-ß3 are distinct from those of TGF-ß1 and that selective short-term TGF-ß2 and TGF-ß3 inhibition can attenuate fibrosis in vivo without promoting excessive inflammation. Isoform-selective inhibition of TGF-ß may therefore provide a therapeutic opportunity for patients with chronic fibrotic disorders. METHODS: Transcriptomic profiling of skin biopsies from patients with systemic sclerosis (SSc) from multiple clinical trials was performed to evaluate the role of TGF-ß3 in this disease. Antibody humanization, biochemical characterization, crystallization, and pre-clinical experiments were performed to further characterize an anti-TGF-ß3 antibody. FINDINGS: In the skin of patients with SSc, TGF-ß3 expression is uniquely correlated with biomarkers of TGF-ß signaling and disease severity. Crystallographic studies establish a structural basis for selective TGF-ß3 inhibition with a potent and selective monoclonal antibody that attenuates fibrosis effectively in vivo at clinically translatable exposures. Toxicology studies suggest that, as opposed to pan-TGF-ß inhibitors, this anti-TGF-ß3 antibody has a favorable safety profile for chronic administration. CONCLUSION: We establish a rationale for targeting TGF-ß3 in SSc with a favorable therapeutic index. FUNDING: This study was funded by Genentech, Inc.

Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. METHODS: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. RESULTS: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). CONCLUSIONS: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.

Development of composite amine functionalized polyester microspheres for efficient CO2 capture.

In order to reduce the impact of greenhouse gases on the environment, the development of various new CO2 capture materials has become a hot spot. In this work, a novel composite amine solid adsorbent was prepared by simultaneously using tetraethylenepentamine (TEPA) and 2-[2-(dimethylamino) ethoxy] ethanol (DMAEE) for amine functionalization on the polyester microsphere carrier. The introduction of methyl methacrylate (MMA) with high glass transition temperature into the polyester carrier makes the carrier microspheres have high hardness. At the same time, the carrier also contains active epoxy groups and hydrophobic glycidyl methacrylate (GMA, which can undergo ring-opening reaction with composite amines to achieve high-load and low-energy chemical grafting of amines on the carrier. The composite aminated polyester microspheres were used as an efficient adsorbent for CO2 in simulated flue gas. The results show that the synergistic effect of TEPA-DMAEE composite amine system in the adsorbent is beneficial to the improvement of CO2 capture capacity. When the total amine content in the impregnating solution is 45 wt% and the composite amine ratio is TEPA: DMAEE = 6: 4, the CO2 adsorption capacity can reach the optimal value of 2.45 mmol/ g at 70 °C. In addition, the composite amine microsphere adsorbent has cyclic regeneration performance. Importantly, through kinetic fitting, the Avrami kinetic model fits the CO2 adsorption better than the quasi-first-order and quasi-second-order kinetic models, which proves that physical adsorption and chemical adsorption coexist in the adsorption process. This simple, long-term stable and excellent selective separation performance makes amine-functionalized adsorbents have potential application prospects in CO2 capture.

A first-in-human, open-label, dose-escalation and dose-expansion phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of QL1604, a humanized anti-PD-1 mAb, in patients with advanced or metastatic solid tumors.

Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed. Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion. Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761.

Investigation of the Nonionic Acidizing Retarder AAO for Reservoir Stimulation.

In the process of matrix acidizing, reducing the reaction rate between hydrochloric acid and carbonate rock to increase oil and gas production has become one of the biggest challenges in reservoir stimulation. An adsorption film formed on rocks can effectively postpone the contact between the hydrogen ion and rock, which is of great significance in decreasing the rate of an acid-rock reaction. In this study, nonionic acidizing retarder AAO was synthesized by acrylamide, allyl poly(ethylene glycol), and octadecyl methacrylate. The structure of AAO was characterized by Fourier transform infrared (FT-IR) spectrometry and 1H nuclear magnetic resonance (1H NMR). The reaction of AAO retard acid and 20% hydrochloric acid with CaCO3 was studied at 50 °C, and the amount of CO2 generated at different times was recorded. The etching time of 0.8% AAO retard acid to CaCO3 could be up to 120 min, whereas 20% hydrochloric acid (without AAO) ended at 45 min, which showed that AAO had the potential to defer the acid-rock reaction. The adsorption behavior of AAO on CaCO3 matched the pseudo-second-order kinetic model well. Meanwhile, the addition of urea greatly reduced the adsorption amount of AAO on CaCO3, which showed that the hydrogen bond was the driving force for the adsorption process. Additionally, the results of X-ray photoelectron spectroscopy (XPS) showed that the N element from acrylamide appeared on the surface of CaCO3 after adsorption. Scanning electron microscopy (SEM) demonstrated that a smooth and dense thin film existed on the surface of CaCO3 treated with AAO retard acid. The change in the vibration peak of C=O from 1720 to 1650 cm-1 indicated that the ester groups in AAO had been hydrolyzed, which was beneficial to film desorption and the reduction of reservoir damage. Therefore, this paper could help with research on carbonate acidizing for reservoir stimulation.

Sintilimab plus anlotinib as second- or third-line therapy in metastatic non-small cell lung cancer with uncommon epidermal growth factor receptor mutations: A prospective, single-arm, phase II trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR-mutated NSCLC. This study aimed to investigate the efficacy and safety of PD-1 blockade with sintilimab plus anti-angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations. METHODS: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum-based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR). RESULTS: At data cutoff (September 27, 2022), median follow-up was 22.3 months (range, 1.2-37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression-free survival (PFS) was 7.0 (5.4-8.6) months, and median overall survival (OS) was 20.0 (15.6-24.4) months. The 12-month PFS rate (95% CI) was 22.2% (7.4-42.0), and the 12-month OS rate was 66.7% (42.5-82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment-related adverse events (TRAEs); hand-foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed. CONCLUSIONS: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard-of-care treatments. (ClinicalTrials.gov identifier: NCT04790409).

Human-Guided Reinforcement Learning With Sim-to-Real Transfer for Autonomous Navigation.

Reinforcement learning (RL) is a promising approach in unmanned ground vehicles (UGVs) applications, but limited computing resource makes it challenging to deploy a well-behaved RL strategy with sophisticated neural networks. Meanwhile, the training of RL on navigation tasks is difficult, which requires a carefully-designed reward function and a large number of interactions, yet RL navigation can still fail due to many corner cases. This shows the limited intelligence of current RL methods, thereby prompting us to rethink combining RL with human intelligence. In this paper, a human-guided RL framework is proposed to improve RL performance both during learning in the simulator and deployment in the real world. The framework allows humans to intervene in RL's control progress and provide demonstrations as needed, thereby improving RL's capabilities. An innovative human-guided RL algorithm is proposed that utilizes a series of mechanisms to improve the effectiveness of human guidance, including human-guided learning objective, prioritized human experience replay, and human intervention-based reward shaping. Our RL method is trained in simulation and then transferred to the real world, and we develop a denoised representation for domain adaptation to mitigate the simulation-to-real gap. Our method is validated through simulations and real-world experiments to navigate UGVs in diverse and dynamic environments based only on tiny neural networks and image inputs. Our method performs better in goal-reaching and safety than existing learning- and model-based navigation approaches and is robust to changes in input features and ego kinetics. Furthermore, our method allows small-scale human demonstrations to be used to improve the trained RL agent and learn expected behaviors online.

Safety and efficacy of atezolizumab in Chinese patients with previously treated locally advanced or metastatic non-small cell lung cancer: An open-label, single-arm, multicenter study.

OBJECTIVES: To evaluate the long-term safety and efficacy of atezolizumab monotherapy in Chinese patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this open-label, single-arm, multicenter study, patients received atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle. The primary endpoint was incidence of atezolizumab-related serious adverse events (SAEs). Secondary endpoints included other safety and efficacy measures. Patients with available tumor tissue and blood samples underwent biomarker analyses. Patients with available tumor biopsies underwent exome sequencing. RESULTS: The safety and evaluable populations included 101 and 97 patients, respectively. Exome sequencing data were available for 31 patients. Median follow-up time was 27.43 months. Atezolizumab-related SAEs and immune-related adverse events occurred in 25.7% and 47.5% of the safety population, respectively, and in the following subgroups: central nervous system metastases (n = 14), 35.7% and 35.7%; squamous NSCLC (n = 39), 33.3% and 53.8%. The 24-month overall survival rate was 37.4%. Median overall survival and progression-free survival by RECIST v1.1 were 15.31 and 2.86 months, respectively; objective response rate was 16.5% in the evaluable population. PRRC2C (odds ratio: 12.780, P = 0.014) and ZMYND8 (odds ratio: 19.963, P = 0.016) gene mutations were significantly enriched in atezolizumab responders vs non-responders. Patients with CD8+ TILs > 10% vs ≤ 10% were significantly more likely to be atezolizumab responders. CONCLUSION: No new safety concerns were raised, and clinically meaningful benefits of atezolizumab monotherapy were shown. The results of the biomarker analyses may guide future therapeutic strategies.

Interaction between hydrophobic chitosan derivative and asphaltene in heavy oil to reduce viscosity of heavy oil.

The high viscosity of heavy oil made it difficult to exploit and transport heavy oil in pipeline. In this research, N-[(2-hydroxy-3-trimethylammonium) propyl] O-stearoyl chitosan tetraphenylboride (sc-CTS-st) was synthesized from chitosan, 2, 3-epoxy-propyl trimethyl ammonium chloride, sodium tetraphenylboron and stearyl chloride. sc-CTS-st contains long chain saturated aliphatic hydrocarbon, hydroxyl group and benzene ring, which could be dissolved in heavy oil fully and interacted with asphaltene. At 50 °C, the viscosity of heavy oil could be reduced to 13,800 mPa·s at most, with a viscosity reduction rate of 57.54 %. SEM and XRD showed that sc-CTS-st could affect the supramolecular accumulation structure of asphaltenes. Using FT-IR, sc-CTS-st could interact with asphaltene in the form of hydrogen bonds using the polar parts of the molecule, thereby weakening the self-association between asphaltene molecules. Molecular simulation was used to demonstrate the interaction mechanism between chitosan derivatives and asphaltenes. sc-CTS-st interacted with asphaltene through chemical bonding and influenced the self-association of asphaltene molecules. In addition, the non-polar portion of sc-CTS-st molecules could form a coating on the outside of the asphaltenes stacking structure, thus shielding or reducing the polarity of the stacking structure surface.

Serum cytokine analysis in a cohort of advanced non-small cell lung cancer treated with PD-1 inhibitors reveals predictive markers of CXCL12.

Background: The circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes. Methods: Serum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed. Results: Higher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%, p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months; p<0.001) and overall survival (OS) (12.20 vs. 44.84 months; p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%, p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months, p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months, p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%, p<0.001) and DCB (27.3% vs. 73.7%, p<0.001) and the worst mPFS (2.44 vs. 25.35 months, p<0.001) and mOS (11.97 vs. 44.84 months, p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively. Conclusion: Our findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.

The relationship between perfluoroalkyl substances and hypertension: A systematic review and meta-analysis.

Hypertension is an important risk factor for cardiovascular diseases (CVDs) and a leading cause of premature death. Epidemiological studies have found that perfluoroalkyl substances (PFASs) are associated with hypertension. However, the correlation between PFASs and hypertension has not been systematically reported. Based on evidence from population epidemiological surveys, we conducted a meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess the correlation between PFASs exposure and hypertension. In this study, three databases of PubMed, Web of science, Embase were searched and 13 literatures with 81,096 participants were included. Literature heterogeneity was evaluated by I2 statistic, and the random effect model (I2 > 50%) and fixed effect model (I2 < 50%) were used to combine the studies in meta-analysis. The results showed that PFNA (OR = 1.11, 95% CI: 1.04-1.19), PFOA (OR = 1.12, 95% CI: 1.02-1.23), PFOS (OR = 1.19, 95% CI: 1.06-1.34) and PFHxS (OR = 1.03, 95% CI: 1.00-1.06) were significantly associated with hypertension, while other types of PFASs (∑PFAS, PFDA, PFUnDA) had no statistical significance. In addition, PFNA (OR = 1.12, 95% CI: 1.03-1.22), PFOA (OR = 1.12, 95% CI: 1.01-1.25) and PFOS (OR = 1.12, 95% CI: 1.00-1.25) exposure were positively correlated with the risk of hypertension in men, but not in women. Our study reveals that PFASs are risk factors for hypertension, with notable gender differences observed in PFASs-exposed populations. Specifically, males exposed to PFNA, PFOA, and PFOS exhibit a higher risk of hypertension compared to females. However, further investigations are needed to delve into the precise mechanism through which PFASs contribute to the development of hypertension.

Differentiable Integrated Motion Prediction and Planning With Learnable Cost Function for Autonomous Driving.

Predicting the future states of surrounding traffic participants and planning a safe, smooth, and socially compliant trajectory accordingly are crucial for autonomous vehicles (AVs). There are two major issues with the current autonomous driving system: the prediction module is often separated from the planning module, and the cost function for planning is hard to specify and tune. To tackle these issues, we propose a differentiable integrated prediction and planning (DIPP) framework that can also learn the cost function from data. Specifically, our framework uses a differentiable nonlinear optimizer as the motion planner, which takes as input the predicted trajectories of surrounding agents given by the neural network and optimizes the trajectory for the AV, enabling all operations to be differentiable, including the cost function weights. The proposed framework is trained on a large-scale real-world driving dataset to imitate human driving trajectories in the entire driving scene and validated in both open-loop and closed-loop manners. The open-loop testing results reveal that the proposed method outperforms the baseline methods across a variety of metrics and delivers planning-centric prediction results, allowing the planning module to output trajectories close to those of human drivers. In closed-loop testing, the proposed method outperforms various baseline methods, showing the ability to handle complex urban driving scenarios and robustness against the distributional shift. Importantly, we find that joint training of planning and prediction modules achieves better performance than planning with a separate trained prediction module in both open-loop and closed-loop tests. Moreover, the ablation study indicates that the learnable components in the framework are essential to ensure planning stability and performance. Code and Supplementary Videos are available at https://mczhi.github.io/DIPP/.

LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung.

Idiopathic pulmonary fibrosis is a progressive fibrotic disease characterized by excessive deposition of (myo)fibroblast produced collagen fibrils in alveolar areas of the lung. Lysyl oxidases (LOXs) have been proposed to be the central enzymes that catalyze the cross-linking of collagen fibers. Here, we report that, while its expression is increased in fibrotic lungs, genetic ablation of LOXL2 only leads to a modest reduction of pathological collagen cross-linking but not fibrosis in the lung. On the other hand, loss of another LOX family member, LOXL4, markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Furthermore, knockout of both Loxl2 and Loxl4 does not offer any additive antifibrotic effects when compared to Loxl4 deletion only, as LOXL4 deficiency decreases the expression of other LOX family members including Loxl2. On the basis of these results, we propose that LOXL4 is the main LOX activity underlying pathological collagen cross-linking and lung fibrosis.

AA16 Oxidoreductases Boost Cellulose-Active AA9 Lytic Polysaccharide Monooxygenases from Myceliophthora thermophila.

Copper-dependent lytic polysaccharide monooxygenases (LPMOs) classified in Auxiliary Activity (AA) families are considered indispensable as synergistic partners for cellulolytic enzymes to saccharify recalcitrant lignocellulosic plant biomass. In this study, we characterized two fungal oxidoreductases from the new AA16 family. We found that MtAA16A from Myceliophthora thermophila and AnAA16A from Aspergillus nidulans did not catalyze the oxidative cleavage of oligo- and polysaccharides. Indeed, the MtAA16A crystal structure showed a fairly LPMO-typical histidine brace active site, but the cellulose-acting LPMO-typical flat aromatic surface parallel to the histidine brace region was lacking. Further, we showed that both AA16 proteins are able to oxidize low-molecular-weight reductants to produce H2O2. The oxidase activity of the AA16s substantially boosted cellulose degradation by four AA9 LPMOs from M. thermophila (MtLPMO9s) but not by three AA9 LPMOs from Neurospora crassa (NcLPMO9s). The interplay with MtLPMO9s is explained by the H2O2-producing capability of the AA16s, which, in the presence of cellulose, allows the MtLPMO9s to optimally drive their peroxygenase activity. Replacement of MtAA16A by glucose oxidase (AnGOX) with the same H2O2-producing activity could only achieve less than 50% of the boosting effect achieved by MtAA16A, and earlier MtLPMO9B inactivation (6 h) was observed. To explain these results, we hypothesized that the delivery of AA16-produced H2O2 to the MtLPMO9s is facilitated by protein-protein interaction. Our findings provide new insights into the functions of copper-dependent enzymes and contribute to a further understanding of the interplay of oxidative enzymes within fungal systems to degrade lignocellulose.