Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2.

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes that link substrate release and opening of the cytoplasmic gate and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Neuroprotective macromolecular methylprednisolone prodrug nanomedicine prevents glucocorticoid-induced muscle atrophy and osteoporosis in a rat model of spinal cord injury.

To address the adverse side effects associated with systemic high-dose methylprednisolone (MP) therapy for acute spinal cord injury (SCI), we have developed a N-2-hydroxypropyl methacrylamide copolymer-based MP prodrug nanomedicine (Nano-MP). Intravenous Nano-MP selectively targeted to the inflamed SCI lesion and significantly improved neuroprotection and functional recovery after acute SCI. In the present study, we comprehensively assessed the potential adverse side effects associated with the treatment in the SCI rat models, including reduced body weight and food intake, impaired glucose metabolism, and reduced musculoskeletal mass and integrity. In contrast to free MP treatment, intravenous Nano-MP after acute SCI not only offered superior neuroprotection and functional recovery but also significantly mitigated or even eliminated the aforementioned adverse side effects. The superior safety features of Nano-MP observed in this study further confirmed the clinical translational potential of Nano-MP as a highly promising drug candidate for better clinical management of patients with acute SCI.

Faecal contamination in China: Trends, sources, and driving mechanisms.

Faecal contamination of surface waters is a global public health and economic burden. Here, we constructed a 30-year dataset to analyse the spatiotemporal trends and driving mechanisms of faecal coliforms (FCs) in China. We found that previous national policies to reduce water pollution have significantly improved the quality of surface water and, correspondingly, faecal contamination. However, the downward trend in FC levels has been more gradual than that for physico-chemical pollutants, and this trend may be exaggerated. Our results show that the driving mechanisms of faecal pollution were seasonal and complex. During the dry season, forests and grasslands were the source landscapes that exacerbated faecal pollution; during the wet season, urbanisation dominated, highlighting China's poorly designed drainage systems. Our projections revealed that faecal contamination will continue to worsen from 2022 to 2035, highlighting the need for pollution control. In the future, faecal indicators should be included in routine monitoring, evaluation, and assessment at the national level. Moreover, coordinated design of forest, grassland, and wetland landscapes is recommended for faecal pollution control at the regional level, whereas stormwater-related source control needs to be further strengthened at the urban level.

Sandwiched-structure fabric-based high-performance moisture-enabled electricity generators for the power supply of small electronics.

In response to the energy crisis caused by the exhaustion of fossil energy sources, as well as to combat global warming and achieve carbon neutrality, a sandwiched-structure fabric-based moisture-enabled electricity generator (SMEG) has been developed. Cotton fabric coated with MWCNT and PEDOT: PSS solution is used as the upper and bottom electrodes, while the acid-treated cotton fabric with coating PVA and HCl hydrogel electrolyte serves as the middle layer. A single SMEG can generate a maximum open-circuit voltage (Voc) of 0.44 V and a maximum short-circuit current (Isc) of 30 µA. When a drop of LiCl is dripped on one side of SMEGs, the maximum Voc and Isc increases to 0.57 V and 66 µA, respectively. The decline in output performance slows down when LiCl is applied. The Voc increases almost linearly in series and reaches 3.55 V when six SMEGs are connected, while the Isc increases linearly in parallel and reaches 204 µA when six SMEGs are connected. The maximum power density of a single SMEG yields 0.29 µW/cm2 with an external resistance of 1 kΩ. The series connection of six SMEGs successfully lit an LED and a calculator under ambient humidity conditions, demonstrating their potential application in small electronics.

Single nucleotide polymorphisms of GEMIN3 modify the risk of primary Sjögren's syndrome in female patients.

BACKGROUND: MicroRNA (miRNA)-processing machinery may modify the risk of primary Sjögren's syndrome (pSS) by altering miRNA expression profiles. Inflammatory cytokines and reactive oxygen species (ROS) are also involved in pSS; however, the role of altered miRNAs expression in its pathogenesis is still unclear. We aimed to evaluate the relationship between single-nucleotide polymorphisms (SNPs) in miRNA processing machinery genes, including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348), and the risk of pSS in female patients. The potential associations of cytokines and ROS with pSS-susceptible SNPs were also evaluated. METHODS: The SNPs confirmed by polymerase chain reaction ligase detection reaction were genotyped in 74 female patients with pSS and 77 controls. The relationship was analyzed by Student's t-test, Wilcoxon rank-sum test, chi-square test, Pearson's correlation test, and binary logistic regression analysis. RESULTS: For rs197412 of the GEMIN3 gene, the genotype TT carrier was associated with a 2.172-fold increased risk for pSS when compared with that of CT+CC carrier (odds ratio: 2.172, 95% CI, 1.133-4.166, p=0.019). Simultaneously, the pSS-susceptible TT carriers were associated with increased interferon-γ (IFN-γ) (P<0.001) and tumor necrosis factor-α (TNF-α) (P=0.003) levels when compared with that of CT+CC genotype carriers in female patients with pSS. The subsequent analysis also showed a weak positive correlation between IFN-γ and TNF-α levels (r=0.271, P=0.019). CONCLUSION: The predictors of GEMIN3 SNPs might modify pSS development in females by mediating the expression of miRNAs and therefore regulate the levels of IFN-γ and TNF-α.

Controlled Twill Surface Structure Endowing Nanofiber Composite Membrane Excellent Electromagnetic Interference Shielding.

Inspired by the Chinese Knotting weave structure, an electromagnetic interference (EMI) nanofiber composite membrane with a twill surface was prepared. Poly(vinyl alcohol-co-ethylene) (Pva-co-PE) nanofibers and twill nylon fabric were used as the matrix and filter templates, respectively. A Pva-co-PE-MXene/silver nanowire (Pva-co-PE-MXene/AgNW, PMxAg) membrane was successfully prepared using a template method. When the MXene/AgNW content was only 7.4 wt% (PM7.4Ag), the EMI shielding efficiency (SE) of the composite membrane with the oblique twill structure on the surface was 103.9 dB and the surface twill structure improved the EMI by 38.5%. This result was attributed to the pre-interference of the oblique twill structure in the direction of the incident EM wave, which enhanced the probability of the electromagnetic waves randomly colliding with the MXene nanosheets. Simultaneously, the internal reflection and ohmic and resonance losses were enhanced. The PM7.4Ag membrane with the twill structure exhibited both an outstanding tensile strength of 22.8 MPa and EMI SE/t of 3925.2 dB cm-1. Moreover, the PMxAg nanocomposite membranes demonstrated an excellent thermal management performance, hydrophobicity, non-flammability, and performance stability, which was demonstrated by an EMI SE of 97.3% in a high-temperature environment of 140 °C. The successful preparation of surface-twill composite membranes makes it difficult to achieve both a low filler content and a high EMI SE in electromagnetic shielding materials. This strategy provides a new approach for preparing thin membranes with excellent EMI properties.

Propofol Protects the Blood-Brain Barrier After Traumatic Brain Injury by Stabilizing the Extracellular Matrix via Prrx1: From Neuroglioma to Neurotrauma.

The purpose of this study is to explore the shared molecular pathogenesis of traumatic brain injury (TBI) and high-grade glioma and investigate the mechanism of propofol (PF) as a potential protective agent. By analyzing the Chinese glioma genome atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we compared the transcriptomic data of high-grade glioma and TBI patients to identify common pathological mechanisms. Through bioinformatics analysis, in vitro experiments and in vivo TBI model, we investigated the regulatory effect of PF on extracellular matrix (ECM)-related genes through Prrx1 under oxidative stress. The impact of PF on BBB integrity under oxidative stress was investigated using a dual-layer BBB model, and we explored the protective effect of PF on tight junction proteins and ECM-related genes in mice after TBI. The study found that high-grade glioma and TBI share ECM instability as an important molecular pathological mechanism. PF stabilizes the ECM and protects the BBB by directly binding to Prrx1 or indirectly regulating Prrx1 through miRNAs. In addition, PF reduces intracellular calcium ions and ROS levels under oxidative stress, thereby preserving BBB integrity. In a TBI mouse model, PF protected BBB integrity through up-regulated tight junction proteins and stabilized the expression of ECM-related genes. Our study reveals the shared molecular pathogenesis between TBI and glioblastoma and demonstrate the potential of PF as a protective agent of BBB. This provides new targets and approaches for the development of novel neurotrauma therapeutic drugs.

Healthy dietary patterns are associated with exposure to environmental chemicals in a pregnancy cohort.

Healthy dietary patterns, such as the alternate Mediterranean diet and alternate Healthy Eating Index, benefit cardiometabolic health. However, several food components of these dietary patterns are primary sources of environmental chemicals. Here, using data from a racially and ethnically diverse US cohort, we show that healthy dietary pattern scores were positively associated with plasma chemical exposure in pregnancy, particularly for the alternate Mediterranean diet and alternate Healthy Eating Index with polychlorinated biphenyls and per- and poly-fluoroalkyl substances. The associations appeared stronger among Asian and Pacific Islanders. These findings suggest that optimizing the benefits of a healthy diet requires concerted regulatory efforts aimed at lowering environmental chemical exposure.

Recent advancement of sonogenetics: A promising noninvasive cellular manipulation by ultrasound.

Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques. Sonogenetics, a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells, is gaining prominence along with optogenetics, electrogenetics, and magnetogenetics. Upon stimulation with ultrasound, these proteins trigger a cascade of cellular activities and functions. Unlike traditional ultrasound modalities, sonogenetics offers enhanced spatial selectivity, improving precision and safety in disease treatment. This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications, including neuromodulation, oncologic treatments, stem cell therapy, and beyond. Although current literature predominantly emphasizes ultrasonic neuromodulation, this review offers a comprehensive exploration of sonogenetics. We discuss ultrasound properties, the specific ultrasound-sensitive proteins employed in sonogenetics, and the technique's potential in managing conditions such as neurological disorders, cancer, and ophthalmic diseases, and in stem cell therapies. Our objective is to stimulate fresh perspectives for further research in this promising field.

Performance evaluation and clinical application of the UA-5600 automatic dry chemistry urine analyzer in renal diseases.

Background: Urine testing as a routine screening programme, abnormal test results can be suggestive to clinicians but can sometimes be overlooked, and the establishment of a diagnostic model can better assist clinicians in identifying potential problems. BLD (blood), LEU (leukocyte), PRO (protein) and GLU (glucose) are the four most important parameters in urine testing, and the accuracy of their results is a key concern for clinicians, so it is essential to verify the accuracy of their results. In this study, we evaluated the analytical and clinical performance of Mindray's automatic urine dry chemistry analyzer, the UA-5600 (Hereinafter referred to as the (UA-5600), and the test strips configured with the instrument, and developed a machine-learning (ML) model for kidney disease screening from the results of 11 parameters output from the UA-5600 with the aim of detecting abnormal urine test results. Methods: Urine samples from outpatients and inpatients at The First Affiliated Hospital of Sun Yat-sen University were collected from August to September 2022 to evaluate the performance of the Mindray UA-5600 dry chemistry analyzer and test strips. The evaluation of the UA-5600 and its test strips focused on the agreement of the urine BLD and LEU readings with the RBC (red blood cell) and WBC (white blood cell) counts obtained by the Mindray EH-2090 urine formed element analyzer. We also compared the PRO and GLU readings with the results of the Mindray BS-2800M biochemistry analyzer. Urine samples from outpatients and inpatients were retrospectively analysed and grouped according to LIS diagnosis. Additionally, eight ML models for kidney disease screening were developed using 11 parameters measured by the UA-5600. And the model was validated by the validation set. Results: The UA-5600 had an 89.55% concordance rate for BLD and a 91.04% concordance rate for LEU compared to the EH-2090 analyzer. When benchmarked against the BS-2800M, the concordance rates for PRO and GLU were 94.14% and 95.20%, respectively. A total of 1,691 samples were used for the construction of the ML models, of which 346 patients (135 males and 211 females, age range: 18 to 98 years) diagnosed with renal disease, and 1,345 patients (397 males and 948 females, age range: 18 to 92 years) with non-renal disease diagnosed with other conditions. Notably, the Naïve Bayes (NB) model, which was built from the UA-5600 parameters, demonstrated superior predictive capabilities for renal disease, with an area under the receiver operating characteristic curve of 0.9470, a sensitivity of 0.7767, and a specificity of 0.9457. Conclusions: The Mindray UA-5600 demonstrates robust detection abilities for both BLD and LEU, and its results for PRO and GLU align closely with those obtained from the chemistry analyzer. The NB model has a good screening ability and shows promise as an effective screening tool.

Gustative Roussy Immune Score is a Predictor for Major Pathological Response in Rectal Cancer: A Result from the Preoperative Intraarterial Chemoembolization Combined with Radiotherapy (PCAR) Study.

Despite the emergence of various treatment strategies for rectal cancer based on neoadjuvant chemoradiotherapy, there is currently a lack of reliable biomarkers to determine which patients will respond well to neoadjuvant chemoradiotherapy. Through collecting hematological and biochemical parameters data of patients prior to receiving neoadjuvant chemoradiotherapy, we evaluated the predictive value of systemic inflammatory indices for pathological response and prognosis in rectal cancer patients. We found that baseline GRIm-Score was an independent predictor for MPR in rectal cancer patients. However, no association was observed between several commonly systemic inflammation indices and long-term outcome.

Long-Term Outcomes of Sex Differences in Three-Vessel Coronary Disease with Different Treatment Strategies: A Large Cohort Study.

Aim: The information assessing sex differences in outcomes of patients with three-vessel coronary disease (TVD) after different treatment strategies is sparse. This study aimed to investigate long-term outcomes of TVD among women compared with men after medical therapy (MT) alone, percutaneous coronary intervention (PCI), or coronary artery bypass grafting surgery (CABG). Methods: Consecutive 8943 patients with TVD were enrolled. Associations between sex and all-cause death and major adverse cardiac and cerebrovascular events (MACCE) (all-cause death, myocardial infarction, or stroke) were assessed. Results: Of the 8943 patients, 1821 (20.4%) were women. During a median follow-up of 6.6 years, women had comparable incidences of all-cause death (16.6% vs. 14.9%, P = 0.079) and MACCE (27.2% vs. 26.1%, P = 0.320) to men. After multivariable analysis, women showed lower adjusted risks of all-cause death (HR: 0.777; P = 0.001) and MACCE (HR: 0.870; P = 0.016) than men in the entire cohort. Subgroup analysis revealed that the less all-cause death risk of women relative to men was significant in PCI (HR: 0.702; P = 0.009), and CABG groups (HR: 0.708; P = 0.047), but not in MT alone group. Lower MACCE risk for women vs. men was significant only in PCI group (HR: 0.821; P = 0.037). However, no significant interaction between sex and three strategies was observed for all-cause death (P for interaction = 0.312) or MACCE (P for interaction = 0.228). Conclusions: The cardiovascular prognosis of TVD female patients is better than that of men, which has no interaction with the treatment strategies received (MT alone, PCI, or CABG).

Piston Error Automatic Correction for Segmented Mirrors via Deep Reinforcement Learning.

The segmented mirror co-phase error identification technique based on supervised learning methods has the advantages of simple application conditions, no dependence on custom sensors, a fast calculation speed, and low computing power requirements compared with other methods. However, it is often difficult to obtain a high accuracy in practical application situations with this method because of the difference between the training model and the actual model. The reinforcement learning algorithm does not need to model the real system when operating the system. However, it still retains the advantages of supervised learning. Thus, in this paper, we placed a mask on the pupil plane of the segmented telescope optical system. Moreover, based on the wide spectrum, point spread function, and modulation transfer function of the optical system and deep reinforcement learning-without modeling the optical system-a large-range and high-precision piston error automatic co-phase method with multiple-submirror parallelization was proposed. Finally, we carried out relevant simulation experiments, and the results indicate that the method is effective.

A simple projection method to correlate the principal mechanical direction with the principal microstructural direction of human osteoporotic femoral heads.

The mechanics of the trabecular bone is related to its structure; this work aimed to propose a simple projection method to clarify the correlation between the principal mechanical direction (PMD) and the principal microstructural direction (PMSD) of trabecular bones from osteoporotic femoral heads. A total of 529 trabecular cubes were cropped from five osteoporotic femoral heads. The micro computed tomography (µCT) sequential images of each cube were first projected onto the three Cartesian coordinate planes to have three overlapped images, and the trabecular orientation distribution in the three images was analyzed. The PMSD corresponding to the greatest distribution frequency of the trabecular orientation in the three images was defined. Then, the voxel finite element (FE) models of the cubes were reconstructed and simulated to obtain their compliance matrices, and the matrices were subjected to transversal rotation to find their maximum elastic constants. The PMD corresponding to the maximum elastic constant was defined. Subsequently, the correlation of the defined PMSD and PMD was analyzed. The results showed that PMSD and PMD of the trabecular cubes did not show a significant difference at the xy- and yz-planes except that at the zx-plane. Despite this, the mean PMSD-PMD deviations at the three coordinate planes were close to 0°, and the PMSD-PMD fitting to the line PMSD = PMD demonstrated their high correlation. This study might be helpful to identify the loading direction of anisotropic trabecular bones in experiments by examining the PMSD and also to guide bone scaffold design for bone tissue repair.

Computational modeling of the physical features that influence breast cancer invasion into adipose tissue.

Breast cancer invasion into adipose tissue strongly influences disease progression and metastasis. The degree of cancer cell invasion into adipose tissue depends on both biochemical signaling and the mechanical properties of cancer cells, adipocytes, and other key components of adipose tissue. We model breast cancer invasion into adipose tissue using discrete element method simulations of active, cohesive spherical particles (cancer cells) invading into confluent packings of deformable polyhedra (adipocytes). We quantify the degree of invasion by calculating the interfacial area At between cancer cells and adipocytes. We determine the long-time value of At vs the activity and strength of the cohesion between cancer cells, as well as the mechanical properties of the adipocytes and extracellular matrix in which adipocytes are embedded. We show that the degree of invasion collapses onto a master curve as a function of the dimensionless energy scale Ec , which grows linearly with the cancer cell velocity persistence time and fluctuations, is inversely proportional to the system pressure, and is offset by the cancer cell cohesive energy. When E c > 1 , cancer cells will invade the adipose tissue, whereas for E c < 1 , cancer cells and adipocytes remain de-mixed. We also show that At decreases when the adipocytes are constrained by the ECM by an amount that depends on the spatial heterogeneity of the adipose tissue.

Recent Advances in Environment-Friendly Polyurethanes from Polyols Recovered from the Recycling and Renewable Resources: A Review.

Polyurethane (PU) is among the most universal polymers and has been extensively applied in many fields, such as construction, machinery, furniture, clothing, textile, packaging and biomedicine. Traditionally, as the main starting materials for PU, polyols deeply depend on petroleum stock. From the perspective of recycling and environmental friendliness, advanced PU synthesis, using diversified resources as feedstocks, aims to develop versatile products with excellent properties to achieve the transformation from a fossil fuel-driven energy economy to renewable and sustainable ones. This review focuses on the recent development in the synthesis and modification of PU by extracting value-added monomers for polyols from waste polymers and natural bio-based polymers, such as the recycled waste polymers: polyethylene terephthalate (PET), PU and polycarbonate (PC); the biomaterials: vegetable oil, lignin, cashew nut shell liquid and plant straw; and biomacromolecules: polysaccharides and protein. To design these advanced polyurethane formulations, it is essential to understand the structure-property relationships of PU from recycling polyols. In a word, this bottom-up path provides a material recycling approach to PU design for printing and packaging, as well as biomedical, building and wearable electronics applications.

Compact high-power 320-nm continuous-wave single-frequency laser based on power scaling of a diode-pumped Pr:LiYF4 ring laser at red.

Single-frequency (SF) lasers in the visible spectral region are usually obtained through an indirect method, i.e., frequency doubling of near-infrared SF lasers. In this work, we report on the direct generation of a high-power continuous-wave (CW) SF laser in red based on a diode-pumped Pr:LiYF4 (YLF) ring cavity technology. A maximum output power is scaled to 3.98 W at 640 nm with a linewidth of about 17.2 MHz and a power stability of 0.6%. Moreover, by inserting a LBO crystal into the ring cavity for intracavity frequency doubling of the 640 nm SF laser, we have also successfully demonstrated an ultraviolet (UV) SF laser at 320 nm, for the first time to the best of our knowledge, with a maximum power of 670 mW. This work provides a promising route for the development of simple, compact, and high-power SF lasers operating in visible and UV spectral regions.

Scalable Production of 2D Non-Layered Metal Oxides through Metal-Organic Gel Rapid Redox Transformation.

Two-dimensional (2D) nonlayered metal compounds with porous structure show broad application prospects in electrochemistry-related fields due to their abundant active sites, open ions/electrons diffusion channels, and faradaic reactions. However, scalable and universal synthesis of 2D porous compounds still remains challenging. Here, inspired by blowing gum, a metal-organic gel (MOG) rapid redox transformation (MRRT) strategy is proposed for the mass production of a wide variety of 2D porous metal oxides. Adequate crosslinking degree of MOG precursor and its rapid redox with NO3- are critical for generating gas pressure from interior to exterior, thus blowing the MOG into 2D carbon nanosheets, which further act as self-sacrifice template for formation of oxides with porous and ultrathin structure. The versatility of this strategy is demonstrated by the fabrication of 39 metal oxides, including 10 transition metal oxides, one II-main group oxide, two III-main group oxides, 22 perovskite oxides, four high-entropy oxides. As an illustrative verification, the 2D transition metal oxides exhibit excellent capacitive deionization (CDI) performance. Moreover, the assembled CDI cell could act as desalting battery to supply electrical energy during electrode regeneration. This MRRT strategy offers opportunities for achieving universal synthesis of 2D porous oxides with nonlayered structures and studying their electrochemistry-related applications.