Rheological Properties of Silica-Fume-Modified Bioasphalt and Road Performance of Mixtures.

The objective of this research is to enhance the high-temperature antirutting and antiaging characteristics of bioasphalt. In this study, silica fume (SF) was selected to modify bioasphalt. The dosage of bio-oil in bioasphalt was 5%, and the dosage of SF was 2%, 4%, 6%, 8%, and 10% of bioasphalt. The high- and low-temperature characteristics, aging resistance, and temperature sensitivity of Bio + SF were evaluated by temperature sweep (TS), the multiple stress creep recovery (MSCR) test, the bending beam rheology (BBR) test, and the viscosity test. Meanwhile, the road behavior of the Bio + SF mixture was evaluated using the rutting test, low-temperature bending beam test, freeze-thaw splitting test, and fatigue test. The experimental results showed that the dosage of SF could enhance the high-temperature rutting resistance, aging resistance, and temperature stability of bioasphalt. The higher the dosage of SF, the more significant the enhancement effect. However, incorporating SF weakened bioasphalt's low-temperature cracking resistance properties. When the SF dosage was less than 8%, the low-temperature cracking resistance of Bio + SF was still superior to that of matrix asphalt. Compared with matrix asphalt mixtures, the dynamic stability, destructive strain, freeze-thaw splitting strength ratio, and fatigue life of 5%Bio + 8%SF mixtures increased by 38.4%, 49.1%, 5.9%, and 68.9%, respectively. This study demonstrates that the development of SF-modified bioasphalt could meet the technical requirements of highway engineering. Using SF and bio-oil could decrease the consumption of natural resources and positively reduce environmental pollution.

Chemical Space Profiling of SARS-CoV-2 PLpro Using DNA-Encoded Focused Libraries.

DNA-encoded library (DEL) technology is gaining attention for its rapid construction and deconvolution capabilities. Our study explored a novel strategy using rational DELs tailored for the SARS-CoV-2 papain-like protease, which revealed new fragments. Structural changes post-DEL screening mimic traditional medicinal chemistry lead optimization. We unveiled unique aromatic structures offering an alternative optimization path. Notably, we identified superior binding fragments targeting the BL2 groove. Derivative 16 emerged as the most promising by exhibiting IC50 values of 0.25 µM. Derivative 6, which features an aromatic fragment capped with a naphthalene moiety, showed IC50 values of 2.91 µM. Molecular modeling revealed hydrogen bond interactions with Lys157 residue and potential covalent interactions with nearby amino acid residues. This research underscored DEL's potential for fragment-based drug discovery against SARS-CoV-2 protease.

Therapeutic roles of platelet-rich plasma to restore female reproductive and endocrine dysfunction.

Millions of women worldwide are infertile due to gynecological disorders, including premature ovarian insufficiency, polycystic ovary syndrome, Asherman syndrome, endometrial atrophy, and fallopian tube obstruction. These conditions frequently lead to infertility and have a substantial impact on the quality of life of the affected couples, primarily because of their psychological implications and high financial costs. Recently, using platelets to stimulate cell proliferation and tissue differentiation has emerged as a promising approach in regenerative medicine. Platelet-rich plasma (PRP) shows considerable potential for promoting endometrial hypertrophy and follicle development, making it a promising therapeutic option for tissue repair or replacement. This review provides an overview of the recent advancements and underlying mechanisms of PRP therapy for various female reproductive diseases and presents new therapeutic options for addressing female infertility.

A Vancomycin-Templated DNA-Encoded Library for Combating Drug-Resistant Bacteria.

It is an urgent need to tackle the global crisis of multidrug-resistant bacterial infections. We report here an innovative strategy for large-scale screening of new antibacterial agents using a whole bacteria-based DNA-encoded library (DEL) of vancomycin derivatives via peripheral modifications. A bacterial binding affinity assay was established to select the modification fragments in high-affinity compounds. The optimal resynthesized derivatives demonstrated excellently enhanced activity against various resistant bacterial strains and provided useful structures for vancomycin derivatization. This work presents the new concept in a natural product-templated DEL and in antibiotic discovery through bacterial affinity screening, which promotes the fight against drug-resistant bacteria.

New Perspectives on the Role and Therapeutic Potential of Melatonin in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. It is essential to develop novel interventions to prevent/delay CVDs by targeting their fundamental cellular and molecular processes. Melatonin is a small indole molecule acting both as a hormone of the pineal gland and as a local regulator molecule in various tissues. It has multiple features that may contribute to its cardiovascular protection. Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiological barriers. Additionally, this indoleamine also serves as a safe exogenous therapeutic agent. Increasing evidence has demonstrated the beneficial effects of melatonin in preventing and improving cardiovascular risk factors. Exogenous administration of melatonin, as a result of its antioxidant and anti-inflammatory properties, has been reported to decrease blood pressure, protect against atherosclerosis, attenuate molecular and cellular damage resulting from cardiac ischemia/reperfusion, and improve the prognosis of myocardial infarction and heart failure. This review aims to summarize the beneficial effects of melatonin against these conditions, the possible protective mechanisms of melatonin, and its potential clinical applicability in CVDs.

Mechanisms of anaerobic treatment of sulfate-containing organic wastewater mediated by Fe0 under different initial pH values.

The anaerobic treatment of sulfide-containing organic wastewater (SCOW) is significantly affected by pH, causing dramatic decrease of treatment efficiency when pH deviates from its appropriate range. Fe0 has proved as an effective strategy on mitigating the impact of pH. However, systematic analysis of the influence mechanism is still lacking. To fill this gap, the impact of different initial pH values on anaerobic treatment efficiency of SCOW with Fe0 addition, the change of fermentation type and methanogens, and intra-extracellular electron transfer were explored in this study. The results showed that Fe0 addition enhanced the efficacy of anaerobic treatment of SCOW at adjusted initial pH values, especially at pH 6. Mechanism analysis showed that respiratory chain-related enzymes and electron shuttle secretion and resistance reduction were stimulated by soluble iron ions generated by Fe0 at pH 6, which accelerated intra-extracellular electron transfer of microorganisms, and ultimately alleviated the impact of acidic pH on the system. While at pH 8, Fe0 addition increased the acetogenic bacteria abundance, as well as optimized the fermentation type and improved the F420 coenzyme activity, resulting in the enhancement of treatment efficiency in the anaerobic system and remission of the effect of alkaline pH on the system. At the neutral pH, Fe0 addition had both advantages as stimulating the secretion of respiratory chain and electron transfer-related enzymes at pH 6 and optimizing the fermentation type pH 8, and thus enhanced the treatment efficacy. This study provides important insights and scientific basis for the application of new SCOW treatment technologies.

Downscaling of environmental indicators: A review.

Environmental indicators at different scales are important for environmental management, daily life, and scientific research. Because of the lack of statistics below a national scale for many environmental indicators, scholars have developed various downscaling methods to obtain finer-scale and diverse forms of data for different environmental indicators. However, the existing downscaling methods for environmental indicators are diverse and fragmented. Here, we reviewed the downscaling methods by reclassifying the environmental indicators from a life cycle perspective into five categories: natural resources use and related attributes; material and energy consumption; environmental discharge; climate change; and environmental footprints. We first provide a general introduction to downscaling theory in the environmental field, including definitions, techniques, and evolution. We then elaborate on downscaling methods and make an inventory of the five categories of environmental indicators. We summarize the downscaling methods commonly applied to specific indicators, scale transformation, the strengths and limitations of corresponding methods, and provide specific examples. Next, we discuss ways to select or construct downscaling methods based on four principles: objective orientation, data accessibility, model feasibility, and model adjustment. Finally, we explore the future direction of downscaling and provide insights for improving downscaling for environmental indicators. In this review, we generalize and clarify the downscaling techniques for environmental indicators, which will help facilitate the appropriate selection of downscaling methods by researchers.

Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach.

The DNA-encoded library (DEL) is a powerful hit generation tool for chemical biology and drug discovery; however, the optimization of DEL hits remained a daunting challenge for the medicinal chemistry community. In this study, hit compounds targeting the WIN binding domain of WDR5 were discovered by the initial three-cycle linear DEL selection, and their potency was further enhanced by a cascade DEL selection from the focused DEL designed based on the original first run DEL hits. As expected, these new compounds from the second run of focused DEL were more potent WDR5 inhibitors in the protein binding assay confirmed by the off-DNA synthesis. Interestingly, selected inhibitors exhibited good antiproliferative activity in two human acute leukemia cell lines. Taken together, this new cascade DEL selection strategy may have tremendous potential for finding high-affinity leads against WDR5 and provide opportunities to explore and optimize inhibitors for other targets.

Sulfhydryl-Functionalized Amino Group Polymer Microcomposites toward Efficient Adsorption of Aqueous Cr(VI), As(III), Cd(II), and Pb(II).

The development of efficient adsorbents for heavy metal pollution, especially five toxic heavy metals, has attracted great research interest. Polymer-based adsorbents have aroused research value for their abundant functional groups and high porosity to the ability to capture metal ions. We designed a sulfhydryl-functionalized polymer microcomposite to take up Cr(VI), As(III), Cd(II), and Pb(II). The adsorption capacity achieved was 64.2 mg g-1 for Cr(VI), 44.9 mg g-1 for As(III), 35.5 mg g-1 for Cd(II), and 18.2 mg g-1 for Pb(II). Langmuir and Sips isotherm model is dominant for As(III), Cd(II), and Pb(II) adsorption. Pseudo-second-order kinetic models can better describe the adsorption behavior of Cr(VI), implying that chemisorption is accompanied by Cr(VI) adsorption. Cr(VI) simultaneous reduction to Cr(III) through the benzenoid amine oxidate pathway was the dominant mechanism, precipitation for Cd(II) adsorption was convinced, and chelation between As(III)/Pb(II) and─SH group and complexation between Pb(II) and C═O or benzene hydroxyl were a plausible mechanism for As(III) and Pb(II) adsorption.

Prefrontal cortex activity of active motion, cyclic electrical muscle stimulation, assisted motion, and imagery of wrist extension in stroke using fNIRS.

OBJECTIVES: This study aimed to determine whether the prefrontal cortex (PFC) was activated during four training approaches for wrist extension in patients with stroke, including active motion, cyclic electrical muscle stimulation (EMS), assisted motion, and motor imagery (MI). MATERIALS AND METHODS: We conducted a cross-sectional study involving 16 patients with stroke, and adopted functional near-infrared spectroscopy (fNIRS) to observe PFC activity during four treatment paradigms. The beta value of 53 channels in fNIRS under each paradigm, compared to the baseline, was evaluated using single sample t-test. The one-way analysis of variance with post hoc analysis was employed to compare the difference of significantly activated channels among four treatment paradigms. RESULTS: This study revealed that the active motion (t values ranging from 2.399 to 4.368, p values <0.05), as well as MI of wrist extension (t values ranging from 2.161 to 4.378, p values <0.05), significantly increased HBO concentration across the entire PFC. The cyclic EMS enhanced the activation of Broca's area and frontal pole (FP) (t values ranging from -2.540 to 2.303, p values <0.05). The assisted motion induced significant activation in Broca's area, dorsolateral prefrontal cortex, and FP (t values ranging from -2.226 to 3.056, p values <0.05). The difference in ΔHBO among the four tasks was seen in Broca's area, FP, and frontal eye field. CONCLUSIONS: Active wrist extension and MI activate most PFC areas, whereas assisted motion and single-use of cyclic EMS have limited effectiveness for PFC activation in stroke patients.

ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries.

DNA-encoded chemical library (DEL) has been extensively used for lead compound discovery for decades in academia and industry. Incorporating an electrophile warhead into DNA-encoded compounds recently permitted the discovery of covalent ligands that selectively react with a particular cysteine residue. However, noncysteine residues remain underexplored as modification sites of covalent DELs. Herein, we report the design and utility of tyrosine-targeting DELs of 67 million compounds. Proteome-wide reactivity analysis of tyrosine-reactive sulfonyl fluoride (SF) covalent probes suggested three enzymes (phosphoglycerate mutase 1, glutathione s-transferase 1, and dipeptidyl peptidase 3) as models of tyrosine-targetable proteins. Enrichment with SF-functionalized DELs led to the identification of a series of tyrosine-targeting covalent inhibitors of the model enzymes. In-depth mechanistic investigation revealed their novel modes of action and reactive ligand-accessible hotspots of the enzymes. Our strategy of combining activity-based proteome profiling and covalent DEL enrichment (ABPP-CoDEL), which generated selective covalent binders against a variety of target proteins, illustrates the potential use of this methodology in further covalent drug discovery.

Optimization Design and Mechanical Performances of Plant-Mix Hot Recycled Asphalt Using Response Surface Methodology.

This study aimed to explore the influence of material design parameters on the physical and mechanical properties of recycled asphalt. A Box-Behnken design was employed to determine the optimal preparation scheme for 17 groups of recycled asphalt. The effects of styreneic methyl copolymer (SMC) regenerant content, styrene-butadiene-styrene (SBS)-modified asphalt content, and shear temperature on the mechanical properties of recycled asphalt were analyzed using conventional and high/low-temperature rheological tests. The optimal processing parameters were determined by a response surface model based on multiple response indexes. The results revealed that the SBS-modified asphalt content had the most significant effect on the penetration of recycled asphalt. An increase in SMC regenerant content led to a gradual decrease in the rutting factor, while SBS-modified asphalt content had the opposite effect. The usage of SMC regenerant helped to reduce non-recoverable creep compliance by adjusting the proportion of viscoelastic-plastic components in recycled asphalt. Furthermore, the stiffness modulus results indicated that the addition of SMC regenerant improved the recovery performance of recycled asphalt at a low temperature. The recommended contents of SMC regenerant and SBS-modified asphalt are 7.88% and 150%, respectively, with a shear temperature of 157.7 °C.

Recognizing the variation of DNA-P during and after the algal bloom in lake Hulun.

Eutrophication has spread from shallow lakes in temperature zones to lakes in cold regions as a result of a continuous warm climate and human activities. Little proof for the importance of dissolved organic phosphorus (DOP) in contributing to phosphorus cycling and algae growth has been generated for aquatic ecosystems, particularly in cold eutrophic lakes. In this study, a comprehensive in situ study was conducted in overlying water, suspended particulate matter, and sediment during and after algal bloom (in July and September, respectively) in Lake Hulun. Multiple methods of 31P NMR, enzymatic hydrolysis, and UV-visible technologies were combined to detect phosphorus occurrence, bioavailability, and molecular structure from a novel angle. The 31P NMR analysis results showed that DNA-P is mainly stored in the dissolved phase and has not been detected in suspended particulate matter or sediment. Enzymatic hydrolysis was used to determine the bioavailability of DOP, which revealed that in July and September, respectively, 85% and 79% of DOP were hydrolyzable. UV-visible analysis represented that the degree of humification and molecular weight of DOP were high during the algal bloom, but these values considerably dropped following the algal bloom. The large amount of DNA-P present in the overlying water is the main reason for the high degree of humification and high molecular weight of the water body. Besides, Lake Hulun's DNA-P remains highly bioavailable during algal blooms, despite its high degree of humification and molecular weight. These findings can serve as a theoretical basis for understanding the migration and transformation of DOP, as well as the persistence of algal blooms in eutrophic lakes located in cold regions.

Effects of home-based telerehabilitation on dynamic alterations in regional intrinsic neural activity and degree centrality in stroke patients.

Objective: To explore the effects of home-based telerehabilitation (TR) on dynamic alterations in regional intrinsic neural activity and degree centrality in stroke patients by resting-state functional MRI (fMRI) methods. Methods: The neuroimaging data of 52 stroke patients were analyzed. Dynamic regional spontaneous neural activity (dynamic amplitude of low-frequency fluctuations, dALFF; and dynamic regional homogeneity, dReHo) and dynamic degree centrality (dDC) were compared between the TR and conventional rehabilitation (CR) groups. A flexible factorial model was employed to investigate the expected effects. Results: The patients in the TR group showed increased dALFF in the right precuneus and bilateral precentral gyrus (PreCG) and reduced dALFF in the right inferior parietal lobule by the analysis of main effects. Significant differences between groups were detected in the right precuneus, right fusiform gyrus and left middle frontal gyrus for dReHo and in the left cingulate gyrus, right middle temporal gyrus and left precuneus for dDC. A significant correlation was found in the TR group between the changed dALFF in the left PreCG and the changed Fugl-Meyer assessment (FMA) scores from baseline to postrehabilitation. Conclusions: This study implied that home-based TR training can alter the patterns of dynamic spontaneous brain activity and functional connectivity in certain brain regions. The identification of key brain regions by neuroimaging indicators such as dynamic regional brain activity and degree centrality in the recovery process would provide a theoretical basis for noninvasive brain stimulation technology and strategies for formulating targeted rehabilitation programs for stroke patients with motor dysfunction.

Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1H)-one Focused DNA-Encoded Library.

The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3H)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S-transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 µM against SjGST and 2.02 ± 0.20 µM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.

VEGF-B prevents excessive angiogenesis by inhibiting FGF2/FGFR1 pathway.

Although VEGF-B was discovered as a VEGF-A homolog a long time ago, the angiogenic effect of VEGF-B remains poorly understood with limited and diverse findings from different groups. Notwithstanding, drugs that inhibit VEGF-B together with other VEGF family members are being used to treat patients with various neovascular diseases. It is therefore critical to have a better understanding of the angiogenic effect of VEGF-B and the underlying mechanisms. Using comprehensive in vitro and in vivo methods and models, we reveal here for the first time an unexpected and surprising function of VEGF-B as an endogenous inhibitor of angiogenesis by inhibiting the FGF2/FGFR1 pathway when the latter is abundantly expressed. Mechanistically, we unveil that VEGF-B binds to FGFR1, induces FGFR1/VEGFR1 complex formation, and suppresses FGF2-induced Erk activation, and inhibits FGF2-driven angiogenesis and tumor growth. Our work uncovers a previously unrecognized novel function of VEGF-B in tethering the FGF2/FGFR1 pathway. Given the anti-angiogenic nature of VEGF-B under conditions of high FGF2/FGFR1 levels, caution is warranted when modulating VEGF-B activity to treat neovascular diseases.

The correlation between modifications to corneal topography and changes in retinal vascular density and retinal thickness in myopic children after undergoing orthokeratology.

Purpose: This study aimed to investigate the relationship among changes in corneal topography, retinal vascular density, and retinal thickness in myopic children who underwent orthokeratology for 3 months. Method: Thirty children with myopia wore orthokeratology lenses for 3 months. Using optical coherence tomography angiography (OCTA), the retina was imaged as 6 × 6 mm en-face images at baseline and 3 months after orthokeratology. Cornea data was acquired by topography and analyzed by customer MATLAB software. The cornea was divided into 3 zones and 9 sectors. The relative corneal refractive power shift (RCRPS) was used in this study. Changes in retinal vascular density (RVDC) and retinal thickness change (RTC) were associated with RCRPS by using spearman test. Statistical significance was set at p < 0.05. Result: A significant correlation was observed between the RVDC and the RCRPS in many regions (the r was 0.375 ~ 0.548, all p value <0.05). Significant positive correlations were found between RVDC in inner and outer temple regions with RCRPS at inner and outer nasal sectors. There were no significant correlations between RTC and RCRPS in other sectors except in the central cornea and the outer nasal retina (r:0.501, p:0.006). At baseline and 3 months after wearing the orthokeratology lens, no significant differences in the retinal microvasculature or thickness (p > 0.05) were observed at any regions. Conclusion: The correlation between the cornea and the retina was observed after orthokeratology. Cornea changes may affect regional retinal responses accordingly，which may explain how orthokeratology delays myopia progression partially.

Inter-examiner and intra-examiner reliability of optical coherence tomography angiography in vascular density measurement of retinal and choriocapillaris plexuses in healthy children aged 6-15 years.

Objective: This study aimed to test the inter-examiner and intra-examiner reliability of macular vascular density (VD) measurement of retinal and choriocapillaris plexuses in healthy children using optical coherence tomography angiography (OCTA). Materials and methods: Ninety-two school children were prospectively recruited. Macular OCTA images (6 × 6 mm2) were obtained thrice by two examiners using the RTVue-XR Avanti OCT system. The coefficient of variation (COV), intraclass correlation coefficient (ICC), and Bland-Altman plots were used to evaluate the repeatability and reproducibility. Results: Ninety participants aged 6-15 years were enrolled; two participants were excluded because of low-quality images. In the retina, the reproducibility and repeatability of VD became poorer from superficial to deep retinal capillary plexus (superficial: COV = 4.61-11.11%; intermediate: COV = 7.73-14.15%; deep: COV = 14.60-32.28%). For both reproducibility and repeatability, the ICC ranged from moderate to high (superficial plexus: ICC = 0.570-0.976; intermediate plexus: ICC = 0.720-0.968; deep plexus: ICC = 0.628-0.954). In the choroid, the inter-examiner reproducibility and intra-examiner repeatability of the VD measurement of choriocapillaris were excellent in the macula, fovea, parafovea, and perifovea (COV = 1.00-6.10%; ICC = 0.856-0.950). The parameters of the foveal avascular zone (FAZ) also showed significant reproducibility and repeatability (COV = 0.01-0.21%; ICC = 0.743-0.994). Conclusion: The VD measurements of the choriocapillaris and FAZ parameters using OCTA showed excellent inter-examiner and intra-examiner reliability in school children. The reproducibility and repeatability of the VD of three retinal capillary plexuses depended on the depth of the retinal capillary plexus.