Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PLpro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PLpro with the inhibitory constant Ki values from 13.2 to 88.2 nanomolar. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

Design of SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 µM. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

Geological timescales' aging effects of lunar glasses.

Physical aging is a long-lasting research hot spot in the glass community, yet its long-term effects remain unclear because of the limited experimental time. In this study, we discover the extraordinary aging effects in five typical lunar glassy particles with diameters ranging from about 20 to 53 micrometers selected from Chang'e-5 lunar regolith. It is found that geological time scales' aging can lead to unusually huge modulus enhancements larger than 73.5% while much weaker effects on hardness (i.e., varies decoupling evolutions of Young's modulus and hardness during aging) in these lunar glassy samples. Such extraordinary aging effects are primarily attributed to the natural selected complex glassy compositions and structures, consistent with high entropy and minor element doping criteria, prevailing under the special lunar conditions and the extensive aging time for the lunar glasses. This study offers valuable insights for developing high-performance and stable glassy materials for radiation protection and advanced space explorations.

Efficient extraction of nanocellulose from lignocellulose using aqueous butanediol fractionation to improve the performance of waterborne wood coating.

The highly efficient extraction of cellulose from lignocellulose with an excellent yield of 95.2 % and purity of 96.7 % was demonstrated using acid-catalyzed fractionation with aqueous butanediol. This cellulose was subsequently transformed into cellulose nanofibers (CNFs) and cellulose nanocrystals (CNCs) with specific dimensions and surface functional groups through various chemomechanical treatments. The average diameters of CNFs and CNCs produced by sulfuric acid hydrolysis-ultrasonication and deep eutectic solvent treatment-ultrasonication (DES-CNCs) were 29.7, 21.9 and 17.3 nm, respectively. The DES-CNCs were obtained in a good yield of 71 ± 1.27 wt% and exhibited a high zeta potential of -33.5 ± 2.51 mV following posthydrolysis and esterification during the DES treatment. These CNFs and CNCs were used as nanofillers in a waterborne wood coating (WWC), which significantly improved its dynamic viscosity and storage modulus. The addition of these materials also enhanced the mechanical strength of the WWC but had little effect on transmittance. Glossiness, hardness, abrasion resistance and adhesion strength were evaluated, and the DES-CNCs provided the greatest improvements at a low concentration. A plausible reinforcement mechanism was presented. This work provided an efficient cellulose extraction method and detailed structure elucidation of the nanocellulose together with suggestions for value-added applications of cellulosic nanofillers for reinforcing WWC.

Design of sustainable 3D printable polylactic acid composites with high lignin content.

In this study, we report the development of a sustainable polymer system with 50 wt% lignin content, suitable for additive manufacturing and high value-added utilization of lignin. The plasticized polylactic acid (PLA) was incorporated with lignin to develop the bendable and malleable green composites with excellent 3D printing adaptability. The biocomposites exhibit increases of 765.54 % and 125.27 % in both elongation and toughness, respectively. The plasticizer enhances the dispersion of lignin and the molecular mobility of the PLA chains. The good dispersion of lignin particles within the structure and the reduction of chemical cross-linking promote the local relaxation of the polymer chains. The good local relaxation of the polymer chains and the high flexibility allow to obtain a better integration between the printed layers with good printability. This research demonstrates the promising potential of this composite system for sustainable manufacturing and provides insights into novel material design for high-value applications of lignin.

4D printing light-driven actuator with lignin photothermal conversion module.

Light-responsive shape memory polymers are attractive as they can be activated through remote and spatially-controlled light. In this work, 4D printing of poly(lactic acid) (PLA) composites with a near-infrared light-responsive was achieved by using the simple melt blending method and adding 3 wt% of lignin. Lignin with a conjugated structure was used as the photothermal conversion module. The composites exhibited significant photothermal effects under near-infrared (808 nm) laser irradiation, and the laser irradiation was also effective in initiating and controlling the shape memory. The structure of lignin can be improved by the action of dicumyl peroxide (DCP) to enhance the interfacial adhesion between polyamide elastomer (PAE) and polylactic acid (PLA), reduce the size of dispersed phases, and serve as an effective rheological modifier to exhibit the ideal melt viscosity required for 3D printing of composites. The good mechanical, thermal stability, and rheological properties provide assurance for the 4D printing of composites. This research provides an environmentally friendly and practical method for creating composites that have the potential to serve as ideal actuator components in a range of applications.

Ductile poly(lactic acid)-based blends derived from poly(butylene succinate-co-butylene 2,5-thiophenedicarboxylate): Structures and properties.

Because of superior tensile strength, biodegradability, and biocompatibility, poly(lactic acid) (PLA) has emerged as one among the growth-oriented biodegradable materials. But it has been limited to some extent in practical applications due to poor ductility. Consequently, in order to improve the drawback of poor ductility of PLA, ductile blends were obtained by melt-blending of poly(butylene succinate-co-butylene 2,5-thiophenedicarboxylate) (PBSTF25) with PLA. PBSTF25 has a good improvement on the ductility of PLA due to its excellent toughness. Differential scanning calorimetry (DSC) showed that PBSTF25 promoted the cold crystallization of PLA. Wide-angle X-ray diffraction (XRD) results revealed that PBSTF25 experienced stretch-induced crystallization throughout the stretching procedure. Scanning electron microscopy (SEM) showed neat PLA had a smooth fracture surface, but the blends had rough fracture surface. PBSTF25 can improve the ductility and processing properties of PLA. When the addition of PBSTF25 reached 20 wt%, tensile strength was 42.5 MPa and elongation at break increased to 156.6 %, approximately 19 times as much as PLA. The toughening effect of PBSTF25 was better than that of poly(butylene succinate).

Significant Zero Thermal Expansion Via Enhanced Magnetoelastic Coupling in Kagome Magnets.

Zero-thermal-expansion (ZTE) alloys, as dimensionally stable materials, are urgently required in many fields, particularly in highly advanced modern industries. In this study, high-performance ZTE with a negligible coefficient of thermal expansion av as small as 2.4 ppm K-1 in a broad temperature range of 85-245 K is discovered in Hf0.85 Ta0.15 Fe2 C0.01 magnet. It is demonstrated that the addition of trace interstitial atom C into Ta-substituted Hf0.85 Ta0.15 Fe2 exhibits significant capability to tune the normal positive thermal expansion into high-performance ZTE via enhanced magnetoelastic coupling in stabilized ferromagnetic structure. Moreover, direct observation of the magnetic transition between ferromagnetic and triangular antiferromagnetic states via Lorentz transmission electron microscopy, along with corresponding theoretical calculations, further uncovers the manipulation mechanism of ZTE and negative thermal expansion. A convenient and effective method to optimize thermal expansion and achieve ZTE with interstitial C addition may result in broadened applications based on the strong correlation between the magnetic properties and crystal structure.

Efficient downstream valorization of lignocellulose after organosolv fractionation: Synergistic enhancement of waterborne coatings by co-assembled lignin@cellulose nanocrystals.

The simultaneous downstream valorization of cellulose and lignin is an important aspect of efficiently extracting value from lignocellulose. The present work, we demonstrated the preparation of a novel bio-based filler by the co-assembly of cellulose and lignin obtained from a one-pot ethanosolv lignocellulose fractionation process. The cellulose was valorized by forming cellulose nanocrystals (CNCs) through simple bleaching and ultrasonication processes. The lignin fractions demonstrated greater solubility (19.2 mg/mL) and lower molecular weight (6980 g/mol) than conventional industrial lignins. Various lignin@CNCs specimens were prepared via a facile co-assembly of the lignin and CNCs. These entirely bio-based materials could be used as a multifunctional filler to enhance the properties of a waterborne coating (WBC). Specifically, the mechanical properties, coating performance and ultraviolet resistance of a WBC were all significantly improved, demonstrating a synergistic enhancement effect obtained from the CNCs and lignin. In this manner, both cellulose and lignin components were efficiently transformed to value-added fillers for WBC, demonstrating a highly efficient pathway for lignocellulose utilization and downstream value-added applications.

Effects of high-flux hemodialysis combined with levocarnitine on vascular calcification, microinflammation, hepcidin, and malnutrition of elderly patients on maintenance hemodialysis.

BACKGROUND: This study was to investigate the effect of high-flux hemodialysis (HD) combined with levocarnitine on vascular calcification, microinflammation, hepcidin, and malnutrition in elderly patients on maintenance HD (MHD). METHODS: 75 MHD elderly patients admitted to hospital between 1st September 2017 and 31st August 2019 were selected as the study subjects. They were randomly divided by digital table into three groups: low-flux group (n=25), high-flux group (n=25) and joint group (n=25). In the low-flux group, dialyzer had an ultrafiltration coefficient 12 mL/(h·mmHg) and effective surface area of 1.4 m2 compared with 59 mL/(h·mmHg) and 1.8 m2 in the high-flux group. After treatment, the calcification of blood vessels was examined by lateral X-ray, pelvic plain film and bilateral positive position. For patients in all groups, the concentrations of parathyroid hormone (PTH) and ß 2-microglobulin (ß 2-MG) in serum were measured by automatic chemiluminescence; levels of interleukin-6, C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-α) were measured by ELISA before and after treatment; and the level of hepcidin was measured by ELISA. Before and 12 weeks after the treatment, the nutritional status of the patients was evaluated by modified quantitative subjective global assessment (MQSGA), hemoglobin (Hb) and red blood cell count (RBC). Complications in the three groups were recorded, including nausea, chest pain, hypotension, hypertension, pruritus, dry heat, muscle spasm, arrhythmia, and restless legs. RESULTS: Vascular calcification in the joint group was better than the low-flux and high-flux groups (P<0.05). After treatment, the serum PTH and ß 2-mg concentrations in the joint group were lower than those in the other two groups (P<0.05), and the levels of IL-6, CRP, TNF-α and hepcidin in the joint group were significantly lower than those before treatment (P<0.05). After treatment, the MQSGA scores in the joint group were lower than those in the low-flux and high-flux groups (P<0.05), and Hb and RBC were higher (P<0.05). CONCLUSIONS: The combination of high-flux HD and levocarnitine in elderly patients on MHD can increase the clearance of medium and large molecular toxins, effectively correct malnutrition, alleviate microinflammation, delay the progress of vascular calcification, and is safe.

Corrigendum to "A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury".

[This corrects the article DOI: 10.1155/2014/432318.].

Aerosol and Surface Distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospital Wards, Wuhan, China, 2020.

To determine distribution of severe acute respiratory syndrome coronavirus 2 in hospital wards in Wuhan, China, we tested air and surface samples. Contamination was greater in intensive care units than general wards. Virus was widely distributed on floors, computer mice, trash cans, and sickbed handrails and was detected in air ≈4 m from patients.

Fabrication of Microfluidic Chips Based on an EHD-Assisted Direct Printing Method.

Microfluidic chips have been widely used in many areas such as biology, environmental monitoring, and micromixing. With the increasing popularity and complexity of microfluidic systems, rapid and convenient approaches for fabricating microfluidic chips are necessary. In this study, a method based on EHD (electrohydrodynamic)-assisted direct printing is proposed. Firstly, the principle of EHD-assisted direct printing was analyzed. The influence of the operating voltage and moving speed of the work table on the width of a paraffin wax model was studied. Then, two kinds of paraffin wax molds for micromixing with channel widths of 120 µm were prepared. A polydimethylsiloxane (PDMS) micromixer was fabricated by replicating the paraffin wax mold, and the micromixing of blue and yellow dye was realized. The results show that EHD-assisted direct printing can be used to make complex microscale structures, which has the potential to greatly simplify the manufacturing process.

[Angelica Polysaccharide Resists Platelets Apoptosis Induced by LY294002].

OBJECTIVE: To investigate the anti-apoptotic effect of Angelica polysaccharide (APS) on cryopreservated platelets and its mechanism. METHODS: The platelets were divided into 4 group: control group(4 ℃ stored platelets),APS group (APS-treated platelets stored at 4 ℃), LY294002 group (LY294002-treated platelets stored at 4 ℃) and LY294002+APS group(LY294002+APS treated platelets stored at 4 ℃ ). The expression of platelet membrane glycoprotein CD41 and CD61, as well as the platelet apoptotic rate, Caspase 3 expression and mitochondrial membrane potential (MMP) were detected by flow cytometry; the anti-apoptotic mechanism of APS by PI3K /AKT signaling pathway was analyzed by Western blot assay. RESULTS: The apoptosis rate of platelets in LY294002 group obviously increased, the activity of CD41 and CD61 expression gradually decreased along with the enhancement of LY294002 concentrations (r=-0.953)； compared with control group, the apoptosis rate of platelets in LY294002 group was enhanced significantly(P<0.05)，while the apoptosis rate of platelets in LY294002+APS group significantly was reduced(P<0.05) as compare with LY294002 group, which suggest that APS has an anti-apoptotic effect on the cryopreserved platelets. APS decreased the expression of Caspase-3 and inhibited the reduction of mitochondrial membrane potential induced by LY294002, moreover, APS could increase the activation of PI3K /AKT pathway in Plt. CONCLUSION: APS has an anti-apoptotic effect on the cryopreserved platelets through activating the PI3K /AKT pathway, decreasing the expression of apoptosis protease Caspase-3 and inhibiting the reduction of MMP.

[Clinical trials of treatment of post-stroke foot drop by fire-needling plus stuck-needle-stretching].

OBJECTIVE: To compare the therapeutic effect of fire-needling plus stuck-needle-stretching and conventional acupuncture for post-stroke foot drop, so as to provide a reference foundation for optimizing clinical treatment regimen. METHODS: A total of 60 patients with post-stroke foot drop were equally randomized into a treatment group and a control group. In the treatment group, fire-needling plus stuck-needle-stretching was applied to acupoint pairs Jiexi (ST41)-Taichong (LR3), Xiajuxu (ST39)-ST41, Fenglong (ST40)-ST39, shangjuxu (ST37)-ST40, Zusanli (ST36)-ST37, Dubi (ST35)-ST36, Xuanzhong (GB39)-Qiuxu (GB40) on the affected side, and Chengshan (BL57) and Ashi points were swiftly pricked with red-hot filiform needle without needle retaining. In the conventional acupuncture group, the same acupoints were needled with filiform needles, and the treatment for both groups was given once a day, 6 times a week, for consecutive 4 weeks. The spasm severity of posterior triceps of the lower leg was evaluated using modified Ashworth scale, the tibial anterior muscle strength was measured using Lovett' and Martin's methods, the activities of daily living were assessed using modified Barthel's index, the walking ability was evaluated using Holden walking rating scale and the lower limb motor function assessed using Fugl-Meyer assessment scale, and the severity of foot drop was assessed in reference to Garceau criteria. RESULTS: After the treatment, the score of the modified Ashworth scale was significantly reduced (P<0.01), and those of Lovett muscle strength scale, Barthel index, Holden walking rating scale and Fugl-Meyer lower limb motor function scale were considerably increased in both groups versus their own pre-treatment (P<0.01). The therapeutic effect of the treatment group was significantly superior to that of the control group in reducing Ashworth scale score and in increasing the scores of Lovett muscle strength test, Barthel index, Holden walking function scale and Fugl-Meyer lower limb motor function scale (P<0.01). Of the two 30 cases in the control and treatment groups, 10(33.33%)and 14(46.67%) experienced a remarkable improvement, 10(33.33%)and 12(40.00%)were improved, 7(23.33%)and 3(10.00%)had a mild progress, 3(10.00%) and 1(3.33%) failed, with the excellent plus good effective rates being 66.67% and 86.67%, respectively, but without significant difference between the two groups (P>0.05). CONCLUSION: Both fire-needling plus stuck-needle-stretching and conventional acupuncture are effective in the treatment of post-stroke foot drop, but the former is relatively better.

Types and species diversity of Cupressus communities in Southeast Tibet, China.

Cupressus communities are the important parts of natural forests in Southeast Tibet, with significance on plateau biodiversity conservation and ecological security. To clarify their types and plant species diversity, we analyzed species composition and diversity indices, diameter class pattern of constructive species in different communities in Milin County, Lang County and Bomi County, Southeast Tibet. The results showed that Cupressus communities could be classified into four types: C. torulosa-Lonicera lanceolate + Philadelphus tomentosus-Pteris cretica var. nervosa + Digitaria violascens community (Community1), C. gigantea-Desmodium elegans + Sophora moorcroftia-na-Tripogon filiformis + Cymbopogon distans + Orinus thoroldii community (Community2), C. gigantea-Leptodermis purdomii-Chenopodium hybridum + O. thoroldii community (Community 3), and C. gigantea-Ceratostigma minus-A. desertorum + O. thoroldii + Tribulus terrester community (Community 4). Across those four community types, Margalef index, Shannon index, Pielou index and interspecies encounter probability index all ranked with the decreasing order of Community1, Community2, Community 3 and Community 4. Diameter class pattern of the constructive species showed that many young and few middle/old individuals were within the four communities. High mortality rate occurred during the interim period from young to middle age classes. In general, populations of Cupressus plants showed a declining trend.

Angelica Polysaccharide Resists Platelets Apoptosis Induced by LY294002 / 中国实验血液学杂志

OBJECTIVE@#To investigate the anti-apoptotic effect of Angelica polysaccharide (APS) on cryopreservated platelets and its mechanism.@*METHODS@#The platelets were divided into 4 group: control group(4 ℃ stored platelets),APS group (APS-treated platelets stored at 4 ℃), LY294002 group (LY294002-treated platelets stored at 4 ℃) and LY294002+APS group(LY294002+APS treated platelets stored at 4 ℃ ). The expression of platelet membrane glycoprotein CD41 and CD61, as well as the platelet apoptotic rate, Caspase 3 expression and mitochondrial membrane potential (MMP) were detected by flow cytometry; the anti-apoptotic mechanism of APS by PI3K /AKT signaling pathway was analyzed by Western blot assay.@*RESULTS@#The apoptosis rate of platelets in LY294002 group obviously increased, the activity of CD41 and CD61 expression gradually decreased along with the enhancement of LY294002 concentrations (r=-0.953)； compared with control group, the apoptosis rate of platelets in LY294002 group was enhanced significantly(P<0.05)，while the apoptosis rate of platelets in LY294002+APS group significantly was reduced(P<0.05) as compare with LY294002 group, which suggest that APS has an anti-apoptotic effect on the cryopreserved platelets. APS decreased the expression of Caspase-3 and inhibited the reduction of mitochondrial membrane potential induced by LY294002, moreover, APS could increase the activation of PI3K /AKT pathway in Plt.@*CONCLUSION@#APS has an anti-apoptotic effect on the cryopreserved platelets through activating the PI3K /AKT pathway, decreasing the expression of apoptosis protease Caspase-3 and inhibiting the reduction of MMP.

RuBisCO large subunit gene primers for assessing the CO2-assimilating planktonic community structure in Jiaozhou Bay, China.

The protein coding genes (rbcL/cbbL/cbbM) for RuBisCO large subunit, the most abundant protein on earth that drives biological CO2 fixation, were considered as useful marker genes in characterizing CO2-assimilating plankton. However, their community specificity has hindered comprehensive screening of genetic diversity. In this study, six different rbcL/cbbL/cbbM primers were employed to screen clone libraries to identify CO2-assimilating plankton in Jiaozhou Bay. The following community compositions were observed: the community components in Form I A/B rbcL/cbbL clone library mainly comprised Chlorophyta and Proteobacteria, Form ID2 and ID3 libraries consisted of Bacillariophyta, Form II cbbM library consisted of Proteobacteria and Alveolata, and both Form I green and red libraries included Proteobacteria, respectively. At the genus taxonomic level, no overlaps among these clone libraries were observed, except for ID2 and ID3. Overall, the phytoplankton in Jiaozhou Bay mainly consists of Bacillariophyta, Chlorophyta, Cryptophyta, Haptophyceae and Alveolata. The CO2-assimilating prokaryotes mainly consist of Proteobacteria. Considering the high-sequence specificities of these marker genes, we propose that the joint use of multiple primers may be utilized in unveiling the diversity of CO2-assimilating organisms. In addition, designing novel RuBisCO gene primers that generate longer amplicons and have broader phylogenetic coverage may be necessary in the future.

Impact of Cross-Linked Chitosan Sublayer Structure on the Performance of TFC FO PAN Nanofiber Membranes.

Polyacrylonitrile (PAN) is a popular material in membrane field because of its excellent mechanical property, thermal stability, and chemical resistance. Unfortunately, PAN nanofibers produced by electrospinning are not suitable for interfacial polymerization process directly due to its hydrophobicity and large average pore size. In this work, the cross-linked chitosan (CS) solution was coated on the nanofiber surface to fabricate a sublayer, based on which thin-film composite (TFC) membranes were prepared using m-phenylenediamine and 1,3,5-trimesoyl chloride as the monomers. The impact of the different sublayers on the performances of TFC PAN nanofiber membranes for forward osmosis (FO) was studied by varying cross-linked CS concentrations. The results indicated that the increased CS concentration not only led to the relatively denser polyamide layer, but also changed its morphology. In the reverse osmosis process, NaCl rejection increased from 46.5 to 83.5%. Salt flux from feed solution to draw solution decreased from 25.8 to 8.9 g·m-2·h-1 (0.1 M NaCl solution as feed, 2 M glucose solution as draw solution, FO mode). This study found that the sublayer had noteworthy impact on the separation layer and helped us to pave the way to design high-performance FO membranes.

Bacterial lipid droplets bind to DNA via an intermediary protein that enhances survival under stress.

Lipid droplets (LDs) are multi-functional organelles consisting of a neutral lipid core surrounded by a phospholipid monolayer, and exist in organisms ranging from bacteria to humans. Here we study the functions of LDs in the oleaginous bacterium Rhodococcus jostii. We show that these LDs bind to genomic DNA through the major LD protein, MLDS, which increases survival rate of the bacterial cells under nutritional and genotoxic stress. MLDS expression is regulated by a transcriptional regulator, MLDSR, that binds to the operator and promoter of the operon encoding both proteins. LDs sequester MLDSR, controlling its availability for transcriptional regulation. Our findings support the idea that bacterial LDs can regulate nucleic acid function and facilitate bacterial survival under stress.