Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.

Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.

Effect of intravenous vitamin C on adult septic patients: a systematic review and meta-analysis.

Background: An increasing number of studies indicate that vitamin C (VC) reduces the mortality of adult septic patients, while some articles suggest otherwise. We performed this systematic review and meta-analysis to resolve the discrepancies in reported results concerning the efficacy of VC in septic patients. Methods: We comprehensively searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled trials for randomized controlled trials (RCTs) evaluating the efficacy of intravenous VC (IVVC) on adult septic patients published from inception to November 28, 2022. The quality of outcomes for eligible studies was assessed using the Recommendations Assessment, Development, and Evaluation methodology. The results were analyzed using the pooled mean difference (MD) or risk ratio (RR) and 95% confidence intervals (CIs). Results: Twenty-two studies (3,570 adult septic patients) were included. IVVC treatment did not improve 28-day mortality compared to the control group (RR, 0.92; 95% CI, 0.81-1.04; I2 = 26%; evidence risk, moderate). IVVC monotherapy decreased mortality (RR, 0.69; 95% CI, 0.52-0.93; I2 = 57%), whereas combination therapy did not affect mortality (RR, 1.03; 95% CI, 0.90-1.17; I2 =0%). IVVC had a trend to decrease the mortality of septic patients (RR, 0.83; 95% CI, 0.69-1.00; I2 = 33%) but did not affect septic shock patients (RR, 1.01; 95% CI, 0.85-1.21; I2 = 18%). IVVC reduced the duration of vasopressor use (MD, -8.45; 95% CI, -15.43 to -1.47; evidence risk, very low) but did not influence the incidence of AKI, ICU length of stay, duration of mechanical ventilation. Conclusions: IVVC treatment did not improve the 28-day mortality in septic patients. Subgroup analysis indicated that VC had a trend to decrease the 28-day mortality in patients with sepsis but not septic shock. IVVC monotherapy, rather than combination therapy, decreased the 28-day mortality in septic patients. The findings imply that Hydrocortisone, Ascorbic acid, Thiamine (HAT) combination therapy is not superior to IVVC monotherapy for septic patients. These findings warrant further confirmation in future studies, which should also investigate the mechanisms underlying the enhanced efficacy of IVVC monotherapy in septic patients. Systematic review registration: https://inplasy.com/.

Modified ulnar lengthening for correction of the Masada type 2 forearm deformity in hereditary multiple exostosis.

Few articles have reported on the treatment of Masada type 2 forearm deformities in hereditary multiple exostosis, possibly because of the high redislocation rate and other complications. This study precisely declares the use of modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities. 20 children with Masada type 2 forearm deformities were admitted for surgical treatment at our hospital from February 2014 to February 2021. There were 13 girls and 7 boys, ranging in age from 3.5 to 15 years (mean: 9 years) at the time of operation. We removed the prominent osteochondromas of the distal ulna and the proximal radius, positioned a classic Ilizarov external fixator on the forearm and then performed ulnar transverse one-third proximal diaphyseal subperiosteal osteotomy. We adopted modified ulnar lengthening postoperatively. The effects of surgical correction of deformity and functional improvement of the limb were assessed via regular follow-up and X-ray. The patients were followed up for 36 months, and the ulna was lengthened 26.99 mm on average; all radial heads remained relocated. The radiographic evaluations, including relative ulnar shortening, radial articular angle, and carpal slip, were improved. The functions of the elbow and forearm were all improved after surgery. Modified ulnar lengthening by an Ilizarov external fixation with tumour excision for the treatment of Masada type 2 forearm deformities in hereditary multiple exostoses has been proven to be an effective and reliable technique in the early stage.

Phenyldivinylsulfonamides for the construction of antibody-drug conjugates with controlled four payloads.

Phenyldivinylsulfonamides emerged from a series of divinylsulfonamides, demonstrating their ability to effectively re-bridge disulfide bonds. This kind of linkers was attached to monomethyl auristatin E (MMAE) and further conjugated with a model antibody, trastuzumab. After optimization, the linker 20 can deliver stable and highly homogenous DAR (Drug-to-Antibody Ratio) four antibody-drug conjugates (ADCs). The method was also applicable for other IgG1 antibodies to obtain ADCs with controlled four payloads. Moreover, the MMAE-bearing ADC is potent, selective and efficacious against target cell lines.

Impact of statin use on breast cancer recurrence and mortality before and after diagnosis: a systematic review and meta-analysis.

Objective: Breast cancer is one of the most common causes of death among women. Statins, typically used for cholesterol management, have been hypothesized to reduce recurrence and mortality rates in breast cancer. However, this association remains a subject of debate. This study evaluates the potential impact of statins on breast cancer recurrence and mortality. Methods: A comprehensive search was conducted in the PubMed, EMBASE, and Cochrane databases for articles published up to June 2023. These articles examined the effect of statins on breast cancer recurrence and mortality both before and after diagnosis. The analysis was performed using random-effects models, calculating pooled hazard ratios (HR) and their 95% confidence intervals (CI). Results: A total of 31 cohort studies, involving 261,834 female breast cancer patients, were included in this analysis. It was found that statin use prior to diagnosis was associated with a decrease in overall mortality (HR, 0.8; 95% CI, 0.69-0.93; I2 = 77.6%; P = 0.001) and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67-0.87; I2 = 72.7%; P = 0.005). Additionally, statin use after diagnosis was observed to reduce the recurrence of breast cancer (HR, 0.71; 95% CI, 0.61-0.82; I2 = 60%; P = 0.003), overall mortality (HR, 0.81; 95% CI, 0.70-0.92; I2 = 80.7%; P < 0.001), and breast cancer-specific mortality (HR, 0.76; 95% CI, 0.67-0.86; I2 = 74.5%; P < 0.001). Conclusions: The findings of this study indicate that statin usage, both before and after breast cancer diagnosis, may be associated with reduced risks of overall and breast cancer-specific mortality, as well as lower recurrence rates.

Design and Joint Position Control of Bionic Jumping Leg Driven by Pneumatic Artificial Muscles.

Using the skeletal structure and muscle distribution of the hind limbs of a jumping kangaroo as inspiration, a bionic jumping leg was designed with pneumatic artificial muscles (PAMs) as actuators. Referring to the position of biarticular muscles in kangaroos, we constructed a bionic joint using biarticular and monoarticular muscle arrangements. At the same time, the problem of the joint rotation angle limitations caused by PAM shrinkage was solved, and the range of motion of the bionic joint was improved. Based on the output force model of the PAM, we established a dynamic model of the bionic leg using the Lagrange method. In view of the coupling problem caused by the arrangement of the biarticular muscle, an extended state observer was used for decoupling. The system was decoupled into two single-input and single-output systems, and angle tracking control was carried out using active disturbance rejection control (ADRC). The simulation and experimental results showed that the ADRC algorithm had a better decoupling effect and shorter adjustment time than PID control. The jumping experiments showed that the bionic leg could jump with a horizontal displacement of 320 mm and a vertical displacement of 150 mm.

Preparation and characterization of soybean protein isolate-dextran conjugate-based nanogels.

Soybean protein isolate (SPI)-dextran conjugate-based nanogels were prepared via the Maillard reaction combined with protein self-assembly in this study. The dextran molecular weight (40 kDa), SPI/dextran mass ratio (1:1.75), and incubation time (3.3 d) for preparing SPI-dextran conjugate (SDC) were firstly optimized. The SDC was confirmed by analyzing the changes in protein composition and infrared absorption bands and showed loosened tertiary conformation, reduced surface hydrophobicity, decreased Z-average hydrodynamic diameter (Dh) and zeta potential, and improved emulsifying properties compared to the native SPI. Effects of conjugate concentration, pH, heating temperature, and time on Dh and polydispersity index were also evaluated. The SDC-based nanogels were translucent in aqueous solution and exhibited a spherical core-shell structure with a Dh of ∼104.4 nm and a good stability against thermal treatment, ionic strength, and storage. Results demonstrated the SDC-based nanogels possessed a potential to be used as desirable nanocarriers for encapsulating hydrophobic bioactive compounds.

Intelligent Algorithm-Based Multislice Spiral Computed Tomography to Diagnose Coronary Heart Disease.

In this study, dictionary learning and expectation maximization reconstruction (DLEM) was combined to denoise 64-slice spiral CT images, and results of coronary angiography (CAG) were used as standard to evaluate its clinical value in diagnosing coronary artery diseases. 120 patients with coronary heart disease (CHD) confirmed by CAG examination were retrospectively selected as the research subjects. According to the random number table method, the patients were divided into two groups: the control group was diagnosed by conventional 64-slice spiral CT images, and the observation group was diagnosed by 64-slice spiral CT images based on the DLEM algorithm, with 60 cases in both groups. With CAG examination results as the standard, the diagnostic effects of the two CT examination methods were compared. The results showed that when the number of iterations of maximum likelihood expectation maximization (MLEM) algorithm reached 50, the root mean square error (RMSE) and peak signal to noise ratio (PSNR) values were similar to the results obtained by the DLEM algorithm under a number of iterations of 10 when the RMSE and PSNR values were 18.9121 dB and 74.9911 dB, respectively. In the observation group, 28.33% (17/60) images were of grade 4 or above before processing; after processing, it was 70% (42/60), significantly higher than the proportion of high image quality before processing. The overall diagnostic consistency, sensitivity, specificity, and accuracy (88.33%, 86.67%, 80%, and 85%) of the observation group were better than those in the control group (60.46%, 62.5%, 58.33%, and 61.66%). In conclusion, the DLEM algorithm has good denoising effect on 64-slice spiral CT images, which significantly improves the accuracy in the diagnosis of coronary artery stenosis and has good clinical diagnostic value and is worth promoting.

Drug-induced QT Prolongation Atlas (DIQTA) for enhancing cardiotoxicity management.

Drug-induced prolongation of the QT interval is common in a variety of pharmaceutical treatments and can lead to serious clinical outcomes. Although substantial efforts have been made to prevent drug-induced QT interval prolongation, the lack of a centralized data source remains the main obstacle to further study of the underlying mechanism and the development of effective prediction strategies. To fill this gap, we propose a schema for stratifying the risk of marketed QT prolonging drugs based on US Food and Drug Administration (FDA)-approved drug labeling and developed a Drug-Induced QT Prolongation Atlas (DIQTA). Potential application of DIQTA was shown by precision dosing in off-label use and therapeutic strategy optimization, as well as the facilitation of artificial intelligence (AI)-based modeling in predictive toxicity.

Synthesis and Evaluation of Reactive Oxygen Species Sensitive Prodrugs of a NAMPT Inhibitor FK866.

NAMPT is an attractive target in cancer therapy and numerous NAMPT inhibitors have been developed. However, the clinical activities of NAMPT inhibitors have displayed disappointing results in clinical trials for their dose-limiting toxicities. In this study, reactive oxygen species (ROS)-responsive prodrugs of a NAMPT inhibitor FK866 were designed and synthesized. A short synthesis method was developed to shield the activity of FK866 through a quaternary ammonium connection. Two prodrugs, with boronic acid as a responsive group to ROS, were prepared and one of the prodrugs 122-066 also contained a fluorescence carrier. Both of the prodrugs released the active compound by the treatment of H2O2,, and the biological evaluation showed that they exhibited a higher potency in cells with high levels of ROS. Moreover, prodrug 122-066 had the ability to release FK866 and simultaneously induce the fluorescence activation under the stimulation of H2O2. This method has the potential to improve the therapeutic window of NAMPT inhibitors.

Site-specific construction of triptolide-based antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have emerging as efficient agents to target deliver cytotoxic drugs and reduce their off-target side effects. Triptolide has attracted attention to be used in ADC development. Herein, three rationally designed triptolide drug-linkers have been synthesized for use in site-specific construction of ADCs. Carbamates that were supposed to be more stable than carbonates were introduced to attach triptolide to the linkers. PEG and discrete PEG chains were incorporated to improve the hydrophilicity of drug-linkers. The ADCs were finally site-specifically prepared by conjugation of the drug-linkers to trastuzumab through disulfide re-bridging approach. The preliminary anti-tumor activities of these ADCs were evaluated and they displayed high potencies against HER2-targeted cancer in vitro and in vivo.

Accurate Retention Time Prediction Based on Monolinked Peptide Information to Confidently Identify Cross-Linked Peptides.

Cross-linking mass spectrometry methods have not been successfully applied to protein-protein interaction discovery at a proteome-wide level mainly due to the computation complexity (O (n2)) issue. In a previous report, we proposed a decision tree searching strategy (DTSS), which can reduce complexity by orders of magnitude. In this study, we further found that the monolinked peptides carry out the information on the retention time of the corresponding cross-linked pairs; therefore, the retention time of cross-linked peptide pairs can be predicted accurately. By utilizing the retention time as an extra filter, the false positive rate can be reduced by around 86% with a sensitivity loss of 10%. The method combined with DTSS (T-DTSS) not only benefits improving identification confidence but also leads to lower cutoff scores and facilitates substantially increasing inter-cross-link identification. T-DTSS was successfully applied to the identification of inter-cross-links obtained from Escherichia coli cell lysate cross-linked by a newly synthesized enrichable cross-linker, pDSBE. The approach can be applicable to both cleavable and noncleavable methods.

Combretastatin A4-derived payloads for antibody-drug conjugates.

We describe the use of natural product combretastatin A4 (CA4) as a versatile new payload for the construction of antibody-drug conjugates (ADCs). Cetuximab conjugates consisting of CA4 derivatives were site-specially prepared by disulfide re-bridging approach using cleavable and non-cleavable linkers. These ADCs retained antigen binding and internalization efficiency and exhibited high potencies against cancer cell lines in vitro. The conjugates also demonstrated significant antitumor activities in EGFR-positive xenograft models without observed toxicities. CA4 appears to be a viable payload option for ADCs research and development.

Divinylsulfonamides enable the construction of homogeneous antibody-drug conjugates.

Methods that site-specifically attach payloads to an antibody with controlled DAR (Drug-Antibody Ratio) are highly desirable for the generation of homogeneous antibody-drug conjugates (ADCs). We describe the use of N-phenyl-divinylsulfonamide scaffold as a linker platform to site-specifically construct homogeneous DAR four ADCs through a disulfide re-bridging approach. Several monomethyl auristatin E (MMAE)-linkers were synthesized and the drug-linkers that contain electron-donating groups on the phenyl of the linker showed high stability. Her2-targeted MMAE-linker-herceptin and EGFR targeted MMAE-linker-cetuximab conjugates were prepared. The conjugates demonstrated high efficacy and selectivity for killing target-positive cancer cells in vitro. The EGFR-targeted conjugates also showed significant antitumor activities in vivo.

Decision Tree Searching Strategy to Boost the Identification of Cross-Linked Peptides.

We describe an efficient decision tree searching strategy (DTSS) to boost the identification of cross-linked peptides. The DTSS approach allows the identification of a wealth of complementary information to facilitate the construction of more protein-protein interaction networks for human cell lysate, which was tested by the use of a recently reported cross-linking data set (ACS Cent. Sci. 2019, 5, 1514-1522). A variant of the PhoX-linker, named pDSPE, was synthesized and applied to cross-link Escherichia coli cell lysate to demonstrate that the acquisition of doubly charged ions can significantly improve identification results. The method can be seamlessly integrated to other search engines to maximize the number of identified cross-links.

Polymer network-derived nitrogen/sulphur co-doped three-dimensionally interconnected hierarchically porous carbon for oxygen reduction, lithium-ion battery, and supercapacitor.

Rational design and simple synthesis of carbon-based materials with high electrocatalytic activity are essential for their practical applications in electrochemical energy conversion and storage devices. Herein, we report the synthesis of nitrogen, sulfur co-doped three-dimensional interconnected hierarchically porous carbon (NSHPC) by zinc acetate assisted pyrolysis of polymer networks. The thus-synthesized NSHPC has a specific surface area of 1057 cm2 g-1 with the coexistence of micro- and meso-pores. As metal-free electrocatalyst, the NSHPC exhibits a promising activity towards oxygen reduction reactions as evidenced by the slightly negative shift of half-wave potential compared with commercial Pt/C catalyst. The assembled lithium ion battery using NSHPC as anode delivers the reversible capacity of 740 and 470 mA h g-1 at current densities of 2 and 5 A g-1 without performance decay after 1000 charge-discharge cycles. Moreover, the assembled supercapacitor using NSHPC as electrode has the capacitance of 203 F g-1 at 1 A g-1.

Drastically enhanced visible light-driven H2 evolution by anchoring TiO2 nanoparticles on molecularly grafted carbon nitride nanosheets via a multiple modification strategy.

The development of graphitic carbon nitride (CN) based photocatalysts towards efficient visible light-driven H2 evolution is highly desired for solar energy conversion. It is well-known that bulk CN materials possess three intrinsic problems, namely, high charge recombination loss, low specific surface area, and limited sunlight harvesting range. To simultaneously overcome the abovementioned drawbacks of CN, we report an innovative multiple modification strategy, involving molecular grafting of the CN network, exfoliation to ultrathin nanosheets, and hybridization with TiO2 photocatalysts. The visible light utilization ability, specific surface area, and charge separation efficiency of the CN materials improved accordingly. As expected, the TiO2/CNX-NS heterojunction photocatalyst exhibited remarkably enhanced visible light-driven H2 production rate of 138.4 µmol h-1, which was about 4.6 times higher than that of pristine CN. The excellent photocatalytic performance under visible light confirmed the successful improvement in the corresponding drawbacks of CN by each modification. In this study, we propose the possibility of combining multiple modifications in the same system to synthesize an excellent visible light-driven photocatalyst for solar-to-fuel conversion.

New route to synthesize highly active nanocrystalline sulfated titania-silica: synergic effects between sulfate species and silica in enhancing the photocatalysis efficiency.

A simple and efficient approach has been set up for fabricating highly active sulfated titania-silica (SO(4)(2-)/TiO(2)-SiO(2)): Ti(SO(4))(2) was hydrolyzed in the presence of silica, making it possible to sulfate titania and form titania-silica mixed oxide in one step. This study was focused on investigating the roles of sulfate species and silica in improving the physicochemical properties and photoactivity of SO(4)(2-)/TiO(2)-SiO(2) through comparison with sulfated titania (SO(4)(2-)/TiO(2)) and sulfate-free catalysts (TiO(2) and TiO(2)-SiO(2)). Various characterization methods, including X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and surface photovoltage spectroscopy (SPS), were employed to test these materials. The results revealed that for SO(4)(2-)/TiO(2) and TiO(2)-SiO(2) the sole presence of either sulfate species or silica imposes negative effects on the photocatalysis behavior of titania, leading them to have negligible photoactivities. On the contrary, in the case of SO(4)(2-)/TiO(2)-SiO(2), sulfate species and silica were proved to act in a cooperative manner; therefore, the following enhanced structure and surface properties of SO(4)(2-)/TiO(2)-SiO(2) were obtained: (i) relatively well-crystallized and smaller-size (15.4 nm) anatase-phase titania was formed upon 500 degrees C calcination without forming rutile phase and (ii) the formation of active surface sulfate species promotes the separation of photoinduced electron-hole pairs and therefore accelerates the photocatalysis reaction. Therefore, its photoactivity is enhanced as a result of the favorable synergic effects between sulfate species and silica due to their simultaneous presence.

Synthesis of highly active sulfate-promoted rutile titania nanoparticles with a response to visible light.

Highly active sulfate-promoted rutile titania (SO(4)(2-)/TiO(2)) with smaller band gap was prepared by an in situ sulfation method, that is, under moderate conditions, sulfate-promoted rutile titania was directly obtained via precipitating Ti(SO(4))(2) in NaOH solution followed by peptizing in HNO(3) without the phase transformation from anatase to rutile. Thus, the negative impacts of phase transformation from anatase to rutile on the structure, surface, and photoactivity properties of the catalysts due to higher calcination temperature can be avoided. The catalysts were characterized by means of thermal analysis, Brunauer-Emmett-Teller analysis (BET), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), UV-visible spectroscopy, FT-IR pyridine adsorption, and temperature-programmed desorption (TPD). The results show sulfate species are sensitive to the variation of calcination temperature. In the process of peptizing, sulfate species are homogeneously dispersed throughout the bulk of catalysts, allowing sulfate species to penetrate into the network of TiO(2) effectively. After being calcined at 300 degrees C, sulfate species occupy oxygen sites to form Ti-S bonds, as evidenced by XPS results. As calcination temperature is further increased to 600 degrees C or above, the active sulfate species on the catalyst surface are destroyed, and the sulfate species in the network of TiO(2) are expelled out onto the surface to form inactive sulfate species. Thus, Ti(3+) defects will be produced on the catalyst surface. Accompanying this process, surface area is decreased promptly, and crystalline size is greatly increased via two fast growth phases due to the decomposition of sulfate species with different binding forces. Most importantly, the band gap of SO(4)(2-)/TiO(2) is remarkably shifted to the visible light region due to the formation of Ti-S bonds, and with increasing calcination temperature the visible light absorption capability is reduced due to breakage of Ti-S bonds. The excellent photoactivity of 300 degrees C calcined SO(4)(2-)/TiO(2) can be explained by its small crystalline size, high surface area, loose and porous microstructure, and the generation of Brønsted acidity on its surface.

Photocatalytic oxidation of heptane in the gas-phase over TiO2.

In this paper, gas-phase photocatalytic oxidation (PCO) of heptane over UV-illuminated TiO2 was carried out at ambient temperature in a batch reactor. Complete oxidation of heptane with almost stoichiometric production of CO2 and H2O was observed. The intermediates detected were propanal, butanal, 3-heptanone, 4-heptanone and carbon monoxide. A scheme of the possible mechanism for PCO of heptane over TiO2 was suggested. Langmuir-Hinshelwood kinetics equation was obtained from the results at different initial concentrations of heptane, oxygen, moisture and light intensity. The photocatalytic activity of TiO2 can be sustained indefinitely. This can be attributed to the production of water in the system, which can replenish the consumed hydroxyl radicals.