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Human herpesvirus 6 (HHV6) encephalitis is a rare but life-threatening complication for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, reports on susceptibility factors and clinical outcomes are limited. We enrolled HHV6 encephalitis patients following allo-HSCT between 2018 and 2022, then conducted a 1:4 nested case-control cohort study to evaluate risk factors and long-term outcomes. Among 1350 patients, 20 (1.48%) developed HHV6 encephalitis, with a median onset time of 25.5 days after HSCT. Patient age<30 (odds ratio [OR], 3.24, P = 0.016) and NK cell count<115/ul at 21 days (OR, 6.07, P = 0.018) were identified as independent risk factors in multivariate analysis. Moreover, the HHV6 encephalitis group was significantly associated with higher incidence of grade II-IV graft-versus-host disease (aGVHD) (hazard ratio [HR], 5.52, P < 0.001) and transplant-associated microangiopathy (HR,9.86, P < 0.001), and demonstrated a significantly higher non-relapse mortality (NRM) (HR, 5.28, P = 0.004) and a lower overall survival (HR, 4.34, P = 0.001) or progression-free survival (HR, 3.94, P = 0.001) compared to control group. In conclusion, patients <30 years old or with delayed NK cell recovery are more susceptible to HHV6 encephalitis after allo-HSCT, and patients with HHV6 encephalitis after transplantation have poorer clinical outcomes.

Purpose: For the vibrating machine with linear motion, the traditional driving method is utilizing the self-synchronization of double vibrators, or using a single motor to drive a pair of forced synchronization vibrators by the gear meshing. In this paper, we propose and study a special linear motion vibrating system (VS) driven by only the single vibrator, where the vibrator is mounted on a pendulum (so called pendulum bob) and no synchronization strategy is involved. Methods: The Lagrange’s equation is used to obtain the motion differential equations of the system. Based on the vibration mechanics principle, the theory condition to guarantee the linear motion of the main working rigid frame (MWRF) is deduced, and the double frequency vibrating transmission (VT) between the pendulum and the MWRF is investigated. Simultaneously, some qualitative analyses are given to further reveal the special motion characteristics of the system by numeric. The the Runge-Kutta routine is applied directly to the motion differential equations of the system and the experiment is carried out to further verify the validity of the theoretical results. Results: The results show that the special linear motion of the MWRF can be realized for the proposed dynamic model when satisfying the corresponding theory condition in the absence of self-synchronous or forced synchronization strategy, and in this case the system stability is relatively strong. Conclusion: To guarantee the linear motion of the MWRF, the stiffness and damping, generating from the connection coupling between the pendulum and the MWRF, should be minimized. The present work can offer a reference to design a new kind of vibrating machine with linear motion. In engineering, the desired linear motion vibration amplitude of MWRF can be reached by adjusting the parameters of vibrator and considering the theory condition of implementing linear motion.

In present work, the double and triple-frequency synchronization behaviors of a vibrating mechanical system with two different driving frequencies, driven by three reversed rotating exciters, are investigated by theory, numeric, and experiment. Based on Lagrange’s equations, the dynamic model corresponding to vibrating machine is proposed and motion differential equations are constructed. The Bogoliubov standard formal equations for three exciters are established, by introducing the asymptotic method, in which the synchronization problem is converted into that of the existence and stability of zero-valued solution of the average differential equations. The synchronization criterion of satisfying the synchronous operation is deduced. According to the Routh–Hurwitz criterion, the stability criterion of the synchronous states is achieved analytically. Based on the obtained theory results, the stability characteristics of the system, are numerically discussed in detail, including the stability ability coefficients and stable phase differences. Finally, simulations and experiments under the condition of two different driving frequencies, are performed to further examine the validity of the theoretical and numerical qualitative results. The present work can provide a theoretical reference for designing some new types of the vibrating machines with adjustable frequencies and motion trajectories.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial–mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.

A regioselective coupling of aliphatic ketones with alkenes has been realized by cathodic reduction. This reaction enables the formation of ketyl radicals and the activation of challenging alkenes under mild electrolysis conditions, providing an effective protocol for accessing diverse tertiary alcohols with substrate-dependent regioselectivity. The practicability of this reaction is demonstrated by scale-up experiments. The hydrogen source for the products, the migration isomerization of allylarenes, and the applicability of internal alkenes are demonstrated by control experiments.

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial–mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.

This paper aims at investigating the times–frequency synchronization of the three exciters in a far super-resonant vibrating system. Based on the asymptotic method, the Bogoliubov standard formal equations of the three exciters are constructed, and the criterion of the double-frequency synchronization for the simplified form is deduced. Meanwhile, the stability criterion of the synchronous states is derived by complying with the Routh–Hurwitz principle. The stability characteristics of double-frequency synchronization are qualitatively discussed by numeric, including the stable phase differences and stability ability among the three exciters. Finally, the corresponding simulations and experiments for the double-frequency synchronization are carried out, respectively. According to the comparisons and analyses of results for theory, numeric, simulation and experiment, including the stable phase differences among the three exciters, responses of the system, synchronous rotational velocities, etc., it is shown that the feasibility of the used theory method and the validity of the obtained results are verified. This paper can also provide a theoretical reference for designing new types of vibrating equipment in engineering with two different driving frequencies.

A new dynamical model with five rigid frames (RFs), driven by two counter-rotating exciters, is proposed to explore the synchronization, stability, and motion characteristics of the system in this paper. The motion differential equations and the corresponding responses of the system are given firstly. Using the average method, the average torque balance equations for the two exciters are deduced. According to the relationship between the difference of the dimensionless effective output electromagnetic torques for the two motors and the coupling torques of the system, the theory condition of realizing synchronization is obtained. Based on the Hamilton’s theory, the theory condition of stability of the system is deduced. The stability and motion characteristics of the system for different resonant regions are qualitatively discussed in numeric, including the stable phase difference of the two exciters, relative phase relationships among the five rigid frames, amplitude-frequency characteristics, stability coefficients, and the effective load torque between the two exciters. Simulations are carried out to further quantitatively validate the feasibility of the above theoretical and numerical qualitative results. It is shown that in engineering the reasonable working points of the system should be selected in Region II, only in this way, can the synchronous and stable relative linear motion of the system with the zero stable phase difference in vertical direction be realized, and in this case, the vibrations of the four inner rigid frames (IRFs) in the horizontal direction are compensated with each other, and the energy is also saved due to utilizing the resonant effect. Based on the present work, some new types of vibrating coolers/dryers or vibrating screening machines can be designed.

An electrochemical protocol for the construction of substituted isoindolinones via reduction/amidation of 2-carboxybenzaldehydes and amines has been realized. Under metal-free and external-reductant-free electrolytic conditions, the reaction achieves the cascade formation of intermolecular C–N bonds and provides a series of isoindolinones in moderate to good yields. The deuterium-labeling experiment proves that the hydrogen in the methylene of the product is mainly provided by H2O in the system.

Soliseptide A (1), a cyclic hexapeptide possessing piperazic acid groups, together with two known azalomycin derivatives (2and 3) were isolated from Streptomyces solisilvaeHNM30702. Their structures were determined through spectroscopic methods and single crystal X-ray diffraction analysis. Soliseptide A (1) possessed a cyclic hexapeptide core featured with two piperazic acid units rarely discovered in nature, and exhibited weak antibacterial and antiviral activities. Besides, compounds 2and 3displayed significant fungicidal effects.

The opening of the five-membered ring is the essential step for phthalimide and its derivatives to be used as the reactants in many chemical synthetic routes. Reportedly, such ring opening follows the concerted mechanism in methanol solvent, which, however, has an unreasonably high energy barrier (36.3 kcal mol-1at the M06-2X/6-311++G(d,p) level of theory). By density functional theory calculations, we report that this ring opening prefers the alternatively stepwise mechanism. The stepwise mechanism has a much lower energy barrier (21.0 kcal mol-1at the same level of theory) and thus is much more completive than the concerted one. The stepwise mechanism should be considered as the dominant mechanism responsible for the phthalimide ring opening when studying the kinetics of the relevant synthetic reactions in the future.

Aging and regeneration are heavily linked processes. While it is generally accepted that regenerative capacity declines with age, some vertebrates, such as newts, can bypass the deleterious effects of aging and successfully regenerate a lens throughout their lifetime.

observations were conducted on the phenomenon of flash evaporation. The bubbles appear and grow due to the liquid becomes superheated by a sudden decrease in pressure. During experiments the pure water is flashed at an initial temperature range of 55-90℃, an initial liquid film height range of 10-60mm, and a superheat range of 2-22K. The spatial and temporal distribution of the bubbles are analyzed during the flashing. And the distribution of bubbles under different superheat and the photo of the behaviors of bubbles were studied. The flashing evaporation can be divided into three stages according to the rate of the bubbles number change and the NEF(non-equilibrium fraction) can express the rate of bubble number at different stages. The number of bubbles is affected by the difference of enthalpy under the same volume of the liquid.

Energy conversion of pure water during the static flash evaporation is analysed with water static pressure taken into consideration.The experiment is conducted by varying the initial temperature and height of water in the range of 50 ℃ to 80 ℃ and 3 mm to 60 mm, respectively. The enthalpy difference is the main driving force of the flashing and the superheat can represents the enthalpy difference at the macro level which can be calculated by measuring the temperature of the water. The results indicates that the the gravity has a great effect on the energy conversion during the flashing. According to the evolution of the NEF, the flashing can be divided into rapid evaporation stage(RES) and gradual evaporation stage(GES) and the heat and mass transfer obviously show differences at the two stages. The NEFtpand τtpare introduced as evaluation index to express the completeness of the flashing during the RES and the duration of RES. The initial height of water can increase NEFtpand τtpand the superheat show different effect on the NEFtp. The gravity restrains the growth of the bubbles and extend the the duration of RES. The initial height and superheat positively increase the evaporated mass and mass flow rate during the flashing. It is clear that the gravity can not be ignore when the flashing is studied.

Although continuous flow synthesis using microtubing reactors has provided a wealth of opportunities for homogeneous photochemical synthesis and has proven particularly beneficial in scaling up processes, employing continuous flow technology to scale up heterogeneous photoreactions is challenging due to the issues including handling of solids, poor light penetration, and commonly lengthy reaction time. Here we present a solution to these issues by changing the continuous flow mode to a high-speed circulation flow mode. The high flow rate set in a circulation flow reactor overcomes solid sedimentation to prevent clogging and improve the mixing efficiency. We successfully conducted 100 g-scale C–N and C–S cross-couplings using a heterogeneous photocatalyst and a nickel catalyst in the flow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve a kilogram-scale synthesis without obvious deactivation. Semicontinuous production was achieved via automated feeding and collection, and a photopromoted gas/liquid/solid three-phase trifluoromethylation reaction was employed. A kilogram-scale amount of starting material was successfully transformed, resulting in a 43.2% yield of trifluridine. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist’s toolbox because of its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety, and tolerance of solids.

Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.

Iakyricidins A–D (1–4), a carbonyl-containing piericidin derivative and three novel piericidin analogues bearing cyclic skeletons, were isolated from the mangrove sediment derived strain Streptomyces iakyrusSCSIO NS104. These structures were established by spectroscopic techniques, Mosher’s method, and ECD calculations. Compounds 2–4represent a novel skeleton of piericidins with branched chain C–C cyclization, and their biosynthetic pathways are proposed. Compound 1, the first natural carbonyl-containing piericidin derivate, exhibited potent antiproliferative activity against ACHN with an IC50value of 20 nM.

ABSTRACTRecent studies have revealed that chemokine-like factor-like MARVEL transmembrane domain-containing family member 6 (CMTM6) promotes tumor progression and modulates tumor immunity by regulating programmed death-ligand 1 stability; however, its intrinsic functions and regulatory mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly understood. Here, we show that CMTM6 is upregulated in ccRCC tissues and is strongly associated with advanced tumor grades, early metastases, and a worse prognosis. CMTM6 depletion significantly impaired the proliferation, migration, and invasion of ccRCC cells in vitroand in xenograft mouse models in vivo. In addition, targeting CMTM6 promotes anti-tumor immunity, represented by increased infiltration of CD4+and CD8+T cells in syngeneic graft mouse models. Further research revealed that loss of CMTM6 triggered aberrant activation of DNA damage response, resulting in micronucleus formation and G2/M checkpoint arrest, finally leading to cellular senescence with robust upregulation of numerous chemokines and cytokines. Our findings show for the first time the novel role of CMTM6 in maintaining cancer genome stability and facilitating tumor-mediated immunosuppression, linking DNA damage signaling to the secretion of inflammatory factors. Targeting CMTM6 may improve the treatment of patients with advanced ccRCC.

For a vibrating system where the pendulum and vibrators are coupled together, the relevant dynamic model and the corresponding synchronization problem are rarely studied, due to its complex dynamic coupling relationships. In this paper, a vibrator–pendulum coupling system is proposed to study its synchronization principle; here, the pendulum is driven by the synchronous motion of the two vibrators directly. By exploiting the system motion differential equations and their vibration responses, the synchronization criterion of the two vibrators is deduced via the average method. After that, the stability criterion for the synchronous states is presented according to the convergence and divergence characteristics of the perturbed differential equation in the balanced state. Based on the theoretical results, the synchronous stable states and motion characteristics of the system under different parameter conditions are discussed by numerical qualitative analyses, and the reasonable parameters matching principles in designing the real vibrating machine are provided. A series of numerical simulations and experiments are further given to examine the validity of the theoretical methods and the obtained results. The dynamic model and research results presented in this paper can be applied to design a new kind of vibrating jaw crusher; in this case, the pendulum is served as the moving jaw and can work with its swing motion trajectory under the premise of the stable zero-phase difference between the two vibrators.

An efficient cathodic carbonyl alkylation of aryl ketones or aldehydes with unactivated alkyl halides has been realized through the electrochemical activation of iron. The protocol is believed to include a radical–radical coupling or nucleophilic addition process, and the formation of ketyl radicals and alkyl radicals has been demonstrated. The protocol provides various tertiary or secondary alcohols by the formation of intermolecular C–C bonds under safe and mild conditions, is scalable, consumes little energy, and exhibits a broad substrate scope.

Guided by Global Natural Products Social molecular networking, two p-terphenyl derivatives and one 4,5-diphenyl-2-pyrone analogue, peniterphenyls A–C (1–3), together with five known p-terphenyl derivatives (4–8) and sulochrin (9), were obtained from a deep-sea-derived Penicilliumsp. SCSIO41030. Their structures were elucidated using extensive NMR spectroscopic and HRESIMS data and by comparing the information with literature data. Peniterphenyl B (2) represented the first reported natural product possessing a 4,5-diphenyl-substituted 2-pyrone derivative. The p-terphenyl derivatives displayed inhibitory activities against HSV-1/2 with EC50values ranging from 1.4 ± 0.6 to 9.3 ± 3.7 μM in Vero cells, which showed that they possessed antiviral activities with low cytotoxicity, superior to the current clinical drug acyclovir (EC503.6 ± 0.7 μM). Peniterphenyl A (1) inhibited HSV-1/2 virus entry into cells and may block HSV-1/2 infection through direct interaction with virus envelope glycoprotein D to interfere with virus adsorption and membrane fusion, and thus differs from the nucleoside analogues such as acyclovir. Our study indicated peniterphenyl A (1) could be a promising lead compound against HSV-1/2.

To solve the problem of detecting the cone bucket target on both sides of the FSAC racing car, a new target detection method based on Faster R-CNN is proposed. The method uses a deep residual network as a feature extraction network to fully extract sample data features. In the Region Proposal Network (RPN), the anchor boxes are divided into finer parts to enhance the detection effect on the small target cones. Optimize the Non-maximum Suppression (NMS) algorithm to extract the proposal box and reduce the missed detection rate of the adjacent cone bucket target. The target detection network model is obtained by training on the self-made cone bucket dataset. The experimental results show that the improved algorithm based on Faster R-CNN is robust to the detection of cone bucket targets.