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Chemical biology and the application of small molecules has proven to be a potent perturbation strategy, especially for the functional elucidation of proteins, their networks, and regulators. In recent years, the cellular thermal shift assay (CETSA) and its proteome-wide extension, thermal proteome profiling (TPP), have proven to be effective tools for identifying interactions of small molecules with their target proteins, as well as off-targets in living cells. Here, we asked the question whether isothermal dose–response (ITDR) CETSA can be exploited to characterize secondary effects downstream of the primary binding event, such as changes in post-translational modifications or protein–protein interactions (PPI). By applying ITDR-CETSA to MAPK14 kinase inhibitor treatment of living HL-60 cells, we found similar dose–responses for the direct inhibitor target and its known interaction partners MAPKAPK2 and MAPKAPK3. Extension of the dose–response similarity comparison to the proteome wide level using TPP with compound concentration range (TPP-CCR) revealed not only the known MAPK14 interaction partners MAPKAPK2 and MAPKAPK3, but also the potentially new intracellular interaction partner MYLK. We are confident that dose-dependent small molecule treatment in combination with ITDR-CETSA or TPP-CCR similarity assessment will not only allow discrimination between primary and secondary effects, but will also provide a novel method to study PPI in living cells without perturbation by protein modification, which we named “small molecule arranged thermal proximity coaggregation” (smarTPCA).

In the present work, meso-tetrakis(2,4,6-trimethylphenyl) porphyrinato)zinc(II): ([Zn(TMP)] (1), meso-tetrakis-(tetraphenyl)porphyrin iron(III))chloride): [Fe(TPP)Cl] (2), and meso-tetrakis(phenyl)porphyrin manganese(III) chloride): [Mn(TPP)Cl] (3) were synthesized. Then, the three prepared porphyrinic complexes (1–3) were functionalized with branched polyethyleneimine (PEI). The prepared complexes were thoroughly analyzed using several analytical techniques, including 1H NMR, FT-IR, UV-vis, XRD, XRF, TGA-DTA, SEM, and EDX. The presence of sharp main peaks at 2θ between 10° and 80°, in XRD analysis, for all studied compounds suggested the crystalline nature of the porphyrinic complexes. The morphological properties of the porphyrininc complexes were significantly affected by the chemical modification with polyethyleneimine. EDX result confirmed the complexation of zinc, iron, and manganese metals with the porphyrinic core. The increase in carbon and nitrogen contents after the addition of polyethyleneimine to the complexes (1–3) was noticeable. After thermal decomposition, the total mass loss was equal to 92.97%, 66.77%, and 26.78% for complexes (1), (2), and (3), respectively. However, for the complex (1)-PEI, complex (2)-PEI, and complex (3)-PEI, the total mass losses were 83.12%, 81.88%, and 35.78%, respectively. The synthetic compounds were additionally utilized for the adsorption of Naphthol blue black B from water. At optimum adsorption conditions (T = 20 °C, time = 60 min, pH = 5), the highest adsorption capacities were 154 mg/g, 139 mg/g, and 119 mg/g for complex (3)-PEI, complex (2)-PEI, and complex (1)-PEI, respectively. The adsorption mechanism followed the pseudo second order, the Freundlich, and the Temkin models. The results indicated that the adsorption process is reliant on chemical interactions. It was also governed by intraparticular diffusion and other kinetic phenomena.

The protective role of puerarin (PUE) against myocardial infarction is closely related to its regulation on mitochondria. However, free PUE can hardly reach the mitochondria of ischemic cardiomyocytes due to the lack of mitochondrial targeting of PUE. Here PUE was loaded into mitochondria-targeted micelles (PUE@TPP/PEG-PE) for precisely delivering PUE into mitochondria with the aim of enhancing the anti-apoptosis effect. The mitochondriotropic polymer TPP-PEG-PE was synthesized for the preparation of PUE@TPP/PEG-PE micelles modified with triphenylphosphonium (TPP) cation. The physicochemical properties and anti-apoptosis effect of PUE@TPP/PEG-PE micelles were investigated. The coumarin 6 (C6)-labeled TPP/PEG-PE (C6@TPP/PEG-PE) micelles were used to observe the enhanced cellular uptake, mitochondrial targeting and lysosomes escape. Moreover, in vivo and ex vivo biodistribution of lipophilic near-infrared dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR)-labeled PUE@TPP/PEG-PE (DiR@TPP/PEG-PE) micelles were detected through fluorescence imaging. The successful synthesis of TPP-PEG-PE conjugate was confirmed. PUE@TPP/PEG-PE micelles had a particle size of 17.1 nm, a zeta potential of -6.2 mV, and a sustained-release behavior. The in vitro results showed that the intracellular uptake of C6@TPP/PEG-PE micelles was significantly enhanced in H9c2 cells. C6@TPP/PEG-PE micelles could deliver C6 to mitochondria and reduce the capture of lysosomes. In addition, compared with the PUE@PEG-PE micelles and free PUE, the PUE@TPP/PEG-PE micelles exerted an enhanced protective effect against isoprenaline-induced H9c2 cell apoptosis, as evident by the decreased percentage of apoptotic cells, Caspase-3 activity, ROS level, Bax expression, and increased Bcl-2 expression. The in vivo detecting results of the targeting effect using DiR probe also indicated that TPP/PEG-PE micelles could accumulate and retain in the ischemic myocardium. The results of this study demonstrate the promising potential of applying PUE@TPP/PEG-PE micelles in mitochondria-targeted drug delivery to achieve maximum therapeutic effects of PUE.

Whey protein isolate (WPI), employed as a carrier for a wide range of bioactive substances, suffers from a lack of colloidal stability in physiological conditions. Herein, we developed innovative stabilized PolyElectrolyte Nanoparticles (PENs) obtained by two techniques: polyelectrolyte complexation of negatively charged WPI and positively charged chitosan (CS), and ionic gelation in the presence of polyanion tripolyphosphate (TPP). Therefore, the WPI-based core was coated with a CS-based shell and then stabilized by TPP at pH 8. The nanostructures were characterized by physiochemical methods, and their encapsulation efficiency and in vitro release were evaluated. The spherical NPs with an average size of 248.57 ± 5.00 nm and surface charge of +10.80 ± 0.43 mV demonstrated high encapsulation efficiency (92.79 ± 0.69) and sustained release of a positively charged chemotherapeutic agent such as doxorubicin (DOX). Z-average size and size distribution also presented negligible increases in size and aggregates during the three weeks. The results obtained confirm the effectiveness of the simultaneous application of these methods to improve the colloidal stability of PEN.

The government tried to close illegal sites and conduct a copyright protection campaign intensively. However, it takes a lot of time to prevent illegal sites to block, and there is a limitation when internet browsers used a secure protocol. In order to implement effective policies, DNS servers and SNI fields were blocked since 2019. But SNI field blocking is not a solution of effective blocking because of technical problems. The risk of invading Internet users' access to information has also increased due to the strengthening of access blocking technology and excessive review by government agencies. The government's method of blocking illegal sites is technically circumvented, so there is a problem in its implementation, and it is necessary to start again from collecting public opinion due to the effectiveness and lack of transparency in terms of control. International judicial assistance should be activated to allow direct disposal of the server operating overseas, not to block access to domestic telecommunication network.

Background Totally preperitoneal hernioplasty (TPP) is a concept which was introduced for distinguishing with totally extraperitoneal (TEP). There is few evidence reflecting the single incision laparoscopic totally preperitoneal (SIL-TPP) characteristic. The aim of study is to demonstrate the feasibility of single incision laparoscopic totally preperitoneal hernioplasty (SIL-TPP) and compare the outcomes with the single incision laparoscopic totally extraperitoneal hernioplasty (SIL-TEP) technique. Methods During August 2018 and July 2022, 200 inguinal hernia patients received SIL-TPP and 56 patients received SIL-TEP in the First hospital of Ningbo university. The demographics, clinical characteristics, intraoperative and postoperative parameters were retrospectively analysed. Results SIL-TPP and SIL-TEP hernia repair were successfully conducted in all patients. There was no conversation happened in two group. Patients’ demographics were comparable when compared between the two groups adding the comparison initial 52 cases analysis ( P  > 0.05). The mean unilateral hernia operative time was significant shorter in the SIL-TPP group than SIL-TEP group (unilateral: 81.38 ± 25.32 vs. 95.96 ± 28.54, P: 0.001). Further study of unilateral hernia operative time revealed the mean indirect hernia operative time was significant shorter in the SIL-TPP group than SIL-TEP group (indirect: 81.38 ± 25.33 vs. 95.87 ± 28.54, P: 0.001). The unilateral hernia operation time trend of initial 52 cases of two group analysis revealed the operation time of SIL-TPP reduced faster than SIL-TEP along with treating number increasing (Figs. 2 and 3). The comparison of initial equal quantity unilateral hernia patient mean operative time revealed the SIL-TPP group was significant shorter than SIL-TEP group (85.77 ± 22.76 vs. 95.87 ± 28.54, P: 0.049). The rate of peritoneum tearing of SIL-TPP group was significant high than SIL-TEP ( P  = 0.005). Conclusion SIL-TPP hernia repair is a superior procedure and possess its own distinguished advantages. We recommend it rather than SIL-TEP for treating inguinal hernia, especially for indirect hernia. However, large-scale randomized controlled trials comparing SIL-TPP and SIL-TEP are needed to confirm these results.

Dense and efficient circuits with component sizes approaching the physical limit is the hallmark of high performance integration. Ultimately, these features and their pursuit enabled the multi-decade lasting exponential increase of components on integrated electronic chips according to Moore’s law, which culminated with the high performance electronics we know today. However, current fabrication technology is mostly constrained to 2D lithography, and thermal energy dissipation induced by switching electronic signal lines presents a fundamental challenge for truly 3D electronic integration. Photonics reduces this problem, and 3D photonic integration is therefore a highly sought after technology that strongly gains in relevance due to the need for scalable application-specific integrated circuits for neural networks. Direct laser writing of a photoresin is a promising high-resolution and complementary metal-oxide-semiconductor (CMOS) compatible tool for 3D photonic integration. Here, we combine one and two-photon polymerization (TPP) for waveguide integration for the first time, dramatically accelerating the fabrication process and increasing optical confinement. 3D additive printing is based on femtosecond TPP, while blanket irradiation with a UV lamp induces one-photon polymerization (OPP) throughout the entire 3D chip. We locally and dynamically adjust writing conditions to implement (3 + 1)D -TPP: waveguide cores are printed with a small distance between neighboring writing voxels to ensure smooth interfaces, mechanical support structures are printed at maximal distance between the voxels to speed up the process. Finally, the entire chip’s volume not part of waveguide cores or mechanical support is polymerized in a single instance by UV blanket irradiation. This decouples fabrication time from the passive volume’s size. We succeed in printing vertical single-mode waveguides of 6 mm length that reach numerical apertures up to NA = 0.16. Noteworthy, we achieve exceptionally low −0.26 dB injection losses and very low propagation losses of −1.36 dB/mm at = 660 nm, which is within one order of magnitude of standard integrated silicon photonics. Finally, the optical performance of our waveguides does not deteriorate for at least ∼3000 h after printing, and remains stable during ∼600 h of continuous operation with 0.25 mW injected light.

Parkinson’s disease is the second leading neurodegenerative disease of aging. For over five decades, oral levodopa has been used to manage the progressive motor deficits that are the hallmark of the disease. However, individual dose requirements are highly variable, and patients typically require increased levodopa dosage as the disease progresses, which can cause undesirable side effects. It has become increasingly apparent that the gut microbiome can have a major impact on the metabolism and efficacy of therapeutic drugs. In this Perspective, we examine recent studies highlighting the impact of metabolism by Enterococcus faecalis, a common commensal gut bacterium, on levodopa bioavailability. E. faecalis expresses a highly conserved tyrosine decarboxylase that promiscuously converts levodopa to dopamine in the gut, resulting in decreased neuronal uptake of levodopa and reduced dopamine formation in the brain. Mitochondria-targeted antioxidants conjugated to a triphenylphosphonium moiety have shown promise in transiently suppressing the growth of E. faecalis and decreasing microbial levodopa metabolism, providing an approach to modulating the microbiome that is less perturbing than conventional antibiotics. Thus, mitigating metabolism by the gut microbiota is an attractive therapeutic target to preserve and potentiate the efficacy of oral levodopa therapy in Parkinson’s disease.

Objective The aim of this study was to introduce and assess the safety and feasibility of single incision laparoscopic totally preperitoneal hernioplasty (SIL-TPP) for bilateral inguinal hernia repair. Method Forty-two SIL-TPP procedures for bilateral inguinal hernia repair were conducted from June 2018 to July 2022 at the First Affiliated Hospital of Ningbo University using standard laparoscopic instruments and a single-port device. Clinical data such as demographic intraoperative parameters and short-term postoperative outcomes were collected and analysed. Results SIL-TPP was successful in 42 bilateral inguinal hernia patients, and no conversion occurred. Of these 42 patients, 38 were males and 4 were females. The average age was 57.4 ± 17 years. The participants’ mean BMI was 22.67 ± 2.19 kg/m2 (range from 18.65 to 28.71 kg/m2). There were 4 types of bilateral hernias. The percentage of patients who underwent surgery before the SIL-TPP procedure in the same region was 21.43% (9/42). The mean operative time was 114 ± 34.24 min (range, 70–215 min). A total of 11 intraoperative complications occurred in 42 bilateral inguinal hernia patients, including unintentional peritoneum tears and hernia sac tears. No major complications occurred in the study. The postoperative complication rate was 2.38% (1/42). One patient experienced intestinal obstruction after the operation that resolved spontaneously without treatment. The surgical time in the SIL-TPP group decreased gradually as the number of operations increased. Moreover, the operation time trend decreased linearly ( P  < 0.0001, R²=0.42). Conclusion SIL-TPP is a safe and feasible procedure for treating bilateral inguinal hernias. The SIL-TPP procedure requires distinct skills and has specific advantages in treating bilateral hernias. Large-scale randomized controlled studies comparing SIL-TPP with conventional single-port and three-port laparoscopic TEP for bilateral inguinal hernia are needed to confirm these results.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of old age. Accumulation of β-amyloid peptide (Aβ) and mitochondrial dysfunction results in chronic microglial activation, which enhances neuroinflammation and promotes neurodegeneration. Microglia are resident macrophages of the brain and spinal cord which play an important role in maintaining brain homeostasis through a variety of phenotypes, including the pro-inflammatory phenotype and anti-inflammatory phenotypes. However, persistently activated microglial cells generate reactive species and neurotoxic mediators. Therefore, inhibitors of microglial activation are seen to have promise in AD control. The modified TPP/MoS2 QD blend is a mitochondrion-targeted nanomaterial that exhibits cytoprotective activities and antioxidant properties through scavenging free radicals. In the present study, the cell viability and cytotoxicity of the DSPE-PEG-TPP/MoS2 QD blend on microglial cells stimulated by Aβ were investigated. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also assessed. In addition, pro-inflammatory and anti-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), transforming growth factor beta (TGF-β), inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-I) were measured in the presence or absence of the DSPE-PEG-TPP/MoS2 QD blend on an immortalized microglia cells activated by accumulation of Aβ. We found that the DSPE-PEG-TPP/MoS2 QD blend was biocompatible and nontoxic at specific concentrations. Furthermore, the modified TPP/MoS2 QD blend significantly reduced the release of free radicals and improved the mitochondrial function through the upregulation of MMP in a dose-dependent manner on microglial cells treated with Aβ. In addition, pre-treatment of microglia with the DSPE-PEG-TPP/MoS2 QD blend at concentrations of 25 and 50 μg/mL prior to Aβ stimulation significantly inhibited the release and expression of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and iNOS. Nevertheless, the anti-inflammatory cytokines TGF-β and Arg-I were activated. These findings suggest that the modified TPP/MoS2 QD blend reduced oxidative stress, inflammation and improved the mitochondrial function in the immortalized microglial cells (IMG) activated by Aβ. Overall, our research shows that the DSPE-PEG-TPP/MoS2 QD blend has therapeutic promise for managing AD and can impact microglia polarization.