MiR-431 promotes cardiomyocyte proliferation by targeting FBXO32 expression.

BACKGROUND: The induction of cardiomyocyte (CM) proliferation is a promising approach for cardiac regeneration following myocardial injury. MicroRNAs (miRNAs) have been reported to regulate CM proliferation. In particular, miR-431 expression decreases during cardiac development, according to Gene Expression Omnibus (GEO) microarray data. However, whether miR-431 regulates CM proliferation has not been thoroughly investigated. METHODS: We used integrated bioinformatics analysis of GEO datasets to identify the most significantly differentially expressed miRNAs. Real-time quantitative PCR and fluorescence in situ hybridization were performed to determine the miRNA expression patterns in hearts. Gain- and loss-of-function assays were conducted to detect the role of miRNA in CM proliferation. Additionally, we detected whether miR-431 affected CM proliferation in a myocardial infarction model. The TargetScan, miRDB and miRWalk online databases were used to predict the potential target genes of miRNAs. Luciferase reporter assays were used to study miRNA interactions with the targeting mRNA. RESULTS: First, we found a significant reduction in miR-431 levels during cardiac development. Then, by overexpression and inhibition of miR-431, we demonstrated that miR-431 promotes CM proliferation in vitro and in vivo, as determined by immunofluorescence assays of 5-ethynyl-2'-deoxyuridine (EdU), pH3, Aurora B and CM count, whereas miR-431 inhibition suppresses CM proliferation. Then, we found that miR-431 improved cardiac function post-myocardial infarction. In addition, we identified FBXO32 as a direct target gene of miR-431, with FBXO32 mRNA and protein expression being suppressed by miR-431. FBXO32 inhibited CM proliferation. Overexpression of FBXO32 blocks the enhanced effect of miR-431 on CM proliferation, suggesting that FBXO32 is a functional target of miR-431 during CM proliferation. CONCLUSION: In summary, miR-431 promotes CM proliferation by targeting FBXO32, providing a potential molecular target for preventing myocardial injury.

Enhancing the activity of zearalenone lactone hydrolase toward the more toxic α-zearalanol via a single-point mutation.

Zearalenone (ZEN) and its derivatives are estrogenic mycotoxins known to pose significant health threats to humans and animals. Especially, the derivative α-zearalanol (α-ZAL) is over 10 times more toxic than ZEN. Simultaneous degradation of ZEN and its derivatives, especially α-ZAL, using ZEN lactone hydrolases (ZHDs) is a promising solution to eliminate their potential hazards to food safety. However, most available ZHDs exhibit limited activity toward the more toxic α-ZAL compared to ZEN. Here, we identified a broad-substrate spectrum ZHD, named ZHDAY3, from Exophiala aquamarina CBS 119918, which could not only efficiently degrade ZEN but also exhibited 73% relative activity toward α-ZAL. Through rational design, we obtained the ZHDAY3(N153H) mutant, which exhibited the highest specific activity (253.3 ± 4.3 U/mg) reported so far for degrading α-ZAL. Molecular docking, structural comparative analysis, and kinetic analysis collectively suggested that the shorter distance between the side chain of the catalytic residue His242 and the lactone bond of α-ZAL and the increased binding affinity to the substrate were mainly responsible for the improved catalytic activity of ZHDAY3(N153H) mutant. This mechanism was further validated through additional molecular docking of 18 mutants and experimental verification of six mutants.IMPORTANCEThe mycotoxins zearalenone (ZEN) and its derivatives pose a significant threat to food safety. Here, we present a highly promising ZEN lactone hydrolase (ZHD), ZHDAY3, which is capable of efficiently degrading both ZEN and the more toxic derivative α-ZAL. Next, the ZHDAY3(N153H) mutant obtained by single-point mutation exhibited the highest specific activity for degrading α-ZAL reported thus far. We further elucidated the molecular mechanisms underlying the enhanced hydrolytic activity of ZHDAY3(N153H) toward α-ZAL. These findings represent the first investigation on the molecular mechanism of ZHDs against α-ZAL and are expected to provide a significant reference for further rational engineering of ZHDs, which will ultimately contribute to addressing the health risks and food safety issues posed by ZEN-like mycotoxins.

Atomic Origins of Enhanced Ferroelectricity in Nanocolumnar PbTiO3 /PbO Composite Thin Films.

Nanocomposite films hold great promise for multifunctional devices by integrating different functionalities within a single film. The microstructure of the precipitate/secondary phase is an essential element in designing composites' properties. The interphase strain between the matrix and secondary phase is responsible for strain-mediated functionalities, such as magnetoelectric coupling and ferroelectricity. However, a quantitative microstructure-dependent interphase strain characterization has been scarcely studied. Here, it is demonstrated that the PbTiO3 (PTO)/PbO composite system can be prepared in nano-spherical and nanocolumnar configurations by tuning the misfit strain, confirmed by a three-dimensional reconstructive microscopy technique. With the atomic resolution quantitative microscopy with a depth resolution of a few nanometers, it is discovered that the strained region in PTO is much larger and more uniform in nanocolumnar compared to nano-spherical composites, resulting in much enhanced ferroelectric properties. The interphase strain between PbO and PTO in the nanocolumnar structure leads to a giant c/a ratio of 1.20 (bulk value of 1.06), accompanied by a Ti polarization displacement of 0.48 Å and an effective ferroelectric polarization of 241.7 µC cm-2 , three times compared to the bulk value. The quantitative atomic-scale strain and polarization analysis on the interphase strain provides an important guideline for designing ferroelectric nanocomposites.

A source for awareness-dependent figure-ground segregation in human prefrontal cortex.

Figure-ground modulation, i.e., the enhancement of neuronal responses evoked by the figure relative to the background, has three complementary components: edge modulation (boundary detection), center modulation (region filling), and background modulation (background suppression). However, the neuronal mechanisms mediating these three modulations and how they depend on awareness remain unclear. For each modulation, we compared both the cueing effect produced in a Posner paradigm and fMRI blood oxygen-level dependent (BOLD) signal in primary visual cortex (V1) evoked by visible relative to invisible orientation-defined figures. We found that edge modulation was independent of awareness, whereas both center and background modulations were strongly modulated by awareness, with greater modulations in the visible than the invisible condition. Effective-connectivity analysis further showed that the awareness-dependent region-filling and background-suppression processes in V1 were not derived through intracortical interactions within V1, but rather by feedback from the frontal eye field (FEF) and dorsolateral prefrontal cortex (DLPFC), respectively. These results indicate a source for an awareness-dependent figure-ground segregation in human prefrontal cortex.

Purification, Structural Characterization, and Antitumor Activity of a Polysaccharide from Perilla Seeds.

A previous study found that a crude Perilla seed polysaccharide (PFSP) fraction exhibited obviously antitumor activity; however, the structural characterization and antitumor properties of this polysaccharide remain unclear. In this study, the PFSP was extracted and purified via combined column chromatography, and the structure of a single polysaccharide fraction was characterized by methylation, IC, GC-MS, NMR, and AFM. The results demonstrated that the efficient antitumor polysaccharide fraction PFSP-2-1 was screened from PFSP with a relative molecular weight of 8.81 × 106 Da. The primary structure of the PFSP main chain was →1)-Araf-(5→, →1,3)-Galp-(6→, →1)-Galp-(6→, →1,3)-Araf-(5→ and →1)-Xylp-(4→, and that of the side chains was →1)-Arap, →1,3)-Galp-(6→, →1)-Araf and →1)-Glcp-(4→, →1)-Galp-(3→ and →1)-Glcp, leading to a three-dimensional helical structure. CCK-8 experiments revealed that PFSP-2-1 significantly inhibited the growth of human hepatocellular carcinoma cells in vitro (p < 0.05), and its inhibitory effect positively correlation with the concentration of PFSP-2-1, and when the concentration of PFSP-2-1 was 1600 µg/mL, it showed the highest inhabitation rate on three hepatocellular carcinoma cells (HepG-2, Hep3b, and SK-Hep-1), for which the survival rates of HepG-2, Hep3b, and SK-Hep-1 were 53.34%, 70.33%, and 71.06%. This study clearly elucidated the structure and antitumor activity of PFSP-2-1, which lays a theoretical foundation for revealing the molecular mechanism of antitumor activity of Perilla seed polysaccharides and provides an important theoretical basis for the development of high-value Perilla.

An awareness-dependent mapping of saliency in the human visual system.

The allocation of exogenously cued spatial attention is governed by a saliency map. Yet, how salience is mapped when multiple salient stimuli are present simultaneously, and how this mapping interacts with awareness remains unclear. These questions were addressed here using either visible or invisible displays presenting two foreground stimuli (whose bars were oriented differently from the bars in the otherwise uniform background): a high salience target and a distractor of varied, lesser salience. Interference, or not, by the distractor with the effective salience of the target served to index a graded or non-graded nature of salience mapping, respectively. The invisible and visible displays were empirically validated by a two-alternative forced choice test (detecting the quadrant of the target) demonstrating subjects' performance at or above chance level, respectively. By combining psychophysics, fMRI, and effective connectivity analysis, we found a graded distribution of salience with awareness, changing to a non-graded distribution without awareness. Crucially, we further revealed that the graded distribution was contingent upon feedback from the posterior intraparietal sulcus (pIPS, especially from the right pIPS), whereas the non-graded distribution was innate to V1. Together, this awareness-dependent mapping of saliency reconciles several previous, seemingly contradictory findings regarding the nature of the saliency map.

Quantitative investigation of laser ablation based on real-time temperature variations and OCT images for laser treatment applications.

BACKGROUND AND OBJECTIVE: Lasers are widely employed in clinical applications. In vivo monitoring of real-time information about different-wavelength laser surgeries would provide important surgical feedback for surgeons or clinical therapy instruments. However, the quantitative effect of laser ablation or vaporization still needs to be further explored and investigated. Here, we investigate and quantitatively evaluate the ablation variations and morphological changes of two laser ablation models: point- and sweeping-based models. METHODS: An infrared thermal imager was used to monitor the temperature variations, and curve fitting was used to build the relationship between the laser radiation duration/sweeping speed and quantitative parameters of the ablated areas. Optical coherence tomography (OCT) images were used to visualize the inner structure and evaluate the depth of the ablated craters. Optical attenuation coefficients (OACs) were computed to characterize the normal and ablated tissues. RESULTS: The results demonstrated that there was a good linear relationship between radiation duration and temperature variation. Similarly, a linear relationship was observed between the sweeping speed and quantitative parameters of craters or scratches (width and depth). The mean OAC of normal tissues was significantly distinguished from the mean OACs of the ablated craters or scratches. CONCLUSION: Laser ablation was investigated based on a quantitative parameter analysis, thermal detection, and OCT imaging, and the results successfully demonstrated that there is a linear relationship between the laser parameters and quantitative parameters of the ablated tissues under the current settings. Such technology could be used to provide quantitative solutions for exploring the laser-tissue biological effect and improve the performance of medical image-guided laser ablation in the future.

The Plasmid pEX18Gm Indirectly Increases Caenorhabditis elegans Fecundity by Accelerating Bacterial Methionine Synthesis.

Plasmids are mostly found in bacteria as extrachromosomal genetic elements and are widely used in genetic engineering. Exploring the mechanisms of plasmid-host interaction can provide crucial information for the application of plasmids in genetic engineering. However, many studies have generally focused on the influence of plasmids on their bacterial hosts, and the effects of plasmids on bacteria-feeding animals have not been explored in detail. Here, we use a "plasmid-bacteria-Caenorhabditis elegans" model to explore the impact of plasmids on their host bacteria and bacterivorous nematodes. First, the phenotypic responses of C. elegans were observed by feeding Escherichia coli OP50 harboring different types of plasmids. We found that E. coli OP50 harboring plasmid pEX18Gm unexpectedly increases the fecundity of C. elegans. Subsequently, we found that the plasmid pEX18Gm indirectly affects C. elegans fecundity via bacterial metabolism. To explore the underlying regulatory mechanism, we performed bacterial RNA sequencing and performed in-depth analysis. We demonstrated that the plasmid pEX18Gm upregulates the transcription of methionine synthase gene metH in the bacteria, which results in an increase in methionine that supports C. elegans fecundity. Additionally, we found that a pEX18Gm-induced increase in C. elegans can occur in different bacterial species. Our findings highlight the plasmid-bacteria-C. elegans model to reveal the mechanism of plasmids' effects on their host and provide a new pattern for systematically studying the interaction between plasmids and multi-species.

Facilitating the Deprotonation of OH to O through Fe4+ -Induced States in Perovskite LaNiO3 Enables a Fast Oxygen Evolution Reaction.

Aliovalent doping is widely adopted to tune the electronic structure of transition-metal oxides for design of low-cost, active electrocatalysts. Here, using single-crystalline thin films as model electrocatalysts, the structure-activity relationship of Fe states doping in perovskite LaNiO3 for oxygen evolution reaction (OER) is studied. Fe4+ state is found to be crucial for enhancing the OER activity of LaNiO3 , dramatically increasing the activity by six times, while Fe3+ has negligible effect. Spectroscopic studies and DFT calculations indicate Fe4+ states enhance the degree of Ni/Fe 3d and O 2p hybridization, and meanwhile produce down-shift of the unoccupied density of states towards lower energies. Such electronic features reduce the energy barrier for interfacial electron transfer for water oxidization by 0.2 eV. Further theoretical calculations and H/D isotope experiments reveal the electronic states associated with Fe4+ -O2- -Ni3+ configuration accelerate the deprotonation of *OH to *O (rate-determining step), and thus facilitate fast OER kinetics.

Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway.

Post-translational modification (PTM) by small ubiquitin-like modifier (SUMO) is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting protein kinase B (Akt) SUMOylation can promote cardiac regeneration. Quantitative PCR and Western blotting results showed that small ubiquitin-like modifier-specific protease 2 (SENP2) is up-regulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte (CM) dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to CM proliferation and angiogenesis. Mechanistically, the loss of SENP2 up-regulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3ß levels and subsequently promoting CM proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes CM differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.

Characteristic Lengths of Interlayer Charge Transfer in Correlated Oxide Heterostructures.

Using interlayer interaction to control functional heterostructures with atomic-scale designs has become one of the most effective interface-engineering strategies nowadays. Here, we demonstrate the effect of a crystalline LaFeO3 buffer layer on amorphous and crystalline LaAlO3/SrTiO3 heterostructures. The LaFeO3 buffer layer acts as an energetically favored electron acceptor in both LaAlO3/SrTiO3 systems, resulting in modulation of interfacial carrier density and hence metal-to-insulator transition. For amorphous and crystalline LaAlO3/SrTiO3 heterostructures, the metal-to-insulator transition is found when the LaFeO3 layer thickness crosses 3 and 6 unit cells, respectively. Such different critical LaFeO3 thicknesses are explained in terms of distinct characteristic lengths of the redox-reaction-mediated and polar-catastrophe-dominated charge transfer, controlled by the interfacial atomic contact and Thomas-Fermi screening effect, respectively. Our results not only shed light on the complex interlayer charge transfer across oxide heterostructures but also provide a new route to precisely tailor the charge-transfer process at a functional interface.

Redox-Mediated Ambient Electrolytic Nitrogen Reduction for Hydrazine and Ammonia Generation.

This work presents a redox-mediated electrolytic nitrogen reduction reaction (RM-eNRR) using polyoxometalate (POM) as the electron and proton carrier which frees the TiO2 -based catalyst from the electrode and shifts the reduction of nitrogen to a reactor tank. The RM-eNRR process has achieved an ammonium production yield of 25.1 µg h-1 or 5.0 µg h-1 cm-2 at an ammonium concentration of 6.7 ppm. With high catalyst loading, 61.0 ppm ammonium was accumulated in the electrolyte upon continuous operation, which is the highest concentration detected for ambient eNRR so far. The mechanism underlying the RM-eNRR was scrutinized both experimentally and computationally to delineate the POM-mediated charge transfer and hydrogenation process of nitrogen molecule on the catalyst. RM-eNRR is expected to provide an implementable solution to overcome the limitations in the conventional eNRR process.

Phase Diagram and Superconducting Dome of Infinite-Layer Nd_{1-x}Sr_{x}NiO_{2} Thin Films.

Infinite-layer Nd_{1-x}Sr_{x}NiO_{2} thin films with Sr doping level x from 0.08 to 0.3 are synthesized and investigated. We find a superconducting dome x between 0.12 and 0.235 accompanied by a weakly insulating behavior in both under- and overdoped regimes. The dome is akin to that in the electron-doped 214-type and infinite-layer cuprate superconductors. For x≥0.18, the normal state Hall coefficient (R_{H}) changes the sign from negative to positive as the temperature decreases. The temperature of the sign changes decreases monotonically with decreasing x from the overdoped side and approaches the superconducting dome at the midpoint, suggesting a reconstruction of the Fermi surface with the dopant concentration across the dome.

SM22α (Smooth Muscle 22α) Prevents Aortic Aneurysm Formation by Inhibiting Smooth Muscle Cell Phenotypic Switching Through Suppressing Reactive Oxygen Species/NF-κB (Nuclear Factor-κB).

Objective- Vascular smooth muscle cell phenotypic transition plays a critical role in the formation of abdominal aortic aneurysms (AAAs). SM22α (smooth muscle 22α) has a vital role in maintaining the smooth muscle cell phenotype and is downregulated in AAA. However, whether manipulation of the SM22α gene influences the pathogenesis of AAA is unclear. Here, we investigated whether SM22α prevents AAA formation and explored the underlying mechanisms. Approach and Results- In both human and animal AAA tissues, a smooth muscle cell phenotypic switch was confirmed, as manifested by the downregulation of SM22α and α-SMA (α-smooth muscle actin) proteins. The methylation level of the SM22α gene promoter was dramatically higher in mouse AAA tissues than in control tissues. SM22α knockdown in ApoE-/- (apolipoprotein E-deficient) mice treated with Ang II (angiotensin II) accelerated the formation of AAAs, as evidenced by a larger maximal aortic diameter and more medial elastin degradation than those found in control mice, whereas SM22α overexpression exerted opposite effects. Similar results were obtained in a calcium chloride-induced mouse AAA model. Mechanistically, SM22α deficiency significantly increased reactive oxygen species production and NF-κB (nuclear factor-κB) activation in AAA tissues, whereas SM22α overexpression produced opposite effects. NF-κB antagonist SN50 or antioxidant N-acetyl-L-cysteine partially abrogated the exacerbating effects of SM22α silencing on AAA formation. Conclusions- SM22α reduction in AAAs because of the SM22α promoter hypermethylation accelerates AAA formation through the reactive oxygen species/NF-κB pathway, and therapeutic approaches to increase SM22α expression are potentially beneficial for preventing AAA formation.

Long Non-coding RNA ECRAR Triggers Post-natal Myocardial Regeneration by Activating ERK1/2 Signaling.

Reactivating post-natal myocardial regeneration potential may be a feasible strategy to regenerate the injured adult heart. Long non-coding RNAs (lncRNAs) have been implicated in regulating cellular differentiation, but whether they can elicit a regenerative response in the post-natal heart remains unknown. In this study, by characterizing the lncRNA transcriptome in human hearts during the fetal-to-adult transition, we found that 3,092 lncRNAs were differentially expressed, and we further identified a novel upregulated fetal lncRNA that we called endogenous cardiac regeneration-associated regulator (ECRAR), which promoted DNA synthesis, mitosis, and cytokinesis in post-natal day 7 and adult rat cardiomyocytes (CMs). Overexpression of ECRAR markedly stimulated myocardial regeneration and induced recovery of cardiac function after myocardial infarction (MI). Knockdown of ECRAR inhibited post-natal day 1 CM proliferation and prevented post-MI recovery. ECRAR was transcriptionally upregulated by E2F transcription factor 1 (E2F1). In addition, ECRAR directly bound to and promoted the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), resulting in downstream targets of cyclin D1 and cyclin E1 activation, which, in turn, activated E2F1. The E2F1-ECRAR-ERK1/2 signaling formed a positive feedback loop to drive cell cycle progression, and, therefore, it promoted CM proliferation. These findings indicated that our newly discovered ECRAR may be a valuable therapeutic target for heart failure.

[Neural mechanisms of visual selective attention].

Because of a limited capacity of information processing in the brain, the efficient processing of visual information requires selecting only a very small fraction of visual inputs at any given moment in time. Attention is the main mechanism that controls this selection process, namely selective attention. Selective attention is the mechanism by which the subset of incoming information is preferentially processed from the complex external environment. Research on selective attention has two key issues. One is what targets (inputs) are selected by attention. There are three different types of selective attention according to its selected target: space-based, feature-based, and object-based attention. Another issue is how selective attention is generated. There are two different types of selective attention according to its generating source: top-down and bottom-up attention. In this review, these two issues are introduced to systematically discuss the neural mechanism of visual selective attention.

Loss of long non-coding RNA CRRL promotes cardiomyocyte regeneration and improves cardiac repair by functioning as a competing endogenous RNA.

Long noncoding RNAs (lncRNAs) play critical roles in the development of myocardial hypertrophy and may stimulate endogenous myocardial regeneration to prevent heart failure after myocardial infarction (MI). However, whether lncRNAs are involved in regulating myocardial regeneration after MI remains unclear. The present study aimed to identify human-derived lncRNAs that are involved in endogenous cardiomyocyte (CM) regeneration. By analyzing publicly available RNA-seq data of human fetal and normal adult cardiac tissues, we identified a novel human-derived adult upregulated lncRNA designated cardiomyocyte regeneration-related lncRNA (CRRL). Bioinformatics analysis indicated that CRRL is involved in the negative regulation of CM proliferation. First, we observed that the loss of CRRL attenuates post-MI remodeling and preserves cardiac function in adult rats. Through loss-of-function approaches, we found that CRRL knockdown promotes neonatal rat CM proliferation both in vivo and in vitro. Furthermore, we demonstrated that CRRL acts as a competing endogenous RNA (ceRNA) by directly binding to miR-199a-3p and thereby increasing the expression of Hopx, a target gene of miR-199a-3p and a critical negative regulatory factor of CM proliferation. Thus, CRRL suppresses cardiomyocyte regeneration by directly binding to miR-199a-3p, indicating that loss of CRRL facilitates myocardial regeneration and may be a new potential therapeutic strategy for heart failure.

Indole-3-Acetic Acid Biosynthesis Pathways in the Plant-Beneficial Bacterium Arthrobacter pascens ZZ21.

Arthrobacter pascens ZZ21 is a plant-beneficial, fluoranthene-degrading bacterial strain found in the rhizosphere. The production of the phytohormone indole-3-aectic acid (IAA) by ZZ21 is thought to contribute to its ability to promote plant growth and remediate fluoranthene-contaminated soil. Using genome-wide analysis combined with metabolomic and high-performance liquid chromatography-mass spectrometry (HPLC-MS) analyses, we characterized the potential IAA biosynthesis pathways in A. pascens ZZ21. IAA production increased 4.5-fold in the presence of 200 mg·L-1 tryptophan in the culture medium. The transcript levels of prr and aldH, genes which were predicted to encode aldehyde dehydrogenases, were significantly upregulated in response to exogenous tryptophan. Additionally, metabolomic analysis identified the intermediates indole-3-acetamide (IAM), indole-3-pyruvic acid (IPyA), and the enzymatic reduction product of the latter, indole-3-lactic acid (ILA), among the metabolites of ZZ21, and subsequently also IAM, ILA, and indole-3-ethanol (TOL), which is the enzymatic reduction product of indole-3-acetaldehyde, by HPLC-MS. These results suggest that the tryptophan-dependent IAM and IPyA pathways function in ZZ21.

[Progress on pharmacokinetic study of antibody-drug conjugates].

Antibody-drug conjugate (ADC) is a new class of therapeutics composed of a monoclonal antibody and small cytotoxin moieties conjugated through a chemical linker. ADC molecules bind to the target antigens expressed on the tumor cell surfaces guided by the monoclonal antibody component. The binding ADC molecules can be internalized and subsequently the toxin moieties can be released within the tumor cells via chemical and/or enzymatic reactions to kill the target cells. The conjugation combines the merits of both components, i.e., the high target specificity of the monoclonal antibody and the highly potent cell killing activity of the cytotoxin moieties. However, such complexities make the pharmacokinetic and metabolic studies of ADCs highly challenging. The major challenges should include characterization of absorption, distribution, metabolism and excretion, investigation of underlying mechanisms, assessment of pharmacokinetic- pharmacodynamic relationship, and analytical method development of ADC drugs. This review will discuss common pharmacokinetic issues and considerations, as well as tools and strategies that can be utilized to characterize the pharmacokinetic and metabolic properties of ADCs.

The Effects of Exogenous Benzoic Acid on the Physicochemical Properties, Enzyme Activities and Microbial Community Structures of Perilla frutescens Inter-Root Soil.

This study analyzed the effects of benzoic acid (BA) on the physicochemical properties and microbial community structure of perilla rhizosphere soil. The analysis was based on high-throughput sequencing technology and physiological and biochemical detection. The results showed that with the increase in BA concentration, soil pH significantly decreased, while the contents of total nitrogen (TN), alkaline nitrogen (AN), available phosphorus (AP), and available potassium (AK) significantly increased. The activities of soil conversion enzymes urease and phosphatase significantly increased, but the activities of catalase and peroxidase significantly decreased. This indicates that BA can increase soil enzyme activity and improve nutrient conversion; the addition of BA significantly altered the composition and diversity of soil bacterial and fungal communities. The relative abundance of beneficial bacteria such as Gemmatimonas, Pseudolabrys, and Bradyrhizobium decreased significantly, while the relative abundance of harmful fungi such as Pseudogymnoascus, Pseudoeurotium, and Talaromyces increased significantly. Correlation analysis shows that AP, AN, and TN are the main physicochemical factors affecting the structure of soil microbial communities. This study elucidates the effects of BA on the physicochemical properties and microbial community structure of perilla soil, and preliminarily reveals the mechanism of its allelopathic effect on the growth of perilla.