Associations of exposure to organochlorine pesticides and polychlorinated biphenyls with chronic kidney disease among adults: the modifying effects of lifestyle.

Exposure to organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) has been reported to be associated with renal impairment and chronic kidney disease (CKD). Nevertheless, the research results thus far have exhibited inconsistency, and the effect of lifestyle on their association is not clear. In this study, we assessed the correlation between serum OCPs/PCBs and CKD and renal function indicators including estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) among 1721 Chinese adults. In order to further investigate the potential impact of lifestyle, we conducted joint associations of lifestyle and OCPs/PCBs on CKD. We found a negative correlation between p,p'-DDE and eGFR, while logistic regression results showed a positive correlation between PCB-153 and CKD (OR, 1.92; 95% CI, 1.21, 3.06). Quantile g-computation regression analyses showed that the association between co-exposure to OCPs/PCBs and CKD was not significant, but p,p'-DDE and PCB-153 were the main contributors to the negative and positive co-exposure effects of eGFR and CKD, respectively, which is consistent with the regression results. Participants with both relatively high PCB-153 exposure and an unhealthy lifestyle had the highest risk of CKD, in the joint association analysis. The observed associations were generally supported by the FAS-eGFR method. Our research findings suggest that exposure to OCPs/PCBs may be associated with decreased eGFR and increased prevalence of CKD in humans, and a healthy lifestyle can to some extent alleviate the adverse association between PCB-153 exposure and CKD.

Synthesis and photoluminescence properties of polymer chains based on pre-designed heterometallic Al4Ln4 molecular rings.

Presented herein is a series of chain compounds based on pre-designed heterometallic aluminum-lanthanide (Al-Ln) Al4Ln4 molecular rings. Their photoluminescence quantum yield (PLQY) with Eu3+ (30.41%) and Tb3+ (41.44%) is at a high level among the clusters containing four Ln ions. This study significantly extends the family of Al-Ln heterometallic clusters and demonstrates the synergistic effect of heterometallic ions in enhancing their properties.

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1.

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15 Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

In-Situ Solid Electrolyte Interface via Dual Reaction Strategy for Highly Reversible Zinc Anode.

In-situ construction of solid electrolyte interfaces (SEI) is an effective strategy to enhance the reversibility of zinc (Zn) anodes. However, in-situ SEI to afford high reversibility under high current density conditions (≥ 20 mA cm-2) is highly desired yet extremely challenging. Herein, we propose a dual reaction strategy of spontaneous electrostatic reaction and electrochemical decomposition for the in-situ construction of SEI, which is composed of organic-rich upper layer and inorganic-rich inner layer. Particularly, in-situ SEI performs as "growth binder" at small current density and "orientation regulator" at high current density, which significantly suppresses side reactions and dendrite growth. The in-situ SEI affords the record-breaking reversibility of Zn anode under practical conditions, Zn//Zn symmetric cells can stably cycle for over 1300 h and 400 h at current densities of 50 mA cm-2 and 100 mA cm-2, respectively, showcasing an exceptional cumulative capacity of 67.5 Ah cm-2. Furthermore, the practicality of this in-situ SEI is verified in Zn//PANI pouch cells with high mass loading of 25.48 mg cm-2. This work provides a universal strategy to design advanced SEI for practical Zn-ion batteries.

Individual-based morphological brain network changes in children with Rolandic epilepsy.

OBJECTIVE: To investigate the local cortical morphology and individual-based morphological brain networks (MBNs) changes in children with Rolandic epilepsy (RE). METHODS: Based on the structural MRI data of 56 children with RE and 56 healthy controls (HC), we constructed four types of individual-based MBNs using morphological indices (cortical thickness [CT], fractal dimension [FD], gyrification index [GI], and sulcal depth [SD]). The global and nodal properties of the brain networks were analyzed using graph theory. The between-group difference in local morphology and network topology was estimated, and partial correlation analysis was further analyzed. RESULTS: Compared with the HC, children with RE showed regional GI increases in the right posterior cingulate gyrus and SD increases in the right anterior cingulate gyrus and medial prefrontal cortex. Regarding the network level, RE exhibited increased characteristic path length in CT-based and FD-based networks, while decreased FD-based network node efficiency in the right inferior frontal gyrus. No significant correlation between altered morphological features and clinical variables was found in RE. CONCLUSIONS: These findings indicated that children with RE have disrupted morphological brain network organization beyond local morphology changes. SIGNIFICANCE: The present study could provide more theoretical basis for exploring the neuropathological mechanisms in RE.

Enhanced anaerobic digestion of waste-activated sludge by thermal-alkali pretreatment: a pilot-scale study.

The composition of waste-activated sludge (WAS) is complex, containing a large amount of harmful substances, which pose a threat to the environment and human health. The reduction and resource utilization of sludge has become a development demand in sludge treatment and disposal. Based on the technical bottlenecks in the practical application of direct anaerobic digestion technology, this study adopted two different thermal and thermal-alkali hydrolysis technologies to pretreat sludge. A pilot-scale experiment was conducted to investigate the experimental conditions, parameters, and effects of two hydrolysis technologies. This study showed that the optimal hydrolysis temperature was 70 °C, the hydrolysis effect and pH can reach equilibrium with the hydrolysis retention time was 4-8 h, and the optimal alkali concentration range was 0.0125-0.015 kg NaOH/kg dry-sludge. Thermal-alkali combination treatment greatly improved the performance of methane production, the addition of NaOH increased methane yield by 31.2% than that of 70 °C thermal hydrolysis. The average energy consumption is 75 kWh/m3 80% water-content sludge during the experiment. This study provides a better pretreatment strategy for exploring efficient anaerobic digestion treatment technologies suitable for southern characteristic sewage sludge.

Intelligent ankle-foot prosthesis based on human structure and motion bionics.

The ankle-foot prosthesis aims to compensate for the missing motor functions by fitting the motion characteristics of the human ankle, which contributes to enabling the lower-limb amputees to take care of themselves and improve mobility in daily life. To address the problems of poor bionic motion of the ankle-foot prosthesis and the lack of natural interaction among the patient, prosthesis, and the environment, we developed a complex reverse-rolling conjugate joint based on the human ankle-foot structure and motion characteristics, the rolling joint was used to simulate the rolling-sliding characteristics of the knee joint. Meanwhile, we established a segmental dynamics model of the prosthesis in the stance phase, and the prosthetic structure parameters were obtained with the optimal prosthetic structure dimensions and driving force. In addition, a carbon fiber energy-storage foot was designed based on the human foot profile, and the dynamic response of its elastic strain energy at different thicknesses was simulated and analyzed. Finally, we integrated a bionic ankle-foot prosthesis and experiments were conducted to verify the bionic nature of the prosthetic joint motion and the energy-storage characteristics of the carbon fiber prosthetic foot. The proposed ankle-foot prosthesis provides ambulation support to assist amputees in returning to social life normally and has the potential to help improve clinical viability to reduce medical rehabilitation costs.

Survivorship Experiences of Allogeneic Hematopoietic Stem Cell Transplantation Survivors: A Qualitative Systematic Review.

BACKGROUND: The number of allogeneic hematopoietic stem cell transplantation (allo-HSCT) survivors is increasing globally. Although qualitative studies in this population are reported, clear understanding of how allo-HSCT survivors experience survivorship is lacking. OBJECTIVE: This study aimed to identify, appraise, and synthesize evidence from qualitative research on survivorship experience among allo-HSCT survivors. METHODS: A qualitative systematic review was conducted. A literature search of 9 databases and OpenGrey, Google Scholar, and Google was performed from inception to February 2023. Two reviewers independently screened and assessed the eligibility of each study. Descriptive information was extracted from the studies by one reviewer and checked by another. Findings were extracted and analyzed using thematic synthesis. RESULTS: Seventeen articles were included. Four themes and 12 subthemes regarding allo-HSCT survivors' experiences emerged: (1) recovery as being a longer process than they thought (influenced by long-term physical symptoms, disturbed by survivorship uncertainty); (2) experiencing a restricted survivorship life (shrunken social world, forced dietary limitations, centered around hospitals); (3) suffering from stigma and discrimination (perceived as a burden, seen differently by others, difficulties establishing and maintaining romantic relationships and marriage, limited opportunities in work); and (4) realizing something positive obtained during survivorship (enriched survivorship self-management skills, enhanced personal growth, developed positive relationships). CONCLUSIONS: The findings reveal the challenges, needs, and growth that allo-HSCT survivors experienced during survivorship. Some understudied areas were identified, which warrant further exploration. IMPLICATIONS FOR PRACTICE: Targeted survivor-centered care should be provided to allo-HSCT survivors, and interventions to resolve issues experienced during survivorship should be developed.

What are they considering when they face a fetus with birth defects? A qualitative study on ethical attitudes of health professionals in China.

BACKGROUND: Birth defects are the leading cause of mortality in newborn babies and children under five years old. In response, the Chinese government has implemented a three-tiered prevention strategy, which has brought ethical concerns about fetuses with birth defects. This study aims to explore the attitudes toward fetuses with birth defects among health professionals engaged in maternal and child health services. METHODS: A qualitative study was conducted among 13 health professionals engaged in maternal and child health services in Hunan Province, China. The questions were designed to elicit the participants' work experience and attitudes toward fetuses with birth defects. The data were collected through in-depth semi-structured interviews, and NVivo 12 was used for data coding and analysis. A thematic analysis approach was employed following the SRQR checklist. RESULTS: Five themes and 13 attributes were generated regarding health professionals' perspectives on fetuses with birth defects. The five themes included: (1) severity and curability of diseases (two attributes), (2) family relations (four attributes), (3) medical assessments (two attributes), (4) social situations (three attributes), (5) self-value orientations (three attributes). The findings showed that the majority of health professionals held the view that a fetus with a curable disease could be born, whereas a fetus with severe disability and teratogenesis should be terminated. Twelve out of the 13 health professionals believed that parents should be the decision-makers, while only one thought that the family should make a decision together. CONCLUSIONS: Attitudes toward birth defects were influenced by various factors, indicating the complexity of real-world cases identified in this study. The findings highlight the dilemmas faced by both families and health professionals regarding birth defects. Adequate medical knowledge and support from society are crucial to inform decision-making among family members. Additionally, standardized norms and policies for birth defects are needed. Establishing an ethics committee for prenatal diagnosis is necessary to address current ethical issues in this field.

All-Fluorinated Electrolyte Engineering Enables Practical Wide-Temperature-Range Lithium Metal Batteries.

The development of lithium metal batteries (LMBs) is severely hindered owing to the limited temperature window of the electrolyte, which renders uncontrolled side reactions, unstable electrolyte/electrode interface (EEI) formation, and sluggish desolvation kinetics for wide temperature operation condition. Herein, we developed an all-fluorinated electrolyte composed of lithium bis(trifluoromethane sulfonyl)imide, hexafluorobenzene (HFB), and fluoroethylene carbonate, which effectively regulates solvation structure toward a wide temperature of 160 °C (-50 to 110 °C). The introduction of thermostable HFB induces the generation of EEI with a high LiF ratio of 93%, which results in an inhibited side reaction and gas generation on EEI and enhanced interfacial ion transfer at extreme temperatures. Therefore, an unparalleled capacity retention of 88.3% after 400 cycles at 90 °C and an improved cycling performance at -50 °C can be achieved. Meanwhile, the practical 1.3 Ah-level pouch cell delivers high energy density of 307.13 Wh kg-1 at 60 °C and 277.99 Wh kg-1 at -30 °C after 50 cycles under lean E/C ratio of 2.7 g/Ah and low N/P ratio of 1.2. This work not only offers a viable strategy for wide-temperature-range electrolyte design but also promotes the practicalization of LMBs.

Demineralization activating highly-disordered lignite-derived hard carbon for fast sodium storage.

Lignite, as one of the coal materials, has been considered a promising precursor for hard carbon anodes in sodium-ion batteries (SIBs) owing to its low cost and high carbon yield. Nevertheless, hard carbon directly derived from lignite pyrolysis typically exhibits highly ordered microstructure with narrow interlayer spacing and relatively unreactive interfacial properties, owing to the abundance of polycyclic aromatic hydrocarbons and inert aromatic rings within its molecular composition. Herein, an innovative demineralization activating strategy is established to simultaneously modulate the interfacial properties and the microstructure of lignite-derived carbon for the development of high-performance SIBs. Demineralization process not only creates numerous void spaces in the matrix of lignite precursor to assist aromatic hydrocarbon rearrangement, thereby reducing the ordering and expanding interlayer spacing, but also exposes more interfacial oxygen-containing functional groups to effectively increasing the sodium storage active sites. As a result, the optimal demineralized lignite-derived hard carbon (DLHC 1300) delivers a high reversible capacity of 335.6 mAh g-1 at 30 mA g-1, superior rate performance of 246.3 mAh g-1 at 6 A g-1 and nearly 100 % capacity retention after 1100 cycles at 1A g-1. Furthermore, the optimized DLHC 1300 material functions as an outstanding anode in sodium ion full cells. This work significantly advances the development of low-cost, high-performance commercial hard carbon anodes for SIBs.

The mediating role of trait impulsivity in the relation between cue-induced craving and functional connectivity within the salience network among abstinent patients with methamphetamine use disorder.

Given the widespread use and relapse of methamphetamine (METH), it has caused serious public health burdens globally. However, the neurobiological basis of METH addiction remains poorly understood. Therefore, this study aimed to use magnetic resonance imaging (MRI) to investigate changes in brain networks and their connection to impulsivity and drug craving in abstinent individuals with METH use disorder (MUDs). A total of 110 MUDs and 55 age- and gender-matched healthy controls (HCs) underwent resting-state functional MRI and T1-weighted imaging scans, and completed impulsivity and cue-induced craving measurements. We applied independent component analysis to construct functional brain networks and multivariate analysis of covariance to investigate group differences in network connectivity. Mediation analyses were conducted to explore the relationships among brain-network functional connectivity (FC), impulsivity, and drug craving in the patients. MUDs showed increased connectivity in the salience network (SN) and decreased connectivity in the default mode network compared to HCs. Impulsivity was positively correlated with FC within the SN and played a completely mediating role between METH craving and FC within the SN in MUDs. These findings suggest alterations in functional brain networks underlying METH dependence, with SN potentially acting as a core neural substrate for impulse control disorders.

Dual-loaded nano pesticide system based on industrial grade scaleable carrier materials with combinatory efficacy and improved safety.

Repeated and widespread use of single chemical pesticides raises concerns about efficiency and safety, developing multi-component synergistic pesticides provides a new route for efficient control of diseases. Most commercial compound formulations are open systems with non-adjustable released rates, resulting in a high frequency of applications. Meanwhile, although nano pesticide delivery systems constructed with different carrier materials have been extensively studied, realizing their actual scale-up production still has important practical significance due to the large-scale field application. In this study, a boscalid and pyraclostrobin dual-loaded nano pesticide system (BPDN) was constructed with industrial-grade carrier materials to facilitate the realization of large-scale production. The optimal industrial-scale preparation mechanism of BPDN was studied with surfactants as key factors. When agricultural emulsifier No.600 and polycarboxylate are used as the ratio of 1:2 in the preparation process, the BPDN has a spherical structure with an average size of 270 nm and exhibits superior physical stability. Compared with commercial formulation, BPDN maintains rate-stabilized release up to 5 times longer, exhibits better dispersion and spreading performance on foliar, has more than 20% higher deposition amounts, and reduces loss. A single application of BPDN could efficiently control tomato gray mold during the growing period of tomatoes due to extended duration and combinatory effectiveness, reducing two application times and labor costs. Toxicology tests on various objects systematically demonstrated that BPDN has improved safety for HepG2 cells, and nontarget organism earthworms. This research provides insight into creating safe, efficient, and environmentally friendly pesticide production to reduce manual operation times and labor costs. Accompanied by production strategies that can be easily scaled up industrially, this contributes to the efficient use of resources for sustainable agriculture.

Rapid Detection of SARS-CoV-2 Variants Using an Angiotensin-Converting Enzyme 2-Based Surface-Enhanced Raman Spectroscopy Sensor Enhanced by CoVari Deep Learning Algorithms.

An integrated approach combining surface-enhanced Raman spectroscopy (SERS) with a specialized deep learning algorithm to rapidly and accurately detect and quantify SARS-CoV-2 variants is developed based on an angiotensin-converting enzyme 2 (ACE2)-functionalized AgNR@SiO2 array SERS sensor. SERS spectra with concentrations of different variants were collected using a portable Raman system. After appropriate spectral preprocessing, a deep learning algorithm, CoVari, is developed to predict both the viral variant species and concentrations. Using a 10-fold cross-validation strategy, the model achieves an average accuracy of 99.9% in discriminating between different virus variants and R2 values larger than 0.98 for quantifying viral concentrations of the three viruses, demonstrating the high quality of the detection. The limit of detection of the ACE2 SERS sensor is determined to be 10.472, 11.882, and 21.591 PFU/mL for SARS-CoV-2, SARS-CoV-2 B1, and CoV-NL63, respectively. The feature importance of virus classification and concentration regression in the CoVari algorithm are calculated based on a permutation algorithm, which showed a clear correlation to the biochemical origins of the spectra or spectral changes. In an unknown specimen test, classification accuracy can achieve >90% for concentrations larger than 781 PFU/mL, and the predicted concentrations consistently align with actual values, highlighting the robustness of the proposed algorithm. Based on the CoVari architecture and the output vector, this algorithm can be generalized to predict both viral variant species and concentrations simultaneously for a broader range of viruses. These results demonstrate that the SERS + CoVari strategy has the potential for rapid and quantitative detection of virus variants and potentially point-of-care diagnostic platforms.

Er-Dong-Xiao-Ke decoction regulates lipid metabolism via PPARG-mediated UCP2/AMPK signaling to alleviate diabetic meibomian gland dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Meibomian gland dysfunction (MGD), complicated by type 2 diabetes, is associated with a high incidence of ocular surface disease, and no effective drug treatment exists. Diabetes mellitus (DM) MGD shows a notable disturbance in lipid metabolism. Er-Dong-Xiao-Ke decoction (EDXKD) has important functions in nourishing yin, clearing heat, and removing blood stasis, which are effective in the treatment of DM MGD. AIM OF THE STUDY: To observe the therapeutic effect of EDXKD on DM MGD and its underlying molecular mechanism. MATERIALS AND METHODS: After establishing a type 2 DM (T2DM)-induced MGD rat model, different doses of EDXKD and T0070907 were administered. The chemical constituents of EDXKD were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the molecular mechanism of EDXKD in treating DM MGD was predicted using network pharmacology. Lipid metabolism in DM meibomian glands (MGs) was analyzed using LC-MS/MS, and lipid biomarkers were screened and identified. Histological changes and lipid accumulation in MGs were detected by staining, and Peroxisome proliferator-activated receptor gamma (PPARG) expression in MG acinar cells was detected by immunofluorescence. The expression of lipid metabolism-related factors was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blotting. RESULTS: EDXKD reduced lipid accumulation in the MGs and improved the ocular surface index in DM MGD rats. The main active components of EDXKD had advantages in lipid regulation. Additionally, the PPARG signaling pathway was the key pathway of EDXKD in the treatment of DM MGD. Twelve lipid metabolites were biomarkers of EDXKD in the treatment of DM MGD, and glycerophospholipid metabolism was the main pathway of lipid regulation. Moreover, EDXKD improved lipid deposition in the acini and upregulated the expression of PPARG. Further, EDXKD regulated the PPARG-mediated UCP2/AMPK signaling network, inhibited lipid production, and promoted lipid transport. CONCLUSION: EDXKD is an effective treatment for MGD in patients with T2DM. EDXKD can regulate lipids by regulating the PPARG-mediated UCP2/AMPK signaling network, as it reduced lipid accumulation in the MGs of DM MGD rats, promoted lipid metabolism, and improved MG function and ocular surface indices.

Discovery of Novel Proteolysis-Targeting Chimera Molecules as Degraders of Programmed Cell Death-Ligand 1 for Breast Cancer Therapy.

The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC50 = 0.609 µM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo. Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.

Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation.

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

Tomato SlWRKY3 Negatively Regulates Botrytis cinerea Resistance via TPK1b.

Botrytis cinerea is considered the second most important fungal plant pathogen, and can cause serious disease, especially on tomato. The TPK1b gene encodes a receptor-like kinase that can positively regulate plant resistance to B. cinerea. Here, we identified a tomato WRKY transcription factor SlWRKY3 that binds to the W-box on the TPK1b promoter. It can negatively regulate TPK1b transcription, then regulate downstream signaling pathways, and ultimately negatively regulate tomato resistance to B. cinerea. SlWRKY3 interference can enhance resistance to B. cinerea, and SlWRKY3 overexpression leads to susceptibility to B. cinerea. Additionally, we found that B. cinerea can significantly, and rapidly, induce the upregulation of SlWRKY3 expression. In SlWRKY3 transgenic plants, the TPK1b expression level was negatively correlated with SlWRKY3 expression. Compared with the control, the expression of the SA pathway marker gene PR1 was downregulated in W3-OE plants and upregulated in W3-Ri plants when inoculated with B. cinerea for 48 h. Moreover, SlWRKY3 positively regulated ROS production. Overall, SlWRKY3 can inhibit TPK1b transcription in tomato, and negatively regulate resistance to B. cinerea by modulating the downstream SA and ROS pathways.

Anatomical factors influencing temporomandibular joint clicking in young adults: temporomandibular joint structure disorder or lateral pterygoid muscle dysfunction?

Objective: This study aimed to investigate the selected anatomical factors that can potentially influence temporomandibular joint (TMJ) clicking in young adults by assessing TMJ structures and lateral pterygoid muscle (LPM) function using magnetic resonance imaging (MRI). Methods: The patients were divided into four groups: the healthy control group; the clicking on mouth opening group; the clicking on mouth closing group; and the clicking on mouth opening and closing group. Additionally, we used clinical palpation to evaluate the masticatory muscles' functional state and employed MRI using the OCOR-T1WI-FSE-CLOSED, OSAG-PDW-FSE-CLOSED, and OSAG-PDW-FSE-OPEN sequences to analyze the texture of the lateral pterygoid muscle (LPM). Results: The proportion of any articular disc or condylar morphology class did not differ significantly between the TMJ clicking and HC groups. The articular disc position did not differ significantly between the TMJ clicking and HC groups. In the TMJ clicking group, the presence of masticatory muscle dysfunction differed significantly between the clicking and non-clicking sides. Moreover, the LPM accounted for the highest proportion among masticatory muscles with tenderness in all TMJ clicking subgroups (77.78%-100%). Therefore, in the TMJ clicking group, the LPM texture was less defined, more uniform in gray scale, and more similar to local texture (p < 0.0001). Conclusion: The occurrence of TMJ clicking in young adults is unrelated to the TMJ structure but related to the function of masticatory muscles, particularly the LPM.