Regulation of Glandular Size and Phytoalexin Biosynthesis by a Negative Feedback Loop in Cotton.

Plants have evolved diverse defense mechanisms encompassing physical and chemical barriers. Cotton pigment glands are known for containing various defense metabolites, but the precise regulation of gland size to modulate defense compound levels remains enigmatic. Here, it is discovered that the VQ domain-containing protein JAVL negatively regulates pigment gland size and the biosynthesis of defense compounds, while the MYC2-like transcription factor GoPGF has the opposite effect. Notably, GoPGF directly activates the expression of JAVL, whereas JAVL suppresses GoPGF transcription, establishing a negative feedback loop that maintains the expression homeostasis between GoPGF and JAVL. Furthermore, it is observed that JAVL negatively regulates jasmonate levels by inhibiting the expression of jasmonate biosynthetic genes and interacting with GoPGF to attenuate its activation effects, thereby maintaining homeostatic regulation of jasmonate levels. The increased expression ratio of GoPGF to JAVL leads to enlarged pigment glands and elevated jasmonates and defense compounds, enhancing insect and pathogen resistance in cotton. These findings unveil a new mechanism for regulating gland size and secondary metabolites biosynthesis, providing innovative strategies for strengthening plant defense.

Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the type I receptor tyrosine kinase family. ROR1 is pivotal in embryonic development and cancer, and serves as a biomarker and therapeutic target. It has soluble and membrane-bound subtypes, with the latter highly expressed in tumors. ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms. Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis. Additionally, ROR1 may regulate the cell cycle, stem cell characteristics, and interact with other signaling pathways to affect cancer progression. This review explores the structure, expression and role of ROR1 in the development of gastrointestinal cancers. It discusses current antitumor strategies, outlining challenges and prospects for treatment.

Short stature with brachydactyly caused by a novel mutation in the IHH gene and response to 4-year growth hormone therapy: a case report.

Background: The etiology of short stature is heterogeneous. The disturbance of endochondral ossification and cartilage matrix synthesis caused by genetic mutations often causes short height combined with skeletal deformities in children. Some patients with minor skeletal abnormalities, such as short fingers and mild limb shortening, may be overlooked by clinicians and misdiagnosed as idiopathic short stature (ISS) or growth hormone deficiency (GHD). Case Description: We conducted a detailed investigation of laboratory and imaging examinations on a family with short stature and non-classical brachydactyly type A1 (BDA1) and summarized the clinical features. They received whole exome sequencing (WES) to reveal the possible genetic variation. A heterozygous mutation in the Indian hedgehog gene (IHH) (c.387_388insC, p.Thr130Hisfs*18) was found in the two siblings and their mother. The siblings both started recombinant human growth hormone (rhGH) therapy (rhGH: 33 µg/kg/day) and followed up for 4 years. After treatment, the siblings' height improved significantly, and they acquired a significant increase in the height standard deviation score (SDS) (the boy: +2.54, the girl: +1.86) during the 4-year therapy. No noticeable adverse effect was observed during rhGH treatment. Conclusions: We found a novel heterozygous pathogenic mutation in the IHH gene in a family and detailed the phenotype with short stature and non-classical BDA1. The therapy of rhGH showed promising effects. To avoid misdiagnosis, clinicians should not overlook minor skeletal anomalies in patients with short stature, especially those with a family history.

Reticular Chemistry Directed "One-Pot" Strategy to in situ Construct Organic Linkers and Zirconium-Organic Frameworks.

Zirconium-based metal-organic frameworks (Zr-MOFs) have emerged as one of the most studied MOFs due to the unlimited numbers of organic linkers and the varying Zr-oxo clusters. However, the synthesis of carboxylic acids, especially multitopic carboxylic acids, is always a great challenge for the discovery of new Zr-MOFs. As an alternative approach, the in situ "one-pot" strategy can address this limitation, where the generation of organic linkers from the corresponding precursors and the sequential construction of MOFs are integrated into one solvothermal condition. Herein, inspired by benzimidazole-contained compounds synthesized via reaction of aldehyde and o-phenylenediamine, tri-, tetra-, penta- and hexa-topic carboxylic acids and a series of corresponding Zr-MOFs can be prepared via the in situ "one-pot" method under the same solvothermal conditions. This strategy can be utilized not only to prepare reported Zr-MOFs constructed using benzimidazole-contained linkers, but also to rationally design, construct and realize functionalities of zirconium-pentacarboxylate frameworks guided by reticular chemistry. More importantly, in situ "one-pot" method can facilitate the discovery of new Zr-MOFs, such as zirconium-hexacarboxylate frameworks. The present study demonstrates the promising potential of benzimidazole-inspired in situ "one-pot" approach in the crystal engineering of structure- and property-specific Zr-MOFs, especially with the guidance of reticular chemistry.

Linking child externalising problems to psychological distress in parents: Mobile phone use by children as a mediator.

Child externalising problems, such as acting out and hostility, have been found to be significant stressors for parents, leading to increased distress levels. This cross-sectional study examined the mediating role of parents' use of mobile phones to soothe or engage children in the association between child externalising problems and distress in parents. Altogether 937 parents of children aged 5-12 reported their child's externalising problems, child's mobile phone use, and their distress through an online survey. The findings indicated that parents of children with high externalising problems are more likely to use mobile phones to soothe their children and keep them engaged in daily activities, which, in turn, is associated with higher distress in parents. Child externalising problems and distress in parents remained significantly and positively associated even after accounting for the mediating effect. The results highlight the child-driven effect on distress in parents through parenting behaviours, indicating the importance of providing alternative parenting strategies to cope with child externalising behaviours, in order to promote parental emotional well-being.

Synovial osteoclastogenesis mediated by chondrocyte-secreted TNFα promotes TMJ condylar resorption.

BACKGROUND: Insufficient occlusal support (IOS) frequently causes subchondral bone absorption in temporomandibular joint osteoarthritis, and the underlying mechanism requires further investigation. METHODS: An IOS model was established by abrading rat molars. Micro-computed tomography was used to evaluate subchondral bone changes. Osteoclastogenesis of synovium-derived macrophages (SDMs) was confirmed by TRAP staining. Cartilage-specific TNFα depletion was achieved by intra-articular injection of adeno-associated virus carrying shRNA against murine TNFα under control of collagen type II. In vitro, chondrocytes were mechanically compressed and conditioned medium (CM) was collected to detect its ability to induce osteoclastogenesis of SDMs. RESULTS: Synovial osteoclastogenesis and condyle resorption were observed following IOS. TNFα level was elevated in hypertrophic chondrocytes after IOS. Synovial Wnt5a level increased, but Wnt3a level decreased after IOS. Depletion of TNFα in chondrocytes alleviated the synovial osteoclastogenesis and condyle bone resorption. In vitro compression of chondrocytes potentiated TNFα expression and secretion. The CM promoted osteoclastogenesis of SDMs, which were partially prohibited by TNFα neutralizing antibody. Furthermore, inhibition of Wnt3a facilitated osteoclastogenesis, whereas inhibition of Wnt5a partially suppressed osteoclastogenesis, of SDMs cultured in CM. CONCLUSION: Chondrocyte-secreted TNFα induced by IOS is a critical regulator of synovial osteoclastogenesis and subsequent condylar resorption, partially through non-canonical Wnt5a pathway.

Restoring colistin sensitivity in colistin-resistant Salmonella and Escherichia coli: combinatorial use of berberine and EDTA with colistin.

The appearance and prevalence of multidrug-resistance (MDR) Gram-negative bacteria (GNB) have limited our antibiotic capacity to control bacterial infections. The clinical efficacy of colistin (COL), considered as the "last resort" for treating GNB infections, has been severely hindered by its increased use as well as the emergence and prevalence of mobile colistin resistance (MCR)-mediated acquired drug resistance. Identifying promising compounds to restore antibiotic activity is becoming an effective strategy to alleviate the crisis of increasing MDR. We first demonstrated that the combination of berberine (BBR) and EDTA substantially restored COL sensitivity against COL-resistant Salmonella and Escherichia coli. Molecular docking indicated that BBR can interact with MCR-1 and the efflux pump system AcrAB-TolC, and BBR combined with EDTA downregulated the expression level of mcr-1 and tolC. Mechanically, BBR combined with EDTA could increase bacterial membrane damage, inhibit the function of multidrug efflux pump, and promote oxidative damage, thereby boosting the action of COL. In addition, transcriptome analysis found that the combination of BBR and EDTA can accelerate the tricarboxylic acid cycle, inhibit cationic antimicrobial peptide (CAMP) resistance, and attenuate Salmonella virulence. Notably, the combination of BBR and EDTA with COL significantly reduced the bacterial load in the liver and spleen of a mice model infected with Salmonella. Our findings revealed that BBR and EDTA can be used as adjuvants collectively with COL to synergistically reverse the COL resistance of bacteria. IMPORTANCE: Colistin is last-resort antibiotic used to treat serious clinical infections caused by MDR bacterial pathogens. The recent emergence of transferable plasmid-mediated COL resistance gene mcr-1 has raised the specter of a rapid worldwide spread of COL resistance. Coupled with the fact of barren antibiotic development pipeline nowadays, a critical approach is to revitalize existing antibiotics using antibiotic adjuvants. Our research showed that berberine combined with EDTA effectively reversed COL resistance both in vivo and in vitro through multiple modes of action. The discovery of berberine in combination with EDTA as a new and safe COL adjuvant provides a therapeutic regimen for combating Gram-negative bacteria infections. Our findings provide a potential therapeutic option using existing antibiotics in combination with antibiotic adjuvants and address the prevalent infections caused by MDR Gram-negative pathogens worldwide.

Improvements in Wear and Corrosion Resistance of Ti-W-Alloyed Gray Cast Iron by Tailoring Its Microstructural Properties.

The improved wear and corrosion resistance of gray cast iron (GCI) with enhanced mechanical properties is a proven stepping stone towards the longevity of its versatile industrial applications. In this article, we have tailored the microstructural properties of GCI by alloying it with titanium (Ti) and tungsten (W) additives, which resulted in improved mechanical, wear, and corrosion resistance. The results also show the nucleation of the B-, D-, and E-type graphite flakes with the A-type graphite flake in the alloyed GCI microstructure. Additionally, the alloyed microstructure demonstrated that the ratio of the pearlite volume percentage to the ferrite volume percentage was improved from 67/33 to 87/13, whereas a reduction in the maximum graphite length and average grain size from 356 ± 31 µm to 297 ± 16 µm and 378 ± 18 µm to 349 ± 19 µm was detected. Consequently, it improved the mechanical properties and wear and corrosion resistance of alloyed GCI. A significant improvement in Brinell hardness, yield strength, and tensile strength of the modified microstructure from 213 ± 7 BHN to 272 ± 8 BHN, 260 ± 3 MPa to 310 ± 2 MPa, and 346 ± 12 MPa to 375 ± 7 MPa was achieved, respectively. The substantial reduction in the wear rate of alloyed GCI from 8.49 × 10-3 mm3/N.m to 1.59 × 10-3 mm3/N.m resulted in the upgradation of the surface roughness quality from 297.625 nm to 192.553 nm. Due to the increase in the corrosion potential from -0.5832 V to -0.4813 V, the impedance of the alloyed GCI was increased from 1545 Ohm·cm2 to 2290 Ohm·cm2. On the basis of the achieved experimental results, it is suggested that the reliability of alloyed GCI based on experimentally validated microstructural compositions can be ensured during the operation of plants and components in a severe wear and corrosive environment. It can be predicted that the proposed alloyed GCI components are capable of preventing the premature failure of high-tech components susceptible to a wear and corrosion environment.

[Research progress of traditional Chinese medicine intervention for ulcerative colitis based on Notch1 signaling pathway].

Ulcerative colitis(UC) is one of the common gastrointestinal diseases worldwide. In recent years, the incidence of UC has been continuously increasing, seriously threatening the health of people globally. It thus has become an urgent problem that needs to be addressed. There is research evidence that intestinal mucosal barrier dysfunction, including changes in intestinal stem cell secretion lineage, mucosal layer damage, disruption of cell junctions, overactive immune function, and imbalanced gut microbiota, is an important pathogenic factor and molecular basis of UC. The Notch signaling pathway is a highly conserved signaling pathway in eukaryotes during evolution, which transmits signals through cell connections between adjacent cells, affecting a series of processes such as cell proliferation, differentiation, development, migration, and apoptosis. Therefore, the Notch signaling pathway can regulate intestinal stem cells, CD4~+T cells, innate lymphoid cells(ILCs), macrophages(MØ), and intestinal microbiota and thus affect the chemical, physical, immune, and biological mucosal barriers of the intestinal mucosa. Its function is extensive and unique, different from those signaling pathways that mainly focus on anti-inflammatory and antioxidant stress. It can explain the therapeutic effects of traditional Chinese medicine from different perspectives. This article reviewed the role of the Notch1 signaling pathway in the pathogenesis of UC and the relevant literature on the targeted prevention and treatment of UC with traditional Chinese medicine, so as to provide new targets and theoretical support for further research on the effective prevention and treatment of UC.

Clinical characteristics and risk factors of post-operative intestinal flora disorder following laparoscopic colonic surgery: A propensity-score-matching analysis.

BACKGROUND: Intestinal flora disorder (IFD) poses a significant challenge after laparoscopic colonic surgery, and no standard criteria exists for its diagnosis and treatment. AIM: To analyze the clinical features and risk factors of IFD. METHODS: Patients with colon cancer receiving laparoscopic surgery were included using propensity-score-matching (PSM) methods. Based on the occurrence of IFD, patients were categorized into IFD and non-IFD groups. The clinical characteristics and treatment approaches for patients with IFD were analyzed. Multivariate regression analysis was performed to identify the risk factors of IFD. RESULTS: The IFD incidence after laparoscopic surgery was 9.0% (97 of 1073 patients). After PSM, 97 and 194 patients were identified in the IFD and non-IFD groups, respectively. The most common symptoms of IFD were diarrhea and abdominal, typically occurring on post-operative days 3 and 4. All patients were managed conservatively, including modulation of the intestinal flora (90.7%), oral/intravenous application of vancomycin (74.2%), and insertion of a gastric/ileus tube for decompression (23.7%). Multivariate regression analysis identified that pre-operative intestinal obstruction [odds ratio (OR) = 2.79, 95%CI: 1.04-7.47, P = 0.041] and post-operative antibiotics (OR = 8.57, 95%CI: 3.31-23.49, P < 0.001) were independent risk factors for IFD, whereas pre-operative parenteral nutrition (OR = 0.12, 95%CI: 0.06-0.26, P < 0.001) emerged as a protective factor. CONCLUSION: A stepwise approach of probiotics, vancomycin, and decompression could be an alternative treatment for IFD. Special attention is warranted post-operatively for patients with pre-operative obstruction or early use of antibiotics.

Red light mitigates Cd toxicity in Egeria densa by restricting Cd accumulation and modulating antioxidant defense system.

Controlling light qualities have been acknowledged as an effective method to enhance the efficiency of phytoremediation, as light has a significant impact on plant growth. This study examined the effects of light qualities on cadmium (Cd) tolerance in aquatic plant Egeria densa using a combination of biochemical and transcriptomic approaches. The study revealed that E. densa exhibits higher resistance to Cd toxicity under red light (R) compared to blue light (B), as evidenced by a significant decrease in photosynthetic inhibition and damage to organelle ultrastructure. After Cd exposure, there was a significantly reduced Cd accumulation and enhanced levels of both glutathione reductase (GR) activity and glutathione (GSH), along with an increase in jasmonic acid (JA) in R-grown E. densa compared to B. Transcriptional analysis revealed that R caused an up-regulation of Cd transporter genes such as ABCG (G-type ATP-binding cassette transporter), ABCC (C-type ATP-binding cassette transporter), and CAX2 (Cation/H+ exchanger 2), while down-regulated the expression of HIPP26 (Heavy metal-associated isoprenylated plant protein 26), resulting in reduced Cd uptake and enhanced Cd exportation and sequestration into vacuoles. Moreover, the expression of genes involved in phytochromes and JA synthesis was up-regulated in Cd treated E. densa under R. In summary, the results suggest that R could limit Cd accumulation and improve antioxidant defense to mitigate Cd toxicity in E. densa, which might be attributed to the enhanced JA and phytochromes. This study provides a foundation for using light control methods with aquatic macrophytes to remediate heavy metal contamination in aquatic systems.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Raman Monitoring of the Electro-Optical Synergy-Induced Enhancements in Carbon-Bromine Bond Cleavage, Reaction Rate, and Product Selectivity of p-Bromothiophenol.

Electro-optical synergy has recently been targeted to improve the separation of hot carriers and thereby further improve the efficiency of plasmon-mediated chemical reactions (PMCRs). However, the electro-optical synergy in PMCRs needs to be more deeply understood, and its contribution to bond dissociation and product selectivity needs to be clarified. Herein, the electro-optical synergy in plasmon-mediated reduction of p-bromothiophenol (PBTP) was studied on a plasmonic nanostructured silver electrode using in situ Raman spectroscopy and theoretical calculations. It was found that the electro-optical synergy-induced enhancements in the cleavage of carbon-bromine bonds, reaction rate, and product selectivity (4,4'-biphenyl dithiol vs thiophenol) were largely affected by the applied bias, laser wavelength, and laser power. The theoretical simulation further clarified that the strong electro-optical synergy is attributed to the matching of energy band diagrams of the plasmonic silver with those of the adsorbed PBTP molecules. A deep understanding of the electro-optical synergy in PBTP reduction and the clarification of the mechanism will be highly beneficial for the development of other highly efficient PMCRs.

Analysis of vibrational dynamics in cell-substrate interactions using nanopipette electrochemical sensors.

Cell-substrate interaction plays a critical role in determining the mechanical status of living cell membrane. Changes of substrate surface properties can significantly alter the cell mechanical microenvironment, leading to mechanical changes of cell membrane. However, it is still difficult to accurately quantify the influence of the substrate surface properties on the mechanical status of living cell membrane without damage. This study addresses the challenge by using an electrochemical sensor made from an ultrasmall quartz nanopipette. With the tip diameter less than 100 nm, the nanopipette-based sensor achieves highly sensitive, noninvasive and label-free monitoring of the mechanical status of single living cells by collecting stable cyclic membrane oscillatory signals from continuous current versus time traces. The electrochemical signals collected from PC12 cells cultured on three different substrates (bare ITO (indium tin oxides) glass, hydroxyl modified ITO glass, amino modified ITO glass) indicate that the microenvironment more favorable for cell adhesion can increase the membrane stiffness. This work provides a label-free electrochemical approach to accurately quantify the mechanical status of single living cells in real-time, which may help to better understand the relationship between the cell membrane and the extra cellular matrix.

Adsorption structures, vibrational Raman spectra and chemical binding properties of thioglycolic acid on Cu(111) surfaces: A DFT study.

Copper is widely used in everyday life and industrial production because of its good electrical and thermal conductivity. To overcome copper oxidation and maintain its good physical properties, small organic molecules adsorbed on the surface of copper make a passivated layer to further avoid copper corrosion. In this work, we have investigated thioglycolic acid (TGA, another name is mercaptoacetic acid) adsorbed on copper surfaces by using density functional theory (DFT) calculations and a periodical slab model. We first get five stable adsorption structures, and the binding interaction between TGA and Cu(111) surfaces by using density of states (DOS), indicating that the most stable configuration adopts a triple-end binding model. Then, we analyze the vibrational Raman spectra of TGA adsorbed on the Cu(111) surface and make vibrational assignments according to the vibrational vectors. Finally, we explore the temperature effect of the thermodynamically Gibbs free energy of TGA on the Cu(111) surface and the antioxidant ability of the small organic molecular layer of copper oxidation on the copper surface. Our calculated results further provide evidences to interpret the stability of adsorption structures and antioxidant properties of copper.

Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

Oral health self-management barriers among rural older adults in Guangxi, China: A qualitative study.

BACKGROUND: Objective: To understand the barriers associated with self-management of oral health among rural older adults in Guangxi, and to explore the high incidence of oral problems. This information will assist in the formulation of relevant strategies to solve the oral health problems in this population. METHODS: Taking a phenomenological approach, the current status of, and barriers to, oral health self-management in rural older adults from different regions of Guangxi were explored. Participants were purposively selected and interviewed face-to-face. RESULTS: The interviews yielded four overarching themes and six corresponding sub-themes pertaining to barriers in oral health self-management. These included: (1) Older adults' understanding of oral health and disease, perceptions of oral health and their oral health behaviours; (2) Problems in accessing oral health information; (3) Role of family support; and (4) Barriers to healthcare that included access to dental services, oral treatment experience and financial burden of access to dental care. CONCLUSION: Rural older adults in Guangxi face oral health self-management barriers. Improving access to oral healthcare services and changing existing oral health perceptions and habits may assist them in overcoming self-management challenges.

Molecular basis of Gabija anti-phage supramolecular assemblies.

As one of the most prevalent anti-phage defense systems in prokaryotes, Gabija consists of a Gabija protein A (GajA) and a Gabija protein B (GajB). The assembly and function of the Gabija system remain unclear. Here we present cryo-EM structures of Bacillus cereus GajA and GajAB complex, revealing tetrameric and octameric assemblies, respectively. In the center of the complex, GajA assembles into a tetramer, which recruits two sets of GajB dimer at opposite sides of the complex, resulting in a 4:4 GajAB supramolecular complex for anti-phage defense. Further biochemical analysis showed that GajA alone is sufficient to cut double-stranded DNA and plasmid DNA, which can be inhibited by ATP. Unexpectedly, the GajAB displays enhanced activity for plasmid DNA, suggesting a role of substrate selection by GajB. Together, our study defines a framework for understanding anti-phage immune defense by the GajAB complex.

The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells.

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility.

Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors Versus Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma with First- or Lower-Order Portal Vein Tumor Thrombosis.

PURPOSE: To compare the efficacy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) (TACE-TKI-ICI) versus TKIs plus ICIs (TKI-ICI) for unresectable hepatocellular carcinoma (HCC) with first- or lower-order portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: A retrospective study was performed in HCC patients with first- or lower-order PVTT receiving TKIs (Lenvatinib or sorafenib) plus ICIs (camrelizumab, sintilimab, or atezolizumab) with or without TACE from four institutions between January 2019 and January 2022. Propensity score-based method was performed to minimize bias by confounding factors. Tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated and compared between the two groups. RESULTS: After inverse probability of treatment weighting, two balanced pseudopopulations were created: 106 patients in the TACE-TKI-ICI group and 109 patients in the TKI-ICI group. The objective response rate was higher in the TACE-TKI-ICI group (50.9% vs. 28.4%, P < 0.001). The median PFS and OS were significantly longer in the TACE-TKI-ICI group than in the TKI-ICI group (PFS: 9.1 vs. 5.0 months, P = 0.005; OS: 19.1 vs. 12.7 months, P = 0.002). In Cox regression, TACE-TKI-ICI treatment was an independent predictor of favorable OS. Treatment-related grade 3/4 AEs were comparable between the two groups (22.6% vs. 17.9%, P = 0.437). CONCLUSION: TACE-TKI-ICI therapy contributed to better tumor control, PFS and OS than TKI-ICI therapy in unresectable HCC patients with first- or lower-order PVTT.