Recent advances in c-Met-based dual inhibitors in the treatment of cancers.

The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.

Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

CD44: a cancer stem cell marker and therapeutic target in leukemia treatment.

CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, cell adhesion, migration, homing and differentiation. CD44 can mediate the interaction between leukemic stem cells and the surrounding extracellular matrix, thereby inducing a cascade of signaling pathways to regulate their various behaviors. In this review, we focus on the impact of CD44s/CD44v as biomarkers in leukemia development and discuss the current research and prospects for CD44-related interventions in clinical application.

Genome-Wide Identification and Expression Profile Analysis of the Phenylalanine Ammonia-Lyase Gene Family in Hevea brasiliensis.

The majority of the world's natural rubber comes from the rubber tree (Hevea brasiliensis). As a key enzyme for synthesizing phenylpropanoid compounds, phenylalanine ammonia-lyase (PAL) has a critical role in plant satisfactory growth and environmental adaptation. To clarify the characteristics of rubber tree PAL family genes, a genome-wide characterization of rubber tree PALs was conducted in this study. Eight PAL genes (HbPAL1-HbPAL8), which spread over chromosomes 3, 7, 8, 10, 12, 13, 14, 16, and 18, were found to be present in the genome of H. brasiliensis. Phylogenetic analysis classified HbPALs into groups I and II, and the group I HbPALs (HbPAL1-HbPAL6) displayed similar conserved motif compositions and gene architectures. Tissue expression patterns of HbPALs quantified by quantitative real-time PCR (qPCR) proved that distinct HbPALs exhibited varying tissue expression patterns. The HbPAL promoters contained a plethora of cis-acting elements that responded to hormones and stress, and the qPCR analysis demonstrated that abiotic stressors like cold, drought, salt, and H2O2-induced oxidative stress, as well as hormones like salicylic acid, abscisic acid, ethylene, and methyl jasmonate, controlled the expression of HbPALs. The majority of HbPALs were also regulated by powdery mildew, anthracnose, and Corynespora leaf fall disease infection. In addition, HbPAL1, HbPAL4, and HbPAL7 were significantly up-regulated in the bark of tapping panel dryness rubber trees relative to that of healthy trees. Our results provide a thorough comprehension of the characteristics of HbPAL genes and set the groundwork for further investigation of the biological functions of HbPALs in rubber trees.

Unraveling a Small Secreted Peptide SUBPEP3 That Positively Regulates Salt-Stress Tolerance in Pyrus betulifolia.

Small secreted peptides (SSPs) play important roles in regulating plants' growth and development in response to external stimulus, but the genes and functions of SSPs in many species are still unknown. Therefore, it is particularly significant to characterize and annotate SSP genes in plant genomes. As a widely used stock of pears, Pyrus betulifolia has strong resistance to biotic and abiotic stresses. In this study, we analyzed the SSPs genes in the genome of P. betulifolia according to their characteristics and homology. A total of 1195 SSP genes were identified, and most of them are signaling molecules. Among these, we identified a new SSP, subtilase peptide 3 (SUBPEP3), which derived from the PA region of preSUBPEP3, increasing the expression level under salt stress. Both adding synthetic peptide SUBPEP3 to the culture medium of pears and the overexpression of SUBPEP3 in tobacco can improve the salt tolerance of plants. In summary, we annotated the SSP genes in the P. betulifolia genome and identified a small secreted peptide SUBPEP3 that regulates the salt tolerance of P. betulifolia, which provides an important theoretical basis for further revealing the function of SSPs.

Modular multi-degree-of-freedom soft origami robots with reprogrammable electrothermal actuation.

Soft robots often draw inspiration from nature to navigate different environments. Although the inching motion and crawling motion of caterpillars have been widely studied in the design of soft robots, the steering motion with local bending control remains challenging. To address this challenge, we explore modular origami units which constitute building blocks for mimicking the segmented caterpillar body. Based on this concept, we report a modular soft Kresling origami crawling robot enabled by electrothermal actuation. A compact and lightweight Kresling structure is designed, fabricated, and characterized with integrated thermal bimorph actuators consisting of liquid crystal elastomer and polyimide layers. With the modular design and reprogrammable actuation, a multiunit caterpillar-inspired soft robot composed of both active units and passive units is developed for bidirectional locomotion and steering locomotion with precise curvature control. We demonstrate the modular design of the Kresling origami robot with an active robotic module picking up cargo and assembling with another robotic module to achieve a steering function. The concept of modular soft robots can provide insight into future soft robots that can grow, repair, and enhance functionality.

pH-responsive albumin-mimetic synthetic nanoprobes for magnetic resonance/fluorescence imaging of thyroid cancer.

The combination of magnetic resonance and fluorescence imaging in dual-modality imaging not only resolves the limitations of conventional single molecular imaging techniques in terms of specificity, sensitivity, and resolution but also expands the possibilities of molecular imaging techniques in diagnostics and therapeutic monitoring. Herein, a novel pH-responsive magnetic resonance/near-infrared fluorescence (MR/NIRF) nanoprobe (MnO2@BSA-Cy5.5) was successfully prepared by biomineralizing manganese dioxide (MnO2) with bovine serum albumin (BSA) while coupling fluorescent dye Cy5.5 for precise tumor detection and visualization. The synthesized MnO2@BSA-Cy5.5 nanoprobes were spherical particles of approximately 22.62 ± 3.31 nm in size, and their relaxation rates and T1 imaging signals were activated-enhanced in an acidic environment. Cytotoxicity assay and hematoxylin and eosin staining demonstrated that MnO2@BSA-Cy5.5 had low cytotoxicity and good biocompatibility. More importantly, active targeting via solid tumor albumin-binding protein receptor and enhanced permeability and retention effect, the probe can be specifically aggregated to the tumor site of the 8305C tumor model and exhibit excellent MR/NIRF imaging properties. Our results show that MnO2@BSA-Cy5.5 has high resolution and sensitivity in tumor imaging and is expected to be applied as an MR/NIRF contrast agent for accurate diagnosis of thyroid cancer.

Effects of Otago exercise program on physical function in older adults: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Maintaining physical function is critical for older adults to achieve healthy aging. The Otago exercise program (OEP) has been widely used to prevent falls for older adults. However, the effects of OEP on physical function remain controversial and the possible effects modifiers have not been assessed. OBJECTIVE: To evaluate the effects of OEP on physical function in older adults and to explore potential moderators underlying the effects of OEP. METHODS: We searched five electronic databases and relevant systematic reviews to identify studies. We included randomized controlled trials (RCTs) evaluating the effects of OEP as a single intervention on physical function among older adults aged 65 and over. Meta-analysis was performed using the random-effects model. Standardized mean differences (SMD) for physical function changes, pertinent to balance, strength, and mobility, were outcome measures. Subgroup analyses on exercise protocol and participants' characteristics were performed. RESULTS: Thirteen RCTs consisting of 2402 participants were included in this systematic review and meta-analysis. Results indicated a significant effect of OEP on balance (SMD = 0.59, 95 % CI: 0.22∼0.96), lower body strength (SMD = 0.93, 95 % CI: 0.31∼1.55), and mobility (SMD = -0.59, 95 % CI: -0.95∼-0.22) against control groups. No significant OEP effects were found on upper body strength (MD = 1.48, 95 % CI: -0.58∼3.55). Subgroup analysis revealed that the video-supported delivery mode was more effective for improving balance (P = 0.04) and mobility (P = 0.02) than the face-to-face mode. Session durations over 30 min was more effective on lower body strength (P < 0.001) and mobility (P < 0.001) than those 1-30 min. Program period of 13-26 weeks was more effective on mobility (P = 0.02) than those of 4-12 weeks. However, the effects of OEP on physical function were not associated with age groups, and baseline falling risks. CONCLUSION: The OEP could improve physical function including balance, lower body strength, and mobility in older adults. Implementing the OEP in video-supported, more than 30 min per session and 4-12 weeks may be the most appropriate and effective exercise protocol for improving physical function among older adults. More RCTs with rigorous design and larger scale are needed to further assess the effectiveness of diverse OEP protocols and quantify the dose-effect relationship.

Intelligent technologies powering clean incineration of municipal solid waste: A system review.

Cleanliness has been paramount for municipal solid waste incineration (MSWI) systems. In recent years, the rapid advancement of intelligent technologies has fostered unprecedented opportunities for enhancing the cleanliness of MSWI systems. This paper offers a review and analysis of cutting-edge intelligent technologies in MSWI, which include process monitoring, intelligent algorithms, combustion control, flue gas treatment, and particulate control. The objective is to summarize current applications of these techniques and to forecast future directions. Regarding process monitoring, intelligent image analysis has facilitated real-time tracking of combustion conditions. For intelligent algorithms, machine learning models have shown advantages in accurately forecasting key process parameters and pollutant concentrations. In terms of combustion control, intelligent systems have achieved consistent prediction and regulation of temperature, oxygen content, and other parameters. Intelligent monitoring and forecasting of carbon monoxide and dioxins for flue gas treatment have exhibited satisfactory performance. Concerning particulate control, multi-objective optimization facilitates the sustainable utilization of fly ash. Despite remarkable progress, challenges remain in improving process stability and monitoring instrumentation of intelligent MSWI technologies. By systematically summarizing current applications, this timely review offers valuable insights into the future upgrade of intelligent MSWI systems.

Distinct characteristics of distant metastasis in early-onset gastric cancer patients compared to late-onset patients: An observational study.

Presently, there is limited understanding of the features of distant metastasis in early-onset gastric cancer (GC). To explore these disparities, a retrospective study utilizing the Surveillance, Epidemiology, and End Results (SEER) database was undertaken. The SEER database was utilized to extract patient data, and multivariate logistic regression analysis was employed to identify the risk factors associated with distant metastasis and liver metastasis. Propensity score matching (PSM) was used to compare the occurrence of liver metastasis among patients based on their age at diagnosis. The study included 2684 early-onset GC patients and 33,289 late-onset GC patients. Preliminary data analysis indicated that early-onset GC patients exhibited more aggressive characteristics such as poor cell differentiation, advanced T stage, and a higher incidence of distant metastasis, excluding liver metastasis. Multivariate logistic regression analysis identified younger age as an independent risk factor for distant metastasis, along with T stage, lymph node metastasis (LNM), and tumor size (>3 cm). Another regression analysis revealed that younger age, diffuse type, and female gender were protective factors against liver metastasis. Through PSM, 3276 early-onset GC patients were matched with an equal number of late-onset GC patients, revealing that patients with early-onset GC had fewer instances of liver metastasis but a higher prevalence of distant metastasis. Our findings suggest that early-onset serves as a protective factor against liver metastasis in GC, while it poses a risk for distant metastasis, likely influenced by the increased prevalence of diffuse-type GC in early-onset patients.

Corrigendum: Tpr deficiency disrupts erythroid maturation with impaired chromatin condensation in zebrafish embryogenesis.

[This corrects the article DOI: 10.3389/fcell.2021.709923.].

SlCRCa is a key D-class gene controlling ovule fate determination in tomato.

Cell fate determination and primordium initiation on the placental surface are two key events for ovule formation in seed plants, which directly affect ovule density and seed yield. Despite ovules form in the marginal meristematic tissues of the carpels, angiosperm carpels evolved after the ovules. It is not clear how the development of the ovules and carpels is coordinated in angiosperms. In this study, we identify the S. lycopersicum CRABS CLAW (CRC) homologue SlCRCa as an essential determinant of ovule fate. We find that SlCRCa is not only expressed in the placental surface and ovule primordia but also functions as a D-class gene to block carpel fate and promote ovule fate in the placental surface. Loss of function of SlCRCa causes homeotic transformation of the ovules to carpels. In addition, we find low levels of the S. lycopersicum AINTEGUMENTA (ANT) homologue (SlANT2) favour the ovule initiation, whereas high levels of SlANT2 promote placental carpelization. SlCRCa forms heterodimer with tomato INNER NO OUTER (INO) and AGAMOUS (AG) orthologues, SlINO and TOMATO AGAMOUS1 (TAG1), to repress SlANT2 expression during the ovule initiation. Our study confirms that angiosperm basal ovule cells indeed retain certain carpel properties and provides mechanistic insights into the ovule initiation.

Contrast-enhanced phase-resolved second harmonic generation microscopy.

The characterization of inverted structures (crystallographic, ferroelectric, or magnetic domains) is crucial in the development and application of novel multi-state devices. However, determining these inverted structures needs a sensitive probe capable of revealing their phase correlation. Here a contrast-enhanced phase-resolved second harmonic generation (SHG) microscopy is presented, which utilizes a phase-tunable Soleil-Babinet compensator and the interference between the SHG fields from the inverted structures and a homogeneous reference. By this means, such inverted structures are correlated through the π-phase difference of SHG, and the phase difference is ultimately converted into the intensity contrast. As a demonstration, we have applied this microscopy in two scenarios to determine the inverted crystallographic domains in two-dimensional van der Waals material MoS2. Our method is particularly suitable for applying in vacuum and cryogenic environments while providing optical diffraction-limited resolution and arbitrarily adjustable contrast. Without loss of generality, this contrast-enhanced phase-resolved SHG microscopy can also be used to resolve other non-centrosymmetric inverted structures, e.g. ferroelectric, magnetic, or multiferroic phases.

[Genetic characterization and drug resistance analysis of Salmonella Kentucky ST314 in Shenzhen in 2010-2021].

OBJECTIVE: To understand the prevalence, genetic characteristics and drug resistance features of Salmonella Kentucky ST314 in Shenzhen. METHODS: Whole genome sequencing of 14 strains of Salmonella Kentucky ST314 collected from 2010-2021 by the Foodborne Disease Surveillance Network of Shenzhen Center for Disease Control and Prevention for phylogenetic evolutionary analysis, drug resistance gene and plasmid detection; drug susceptibility experiments were performed by micro-broth dilution method. RESULTS: A total of 57 strains of Salmonella Kentucky were collected from the foodborne disease surveillance network, 14 of which were ST314. The Shenzhen isolates were clustered with isolates from Southeast Asian countries such as Vietnam and Thailand on clade 314.2, and the single nucleotide polymorphism distance between local strains in Shenzhen was large, indicating dissemination. In this study, a total of 17 drug resistance genes/mutations in 9 categories were detected in the genome of Salmonella Kentucky ST314, carrying 3 extended spectrum beta-lactamases(ESBLs), including bla_(CTX-M-24)(14.3%, 2/14), bla_(CTX-M-55)(7.1%, 1/14), and bla_(CTX-M-130)(14.3%, 2/14), all located on plasmids. Regarding quinolone resistance factors, two plasmid-mediated quinolone resistance(PMQR) genes were identified in the genome: qnrB6(71.4%, 10/14) and aac(6')Ib-cr(78.6%, 11/14), a quinolone resistance quinolone resistance-determining regions(QRDR) mutation T57 S(100%, 14/14). The multi-drug resistance rate of Salmonella Kentucky ST314 in Shenzhen was 92.86%(13/14)with the highest rate of resistance to tetracycline and cotrimoxazole(100%, 14/14), followed by chloramphenicol(92.86%, 13/14), cefotaxime and ampicillin(78.57%, 11/14), ciprofloxacin and nalidixic acid(71.43%, 10/14), and ampicillin-sulbactam had the lowest resistance rate(21.43%, 3/14). CONCLUSION: ST314 is the second most prevalent ST type among Salmonella Kentucky in Shenzhen, mainly isolated from food, especially poultry; phylogenetic analysis suggests that ST314 is a disseminated infection and the genome shows a highly genetically conserved phenotype. Drug resistance of Salmonella Kentucky ST314 is very serious, especially QRDR mutation, PMQR gene co-mediated quinolone resistance and plasmid-mediated cephalosporin resistance are prominent and deserve extensive attention.

HD-Zip proteins modify floral structures for self-pollination in tomato.

Cleistogamy is a type of self-pollination that relies on the formation of a stigma-enclosing floral structure. We identify three homeodomain-leucine zipper IV (HD-Zip IV) genes that coordinately promote the formation of interlocking trichomes at the anther margin to unite neighboring anthers, generating a closed anther cone and cleistogamy (flower morphology necessitating strict self-pollination). These HD-Zip IV genes also control style length by regulating the transition from cell division to endoreduplication. The expression of these HD-Zip IV genes and their downstream gene, Style 2.1, was sequentially modified to shape the cleistogamy morphology during tomato evolution and domestication. Our results provide insights into the molecular basis of cleistogamy in modern tomato and suggest targets for improving fruit set and preventing pollen contamination in genetically modified crops.

Differentiation of Type 17 Mucosal-Associated Invariant T Cells in Circulation Contributes to the Severity of Sepsis.

Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and RAR-related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase-LDHA signaling was required for RAR-related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase-LDHA signaling as a driving force in MAIT17 responses.

Growth hormone promotes myelin repair after chronic hypoxia via triggering pericyte-dependent angiogenesis.

White matter injury (WMI) causes oligodendrocyte precursor cell (OPC) differentiation arrest and functional deficits, with no effective therapies to date. Here, we report increased expression of growth hormone (GH) in the hypoxic neonatal mouse brain, a model of WMI. GH treatment during or post hypoxic exposure rescues hypoxia-induced hypomyelination and promotes functional recovery in adolescent mice. Single-cell sequencing reveals that Ghr mRNA expression is highly enriched in vascular cells. Cell-lineage labeling and tracing identify the GHR-expressing vascular cells as a subpopulation of pericytes. These cells display tip-cell-like morphology with kinetic polarized filopodia revealed by two-photon live imaging and seemingly direct blood vessel branching and bridging. Gain-of-function and loss-of-function experiments indicate that GHR signaling in pericytes is sufficient to modulate angiogenesis in neonatal brains, which enhances OPC differentiation and myelination indirectly. These findings demonstrate that targeting GHR and/or downstream effectors may represent a promising therapeutic strategy for WMI.

Corrigendum: Effectiveness of a multicomponent exercise intervention in community-dwelling older Chinese people with cognitive frailty: protocol for a mixed-methods research.

[This corrects the article DOI: 10.3389/fnagi.2024.1282263.].

Intersectional race-gender stereotypes in natural language.

How are Asian and Black men and women stereotyped? Research from the gendered race and stereotype content perspectives has produced mixed empirical findings. Using BERT models pre-trained on English language books, news articles, Wikipedia, Reddit and Twitter, with a new method for measuring propositions in natural language (the Fill-Mask Association Test, FMAT), we explored the gender (masculinity-femininity), physical strength, warmth and competence contents of stereotypes about Asian and Black men and women. We find that Asian men (but not women) are stereotyped as less masculine and less moral/trustworthy than Black men. Compared to Black men and Black women, respectively, both Asian men and Asian women are stereotyped as less muscular/athletic and less assertive/dominant, but more sociable/friendly and more capable/intelligent. These findings suggest that Asian and Black stereotypes in natural language have multifaceted contents and gender nuances, requiring a balanced view integrating the gender schema theory and the stereotype content model. Exploring their semantic representations as propositions in large language models, this research reveals how intersectional race-gender stereotypes are naturally expressed in real life.

Targeting high circDNA2v levels in colorectal cancer induces cellular senescence and elicits an anti-tumor secretome.

The efficacy of immunotherapy against colorectal cancer (CRC) is impaired by insufficient immune cell recruitment into the tumor microenvironment. Our study shows that targeting circDNA2v, a circular RNA commonly overexpressed in CRC, can be exploited to elicit cytotoxic T cell recruitment. circDNA2v functions through binding to IGF2BP3, preventing its ubiquitination, and prolonging the IGF2BP3 half-life, which in turn sustains mRNA levels of the protooncogene c-Myc. Targeting circDNA2v by gene silencing downregulates c-Myc to concordantly induce tumor cell senescence and the release of proinflammatory mediators. Production of CXCL10 and interleukin-9 by CRC cells is elicited through JAK-STAT1 signaling, in turn promoting the chemotactic and cytolytic activities of CD8+ T cells. Clinical evidence associates increased circDNA2v expression in CRC tissues with reductions in CD8+ T cell infiltration and worse outcomes. The regulatory relationship between circDNA2v, cellular senescence, and tumor-infiltrating lymphocytes thus provides a rational approach for improving immunotherapy in CRC.