Gram-negative bacteria pose a threat to global healthcare mainly because their outer membrane (OM) provides an intrinsic barrier to many antimicrobials. Key to this barrier function is the asymmetric structure of the OM, with phospholipids constituting the inner leaflet and lipopolysaccharides, the outer leaflet. Although the mechanism of phospholipid transport between the inner membrane (IM) and OM remains poorly understood, recent studies implicate TamB, YhdP, and YdbH as functionally redundant proteins mediating this process in Escherichia coli. Accordingly, the collective loss of these three paralogs is lethal, and any one of them is sufficient for growth. YdbH is anchored to the IM, and its periplasmic repeating β-sheet groove domain interacts with the OM lipoprotein YnbE via β-strand augmentation to form an intermembrane bridge. Additionally, YnbE multimerizes, and the periplasmic protein YdbL is proposed to modulate YnbE multimerization to facilitate its stacking on the C-terminus of YdbH. Here, we demonstrate that excess YdbL specifically inhibits the function of the YdbH-YnbE complex since overexpression of ydbL causes lethality in the ΔyhdP ΔtamB double mutant, but the presence of both ydbH and ynbE in trans abrogates this lethality. We resolve high-resolution structural data for YdbL and ascertain its interaction site with the YnbE C-terminal α-helix, with residues mediating this interface highly conserved and critical for YdbL function. Finally, we show that YdbL is protected from degradation by the protease DegP when complexed with YnbE. Overall, our data support a model in which YdbL ensures proper YdbH-YnbE intermembrane bridge formation by directly interacting with YnbE. The mechanism underlying phospholipid transport between the inner and outer membranes of gram-negative bacteria remains enigmatic. Bacterial bridge-like protein systems such as the YdbH-YnbE complex resemble proteins found at membrane contact sites between eukaryotic organelles. These proteins are proposed to mediate intermembrane phospholipid transport, which is essential for growth of the outer membrane (OM). Here, we define the role of YdbL, a periplasmic protein that specifically modulates the YdbH-YnbE system. YdbL directly interacts with YnbE and controls the formation of the YdbH-YnbE complex. Additionally, we reveal that YdbL is selectively degraded by the periplasmic protease DegP. We propose a regulatory model that connects the YdbH-YnbE complex assembly and controls the levels of YdbL, providing new insight into OM homeostasis in gram-negative bacteria.
The rising prevalence of polymyxin resistance in multidrug-resistant Klebsiella pneumoniae presents a critical situation with limited therapeutic options. Genomic sequencing of 15 clinical polymyxin-resistant Klebsiella pneumoniae with multidrug resistance revealed MgrB inactivation, predominantly disrupted by insertion sequences in IS1, IS4, IS5 family, was the leading cause of polymyxin resistance. Comparative transcriptomics of WT, ΔmgrB, and ΔmgrBΔphoP were performed to elucidate the MgrB-PhoPQ regulatory network. This study revealed systemwide analysis of the regulatory network, and identified species-specific PhoPQ regulon in Klebsiella pneumoniae. Beyond the classical MgrB-PhoPQ-ArnBCADTEF pathway, we identified a previously unannotated PhoPQ-regulated gene, 144bp-LN739_RS09850, encoding a homolog of Ecr from Enterobacter cloacae. The protein has been reported to confer colistin heteroresistance, and the underlying mechanism hasn't been functionally validated. This study revealed that overexpression of Ecr homologs decreased colistin susceptibility in both Klebsiella pneumoniae and Enterobacter cloacae, but this phenotype was abolished upon phoP deletion, confirming PhoP's essential role. Consistent with this dependency, comparative transcriptomics of Ecr-overexpressing K. pneumoniae versus control revealed significant up-regulation of mgrB, phoPQ, arnBCADTE, and pmrD. Bacterial two-hybrid assays further demonstrated direct Ecr-PhoQ interaction. EMSA confirmed that PhoP directly binds to ecr promoter in vitro, and β-galactosidase reporter assay demonstrated that PhoP enhanced ecr promoter activity, indicating that PhoP regulates ecr expression by directly controlling its transcription. Collectively, these findings suggest that PhoP may directly activate the transcription of Ecr, Ecr feedback activates the PhoPQ system via interaction with PhoQ, leading to induction of the arn operon and consequent polymyxin resistance.
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, mainly due to cancer cell proliferation and migration. Although chondroitin sulfate (CS) is involved in cancer progression, its regulatory mechanisms remain unclear. To investigate the role and mechanism of chondroitin polymerizing factor 2 (CHPF2) and CS in CRC progression, as well as to evaluate the therapeutic potential of ponicidin. The correlation between CHPF2 and prognosis was analyzed in clinical samples. Mechanistically, ponicidin was found to target CHPF2, suppress CS synthesis, and consequently block the Wnt/β-catenin pathway. Its anti-tumor efficacy was validated in cellular, organoid, and animal models. We identified CHPF2, a key enzyme in CS synthesis, as a critical driver of CRC. CHPF2 is significantly overexpressed in CRC tissues, and its high expression correlates with advanced disease stage and poor patient prognosis. Functionally, CHPF2 drives tumor cell proliferation, migration, and survival by enhancing CS production. Mechanistically, CS promotes the activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT). This effect is associated with CS-dependent modifications of Wnt1; however, further investigation is required to determine whether Wnt1 is directly modified by CS chains or indirectly affected via CS-modified proteoglycans. Furthermore, the natural diterpenoid ponicidin derived from Rabdosia rubescens directly targets CHPF2 and inhibits its enzymatic activity, thereby reducing CS biosynthesis and subsequently blocking the Wnt/β-catenin signaling pathway. The anti-tumor efficacy of ponicidin was validated in cellular models, patient-derived organoids, and primary CRC models, demonstrating its potent inhibitory effects on tumor growth and metastasis. Our study reveals the oncogenic role of the CHPF2/CS axis in CRC, establishes CHPF2 as a novel therapeutic target, and provides compelling preclinical evidence supporting ponicidin as a promising CHPF2-targeted agent for CRC treatment.
Hybridization and adaptive introgression are increasingly recognized as important components of how natural selection shapes plant speciation and ecological diversification, yet their roles in tropical clades remain poorly understood. We investigated these processes in Pandanus Parkinson (Pandanaceae), a palaeotropical tree genus of high ecological significance and the tenth-most diverse tree genus worldwide. Although morphological evidence suggested hybridization across the Indian Ocean, its genomic basis remained untested. Using 398 total samples (331 nuclear ones for Pandanus), we assessed hybridization and adaptive phenotypes by: (i) testing for broad and morphology-specific transoceanic gene flow through genome-wide conflict, gene conflict, and admixture analyses from Angiosperms353 data; (ii) evaluating whether gene flow occurred via long-distance dispersal or through a bridge clade; and (iii) testing directly and indirectly for adaptive introgression. We found strong, statistically significant evidence of bidirectional transoceanic gene flow, with nuclear clade Ba acting as a critical genetic and biogeographical bridge between Asian and Afro-Malagasy lineages. Contrary to predictions, the striking morphological similarity between geographically disjunct "swamp" lineages reflects convergent evolution rather than shared introgressive history, likely shaped by distinct macroclimatic regimes. Support for adaptive introgression in the bridge clade rested on a consilience of independent evidence: inferred chloroplast capture, differential purifying selection on plastome clades, correlated distribution of a novel foliar water-storage trait, and ecological niche overlap, all coinciding with Miocene forest contraction, Tethys Sea closure, and increasing climatic seasonality. These results highlight hybridization's central role in shaping tropical tree diversity and facilitating ecological adaptation under environmental change.
The human microbiome, a dynamic endocrine organ, exerts profound systemic influence through the production of bioactive metabolites. While the microbiome-gut-brain axis is well-established, the direct conduit between the gut microbiota and the reproductive system, the Microbiome-Gut-Gonad Axis, remains an emerging paradigm. This review explored cutting-edge evidence to construct a comprehensive model of the Microbiome-Gut-Gonad axis, focusing on the mechanistic roles of specific microbial metabolites in both physiological reproductive function and the pathogenesis of endocrine disorders. We move beyond mere correlation to elucidate how gut-derived molecules, such as short-chain fatty acids (SCFAs), secondary bile acids, and indole derivatives, directly and indirectly modulate the hypothalamic-pituitary-gonadal (HPG) axis by modulating the production of neuropeptides and hormones (Gonadotropin-releasing hormone (GnRH)) that regulate reproductive functions and also steroidogenesis and gametogenesis. We examine novel mechanisms including: the epigenetic regulation of steroidogenic enzymes by butyrate; the modulation of enterohepatic circulation of estrogens by β-glucuronidase-producing bacteria; and the role of tryptophan metabolites as ligands for aryl hydrocarbon receptor (AhR) in ovarian and testicular function. Furthermore, we critically appraise the disruptive potential of dysbiosis-driven metabolite shifts in PCOS, endometriosis, and male infertility, highlighting microbial metabolite signatures as promising exploratory biomarkers that require standardized, multi-center clinical validation before diagnostic use. At present, these signatures should be considered candidate biomarkers only, because external validation cohorts, assay reproducibility, and clinically meaningful estimates of sensitivity, specificity, predictive values, and clinical utility have not yet been established. Therapeutically, we evaluate innovative interventions, including precision probiotics, postbiotics, and dietary strategies targeting specific bacterial guilds, but these approaches remain investigational because current human evidence is still limited and heterogeneous. Finally, by integrating microbial endocrinology into reproductive medicine, this review establishes a new framework for understanding the etiology of reproductive endocrine disorders and paves the way for microbiome-targeted therapeutic avenues. Importantly, the evidence base is tiered: mechanistic statements in this review are drawn primarily from in vitro and animal studies, human disease links are described separately as observational evidence, and interventional claims are limited to early clinical studies and randomized trial summaries.
Recent multicenter studies aim to define the effects of mothers' blood glucose levels during pregnancy on mammary gland function and breast milk composition. Gene expression measured in cells in milk can serve as a liquid biopsy to evaluate the molecular biology of the mammary gland. Critical to this aim is reproducible and high-quality extraction of RNA from milk and harmonized collection protocols from across centers. To address this, we performed a study to optimize milk RNA quality metrics where samples are collected at multiple centers and shipped to a central laboratory for processing and analysis. Lactating mothers provided breast milk following informed consent. The treatments of the samples were as follows: (1) 200 µL of fresh, never frozen milk used as control (FRESH); (2) 1.7 or 5 mL of milk frozen and thawed on ice before adding TRIzol (FRZ); (3) 200 µL of milk frozen and thawed after adding TRIzol (FRZ 200); and (4) 200 µL of milk with 20 µL of RNA preservative added, frozen and thawed after adding TRIzol (FRZ + INH). In all scenarios, RNA was extracted using TRIzol followed by purification with a Qiagen RNeasy Mini kit. For the FRZ 200 and FRZ 200 + INH samples, TRIzol was directly added at the start of thawing, before extraction. Outcomes included RNA concentration, RNA purity (260/280 ratio), RNA fragmentation (DV 200), RNA integrity number (RIN), quantification via Qubit fluorescence-based assays, and visualization of RNA size on an Agilent TapeStation. A RIN cut-off value ≥ 7 indicated acceptable quality for transcriptomics studies. RNA quality metrics were modeled as continuous outcomes using linear mixed-effects regression models. For FRESH milk (n = 15) the estimated marginal mean (EMM) RIN was 7.48 (SE 0.29). For FRZ 200, (n = 22), the EMM RIN was 6.94 (SE 0.26). Samples of FRZ 200 + INH (n = 21) had an EMM RIN of 7.81 (SE 0.26). However, FRZ (n = 19) samples demonstrated markedly reduced RNA integrity with an EMM RIN of 1.92 (SE 0.26). RIN was not significantly different in FRESH versus FRZ 200 or FRZ 200 + INH milk. FRZ 200 + INH samples showed a statistically significant improvement in RIN compared to FRZ 200 (p = 0.0038). RNA quantities were sufficient for sequencing across all treatments. The addition of TRIzol directly to a 200 µL aliquot of milk at the start of thawing provided the highest integrity of extracted milk RNA, as measured by RIN. Adding RNase inhibitor at the time of sample collection, prior to freezing, also enhanced RNA integrity. We have developed a method to optimize the integrity of RNA from frozen human milk samples. This is a crucial methods improvement for multi-center studies where freezing of milk samples is often required prior to RNA extraction and analysis. These results can inform reproducible research protocols for evaluating the use of breastmilk as a liquid biopsy for mammary gland function.
Global increases in the intensity and frequency of elevated temperatures is threatening ecosystem stability and crop yield. Understanding plant thermomorphogenesis is critical for developing climate-resilient crops, yet the underlying mechanisms remain to be clarified. Here, we identify the BEL1-LIKE HOMEODOMAIN transcription factor BLH1 as a critical negative regulator of thermomorphogenesis that modulates the key BRASSINAZOLE-RESISTANT 1 (BZR1)-PHYTOCHROME INTERACTING FACTOR 4 (PIF4) thermomorphogenic regulatory module. Overexpression of BLH1 or its homologs confers high-temperature (HT) insensitivity, whereas blh higher-order mutants exhibit HT hypersensitivity. BLH1 expression is directly repressed by BZR1 and is down-regulated by HT. We further demonstrate that BLH1 directly binds to the PIF4 promoter to repress its transcription and concurrently interacts with the PIF4 protein to inhibit its activity. Overexpression of BLH1 rescues the elongated hypocotyl phenotype in bzr1-1D or PIF4 overexpression plants. Our findings define a BZR1-BLH1-PIF4 regulatory axis that modulates the BZR1-PIF4-auxin-BR-BZR1 positive feedback loop, ensuring a balanced thermomorphogenic response to HT.
Ischemia-reperfusion injury (IRI) greatly impairs lung transplantation (LTx) outcomes, with no effective treatments. Although existing studies have confirmed that cell death and inflammation responses are critical in LTx-IRI, the specific cell death profiles of various parenchymal and inflammatory cells remain to be elucidated. Using human single-cell RNA sequencing data from LTx-IRI, we identified activation of genes related to cell death and inflammation pathways. We examined the effects and mechanisms of a RIPK3 inhibitor, GSK'872, on IRI with a rat LTx model. GSK'872, added to lung preservation solution, injected to recipients, or in combination, reduced alveolar hemorrhage, perivascular edema, neutrophil infiltration and suppressed necroptosis, pyroptosis, and inflammation in lung tissues. GSK'872 decreased MLKL phosphorylation in type 2 alveolar epithelial cells and macrophages, and RIPK3 phosphorylation in neutrophils. GSK'872 induced apoptosis in RAW264.7 macrophages via RIPK1 and caspase 3 cleavage in a cold ischemia/warm reperfusion (CI/R) cell culture model. GSK'872 inhibited lipopolysaccharide (LPS)-stimulated neutrophil extracellular traps (NETs) formation with suppressed necroptosis and pyroptosis. GSK'872 did not rescue BEAS-2B lung epithelial cells from CI/R-induced cell death. However, conditioned medium from GSK'872-treated macrophages (after CI/R) or neutrophils (challenged by LPS) reduced CI/R-induced decrease in BEAS-2B cell viability. GSK'872 alleviates LTx-IRI by inhibiting necroptosis and pyroptosis in macrophages and neutrophils directly, and protects lung epithelial cells via blocking soluble mediators indirectly. Administration of GSK'872 to lung preservation solution and/or injection to recipients may be new treatment options for IRI in LTx.
To investigate the factors influencing exercise intention among the people after stroke by developing a comprehensive causal model. This study is the first to examine the factors influencing exercise intention among people after stroke using the Health Action Process Approach (HAPA) theory and structural equation modeling. Data were collected from 299 people after stroke. Perceived benefits and barriers to exercise were evaluated with the Exercise Benefits/Barriers Scale (EBBS). Exercise self-efficacy was assessed using the Exercise self-efficacy scale. Exercise intention was assessed using the Exercise Intention Scale. People after stroke's EBBS score was (112.54 ± 13.67); exercise self-efficacy score was (41.68 ± 10.95); and exercise intention score was (14.41 ± 3.48). The total score of EBBS was positively correlated with the total score of exercise self-efficacy and the total score of exercise intention (r = 0.623, 0.681, both P < 0.05), and the total score of exercise self-efficacy was positively correlated with the total score of exercise intention (r = 0.646, P < 0.05). Structural equation modeling showed several causal pathways. Perceived barriers to exercise had an indirect effect on exercise intentions through exercise self-efficacy (β = -0.183, 95% CI -0.286 to -0.101, P < 0.05). Perceived benefits to exercise not only directly affected exercise intentions (β = 0.246, 95% CI 0.073 to 0.424, P < 0.05), but also indirectly affected exercise intentions through exercise self-efficacy (β = 0.152, 95% CI 0.084 to 0.231, P < 0.05). Additionally, perceived benefits and perceived barriers to exercise negatively influenced each other (β = -0.681, P < 0.05). The perceived benefits and barriers to exercise, exercise intention and exercise self-efficacy level of people after stroke need to be improved. Among them, the influence of exercise self-efficacy on exercise intention is the most significant. Consequently, attention and active measures should be directed toward improving exercise self-efficacy in this population, as this would increase their exercise intention and reduce the risk of relapse.
To investigate the microsurgical anatomy, morphologic variability, and morphometric features of the anterior (AIFA), middle (MIFA), and posterior (PIFA) internal frontal arteries. Seventeen formalin-fixed, latex-injected cadaveric heads (34 hemispheres) were examined using microsurgical techniques. Five hemispheres were excluded due to inadequate vascular filling or preservation, resulting in a final sample of 29 hemispheres. The AIFA, MIFA, and PIFA were identified in 96.5%, 93.1%, and 96.5% of hemispheres, respectively. The most common origin of the AIFA and MIFA was the callosomarginal artery (41.4%), whereas the PIFA most frequently arose from the A4 segment (44.8%). Common trunks were observed between AIFA-MIFA (31%) and MIFA-PIFA (10.3%). Arterial duplications and bihemispheric variants were uncommon. Intrahemispheric anastomoses were identified in 24.1% (AIFA-MIFA), 10.3% (MIFA-PIFA), and 27.6% (PIFA-paracentral lobule artery) of hemispheres. The IFA branches show variability in origin, duplication, and interconnections. These features are directly relevant to interhemispheric surgical approaches, in which injury to the distal ACA branches may result in motor or cognitive deficits. Recognition of these patterns may improve surgical planning and reduce the risk of ischemic complications.
Chimeric RNAs could be originated from chromosome rearrangements at the DNA level or from posttranscriptional RNA fusion events, such as trans-spicing between distal genes and cis-splicing between adjacent genes. In addition to the mechanisms above, we have identified a new type of chimeric RNA, cross-strand chimeric RNA (cscRNA), which are fusion products of the transcripts encoded by the two opposite DNA strands. In this chapter, we present the workflow of cscMap, a specialized bioinformatics pipeline designed for de novo identification of the cscRNAs, directly from RNA deep sequencing data without prior annotations. cscMap employs a series of meticulous measurements to ensure high accuracy in detecting cross-strand junction events. This approach and the cscRNA species could serve as a valuable resource for further exploration of the origins and functions of cscRNAs.
Diffuse gliomas remain among the most surgically challenging tumors, characterized by their infiltrative nature, proximity to eloquent brain structures, and the formidable barrier posed by the BBB to systemic therapeutic delivery. Maximizing extent of resection (EOR) while preserving neurological function remains a central determinant of survival and quality of life, and the iterative integration of intraoperative technologies into surgical practice has become essential to achieving this balance. We performed a comprehensive narrative review of established and emerging intraoperative technologies for glioma surgery, organized around two clinical imperatives: optimizing tumor delineation and safe resection, and enhancing local therapeutic delivery. Awake craniotomy with direct electrical stimulation remains the gold standard for preserving eloquent cortex and subcortical tracts, consistently reducing postoperative neurological deficits while increasing gross total resection rates. Fluorescence-guided surgery with 5-ALA and fluorescein enhances real-time tumor margin visualization, and their combined use achieves greater EOR than either agent alone. Intraoperative MRI compensates for progressive brain shift and, when used alongside 5-ALA, provides the strongest currently available platform for maximizing safe resection. Augmented reality navigation further enhances spatial orientation by overlaying 3D virtual anatomy directly onto the operative field. Emerging tissue characterization tools, including stimulated Raman histology, confocal laser endomicroscopy, and AI-based platforms such as FastGlioma and DeepGlioma, enable rapid intraoperative molecular diagnosis without the delays of conventional frozen section pathology. For therapeutic delivery, low-frequency focused ultrasound and convection-enhanced delivery bypass the BBB to achieve high local drug concentrations, while endovascular intra-arterial infusion enables targeted delivery across the tumor vascular territory. Photodynamic and sonodynamic therapy generate localized cytotoxic effects within the resection cavity at the time of surgery. Intraoperative brachytherapy with Cesium-131 tile implants delivers conformal radiation at the time of resection and may potentiate antitumor immunity. Laser interstitial thermal therapy combines cytoreduction with sustained BBB disruption, creating a therapeutic window for otherwise CNS-impermeant agents including checkpoint inhibitors. The deliberate integration of these complementary modalities into a phase-organized intraoperative workflow, spanning preoperative planning, real-time resection guidance, intraoperative margin and tissue assessment, and post-resection locoregional therapeutic delivery, defines the emerging paradigm of precision glioma surgery. Realizing the full potential of this framework will require prospective validation of combinatorial strategies, standardization of technology integration protocols, and rigorous evaluation of neurological and oncological outcomes.
Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
Microplastic contamination in bottled drinking water is an emerging environmental and public health concern, particularly when bottles are exposed to varying storage and thermal conditions. This study introduces FMIND (fuzzy microplastic inference for detection risk), an IoT-enabled fuzzy inference framework for rapid and low-cost microplastic contamination risk assessment. Bottled water stored in PET and stainless-steel containers under sunlight, shade, and freezer conditions was evaluated using IoT sensors measuring temperature, turbidity, and total dissolved solids (TDS) before and after 30 days of storage. Statistical analysis revealed strong correlations between sensor variations and contamination-related physicochemical indicators, including turbidity (r = 0.861), TDS (r = 0.793), and temperature (r = 0.565) (p < 0.001). The FMIND fuzzy model applied 12 Sugeno rules to generate a contamination risk score (0-100), while the HFIRM-GT enhanced configuration improved classification consistency within the experimental dataset, achieving an F1 score of 0.91. Laboratory validation using FTIR spectroscopy, SEM imaging, and EDAX elemental analysis on selected high-risk samples supported the presence of polymer-associated microplastic fragments in sunlight-exposed PET bottles. The proposed framework does not directly quantify microplastics through IoT sensors; instead, it estimates contamination risk using indirect physicochemical indicators supported by laboratory validation. FMIND integrates IoT sensing, fuzzy reasoning, and chemical validation into a unified and interpretable framework for periodic bottled water contamination risk assessment. The reported predictive performance reflects evaluation within a limited experimental dataset and should be interpreted as preliminary proof-of-concept validation rather than generalized field-scale performance. The system provides a scalable and cost-effective approach that supports Sustainable Development Goal 3 (Good Health and Well-Being), Sustainable Development Goal 6 (Clean Water and Sanitation), and Sustainable Development Goal 12 (Responsible Consumption and Production).
The aberrant activation of the NOTCH1 signaling pathway underlies the aggressive malignancy and poor prognosis of T-cell acute lymphoblastic leukemia (T-ALL). T-ALL cell lines (Jurkat and Molt4) were treated with chiglitazar to evaluate viability, proliferation, apoptosis, and cell cycle. RNA-seq, qRT-PCR, and Western blotting were used to examine NOTCH1 signaling. Mechanistic assays included luciferase reporter, DNA affinity precipitation, co-immunoprecipitation, and ChIP. In vivo, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models were generated by intravenous engraftment of leukemic cells into sublethally irradiated mice, followed by treatment with chiglitazar alone or combined with venetoclax. Therapeutic efficacy was assessed by survival, flow cytometric tumor burden, and histopathology (HE and IHC). We report that therapeutic activation of peroxisome proliferator-activated receptor α (PPARα) significantly represses the leukemogenesis of T-ALL in vitro and in vivo by blocking the NOTCH1 signaling pathway. Mechanistically, PPARα directly binds to the promoter region of the NOTCH1 gene and inhibits its transcriptional activity. Furthermore, PPARα interacts with signal transducer and activator of transcription 3 (STAT3) and attenuates the transcriptional activation effect of STAT3 on the NOTCH1 gene promoter. Importantly, we also found that therapeutic activation of PPARα using chiglitazar synergizes with venetoclax to suppress T-ALL progression in PDX models. We conclude that targeting PPARα to suppress T-ALL progression by blocking the NOTCH1 pathway represents a potential novel therapeutic strategy for the treatment of T-ALL.
The relevance of the topic is determined by data from numerous studies indicating a significantly higher prevalence of stigma toward individuals using psychoactive substances compared to patients with other mental disorders. Stigma is recognized as a key problem in modern healthcare systems and is defined as a systemic factor shaping the entire ecosystem of narcological care. It frequently affects the professional activities of mid-level medical personnel manifesting at interconnected levels and forming a vicious cycle that deteriorates treatment quality and outcomes while undermining the health of the staff themselves. Stereotypical and negative perceptions of patients with addictions among mid-level medical personnel lead to discriminatory care practices: ignoring pain complaints unfounded suspicions and the use of derogatory language in communication and documentation. It is stigmatizing treatment that inflicts the most severe psychological trauma becoming the primary barrier to seeking help again. Intra-organizational stigma directly contributes to adverse clinical outcomes increased relapses and mortality. Combating stigma must become the cornerstone of professional support and training programs for mid-level medical personnel as well as efforts to improve the overall quality of narcological care. Актуальность темы обусловлена тем что по данным многочисленных исследований определяется значительно более высокая распространённость стигмы в отношении лиц употребляющих психоактивные вещество по сравнению с пациентами с другими психическими расстройствами. Стигма признана ключевой проблемой современных систем здравоохранения и определяется как системный фактор всей экосистемы наркологической помощи. Она нередко затрагивает профессиональную деятельность среднего медицинского персонала проявляясь на взаимосвязанных уровнях и формируя порочный круг который ухудшает качество и исходы лечения а также подрывает здоровье самих специалистов. Стереотипные и негативные представления среднего медицинского персонала о пациентах с зависимостями приводят к дискриминационным практикам ухода: игнорированию жалоб на боль необоснованным подозрениям использованию уничижительного языка в общении и документации. Именно стигматизирующее отношение наносит наиболее тяжёлую психологическую травму становясь основным барьером для повторного обращения за помощью. Внутриорганизационная стигма напрямую способствует неблагоприятным клиническим исходам повышению рецидивов и смертности. Борьба со стигмой должна стать краеугольным камнем программ профессиональной поддержки и обучения среднего медицинского персонала повышения качества наркологической помощи в целом.
Lung surfactant is essential for regulating alveolar surface stresses, reducing the work of breathing, maintaining compliance, and preventing collapse. Under pathological conditions such as acute respiratory distress syndrome (ARDS), this functionality is compromised, yet the underlying physical mechanisms remain incompletely understood. Recent work has shown that surfactant failure cannot be described from surface tension alone, but requires consideration of the interfacial dilatational modulus, which quantifies the ability of the interface to sustain stress under deformation. Mechanical instability arises when this stress-bearing capacity is lost, linking alveolar collapse directly to a reduction in the dilatational modulus. However, this response is typically interpreted in terms of equilibrium adsorption and Gibbs elasticity. Here, we demonstrate instead that it reflects the breakdown of nonequilibrium, microstructure-mediated mechanical surface stresses. By combining freestanding thin-film measurements, cryo-TEM imaging, and dilatational rheology, we isolate the effects of extra compressive stress contributions arising from interfacial microstructure and probe the effects of Albumin and lysophosphatidylcholine (LysoPC) on the clinical surfactant Infasurf. We show that LysoPC-induced structural reorganization disrupts the interfacial architecture, suppressing the development of compressive surface stresses and thereby weakening the mechanical integrity of the interface. These results establish a more subtle link between surfactant microstructure and the interfacial stress response, providing a physically grounded framework for surfactant inactivation and suggesting distinct directions for therapeutic design.
Accurate estimation of vehicle dynamic states is crucial for vehicle stability control and autonomous driving systems. However, critical states such as sideslip angle are difficult to measure directly using onboard sensors, especially under complex driving conditions and significant sensor noise. To address these issues, this paper proposes a hybrid vehicle state estimation framework, which integrates closed-form continuous-time (CfC) networks with an enhanced unscented Kalman filter (UKF). In the proposed framework, a CfC-based network is designed to process sequential IMU and GPS measurements and provide preliminary state predictions along with corresponding uncertainty estimates. These predictions of the network are then incorporated into a model-based UKF as pseudo-measurements, and the corresponding uncertainty is utilized to construct the measurement covariance. Furthermore, a data-driven sigma points sampling strategy is developed by exploiting the intrinsic multi-step predictive feature of CfC-models, enabling more accurate approximations of the local observation distribution. The proposed framework is first validated on both KITTI dataset and generated dataset using Carsim. Moreover, real-world experiments are conducted based on a test platform. Experimental results demonstrate that the proposed hybrid framework can simultaneously deal with unknown noise and achieve superior accuracy and robustness compared with learning-based and model-based baselines. We release the source code at https://github.com/HITXCI/w-state.
The miniaturization and integration of electronic/photonic devices demand precise control over light at the micro-scale. However, achieving tailored optical anisotropy through intrinsic material design, rather than external components, remains a significant challenge. Herein, we report a general and programmable strategy for the growth of one-dimensional organic crystals with precisely tunable asymmetric architectures via a spatially defined temperature gradient. By leveraging the competitive, facet-dependent growth kinetics under a thermal bias, continuous and precise control over the structural asymmetry is achieved in single crystals, with a tunable morphological anisotropy ranging from 9% to 81%. The resulting asymmetric crystals exhibit a pronounced direction-dependent optical response, yielding a photoluminescence intensity contrast ratio as high as 113.3, which scales directly with the degree of structural asymmetry. This work establishes a material-based platform for applying direction-dependent photonic properties directly into crystal morphology, paving the way for advanced organic photonic materials with built-in anisotropy.
This study reports the development of an efficient and structurally robust functional hybrid hydrogel composed of a Poly(acrylamide-co-acrylic acid) matrix, reinforced with silver-decorated recycled nano-tungsten oxide (Ag-WO3) composites. To ensure structural longevity and eliminate secondary pollution risks, the recycled nanoparticles derived from industrial scrap were modified via an eco-friendly photo-reduction method and covalently tethered to the polymer backbone using a vinyltrimethoxysilane coupling agent. FT-IR analysis confirmed successful interfacial chemical grafting, which acted as a nano-skeleton reinforcement. Consequently, a dramatic increase in mechanical robustness was achieved, with surface hardness rising from 43 Shore A for the pristine hydrogel to 80 Shore A for the dense hybrid network. Crucially, the hybrid system exhibited exceptional chemo-structural stability across a broad pH spectrum (3-11), maintaining a gel content exceeding 90% with nearly zero detectable leaching or turbidity. Functionally, the Ag-WO3 integrated hydrogel serves as a potent dual-action platform for wastewater purification, achieving 86.5% photocatalytic degradation of Methylene Blue dye under UV irradiation within 60 min, alongside an outstanding 99.98% antibacterial eradication rate against Escherichia coli. By transforming industrial metallurgical scrap into a high-value environmental catalyst, this research offers a sustainable, non-leaching, and scalable platform for advanced wastewater decontamination, directly contributing to the United Nations Sustainable Development Goals (SDG 6: Clean Water and Sanitation, and SDG 12: Responsible Consumption and Production).