A Thermostable mRNA Vaccine against COVID-19.

There is an urgent need for vaccines against coronavirus disease 2019 (COVID-19) because of the ongoing SARS-CoV-2 pandemic. Among all approaches, a messenger RNA (mRNA)-based vaccine has emerged as a rapid and versatile platform to quickly respond to this challenge. Here, we developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor binding domain (RBD) of SARS-CoV-2 as a vaccine candidate (called ARCoV). Intramuscular immunization of ARCoV mRNA-LNP elicited robust neutralizing antibodies against SARS-CoV-2 as well as a Th1-biased cellular response in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse-adapted strain. Additionally, ARCoV is manufactured as a liquid formulation and can be stored at room temperature for at least 1 week. ARCoV is currently being evaluated in phase 1 clinical trials.

ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.

RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model.

Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.

Chemical Flexibility of Atomically Precise Metal Clusters.

Ligand-protected metal clusters possess hybrid properties that seamlessly combine an inorganic core with an organic ligand shell, imparting them exceptional chemical flexibility and unlocking remarkable application potential in diverse fields. Leveraging chemical flexibility to expand the library of available materials and stimulate the development of new functionalities is becoming an increasingly pressing requirement. This Review focuses on the origin of chemical flexibility from the structural analysis, including intra-cluster bonding, inter-cluster interactions, cluster-environments interactions, metal-to-ligand ratios, and thermodynamic effects. In the introduction, we briefly outline the development of metal clusters and explain the differences and commonalities of M(I)/M(I/0) coinage metal clusters. Additionally, we distinguish the bonding characteristics of metal atoms in the inorganic core, which give rise to their distinct chemical flexibility. Section 2 delves into the structural analysis, bonding categories, and thermodynamic theories related to metal clusters. In the following sections 3 to 7, we primarily elucidate the mechanisms that trigger chemical flexibility, the dynamic processes in transformation, the resultant alterations in structure, and the ensuing modifications in physical-chemical properties. Section 8 presents the notable applications that have emerged from utilizing metal clusters and their assemblies. Finally, in section 9, we discuss future challenges and opportunities within this area.

Phosphatidic acid interacts with an HD-ZIP transcription factor GhHOX4 to influence its function in fiber elongation of cotton (Gossypium hirsutum).

Upland cotton, the mainly cultivated cotton species in the world, provides over 90% of natural raw materials (fibers) for the textile industry. The development of cotton fibers that are unicellular and highly elongated trichomes on seeds is a delicate and complex process. However, the regulatory mechanism of fiber development is still largely unclear in detail. In this study, we report that a homeodomain-leucine zipper (HD-ZIP) IV transcription factor, GhHOX4, plays an important role in fiber elongation. Overexpression of GhHOX4 in cotton resulted in longer fibers, while GhHOX4-silenced transgenic cotton displayed a "shorter fiber" phenotype compared with wild type. GhHOX4 directly activates two target genes, GhEXLB1D and GhXTH2D, for promoting fiber elongation. On the other hand, phosphatidic acid (PA), which is associated with cell signaling and metabolism, interacts with GhHOX4 to hinder fiber elongation. The basic amino acids KR-R-R in START domain of GhHOX4 protein are essential for its binding to PA that could alter the nuclear localization of GhHOX4 protein, thereby suppressing the transcriptional regulation of GhHOX4 to downstream genes in the transition from fiber elongation to secondary cell wall (SCW) thickening during fiber development. Thus, our data revealed that GhHOX4 positively regulates fiber elongation, while PA may function in the phase transition from fiber elongation to SCW formation by negatively modulating GhHOX4 in cotton.

FTO-mediated m6A mRNA demethylation aggravates renal fibrosis by targeting RUNX1 and further enhancing PI3K/AKT pathway.

Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.

A versatile fluorescence-quenched substrate for quantitative measurement of glucocerebrosidase activity within live cells.

Loss of activity of the lysosomal glycosidase ß-glucocerebrosidase (GCase) causes the lysosomal storage disease Gaucher disease (GD) and has emerged as the greatest genetic risk factor for the development of both Parkinson disease (PD) and dementia with Lewy bodies. There is significant interest into how GCase dysfunction contributes to these diseases, however, progress toward a full understanding is complicated by presence of endogenous cellular factors that influence lysosomal GCase activity. Indeed, such factors are thought to contribute to the high degree of variable penetrance of GBA mutations among patients. Robust methods to quantitatively measure GCase activity within lysosomes are therefore needed to advance research in this area, as well as to develop clinical assays to monitor disease progression and assess GCase-directed therapeutics. Here, we report a selective fluorescence-quenched substrate, LysoFQ-GBA, which enables measuring endogenous levels of lysosomal GCase activity within living cells. LysoFQ-GBA is a sensitive tool for studying chemical or genetic perturbations of GCase activity using either fluorescence microscopy or flow cytometry. We validate the quantitative nature of measurements made with LysoFQ-GBA using various cell types and demonstrate that it accurately reports on both target engagement by GCase inhibitors and the GBA allele status of cells. Furthermore, through comparisons of GD, PD, and control patient-derived tissues, we show there is a close correlation in the lysosomal GCase activity within monocytes, neuronal progenitor cells, and neurons. Accordingly, analysis of clinical blood samples using LysoFQ-GBA may provide a surrogate marker of lysosomal GCase activity in neuronal tissue.

Rearranging Spin Electrons by Axial-Ligand-Induced Orbital Splitting to Regulate Enzymatic Activity of Single-Atom Nanozyme with Destructive d-π Conjugation.

Most of the nanozymes have been obtained based on trial and error, for which the application is usually compromised by enzymatic activity regulation due to a vague catalytic mechanism. Herein, a hollow axial Mo-Pt single-atom nanozyme (H-MoN5@PtN4/C) is constructed by a two-tier template capture strategy. The axial ligand can induce Mo 4d orbital splitting, leading to a rearrangement of spin electrons (↑ ↑ → ↑↓) to regulate enzymatic activity. This creates catalase-like activity and enhances oxidase-like activity to catalyze cascade enzymatic reactions (H2O2 → O2 → O2•-), which can overcome tumor hypoxia and accumulate cytotoxic superoxide radicals (O2•-). Significantly, H-MoN5@PtN4/C displays destructive d-π conjugation between the metal and substrate to attenuate the restriction of orbitals and electrons. This markedly improves enzymatic performance (catalase-like and oxidase-like activity) of a Mo single atom and peroxidase-like properties of a Pt single atom. Furthermore, the H-MoN5@PtN4/C can deplete overexpressed glutathione (GSH) through a redox reaction, which can avoid consumption of ROS (O2•- and •OH). As a result, H-MoN5@PtN4/C can overcome limitations of a complex tumor microenvironment (TME) for tumor-specific therapy based on TME-activated catalytic activity.

MRI versus Dual-Energy CT in Local-Regional Staging of Gastric Cancer.

Background Preoperative local-regional tumor staging of gastric cancer (GC) is critical for appropriate treatment planning. The comparative accuracy of multiparametric MRI (mpMRI) versus dual-energy CT (DECT) for staging of GC is not known. Purpose To compare the diagnostic accuracy of personalized mpMRI with that of DECT for local-regional T and N staging in patients with GC receiving curative surgical intervention. Materials and Methods Patients with GC who underwent gastric mpMRI and DECT before gastrectomy with lymphadenectomy were eligible for this single-center prospective noninferiority study between November 2021 and September 2022. mpMRI comprised T2-weighted imaging, multiorientational zoomed diffusion-weighted imaging, and extradimensional volumetric interpolated breath-hold examination dynamic contrast-enhanced imaging. Dual-phase DECT images were reconstructed at 40 keV and standard 120 kVp-like images. Using gastrectomy specimens as the reference standard, the diagnostic accuracy of mpMRI and DECT for T and N staging was compared by six radiologists in a pairwise blinded manner. Interreader agreement was assessed using the weighted κ and Kendall W statistics. The McNemar test was used for head-to-head accuracy comparisons between DECT and mpMRI. Results This study included 202 participants (mean age, 62 years ± 11 [SD]; 145 male). The interreader agreement of the six readers for T and N staging of GC was excellent for both mpMRI (κ = 0.89 and 0.85, respectively) and DECT (κ = 0.86 and 0.84, respectively). Regardless of reader experience, higher accuracy was achieved with mpMRI than with DECT for both T (61%-77% vs 50%-64%; all P < .05) and N (54%-68% vs 51%-58%; P = .497-.005) staging, specifically T1 (83% vs 65%) and T4a (78% vs 68%) tumors and N1 (41% vs 24%) and N3 (64% vs 45%) nodules (all P < .05). Conclusion Personalized mpMRI was superior in T staging and noninferior or superior in N staging compared with DECT for patients with GC. Clinical trial registration no. NCT05508126 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Méndez and Martín-Garre in this issue.

Multienzyme-Like Polyoxometalate-Based Single-Atom Enzymes for Cancer-Specific Therapy Through Acid-Triggered Nontoxicity-to-Toxicity Transition.

Single-atom enzymes (SAzymes) exhibit great potential for chemodynamic therapy (CDT); while, general application is still challenged by their instability and unavoidable side effects during delivery. Herein, a manganese-based polyoxometalate single-atom enzyme (Mn-POM SAE) is first introduced into tumor-specific CDT, which exhibits tumor microenvironment (TME)-activated transition of nontoxicity-to-toxicity. Different from traditional POM materials, the aggregates of low-toxic Mn-POM SAE nanospheres are obtained at neutral conditions, facilitating efficient delivery and avoiding toxicity problems in normal tissues. Under acid TME conditions, these nanospheres are degraded into smaller units of toxic Mn(II)-PW11; thus, initiating cancer cell-specific therapy. The released active units of Mn(II)-PW11 exhibit excellent multienzyme-like activities (including peroxidase (POD)-like, oxidase (OXD)-like, catalase (CAT)-like, and glutathione peroxidase (Gpx)-like activities) for the synergistic cancer therapy due to the stabilized high valence Mn species (MnIII/MnIV). As demonstrated by both intracellular evaluations and in vivo experiments, ROS is generated to cause damage to lysosome membranes, further facilitating acidification and impaired autophagy to enhance cancer therapy. This study provides a detailed investigation on the acid-triggered releasing of active units and the electron transfer in multienzyme-mimic-like therapy, further enlarging the application of POMs from catalytical engineering into cancer therapy.

HMGB1-RAGE axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte autophagy and apoptosis in diabetic mice.

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations.

Dynamics of fermentation quality, bacterial communities, and fermentation weight loss during fermentation of sweet sorghum silage.

BACKGROUND: Sweet sorghum is used mainly as an energy crop and feed crop in arid and semiarid regions, and ensiling is a satisfactory method for preserving high-quality sweet sorghum. The aim of this study was to reveal the dynamics of the fermentation quality, bacterial communities, and fermentation weight loss (FWL) of sweet sorghum silage during fermentation. METHODS: Sweet sorghum was harvested at the first inflorescence spikelet stage and ensiled without (CK) or with lactic acid bacterial (LAB) additives (L). After ensiling, samples were collected on days 0, 1, 3, 5, 15, 40, and 100 to assess the fermentation quality, bacterial communities, and FWL. RESULTS: For CK and L, on day 1, the pH was 5.77 and 5.57, respectively, and the lactic acid (LA) was 1.30 and 2.81 g/kg dry matter (DM), respectively. Compared with CK, L had a lower pH and higher LA from days 1 to 5 (P < 0.05), a lower FWL from days 5 to 100 (P < 0.05), and a greater abundance of Lactiplantibacillus from days 1 to 15 (P < 0.05). The main bacterial genera were Leuconostoc and Weissella in CK and Lactiplantibacillus, Leuconostoc, and Weissella in L on day 1; Lactiplantibacillus in all silages from days 3 to 40; and Lactiplantibacillus and Lentilactobacillus in all silages on day 100. CONCLUSIONS: Sweet sorghum silage fermented relatively slowly during the first day. Moreover, inoculation with LAB accelerated fermentation and optimized bacterial communities during the initial fermentation phase. Inoculation with LAB also reduced the silage FWL, and the LAB succession relay occurred in the silage throughout the fermentation process.

Multi-Omics Analysis Reveals Molecular Responses of Alkaloid Content Variations in Lycoris aurea Across Different Locations.

Lycoris aurea, celebrated for its visually striking flowers and significant medicinal value due to the presence of alkaloids such as lycorine and galanthamine, has intricate yet poorly understood regulatory mechanisms. This study provides a detailed examination of the transcriptomic, metabolomic and ecological dynamics of L. aurea, aiming to elucidate the underlying molecular mechanisms of alkaloid biosynthesis. Our comparative analysis across different ecological settings highlighted key genes involved in alkaloid biosynthesis, such as genes encoding aldehyde dehydrogenase and norbelladine 4'-O-methyltransferase, which were distinctively increased in the high alkaloids-producing group. We identified a total of 6871 differentially expressed genes and 915 metabolites involved in pathways like terpenoid backbone biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis. Protein interaction network analysis revealed significant upregulation of photosynthesis, photosystem and photosynthetic membrane pathways in the alkaloids-producing region. Furthermore, our research delineated the interactions among soil microbial communities, genes and plant and soil biochemical properties, noting that bacterial populations correlate with soil properties that favour the activation of metabolic pathways essential for alkaloid production. Collectively, this study advances our understanding of the genetic and metabolic alkaloid biosynthesis pathways in L. aurea, shedding light on the complex interactions that govern alkaloid production.

A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.

High-concentrate diet induce subacute ruminal acidosis (SARA) and cause liver damage in ruminants. It has been reported that forkhead box protein A2 (FOXA2) can enhance mitochondrial membrane potential but its function in mitochondrial dysfunction induced by high concentrate diets is still unknown. Therefore, the aim of this study was to elucidate the effect of high-concentrate (HC) diet on hepatic FOXA2 expression, mitochondrial unfolded protein response (UPRmt), mitochondrial dysfunction and oxidative stress. A total of 12 healthy mid-lactation Holstein cows were selected and randomized into 2 groups: the low concentrate (LC) diet group (concentrate:forage = 4:6) and HC diet group (concentrate:forage = 6:4). The trial lasted 21 d. The rumen fluid, blood and liver tissue were collected at the end of the experiment. The results showed that the rumen fluid pH level was reduced in the HC group and the pH was lower than 5.6 for more than 4 h/d, indicating that feeding HC diets successfully induced SARA in dairy cows. Both FOXA2 mRNA and protein abundance were significantly reduced in the liver of the HC group compared with the LC group. The activity of antioxidant enzymes (CAT, G6PDH, T-SOD, Cu/Zn SOD, Mn SOD) and mtDNA copy number in the liver tissue of the HC group decreased, while the level of H2O2 significantly increased, this increase was accompanied by a decrease in oxidative phosphorylation (OXPHOS). The balance of mitochondrial division and fusion was disrupted in the HC group, as evidenced by the decreased mRNA level of OPA1, MFN1, and MFN2 and increased mRNA level of Drp1, Fis1, and MFF. At the same time, HC diet downregulated the expression level of SIRT1, SIRT3, PGC-1α, TFAM, and Nrf 1 to inhibit mitochondrial biogenesis. The HC group induced UPRmt in liver tissue by upregulating the mRNA and protein levels of CLPP, LONP1, CHOP, Hsp10, and Hsp60. In addition, HC diet could increase the protein abundance of Bax, CytoC, Caspase 3 and Cleaved-Caspase 3, while decrease the protein abundance of Bcl-2 and the Bcl-2/Bax ratio. Overall, our study suggests that the decreased expression of FOXA2 may be related to UPRmt, mitochondrial dysfunction, oxidative stress, and apoptosis in the liver of dairy cows fed a high concentrate diet.

Phosphorylation of WRKY16 by MPK3-1 is essential for its transcriptional activity during fiber initiation and elongation in cotton (Gossypium hirsutum).

Cotton, one of the most important crops in the world, produces natural fiber materials for the textile industry. WRKY transcription factors play important roles in plant development and stress responses. However, little is known about whether and how WRKY transcription factors regulate fiber development of cotton so far. In this study, we show that a fiber-preferential WRKY transcription factor, GhWRKY16, positively regulates fiber initiation and elongation. GhWRKY16-silenced transgenic cotton displayed a remarkably reduced number of fiber protrusions on the ovule and shorter fibers compared to the wild-type. During early fiber development, GhWRKY16 directly binds to the promoters of GhHOX3, GhMYB109, GhCesA6D-D11, and GhMYB25 to induce their expression, thereby promoting fiber initiation and elongation. Moreover, GhWRKY16 is phosphorylated by the mitogen-activated protein kinase GhMPK3-1 at residues T-130 and S-260. Phosphorylated GhWRKY16 directly activates the transcription of GhMYB25, GhHOX3, GhMYB109, and GhCesA6D-D11 for early fiber development. Thus, our data demonstrate that GhWRKY16 plays a crucial role in fiber initiation and elongation, and that GhWRKY16 phosphorylation by GhMPK3-1 is essential for the transcriptional activation on downstream genes during the fiber development of cotton.

Radiomics using CT images for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma: a multi-centric study.

OBJECTIVES: To develop a CT-based radiomics model for preoperative prediction of lymph node (LN) metastasis in perihilar cholangiocarcinoma (pCCA). METHODS: The study enrolled consecutive pCCA patients from three independent Chinese medical centers. The Boruta algorithm was applied to build the radiomics signature for the primary tumor and LN. The k-means algorithm was employed to cluster the selected LNs based on the radiomics signature LN. Support vector machines were used to construct the prediction models. The diagnostic efficiency was measured by the area under the receiver operating characteristic curve (AUC). The optimal model was evaluated in terms of calibration, clinical usefulness, and prognostic value. RESULTS: A total of 214 patients were included in the study (mean age: 61.6 years ± 9.4; 130 male). The selected LNs were classified into two clusters, which were significantly correlated with LN metastasis in all cohorts (p < 0.001). The model incorporated the clinical risk factors, radiomics signature primary tumor, and the LN cluster obtained the best discrimination, with AUC values of 0.981 (95% CI: 0.962-1), 0.896 (95% CI: 0.810-0.982), and 0.865 (95% CI: 0.768-0.961) in the training, internal validation, and external validation cohorts, respectively. High-risk patients predicted by the optimal model had shorter overall survival than low-risk patients (median, 13.7 vs. 27.3 months, p < 0.001). CONCLUSIONS: The study proposed a radiomics model with good performance to predict LN metastasis in pCCA. As a noninvasive preoperative prediction tool, this model may help in patient risk stratification and personalized treatment. CLINICAL RELEVANCE STATEMENT: A CT-based radiomics model accurately predicts lymph node metastasis in perihilar cholangiocarcinoma patients. This noninvasive preoperative tool can aid in patient risk stratification and personalized treatment, potentially improving patient outcomes. KEY POINTS: • The radiomics model based on contrast-enhanced CT is a useful tool for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma. • Radiomics features extracted from lymph nodes show great potential for predicting lymph node metastasis. • The study is the first to identify a lymph node phenotype with a high probability of metastasis based on radiomics.

Development of an AIE-active fluorescent probe for the simultaneous detection of Al3+ and viscosity and imaging in Alzheimer's disease model.

Alzheimer's disease is associated both with imbalances in Al3+ production and changes in viscosity in cells. Their simultaneous measurement could therefore provide valuable insights into Alzheimer's disease pathology. Their simultaneous measurement would therefore be of great value in investigating the pathological mechanism of Alzheimer's disease. We designed a fluorescent probe YM2T with AIE effect that is capable of selectively responding to Al3+ by fluorescence colormetrics and to viscosity by fluorescence "turn on" modes. Additionally, Al3+ and viscosity were simultaneously detected in PC12 cells using the low cytotoxic probe YM2T via blue and green fluorescence channels. More importantly, the YM2T probe was used to image mice with AD. Hence, the YM2T probe shows potential as a useful molecular instrument for studying the pathological impact of Al3+ and viscosity.

The impact of social support on benefit finding among patients with advanced lung cancer and their caregivers: based on actor-partner interdependence mediation model.

PURPOSE: Advanced lung cancer and its treatment serve as a sudden stressful event that profoundly impacts the psychological experience of both the patients and their primary caregiver. This study used dyadic analyses to explore the dyadic effects of social support on benefit finding and whether hope level mediates the patient-caregiver dyads in advanced lung cancer. METHODS: Two hundred ninety-five pairs of patients with advanced lung cancer and primary caregivers completed the Social Support Rating Scale (SSRS), the Herth Hope Index (HHI), and the Benefit Finding Scale (BFS). Dyadic analyses were conducted using structural equation modelling based on the actor-partner interdependence mediation model. RESULTS: The results indicated that for both patients (B = 0.259, 95% CI = 0.135-0.423, P < 0.001) and their primary caregivers (B = 0.596, 95% CI = 0.403-0.838, P < 0.001), hope level mediated the actor effect of social support on benefit finding; social support was positively associated with hope level and further enhanced benefit finding. Regarding partner effects (B = 0.242, 95% CI = 0.119-0.404, P < 0.001), primary caregivers' social support significantly indirectly affected patients' benefit finding through patients' hope level. CONCLUSION: There is an interaction between social support, hope level, and benefit finding in patients with advanced lung cancer and their primary caregivers. Healthcare professionals ought to be vigilant in recognizing patients and caregivers who are vulnerable, have limited social support, and possess diminished hope levels. At the same time, nurses should provide timely psychological support and counseling to patients and their caregivers, encourage them to actively participate in social activities, and inspire their confidence and hope in life, thus improving their benefit findings.

A nomogram for predicting 28-day mortality in elderly patients with acute kidney injury receiving continuous renal replacement therapy: a secondary analysis based on a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common and serious condition, particularly among elderly patients. It is associated with high morbidity and mortality rates, further compounded by the need for continuous renal replacement therapy in severe cases. To improve clinical decision-making and patient management, there is a need for accurate prediction models that can identify patients at a high risk of mortality. METHODS: Data were extracted from the Dryad Digital Repository. Multivariate analysis was performed using least absolute shrinkage and selection operator (LASSO) logistic regression analysis to identify independent risk factors and construct a predictive nomogram for mortality within 28 days after continuous renal replacement therapy in elderly patients with acute kidney injury. The discrimination of the model was evaluated in the validation cohort using the area under the receiver operating characteristic curve (AUC), and calibration was evaluated using a calibration curve. The clinical utility of the model was assessed using decision curve analysis (DCA). RESULTS: A total of 606 participants were enrolled and randomly divided into two groups: a training cohort (n = 424) and a validation cohort (n = 182) in a 7:3 proportion. A risk prediction model was developed to identify independent predictors of 28-day mortality in elderly patients with AKI. The predictors included age, systolic blood pressure, creatinine, albumin, phosphorus, age-adjusted Charlson Comorbidity Index (CCI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and sequential organ failure assessment (SOFA) score. These predictors were incorporated into a logistic model and presented in a user-friendly nomogram. In the validation cohort, the model demonstrated good predictive performance with an AUC of 0.799. The calibration curve showed that the model was well calibrated. Additionally, DCA revealed significant net benefits of the nomogram for clinical application. CONCLUSION: The development of a nomogram for predicting 28-day mortality in elderly patients with AKI receiving continuous renal replacement therapy has the potential to improve prognostic accuracy and assist in clinical decision-making.

AHNAK2 Regulates NF-κB/MMP-9 Signaling to Promote Pancreatic Cancer Progression.

Early metastasis of pancreatic cancer (PaC) is a major cause of its high mortality rate. Previous studies have shown that AHNAK2 is involved in the progression of some tumors and is predicted to be an independent prognostic factor for PaC; however, the specific mechanisms through which AHNAK2 regulates PaC remain unclear. In this study, we examined the role of AHNAK2 in PaC and its potential molecular mechanisms. AHNAK2 mRNA and protein expression in PaC tissues and cells were measured using qRT-PCR and western blot analysis. After AHNAK2 knockdown using small interfering RNA, PaC cells were subjected to CCK-8 scratch, and Transwell assays to assess cell proliferation, migration, and invasion, respectively. Furthermore, the validation of the mechanistic pathway was achieved by western blot analysis. AHNAK2 mRNA and protein levels were up-regulated in PaC and silencing AHNAK2 significantly inhibited the proliferation, migration, and invasion of PaC cells. Mechanistically, AHNAK2 knockdown decreased the expression of phosphorylated p65, phosphorylated IκBα, and matrix metalloproteinase-9 (MMP-9), suggesting that activation of the NF-κB/MMP-9 signaling pathway was inhibited. Importantly, activation of NF-κB reversed the effects of AHNAK2 knockdown. Our findings indicate that AHNAK2 promotes PaC progression through the NF-kB/MMP-9 pathway and provides a theoretical basis for targeting AHNAK2 for the treatment of PaC.