Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence. METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155-/- mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16INK4A expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16INK4A/p21expression and senescence-associated ß-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs. CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.

Sediment subduction in Hadean revealed by machine learning.

Due to the scarcity of rock samples, the Hadean Era predating 4 billion years ago (Ga) poses challenges in understanding geological processes like subaerial weathering and plate tectonics that are critical for the evolution of life. The Jack Hills zircon from Western Australia, the primary Hadean samples available, offer valuable insights into magma sources and tectonic genesis through trace element signatures. However, a consensus on these signatures has not been reached. To address this, we developed a machine learning classifier capable of deciphering the geochemical fingerprints of zircon. This allowed us to identify the oldest detrital zircon originating from sedimentary-derived "S-type" granites. Our results indicate the presence of S-type granites as early as 4.24 Ga, persisting throughout the Hadean into the Archean. Examining global detrital zircon across Earth's history reveals consistent supercontinent-like cycles from the present back to the Hadean. These findings suggest that a significant amount of Hadean continental crust was exposed, weathered into sediments, and incorporated into the magma sources of Jack Hills zircon. Only the early operation of both subaerial weathering and plate subduction can account for the prevalence of S-type granites we observe. Additionally, the periodic evolution of S-type granite proportions implies that subduction-driven tectonic cycles were active during the Hadean, at least around 4.2 Ga. The evidence thus points toward an early Earth resembling the modern Earth in terms of active tectonics and habitable surface conditions. This suggests the potential for life to originate in environments like warm ponds rather than extreme hydrothermal settings.

Atypical dynamic neural configuration in autism spectrum disorder and its relationship to gene expression profiles.

Although it is well recognized that autism spectrum disorder (ASD) is associated with atypical dynamic functional connectivity patterns, the dynamic changes in brain intrinsic activity over each time point and the potential molecular mechanisms associated with atypical dynamic temporal characteristics in ASD remain unclear. Here, we employed the Hidden Markov Model (HMM) to explore the atypical neural configuration at every scanning time point in ASD, based on resting-state functional magnetic resonance imaging (rs-fMRI) data from the Autism Brain Imaging Data Exchange. Subsequently, partial least squares regression and pathway enrichment analysis were employed to explore the potential molecular mechanism associated with atypical neural dynamics in ASD. 8 HMM states were inferred from rs-fMRI data. Compared to typically developing, individuals on the autism spectrum showed atypical state-specific temporal characteristics, including number of states and occurrences, mean life time and transition probability between states. Moreover, these atypical temporal characteristics could predict communication difficulties of ASD, and states assoicated with negative activation in default mode network and frontoparietal network, and positive activation in somatomotor network, ventral attention network, and limbic network, had higher predictive contribution. Furthermore, a total of 321 genes was revealed to be significantly associated with atypical dynamic brain states of ASD, and these genes are mainly enriched in neurodevelopmental pathways. Our study provides new insights into characterizing the atypical neural dynamics from a moment-to-moment perspective, and indicates a linkage between atypical neural configuration and gene expression in ASD.

N6-methyladenosine modification of KLF2 may contribute to endothelial-to-mesenchymal transition in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive disease characterized by pulmonary vascular remodeling. Increasing evidence indicates that endothelial-to-mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs) is a pivotal trigger initiating this remodeling. However, the regulatory mechanisms underlying EndMT in PH are still not fully understood. METHODS: Cytokine-induced hPAECs were assessed using RNA methylation quantification, qRT-PCR, and western blotting to determine the involvement of N6-methyladenosine (m6A) methylation in EndMT. Lentivirus-mediated silencing, overexpression, tube formation, and wound healing assays were utilized to investigate the function of METTL3 in EndMT. Endothelial-specific gene knockout, hemodynamic measurement, and immunostaining were performed to explore the roles of METTL3 in pulmonary vascular remodeling and PH. RNA-seq, RNA Immunoprecipitation-based qPCR, mRNA stability assay, m6A mutation, and dual-luciferase assays were employed to elucidate the mechanisms of RNA methylation in EndMT. RESULTS: The global levels of m6A and METTL3 expression were found to decrease in TNF-α- and TGF-ß1-induced EndMT in human PAECs (hPAECs). METTL3 inhibition led to reduced endothelial markers (CD31 and VE-cadherin) and increased mesenchymal markers (SM22 and N-cadherin) as well as EndMT-related transcription factors (Snail, Zeb1, Zeb2, and Slug). The endothelial-specific knockout of Mettl3 promoted EndMT and exacerbated pulmonary vascular remodeling and hypoxia-induced PH (HPH) in mice. Mechanistically, METTL3-mediated m6A modification of kruppel-like factor 2 (KLF2) plays a crucial role in the EndMT process. KLF2 overexpression increased CD31 and VE-cadherin levels while decreasing SM22, N-cadherin, and EndMT-related transcription factors, thereby mitigating EndMT in PH. Mutations in the m6A site of KLF2 mRNA compromise KLF2 expression, subsequently diminishing its protective effect against EndMT. Furthermore, KLF2 modulates SM22 expression through direct binding to its promoter. CONCLUSIONS: Our findings unveil a novel METTL3/KLF2 pathway critical for protecting hPAECs against EndMT, highlighting a promising avenue for therapeutic investigation in PH.

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension.

BACKGROUND: An imbalance of antiproliferative BMP (bone morphogenetic protein) signaling and proliferative TGF-ß (transforming growth factor-ß) signaling is implicated in the development of pulmonary arterial hypertension (PAH). The posttranslational modification (eg, phosphorylation and ubiquitination) of TGF-ß family receptors, including BMPR2 (bone morphogenetic protein type 2 receptor)/ALK2 (activin receptor-like kinase-2) and TGF-ßR2/R1, and receptor-regulated Smads significantly affects their activity and thus regulates the target cell fate. BRCC3 modifies the activity and stability of its substrate proteins through K63-dependent deubiquitination. By modulating the posttranslational modifications of the BMP/TGF-ß-PPARγ pathway, BRCC3 may play a role in pulmonary vascular remodeling, hence the pathogenesis of PAH. METHODS: Bioinformatic analyses were used to explore the mechanism by which BRCC3 deubiquitinates ALK2. Cultured pulmonary artery smooth muscle cells (PASMCs), mouse models, and specimens from patients with idiopathic PAH were used to investigate the rebalance between BMP and TGF-ß signaling in regulating ALK2 phosphorylation and ubiquitination in the context of pulmonary hypertension. RESULTS: BRCC3 was significantly downregulated in PASMCs from patients with PAH and animals with experimental pulmonary hypertension. BRCC3, by de-ubiquitinating ALK2 at Lys-472 and Lys-475, activated receptor-regulated Smad1/5/9, which resulted in transcriptional activation of BMP-regulated PPARγ, p53, and Id1. Overexpression of BRCC3 also attenuated TGF-ß signaling by downregulating TGF-ß expression and inhibiting phosphorylation of Smad3. Experiments in vitro indicated that overexpression of BRCC3 or the de-ubiquitin-mimetic ALK2-K472/475R attenuated PASMC proliferation and migration and enhanced PASMC apoptosis. In SM22α-BRCC3-Tg mice, pulmonary hypertension was ameliorated because of activation of the ALK2-Smad1/5-PPARγ axis in PASMCs. In contrast, Brcc3-/- mice showed increased susceptibility of experimental pulmonary hypertension because of inhibition of the ALK2-Smad1/5 signaling. CONCLUSIONS: These results suggest a pivotal role of BRCC3 in sustaining pulmonary vascular homeostasis by maintaining the integrity of the BMP signaling (ie, the ALK2-Smad1/5-PPARγ axis) while suppressing TGF-ß signaling in PASMCs. Such rebalance of BMP/TGF-ß pathways is translationally important for PAH alleviation.

Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity. OBJECTIVES: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-(hCGα) and beta-subunits (hCGß), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex. METHODS: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression. RESULTS: Perfluorohexane sulfonic acid (PFHxS) [hCGß: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: -0.09; 95% CI: -0.16, -0.02) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with hCGα and positively with hCGß. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with hCGß only in Black participants (-0.23; 95% CI: -0.37, -0.09) and in participants with high school education or less (-0.14; 95% CI: -0.26, -0.02); conversely, perfluorononanoic acid (PFNA) was negatively associated with hCGα only in White participants (-0.15; 95% CI: -0.27, -0.03) and with hCGß only in participants with a college education or greater (-0.19; 95% CI: -0.36, -0.01). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was <100%. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with hCGα, and PFNA with h-hCG. CONCLUSIONS: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with hCGα and hCGß differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

[Existence forms of Tiantian Capsules and its raw material Aloe in rats].

This study explored the existence forms(original constituents and metabolites) of Tiantian Capsules, Aloe, and Tiantian Capsules without Aloe in rats for the first time, aiming to clarify the contribution of Aloe to the existence form of Tiantian Capsules. Rats were administrated with corresponding drugs by gavage once a day for seven consecutive days. All urine and feces samples were collected during the seven days of administration, and blood samples were collected 0.5, 1, and 1.5 h after the last administration. UHPLC-Q-TOF-MS was employed to detect and identify the original constituents and metabolites in the samples. A total of 34, 28, and 2 original constituents and 64, 94, and 0 metabolites were identified in the samples of rats administrated with Aloe, Tiantian Capsules, and Tiantian Capsules without Aloe, respectively. The main metabolic reactions were methylation, hydrogenation, hydroxylation, dehydroxylation, glucuronidation, and sulfation. This study clarified for the first time the existence forms and partial metabolic pathways of Aloe, Tiantian Capsules, and Tiantian Capsules without Aloe in rats, laying a foundation for revealing their effective forms. The findings are of great significance to the research on the functioning mechanism and quality control of Aloe and Tiantian Capsules.

[Simultaneous determination of seven artemisinin-related compounds in Artemisia annua by UPLC-QQQ-MS/MS].

A variety of compounds in Artemisia annua were simultaneously determined to evaluate the quality of A. annua from multiple perspectives. A method based on ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry(UPLC-QQQ-MS/MS) was established for the simultaneous determination of seven compounds: amorpha-4,11-diene, artemisinic aldehyde, dihydroartemisinic acid, artemisinic acid, artemisinin B, artemisitene, and artemisinin, in A. annua. The content of the seven compounds in different tissues(roots, stems, leaves, and lateral branches) of A. annua were compared. The roots, stems, leaves, and lateral branches of four-month-old A. annua were collected and the content of seven artemisinin-related compounds in different tissues was determined. A multi-reaction monitoring(MRM) acquisition mode of UPLC-QQQ-MS/MS was used, with a positive ion mode of atmospheric pressure chemical ion source(APCI). Chromatographic separation was achieved on an Eclipse Plus RRHD C_(18) column(2.1 mm×50 mm, 1.8 µm). The gradient elution was performed with the mobile phase consisted of formic acid(0.1%)-ammonium formate(5 mmol·L~(-1))(A) and the methanol(B) gradient program of 0-8 min, 55%-100% B, 8-11 min, 100% B, and equilibrium for 3 min, the flow rate of 0.6 mL·min~(-1), the column temperature of 40 ℃, the injection volume of 5 µL, and the detection time of 8 min. Through methodological investigation, a method based on UPLC-QQQ-MS/MS was established for the simultaneous quantitative determination of seven representative compounds involved in the biosynthesis of artemisinin. The content of artemisinin in A. annua was higher than that of artemisinin B, and the content of artemisinin and dihydroartemisinic acid were high in all the tissues of A. annua. The content of the seven compounds varied considerably in different tissues, with the highest levels in the leaves and neither artemisinene nor artemisinic aldehyde was detected in the roots. In this study, a quantitative method based on UPLC-QQQ-MS/MS for the simultaneous determination of seven representative compounds involved in the biosynthesis of artemisinin was established, which was accurate, sensitive, and highly efficient, and can be used for determining the content of artemisinin-related compounds in A. annua, breeding new varieties, and controlling the quality of Chinese medicinal materials.

Study on clinical features and factors related to long-term outcomes of antibody-negative autoimmune encephalitis.

OBJECTIVE: To delineate the clinical characteristics of antibody-negative autoimmune encephalitis (AE) and to investigate factors associated with long-term outcomes among antibody-negative AE. METHODS: Patients diagnosed with antibody-negative AE were recruited from January 2016 to December 2022 at the Second Xiangya Hospital of Central South University. The study assessed the long-term outcomes of antibody-negative AE using the modified Rankin scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Predictors influencing long-term outcomes were subsequently analyzed. External validation of RAPID scores (refractory status epilepticus [RSE], age of onset ≥60 years, ANPRA [antibody-negative probable autoimmune encephalitis], infratentorial involvement, and delay of immunotherapy ≥1 month) was performed. RESULTS: In total, 100 (47 females and 53 males) antibody-negative AE patients were enrolled in this study, with approximately 49 (49%) experiencing unfavorable long-term outcomes (mRS scores ≥3). Antibody-negative AE was subcategorized into ANPRA, autoimmune limbic encephalitis (LE), and acute disseminated encephalomyelitis (ADEM). Psychiatric symptoms were prevalent in LE and ANPRA subtypes, while weakness and gait instability/dystonia were predominant in the ADEM subtype. Higher peak CASE scores (odds ratio [OR] 1.846, 95% confidence interval [CI]: 1.163-2.930, p = 0.009) and initiating immunotherapy within 30 days (OR 0.210, 95% CI: 0.046-0.948, p = 0.042) were correlated with long-term outcomes. Receiver operating characteristic (ROC) analysis returned that the RAPID scores cutoff of 1.5 best discriminated the group with poor long-term outcomes (sensitivity 85.7%, specificity 56.9%). INTERPRETATION: The ANPRA subtype exhibited poorer long-term outcomes compared to LE and ADEM subtypes, and early immunotherapy was crucial for improving long-term outcomes in antibody-negative AE. The use of RAPID scoring could aid in guiding clinical decision making.

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

Therapeutic role of miR-26a on cardiaorenal injury in mice model of angiotensin-II induced chronic kidney disease through inhibition of LIMS1/ILK pathway.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated a microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t-test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS: Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.

CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer.

Cell cycle-dependent protein kinase 12 (CDK12) plays a key role in a variety of carcinogenesis processes and represents a promising therapeutic target for cancer treatment. However, to date, there have been no systematic studies addressing its diagnostic, prognostic and immunological value across cancers. Here, we found that CDK12 was significantly upregulated in various types of cancers, and it expression increased with progression in ten cancer types, including breast cancer, cholangiocarcinoma and colon adenocarcinoma. Moreover, the ROC curves indicated that CDK12 showed diagnostic value in eight cancer types. High CDK12 expression was associated with poor prognosis in eight types of cancer, including low-grade glioma, mesothelioma, melanoma and pancreatic cancer. Furthermore, we conducted immunoassays to explore the exact mechanisms underlying CDK12-induced carcinogenesis, which revealed that increased expression of CDK12 allowed tumours to evade immune surveillance and upregulate immune checkpoint genes. Additionally, mutational studies have shown that amplification and missense mutations are the predominant mutational events affecting CDK12 across cancers. These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.

Inoculation fermentation with Lactobacillus fermentum L28 and Staphylococcus epidermidis S24 for improving the protein degradation of air-dried goose.

The inoculation fermentation technology was applied to the processing of dried cured goose to investigate the protein degradation. Lactobacillus fermentum (L), Staphylococcus epidermidis (S) and mixed strains (L + S) were individually inoculated into the whole goose before drying. We studied the degradation of protein in the air-dried period of goose. The results showed that compared with natural fermentation, inoculation fermentation significantly increased the content of non-protein nitrogen (14.85 mg/g NPN), proteolysis index (8.98% PI), myofibril fragmentation index (89.35 MFI) and total amount of free amino acids (1332.6 mg/g FAA) of dried cured goose. Electrophoresis revealed that the inoculation fermentation accelerated the degradation of macromolecular proteins and the accumulation of small molecular proteins. The degree of protein degradation in four groups of goose was in an order of L + S group > S group > L group > CK group. It suggested that inoculation fermentation could promote the degradation of myofibrillar proteins.

Electrochemical aerobic Wacker-type oxygenation of triaryl substituted alkenes to 1,2,2-triarylethanones.

An effective synthetic approach for various 1,2,2-triarylethanones from triaryl substituted alkenes has been developed via an electrochemical Wacker-type oxygenation with O2 as the sole oxygen source. It presents the first instance of the Wacker-type oxidation expanding its substrate scope to trisubstituted alkenes. The approach is transition-metal-free, compatible with various functional groups, and can be carried out under mild conditions resulting in satisfactory yields. Mechanistic experiments suggest the CO bond formation occurs through reactions between cationic carbon species and the superoxide radical, which involves the 1,2-shift of the electron-rich substituent.

Tannic acid adsorption properties of cellulose nanocrystalline/fish swim bladder gelatin composite sponge.

Foods and beverages with excessive tannins acid (TA) content taste astringent and bitter. The overconsumption of TA could result in nutritional and digestive problems. In this study, the cellulose nanocrystals (CNC)/fish swim bladder gelatin (FG) composite sponge was prepared with glutaraldehyde as a crosslinking agent. The TA adsorption performance of the sponge was discussed. The freeze-dried CNC/FG composite sponge had a porous network structure. CNC was combined into the FG matrix as a reinforcing phase. The mechanical strength, thermal stability, and swelling properties of the composite sponge were improved with the addition of an appropriate amount of CNC. Although CNC decreased the porosity of composite sponge, the increase in active adsorption sites resulted in an overall positive effect on its TA adsorption properties. Under the optimal adsorption conditions, the TA removal rate of 1.0 % CNC composites reached 80.4 %. Furthermore, the sponge retained a TA removal rate of 54 % after five cycles of adsorption and desorption using 50 % ethanol. The results demonstrated that CNC/FG composite sponge has application potential in the field of adsorption materials for TA.

Asymmetric Supercapacitors based on 1,10-phenanthroline-5,6-dione Molecular Electrodes Paired with MXene.

An efficient approach to increase the energy density of supercapacitors is to prepare electrode materials with larger specific capacitance and increase the potential difference between the positive and negative electrodes in the device. Herein, an organic molecular electrode (OME) is prepared by anchoring 1,10-phenanthroline-5,6-dione (PD), which possesses two pyridine rings and an electron-deficient conjugated system, onto reduced graphene oxide (rGO). Because of the electron-deficient conjugated structure of PD molecule, PD/rGOs exhibit a more positive redox peak potential along with the advantages of high capacitance-controlled behaviour and fast reaction kinetics. Additionally, the small energy gap between the lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) leads to increased conductivity in PD/rGO. To assemble the asymmetric supercapacitor (ASC), a two-dimensional metal carbide, as known as MXene, with a chemical composition of Ti3C2Tx is selected as the negative electrode due to its exceptional performance, and PD/rGO-0.5 is employed as the positive electrode. Consequently, the working voltage is expanded up to 1.8 V. Through further electrochemical measurements, the assembled ASC (PD/rGO-0.5//Ti3C2Tx) achieves a remarkable energy density of 36.8 Wh kg-1. Remarkably, connecting two ASCs in series can power 73 LEDs, showcasing its promising potential for energy storage applications.

The effects of oral nutritional supplements interventions on nutritional status in patients undergoing colorectal cancer surgery: A systematic review.

BACKGROUND: The high incidence of malnutrition in patients undergoing colorectal cancer surgery can lead to unplanned weight loss, sarcopenia and reduced grip strength to the extent that it can seriously affect the prognosis of colorectal cancer patients. OBJECTIVE: This study investigated the effect of oral nutritional supplements (ONS) on the prevalence of grip strength, unplanned weight loss and sarcopenia in patients undergoing colorectal cancer surgery. METHODS: We systematically searched randomized controlled studies from CINAHL, PubMed, Embase, Cochrane and Web of Science and three Chinese databases (CNKI, Wan-Fang database, VIP database) from database creation to September 2023. The risk of bias in individual studies was assessed using the Cochrane Collaboration tool, and the certainty of evidence was assessed using the five GRADE criteria. Statistical analysis was performed using the RevMan 5.3 software, and information that could not be meta-analysed was reviewed in the form of a literature summary. RESULTS: Eleven papers met the inclusion criteria with a combined sample size of 1070 cases, including 532 cases in the trial group and 538 cases in the control group. Four papers reported the effect of ONS on grip strength and included very low-quality evidence supporting no effect of ONS on grip strength. Ten studies reported the effect of ONS on body weight and body mass index (BMI) and included very low-quality evidence supporting a positive ONS on weight and BMI changes. Meta-analysis showed a significant reduction in weight loss (12-15 weeks) and BMI loss (12-15 weeks) in patients with colorectal cancer in the ONS group. The effect of ONS on the prevalence of sarcopenia after hospital discharge was reported in two studies, and meta-analysis showed a significant reduction in the prevalence of postoperative sarcopenia in colorectal cancer patients in the ONS group, but the quality of evidence was low. CONCLUSIONS: This study showed that the use of ONS in patients undergoing surgery for colorectal cancer improved patient weight loss and BMI reduction and reduced the prevalence of postoperative sarcopenia but did not improve patient grip strength. The quality of evidence for inclusion in the article was low or very low, and further studies are needed to provide better evidence.

Mediation Analysis using Semi-parametric Shape-Restricted Regression with Applications.

Often linear regression is used to perform mediation analysis. However, in many instances, the underlying relationships may not be linear, as in the case of placentalfetal hormones and fetal development. Although, the exact functional form of the relationship may be unknown, one may hypothesize the general shape of the relationship. For these reasons, we develop a novel shape-restricted inference-based methodology for conducting mediation analysis. This work is motivated by an application in fetal endocrinology where researchers are interested in understanding the effects of pesticide application on birth weight, with human chorionic gonadotropin (hCG) as the mediator. We assume a practically plausible set of nonlinear effects of hCG on the birth weight and a linear relationship between pesticide exposure and hCG, with both exposure-outcome and exposure-mediator models being linear in the confounding factors. Using the proposed methodology on a population-level prenatal screening program data, with hCG as the mediator, we discovered that, while the natural direct effects suggest a positive association between pesticide application and birth weight, the natural indirect effects were negative.