Steering lithium and potassium storage mechanism in covalent organic frameworks by incorporating transition metal single atoms.

Organic electrodes mainly consisting of C, O, H, and N are promising candidates for advanced batteries. However, the sluggish ionic and electronic conductivity limit the full play of their high theoretical capacities. Here, we integrate the idea of metal-support interaction in single-atom catalysts with π-d hybridization into the design of organic electrode materials for the applications of lithium (LIBs) and potassium-ion batteries (PIBs). Several types of transition metal single atoms (e.g., Co, Ni, Fe) with π-d hybridization are incorporated into the semiconducting covalent organic framework (COF) composite. Single atoms favorably modify the energy band structure and improve the electronic conductivity of COF. More importantly, the electronic interaction between single atoms and COF adjusts the binding affinity and modifies ion traffic between Li/K ions and the active organic units of COFs as evidenced by extensive in situ and ex situ characterizations and theoretical calculations. The corresponding LIB achieves a high reversible capacity of 1,023.0 mA h g-1 after 100 cycles at 100 mA g-1 and 501.1 mA h g-1 after 500 cycles at 1,000 mA g-1. The corresponding PIB delivers a high reversible capacity of 449.0 mA h g-1 at 100 mA g-1 after 150 cycles and stably cycled over 500 cycles at 1,000 mA g-1. This work provides a promising route to engineering organic electrodes.

Coexistence within one cell of microvillous and ciliary phototransductions across M1- through M6-IpRGCs.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) serve as primary photoceptors by expressing the photopigment, melanopsin, and also as retinal relay neurons for rod and cone signals en route to the brain, in both cases for the purpose of non-image vision as well as aspects of image vision. So far, six subtypes of ipRGCs (M1 through M6) have been characterized. Regarding their phototransduction mechanisms, we have previously found that, unconventionally, rhabdomeric (microvillous) and ciliary signaling motifs co-exist within a given M1-, M2-, and M4-ipRGC, with the first mechanism involving PLCß4 and TRPC6,7 channels and the second involving cAMP and HCN channels. We have now examined M3-, M5-, and M6-cells and found that each cell likewise uses both signaling pathways for phototransduction, despite differences in the percentage representation by each pathway in a given ipRGC subtype for bright-flash responses (and saturated except for M6-cells). Generally, M3- and M5-cells show responses quite similar in kinetics to M2-responses, and M6-cell responses resemble broadly those of M1-cells although much lower in absolute sensitivity and amplitude. Therefore, similar to rod and cone subtypes in image vision, ipRGC subtypes possess the same phototransduction mechanism(s) even though they do not show microvilli or cilia morphologically.

Solanum aculeatissimum and Solanum torvum chloroplast genome sequences: a comparative analysis with other Solanum chloroplast genomes.

BACKGROUND: Solanum aculeatissimum and Solanum torvum belong to the Solanum species, and they are essential plants known for their high resistance to diseases and adverse conditions. They are frequently used as rootstocks for grafting and are often crossbred with other Solanum species to leverage their resistance traits. However, the phylogenetic relationship between S. aculeatissimum and S. torvum within the Solanum genus remains unclear. Therefore, this paper aims to sequence the complete chloroplast genomes of S. aculeatissimum and S. torvum and analyze them in comparison with 29 other previously published chloroplast genomes of Solanum species. RESULTS: We observed that the chloroplast genomes of S. aculeatissimum and S. torvum possess typical tetrameric structures, consisting of one Large Single Copy (LSC) region, two reverse-symmetric Inverted Repeats (IRs), and one Small Single Copy (SSC) region. The total length of these chloroplast genomes ranged from 154,942 to 156,004 bp, with minimal variation. The highest GC content was found in the IR region, while the lowest was in the SSC region. Regarding gene content, the total number of chloroplast genes and CDS genes remained relatively consistent, ranging from 128 to 134 and 83 to 91, respectively. Nevertheless, there was notable variability in the number of tRNA genes and rRNAs. Relative synonymous codon usage (RSCU) analysis revealed that both S. aculeatissimum and S. torvum preferred codons that utilized A and U bases. Analysis of the IR boundary regions indicated that contraction and expansion primarily occurred at the junction between SSC and IR regions. Nucleotide polymorphism analysis and structural variation analysis demonstrated that chloroplast variation in Solanum species mainly occurred in the LSC and SSC regions. Repeat sequence analysis revealed that A/T was the most frequent base pair in simple repeat sequences (SSR), while Palindromic and Forward repeats were more common in long sequence repeats (LSR), with Reverse and Complement repeats being less frequent. Phylogenetic analysis indicated that S. aculeatissimum and S. torvum belonged to the same meristem and were more closely related to Cultivated Eggplant. CONCLUSION: These findings enhance our comprehension of chloroplast genomes within the Solanum genus, offering valuable insights for plant classification, evolutionary studies, and potential molecular markers for species identification.

Transcriptome and metabolome analysis revealed the dynamic change of bioactive compounds of Fructus Ligustri Lucidi.

BACKGROUND: The Fructus Ligustri Lucidi, the fruit of Ligustrum lucidum, contains a variety of bioactive compounds, such as flavonoids, triterpenoids, and secoiridoids. The proportions of these compounds vary greatly during the different fruit development periods of Fructus Ligustri Lucidi. However, a clear understanding of how the proportions of the compounds and their regulatory biosynthetic mechanisms change across the different fruit development periods of Fructus Ligustri Lucidi is still lacking. RESULTS: In this study, metabolite profiling and transcriptome analysis of six fruit development periods (45 DAF, 75 DAF, 112 DAF, 135 DAF, 170 DAF, and 195 DAF) were performed. Seventy compounds were tentatively identified, of which secoiridoids were the most abundant. Eleven identified compounds were quantified by high performance liquid chromatography. A total of 103,058 unigenes were obtained from six periods of Fructus Ligustri Lucidi. Furthermore, candidate genes involved in triterpenoids, phenylethanols, and oleoside-type secoiridoid biosynthesis were identified and analyzed. The in vitro enzyme activities of nine glycosyltransferases involved in salidroside biosynthesis revealed that they can catalyze trysol and hydroxytyrosol to salidroside and hydroxylsalidroside. CONCLUSIONS: These results provide valuable information to clarify the profile and molecular regulatory mechanisms of metabolite biosynthesis, and also in optimizing the harvest time of this fruit.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

In Situ Construction of Highly Dispersed Pd on Cobalt Nanoparticle on Hollow Functional Cubic Graphene by Double Framework for ORR.

Developing advanced functional carbon materials is essential for electrocatalysis, caused by their vast merits for boosting many key energy conversion reactions. Herein, the covalent organic frameworks (COFs) is utilized on metal-organic frameworks (MOFs) as the template, under the controllable metal atoms thermal migration process successfully in situ constructs Pd-Co alloy nanoparticles on hollow cubic graphene. The electrocatalytic oxygen reduction reaction (ORR) evaluation showed excellent performances with a half-wave potential of 0.866 V, and a limited current density of 4.975 mA cm-2, that superior to the commercial Pt/C and Co nanoparticles. The contrast experiments and X-ray absorption spectrum demonstrated the aggregated electrons at highly dispersed Pd atoms on Co nanoparticle that promoted the main activities. This work not only enlightens the novel carbon materials designing strategies but also suggests heterogeneous electrocatalysis.

Unveiling the Structural Origins of Dynamic Diversity in Pd-Based Metallic Glasses.

The ß-relaxation is one of the major dynamic behaviors in metallic glasses (MGs) and exhibits diverse features. Despite decades of efforts, the understanding of its structural origin and contribution to the overall dynamics of MG systems is still unclear. Here two palladium-based Pd─Cu─P and Pd─Ni─P MGs are reported with distinct different ß-relaxation behaviors and reveal the structural origins for the difference using the advanced X-ray photon correlation spectroscopy and absorption fine structure techniques together with the first-principles calculations. The pronounced ß-relaxation and fast atomic dynamics in the Pd─Cu─P MG mainly come from the strong mobility of Cu atoms and their locally favored structures. In contrast, the motion of Ni atoms is constrained by P atoms in the Pd─Ni─P MG, leading to the weakened ß-relaxation peak and sluggish dynamics. The correlation of atomic dynamics with microscopic structures provides a way to understand the structural origins of different dynamic behaviors as well as the nature of aging in disordered materials.

Effect of CHRDL1 on angiogenesis and metastasis of colorectal cancer cells via TGF-ß/VEGF pathway.

Colorectal cancer (CRC) is a common digestive tract tumor with the third incidence and death in the world. There is still an urgent need for effective therapeutic targets and prognostic markers for CRC. Herein, we report a novel potential target and marker, Chordin like-1 (CHRDL1). The function of CHRDL1 has been reported in gastric cancer, breast cancer, and oral squamous cell carcinoma. However, the biological effect of CHRDL1 in CRC remains unrevealed. Transwell and tube formation experiments were used to determine the biological function of CHRDL1. Western blot and rescue experiments were used to determine the specific mechanisms of CHRDL1. Results showed CHRDL1 is significantly downregulated in CRC cell lines and tissues. In vitro, experiments confirmed that CHRDL1 can inhibit cell growth, migration, invasion, angiogenesis and reverse epithelial-mesenchymal transformation. In vivo, experiments proved that it can inhibit tumor growth and metastasis. Mechanistically, we newly find that CHRDL1 exerts biological functions through the transforming growth factor-beta (TGF-ß)/vascular endothelial growth factor signaling axis in vitro and in vivo. Therefore, we concluded that CHRDL1 reduces the growth, migration, and angiogenesis of CRC cells by downregulating TGF-ß signaling. Our new findings on CHRDL1 may provide a basis for clinical antiangiogenesis therapy and the prognosis of CRC.

Atrial Natriuretic Peptide Alleviates Motion Sickness Potentially through Regulating Endolymph Volume in the Inner Ear Increased by Arginine Vasopressin.

INTRODUCTION: Dimenhydrinate and scopolamine are frequently used drugs, but they cause drowsiness and performance decrement. Therefore, it is crucial to find peripheral targets and develop new drugs without central side effects. This study aimed to investigate the anti-motion sickness action and inner ear-related mechanisms of atrial natriuretic peptide (ANP). METHODS: Endolymph volume in the inner ear was measured with magnetic resonance imaging and expression of AQP2 and p-AQP2 was detected with Western blot analysis and immunofluorescence method. RESULTS: Both rotational stimulus and intraperitoneal arginine vasopressin (AVP) injection induced conditioned taste aversion (CTA) to 0.15% sodium saccharin solution and an increase in the endolymph volume of the inner ear. However, intraperitoneal injection of ANP effectively alleviated the CTA behaviour and reduced the increase in the endolymph volume after rotational stimulus. Intratympanic injection of ANP also inhibited rotational stimulus-induced CTA behaviour, but anantin peptide, an inhibitor of ANP receptor A (NPR-A), blocked this inhibitory effect of ANP. Both rotational stimulus and intraperitoneal AVP injection increased the expression of AQP2 and p-AQP2 in the inner ear of rats, but these increases were blunted by ANP injection. In in vitro experiments, ANP addition decreased AVP-induced increases in the expression and phosphorylation of AQP2 in cultured endolymphatic sac epithelial cells. CONCLUSION: Therefore, the present study suggests that ANP could alleviate motion sickness through regulating endolymph volume of the inner ear increased by AVP, and this action of ANP is potentially mediated by activating NPR-A and antagonising the increasing effect of AVP on AQP2 expression and phosphorylation.

Congenital trans-sellar trans-sphenoidal encephalocele: a systematic review of diagnosis, treatment, and prognosis.

PURPOSE: Clinical presentations encompass respiratory, feeding issues, nasopharyngeal mass, meningitis, CSF leakage, craniofacial anomalies, and endocrine problems. Surgery is the primary treatment, transitioning from frontal craniotomy to endoscopic methods, offering improved outcomes. Yet, more studies are needed. A comprehensive review on trans-sellar trans-sphenoidal encephalocele (TSTSE) is missing. Our study aims to fill this gap, offering a comprehensive perspective for physicians. METHODS: This review adhered to the PRISMA guideline. Eligible studies focused on human subjects, specifically trans-sellar encephaloceles, and provided comprehensive treatment details. English language articles published up to April 11th, 2023, were considered. Two trained researchers conducted article screening using consistent criteria. Data extraction covered various aspects, including clinical presentation, surgical methods, and outcomes, with results presented descriptively in two tables. Due to the rarity of this congenital anomaly, meta-analysis and publication bias assessment were not feasible. Data extraction was independently conducted by two reviewers, with subsequent cross-verification. RESULTS: A total of 36 patients were identified from 14 studies, the most frequently observed clinical presentation was dyspnea (41.67%) and the most frequently observed accompanying anomaly was cleft lip/palate (55.56%). CT and MRI were adopted in nearly all the cases, and trans-nasal approach was the most often used surgical approach (57.14%) with the 'soft material combination' the most commonly used method for cranial base repairment (35.71%). A total of two deaths occurred and diabetes insipidus was the most common perioperative complication which occurred in six surgery patients (21.43%). CONCLUSION: TSTSE predominantly affects males and presents with dyspnea, visual deficits, pituitary insufficiency, and cranial base-related symptoms. Early diagnosis is critical, with advanced imaging playing a key role. Endocrine assessment is vital for hormone management. Surgery offers symptom relief but entails risks, including reported fatalities and complications. The choice between surgery and conservative management requires careful deliberation. The trans-nasal approach is favored for its reduced trauma, yet further research is necessary to validate this preference.

Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment.

An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.

Analysis of risk factors related to early implant failure: A retrospective study.

STATEMENT OF PROBLEM: Factors influencing early implant failure (failure during the healing period) in the rehabilitation and restoration of oral function in partially edentulous patients are unclear. PURPOSE: The purpose of this clinical study was to investigate several factors that may be associated with early implant failure. MATERIAL AND METHODS: This retrospective study was conducted on 3247 implants in 2061 patients between 2009 and 2022. Patient-related and surgery-related factors, including smoking; sex; diabetes; bone grafting; implant length, diameter, and design; adjacent teeth; and insertion torque, were manually retrieved and analyzed. Using univariate and multivariate analyses, a generalized estimating equation (GEE) model with chi-squared tests was employed to evaluate factors related to early implant failure (the failure before restoration) (α=.05). RESULTS: The mean ±standard deviation age of the study patients was 49.2 ±15.0 years (range 18 to 91). Ninety-nine implants (3.05%) failed during the healing period. Three factors were statistically significant regarding early implant failure: smoking (odds ratio [OR]=1.92, P=.008), implant design (tapered implants) (OR=1.84, P=.007), and implant length <10 mm (OR=2.98, P=.011). Factors including diabetes, bone grafting, anatomic location, adjacent teeth (endodontic therapy in the adjacent teeth and the distance between implant and adjacent teeth), healing method, and insertion torque did not exhibit a statistically significant higher early implant failure rate. Ninety-three sites with failed implants received new implants, and 6 of these 93 implants failed during the healing period. CONCLUSIONS: Within the limitation of sample size, smokers, implant length (<10 mm), and implant design (tapered implant) exhibited higher risk of early implant failure in this retrospective study. Implant insertion torque, healing method, adjacent teeth, and diabetes did not significantly influence the risk of early implant failure.

In situ/Operando Synchrotron Radiation Analytical Techniques for CO2/CO Reduction Reaction: From Atomic Scales to Mesoscales.

Electrocatalytic carbon dioxide/carbon monoxide reduction reaction (CO(2)RR) has emerged as a prospective and appealing strategy to realize carbon neutrality for manufacturing sustainable chemical products. Developing highly active electrocatalysts and stable devices has been demonstrated as effective approach to enhance the conversion efficiency of CO(2)RR. In order to rationally design electrocatalysts and devices, a comprehensive understanding of the intrinsic structure evolution within catalysts and micro-environment change around electrode interface, particularly under operation conditions, is indispensable. Synchrotron radiation has been recognized as a versatile characterization platform, garnering widespread attention owing to its high brightness, elevated flux, excellent directivity, strong polarization and exceptional stability. This review systematically introduces the applications of synchrotron radiation technologies classified by radiation sources with varying wavelengths in CO(2)RR. By virtue of in situ/operando synchrotron radiationanalytical techniques, we also summarize relevant dynamic evolution processes from electronic structure, atomic configuration, molecular adsorption, crystal lattice and devices, spanning scales from the angstrom to the micrometer. The merits and limitations of diverse synchrotron characterization techniques are summarized, and their applicable scenarios in CO(2)RR are further presented. On the basis of the state-of-the-art fourth-generation synchrotron facilities, a perspective for further deeper understanding of the CO(2)RR process using synchrotron radiation analytical techniques is proposed.

Rare Earth Evoked Subsurface Oxygen Species in Platinum Alloy Catalysts Enable Durable Fuel Cells.

Alleviating the degradation issue of Pt based alloy catalysts, thereby simultaneously achieving high mass activity and high durability in proton exchange membrane fuel cells (PEMFCs), is highly challenging. Herein, we provide a new paradigm to address this issue via delaying the place exchange between adsorbed oxygen species and surface Pt atoms, thereby inhibiting Pt dissolution, through introducing rare earth bonded subsurface oxygen atoms. We have succeeded in introducing Gd-O dipoles into Pt3 Ni via a high temperature entropy-driven process, with direct spectral evidence attained from both soft and hard X-ray absorption spectroscopies. The higher rated power of 0.93 W cm-2 and superior current density of 562.2 mA cm-2 at 0.8 V than DOE target for heavy-duty vehicles in H2 -air mode suggest the great potential of Gd-O-Pt3 Ni towards practical application in heavy-duty transportation. Moreover, the mass activity retention (1.04 A mgPt -1 ) after 40 k cycles accelerated durability tests is even 2.4 times of the initial mass activity goal for DOE 2025 (0.44 A mgPt -1 ), due to the weakened Pt-Oads bond interaction and the delayed place exchange process, via repulsive forces between surface O atoms and those in the sublayer. This work addresses the critical roadblocks to the widespread adoption of PEMFCs.

Therapeutic effects of a novel venom abstract (ZK002) solution in an alkali-burned corneal wound-healing model.

Purpose: Corneal alkali burns can progress to corneal epithelial defects, inflammation, scarring, and angiogenesis, potentially leading to blindness. Therefore, we examined the therapeutic effects of a novel ophthalmic solution (ZK002) on wound healing in alkali-burned rat corneas. Methods: In this study, we attempted to treat alkali-exposed rat corneas using topical application of either an ophthalmic solution with ZK002 or an anti-vascular endothelial growth factor agent for 14 days. We evaluated corneal edema, corneal neovascularization area, and histological changes. We also assessed the inflammatory (MMP-9, MMP-2, and interleukin-1ß) and angiogenic (vascular endothelial growth factor receptor 2, VEGFR2) markers. Levels of inflammatory (matrix metalloproteinase (MMP)-9, MMP-2, and interleukin-1ß), profibrotic (α-smooth muscle actin, α-SMA; transforming growth factor-ß2,TGF-ß2), and angiogenic (vascular endothelial growth factor-receptor 2, VEGFR2) factors, as well as peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression, were measured. Results: The analyses showed that alkali exposure caused an increase in corneal edema and fibrosis with corneal neovascularization. The accumulation of α-smooth muscle actin-positive myofibroblasts and the deposition of transforming growth factor-ß2 on the alkali-exposed corneas were noted on day 14. The mRNA expression levels of interleukin-1ß, MMP-9, MMP-2, VEGFR2, and profibrotic factors were decreased in the ZK002 group compared with the control group during the early period of corneal alkali burns on day 14. However, the expression level of PPARγ mRNA was increased in the ZK002 group. Conclusions: ZK002 decreased the fibrotic reaction and prevented neovascularization in the cornea after an alkali burn. Therefore, the novel ophthalmic solution ZK002 could be a potentially promising therapeutic clinical treatment for corneal wound healing.

Recent Advances in the HPPH-Based Third-Generation Photodynamic Agents in Biomedical Applications.

Photodynamic therapy has emerged as a recognized anti-tumor treatment involving three fundamental elements: photosensitizers, light, and reactive oxygen species. Enhancing the effectiveness of photosensitizers remains the primary avenue for improving the biological therapeutic outcomes of PDT. Through three generations of development, HPPH is a 2-(1-hexyloxyethyl)-2-devinyl derivative of pyropheophorbide-α, representing a second-generation photosensitizer already undergoing clinical trials for various tumors. The evolution toward third-generation photosensitizers based on HPPH involves structural modifications for multimodal applications and the combination of multifunctional compounds, leading to improved imaging localization and superior anti-tumor effects. While research into third-generation HPPH is beneficial for advancing PDT treatment, equal attention should also be directed toward the other two essential elements and personalized diagnosis and treatment methodologies.

Causal effects of BMI, waist circumference, and body fat percentage on the risk of bladder cancer: A Mendelian randomization study.

The causal role of body mass index (BMI) in bladder cancer (BC) by Mendelian randomization (MR) has not yet been reported. We evaluated the causal associations between the measures of obesity (BMI, waist circumference, and body fat percentage) and BC. We conducted a 2-sample MR analysis to assess the genetic effect of measures of obesity on BC. The BMI dataset (GWAS ID: ukb-b-2303) comprised 454,884 Europeans, and we identified 9,851,867 single nucleotide polymorphisms (SNPs). The waist circumference data (GWAS ID: ukb-b-9405) included 462,166 Europeans and 9,851,867 SNPs. The body fat percentage dataset (GWAS ID: ukb-a-264) contained data from 331,117 Europeans and 10,894,596 SNPs. For the outcome data, the GWAS ID was finn-b-C3_BLADDER, consisting of 1115 cases and 217,677 controls, with 16,380,466 SNPs. The inverse-variance weighted (IVW) model was used as the primary MR analysis. Cochran Q-statistic was used to identify heterogeneity between the SNPs. The MR-Egger and MR-PRESSO methods were employed to assess directional pleiotropy and outlier SNPs. We detected a decisive causal link between BMI and BC by the IVW analysis (odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.08-1.85, P = .011). The IVW analyses revealed a significant correlation between BC and waist circumference (OR = 1.55, 95% CI: 1.08-2.12, P = .016). However, the IVW method (OR = 1.49, 95% CI: 0.99-2.00, P = .05) did not report any statistical significance between body fat percentage and BC. We did not observe heterogeneity and directional pleiotropy in the 3 pairs of MR studies. The 2-sample MR analysis revealed a conceivable causal association between obesity (BMI, waist circumference) and BC.

Construction and validation of machine learning models for predicting distant metastases in newly diagnosed colorectal cancer patients: A large-scale and real-world cohort study.

BACKGROUND: More accurate prediction of distant metastases (DM) in patients with colorectal cancer (CRC) would optimize individualized treatment and follow-up strategies. Multiple prediction models based on machine learning have been developed to assess the likelihood of developing DM. METHODS: Clinicopathological features of patients with CRC were obtained from the National Cancer Center (NCC, China) and the Surveillance, Epidemiology, and End Results (SEER) database. The algorithms used to create the prediction models included random forest (RF), logistic regression, extreme gradient boosting, deep neural networks, and the K-Nearest Neighbor machine. The prediction models' performances were evaluated using receiver operating characteristic (ROC) curves. RESULTS: In total, 200,958 patients, 3241 from NCC and 197,717 CRC from SEER were identified, of whom 21,736 (10.8%) developed DM. The machine-learning-based prediction models for DM were constructed with 12 features remaining after iterative filtering. The RF model performed the best, with areas under the ROC curve of 0.843, 0.793, and 0.806, respectively, on the training, test, and external validation sets. For the risk stratification analysis, the patients were separated into high-, middle-, and low-risk groups according to their risk scores. Patients in the high-risk group had the highest incidence of DM and the worst prognosis. Surgery, chemotherapy, and radiotherapy could significantly improve the prognosis of the high-risk and middle-risk groups, whereas the low-risk group only benefited from surgery and chemotherapy. CONCLUSION: The RF-based model accurately predicted the likelihood of DM and identified patients with CRC in the high-risk group, providing guidance for personalized clinical decision-making.

TAK1 inhibition mitigates intracerebral hemorrhage-induced brain injury through reduction of oxidative stress and neuronal pyroptosis via the NRF2 signaling pathway.

Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-ß-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis. Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays. Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis. Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH.