Palladium-Doped Cs2AgBiBr6 with 1300 nm Near-Infrared Photoresponse.

Lead-free halide double perovskite (HDP) Cs2AgBiBr6 has set a benchmark for research in HDP photoelectric applications due to its attractive optoelectronic properties. However, its narrow absorption range is a key limitation of this material. Herein, a novel dopant, palladium (Pd), is doped into Cs2AgBiBr6 and significantly extends the absorption to ≈1400 nm. Pd2+ ions are partially doped in the host lattice, most probably replacing Ag atoms and introducing a sub-bandgap state within the host bandgap, as indicated by the combination of spectroscopical measurements and theoretical calculations. Importantly, this sub-bandgap state extends the photoresponse of Cs2AgBiBr6 up to the NIR-II region of 1300 nm, setting a new record for HDPs. This work demonstrates a novel and efficient dopant for HDPs and highlights the effectiveness of employing a sub-bandgap to broaden the absorption of HDPs, shedding new light on tailoring large bandgap HDPs for NIR optoelectronic applications.

Association between Bilateral Vertebral Artery Blood Flow Changes and Posterior Circulation Infarction in Patients with Severe Intracranial Stenosis.

INTRODUCTION: The objective of this study was to explore the association between net vertebral artery flow volume (NVAFV), calculated through color duplex ultrasonography, and posterior circulation infarction (PCI) in patients with severe intracranial vertebral artery (VA) stenosis. METHODS: 234 patients with severe intracranial VA stenosis (≥70%) were categorized into the PCI group (n = 139) and the non-PCI group (n = 95) based on cranial MRI diagnosis. The correlation between NVAFV and CT perfusion data was analyzed, and the occurrence of PCI under diverse PCI mechanisms was also investigated. Multifactorial logistic regression and stratified analysis was performed to analyze the association between NVAFV and PCI. Lastly, generalized additive models and smooth curve fitting was utilized to outline relationship between NVAFV and PCI. RESULTS: NVAFV showed a significant correlation with cerebral blood flow, mean transmit time, and time to peak. In the large artery atherosclerosis mechanism, a reduction in NVAFV correlated with a gradual rise in PCI cases (p = 0.002), while this trend lacked significance in the branch artery occlusive disease mechanism (p = 0.993). In the fully adjusted model, each 10 mL/min increase in NVAFV reduced PCI incidence by 11% (OR 0.890, 95% CI 0.840-0.943, p < 0.001), Sensitivity analysis showed similar results; NVAFV presented different PCI risks among various glucose level subgroups, the OR (95% CI) for PCI was 0.788 (0.684, 0.906) in low-glucose group (T1), 0.968 (0.878, 1.066) in moderate-glucose group (T2), and 0.886 (0.801, 0.979) in high-glucose group (T3). Smooth curve fitting demonstrated a linear negative association between NVAFV and PCI. CONCLUSION: NVAFV demonstrated an association with PCI in patients with severe intracranial VA stenosis, it can serve as a reference for identifying high-risk populations of PCI; however, it must be considered in combination with glucose.

Phytoremediation of Pb-polluted soil using bermudagrass: Effect of mowing frequencies.

Plant lead (Pb) tolerance and accumulation are key characteristics affecting phytoremediation efficiency. Bermudagrass is an excellent candidate for the remediation of Pb-polluted soil, and it needs to be mowed regularly. Here, we explored the effect of different mowing frequencies on the remediation of Pb-contaminated soil using bermudagrass. Mowing was found to decrease the biomass and photosynthetic efficiency of bermudagrass under Pb stress, thereby inhibiting its growth. Although mowing exacerbated membrane peroxidation, successive mowing treatments alleviated peroxidation damage by regulating enzymatic and nonenzymatic systems. A comprehensive evaluation of Pb tolerance revealed that all the mowing treatments reduced the Pb tolerance of bermudagrass, and a once-per-month mowing frequency had a less negative effect on Pb tolerance than did more frequent mowing. In terms of Pb enrichment, mowing significantly increased the Pb concentration, total Pb accumulation, translocation factor (TF), and bioenrichment factor (BCF) of bermudagrass. The total Pb accumulation was greatest under the once-a-month treatment, while the TF and BCF values were greatest under the three-times-a-month mowing treatment. Additionally, the decrease in soil pH and DOC were significantly correlated with the soil available Pb content and plant Pb accumulation parameters. The results showed that changes in the rhizosphere are crucial factors regulating Pb uptake in bermudagrass during mowing. Overall, once-a-month mowing minimally affects Pb tolerance and maximizes Pb accumulation, making it the optimal mowing frequency for soil Pb remediation by bermudagrass. This study provides a novel approach for the remediation of Pb-contaminated soil with bermudagrass based on mowing.

APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. HIGHLIGHTS: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

Identification of lncRNA-mRNA network linking ferroptosis and immune infiltration to colon adenocarcinoma suppression.

Background: Colon adenocarcinoma (COAD) is one of the most common malignant tumors. The interplay involving ferroptosis between tumor and immune cells plays a crucial in cancer progression. However, the biological basis of this interplay in COAD development remains elusive. Methods: Transcriptome data of COAD samples were obtained from The Cancer Genome Atlas and National Center for Biotechnology Information databases. Using single-sample gene set enrichment analysis, we calculated the ferroptosis score (FS) and immune cell infiltration levels for each sample, leveraging the expression levels of genes related to ferroptosis and various immune cell types. Samples with FSs greater than the 75th percentile were classified into the high-FS subgroup, while those below the 25th percentile were categorized as the low-FS subgroup. Moreover, tumor tissue samples and adjacent normal tissue samples were collected from twenty colon patients. Using real-time quantitative polymerase chain reaction, we validated the expression of certain genes in these samples. Results: The COAD samples with high FSs experienced favorable survival probability and heightened sensitivity to anticancer drugs, with FSs negatively associated with the pathological stages. Moreover, the up-regulated genes in high-FS subgroup exhibited enrichment in immune-related pathways, suggesting a correlation between immunity and ferroptosis. Importantly, we discovered a key lncRNA-mRNA co-expression network linking tumor cell ferroptosis and immune infiltration (e.g., neutrophil) in the progression and classification of COAD. Further analysis identified several ferroptosis-related lncRNAs (e.g., RP11-399O19.9) within this network, indicating their potential roles in COAD progression and deserving in-depth study. Conclusions: Our findings provide novel insights into the underlying biological basis, particularly involving lncRNAs, at gene expression level associated with ferroptosis in COAD and cancer therapy. Nevertheless, further analysis and validation are required to expand the findings.

Manganese self-boosting hollow nanoenzymes with glutathione depletion for synergistic cancer chemo-chemodynamic therapy.

Chemodynamic therapy (CDT) has outstanding potential as a combination therapy to treat cancer. However, the effectiveness of CDT in the treatment of solid tumors is limited by the overexpression of glutathione (GSH) in the tumor microenvironment (TME). GSH overexpression diminishes oxidative stress and attenuates chemotherapeutic drug-induced apoptosis in cancer cells. To counter these effects, a synergistic CDT/chemotherapy cancer treatment, involving the use of a multifunctional bioreactor of hollow manganese dioxide (HMnO2) loaded with cisplatin (CDDP), was developed. Metal nanoenzymes that can auto-degrade to produce Mn2+ exhibit Fenton-like, GSH-peroxidase-like activity, which effectively depletes GSH in the TME to attenuate the tumor antioxidant capacity. In an acidic environment, Mn2+ catalyzed the decomposition of intra-tumor H2O2 into highly toxic ·OH as a CDT. HMnO2 with large pores, pore volume, and surface area exhibited a high CDDP loading capacity (>0.6 g-1). Treatment with CDDP-loaded HMnO2 increased the intratumor Pt-DNA content, leading to the up-regulation of γ-H2Aχ and an increase in tumor tissue damage. The decreased GSH triggered by HMnO2 auto-degradation protected Mn2+-generated ·OH from scavenging to amplify oxidative stress and enhance the efficacy of CDT. The nanoenzymes with encapsulated chemotherapeutic agents deplete GSH and remodel the TME. Thus, tumor CDT/chemotherapy combination therapy is an effective therapeutic strategy.

Exploring the Association between Cathepsin B and Parkinson's Disease.

OBJECTIVE: The aim of this study is to investigate the association between Cathepsin B and Parkinson's Disease (PD), with a particular focus on determining the role of N-acetylaspartate as a potential mediator. METHODS: We used summary-level data from Genome-Wide Association Studies (GWAS) for a two-sample Mendelian randomization (MR) analysis, exploring the association between Cathepsin B (3301 cases) and PD (4681 cases). A sequential two-step MR approach was applied (8148 cases) to study the role of N-acetylaspartate. RESULTS: The MR analysis yielded that genetically predicted elevated Cathepsin B levels correlated with a reduced risk of developing PD (p = 0.0133, OR: 0.9171, 95% CI: 0.8563-0.9821). On the other hand, the analysis provided insufficient evidence to determine that PD affected Cathepsin B levels (p = 0.8567, OR: 1.0035, 95% CI: 0.9666-1.0418). The estimated effect of N-acetylaspartate in this process was 7.52% (95% CI = -3.65% to 18.69%). CONCLUSIONS: This study suggested that elevated Cathepsin B levels decreased the risk of developing PD, with the mediation effect of N-acetylaspartate. Further research is needed to better understand this relationship.

An antagonist-based two-photon fluorogenic probe for imaging metabotropic glutamate receptor 5 in neuronal cells.

The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible. In this study, we have successfully developed a two-photon fluorogenic probe, mGlu-5-TP, based on the structure of mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP). Due to this antagonist-based probe selectively recognizes mGluR5, high expression of mGluR5 on living SH-SY5Y human neuroblastoma cells has been detected during intracellular inflammation triggered by lipopolysaccharides (LPS). Of particular significance, the probe can be employed along with two-photon fluorescence microscopy to enable real-time visualization of the mGluR5 in Aß fiber-treated neuronal cells, thereby establishing a connection to the progression of Alzheimer's disease (AD). These results revealed that the probe can be a valuable imaging tool for studying mGluR5-related diseases in the nervous system.

The role of CELF family in neurodevelopment and neurodevelopmental disorders.

RNA-binding proteins (RBPs) bind to RNAs and are crucial for regulating RNA splicing, stability, translation, and transport. Among these proteins, the CUGBP Elav-like family (CELF) is a highly conserved group crucial for posttranscriptional regulation by binding to CUG repeats. Comprising CELF1-6, this family exhibits diverse expression patterns and functions. Dysregulation of CELF has been implicated in various neural disorders, encompassing both neurodegenerative and neurodevelopmental conditions, such as Alzheimer's disease and autism. This article aims to provide a comprehensive summary of the CELF family's role in neurodevelopment and neurodevelopmental disorders. Understanding CELF's mechanisms may offer clues for potential therapeutic strategies by regulating their targets in neurodevelopmental disorders.

Cascading Detection of Hydrogen Sulfide and N-Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.

Oxygen self-supplying small size magnetic nanoenzymes for synergistic photodynamic and catalytic therapy of breast cancer.

In recent years, tumor catalytic therapy based on nanozymes has attracted widespread attention. However, its application is limited by the tumor hypoxic microenvironment (TME). In this study, we developed oxygen-supplying magnetic bead nanozymes that integrate hemoglobin and encapsulate the photosensitizer curcumin, demonstrating reactive oxygen species (ROS)-induced synergistic breast cancer therapy. Fe3O4 magnetic bead-mediated catalytic dynamic therapy (CDT) generates hydroxyl radicals (˙OH) through the Fenton reaction in the tumor microenvironment. The Hb-encapsulated Fe3O4 magnetic beads can be co-loaded with the photosensitizer/chemotherapeutic agent curcumin (cur), resulting in Fe3O4-Hb@cur. Under hypoxic conditions, oxygen molecules are released from Fe3O4-Hb@cur to overcome the TME hypoxia, resulting in comprehensive effects favoring anti-tumor responses. Upon near-infrared (NIR) irradiation, Fe3O4-Hb@cur activates the surrounding molecular oxygen to generate a certain amount of singlet oxygen (1O2), which is utilized for photodynamic therapy (PDT) in cancer treatment. Meanwhile, we validated that the O2 carried by Hb significantly enhances the intracellular ROS level, intensifying the catalytic therapy mediated by Fe3O4 magnetic beads and inflicting lethal damage to cancer cells, effectively inhibiting tumor growth. Therefore, significant in vivo synergistic therapeutic effects can be achieved through catalytic-photodynamic combination therapy.

Multi-Omics Characteristics of Ferroptosis Associated with Colon Adenocarcinoma Typing and Survival.

BACKGROUND: Ferroptosis, an iron-dependent form of cell death, plays a crucial role in the progression of various cancers, including colon adenocarcinoma (COAD). However, the multi-omics signatures relevant to ferroptosis regulation in COAD diagnosis remain to be elucidated. METHODS: The transcriptomic, miRNAomic, and methylomic profiles of COAD patients were acquired from the Cancer Genome Atlas (TCGA). Ferroptosis activity in these patients was determined, represented by a ferroptosis score (FS), using single-sample gene set enrichment analysis (ssGSEA) based on the expression of ferroptosis-related genes. RESULTS: Results showed that the COAD patients with high-FS displayed favorable survival outcomes and heightened drug sensitivity. They also exhibited an up-regulation of genes involved in immune-related pathways (e.g., tumor necrosis factor signaling pathway), suggesting a correlation between immunity and ferroptosis in COAD progression. Furthermore, three survival prediction models were established based on 10 CpGs, 12 long non-coding RNAs (lncRNAs), and 14 microRNAs (miRNAs), respectively. These models demonstrated high accuracy in predicting COAD survival, achieving areas under the curve (AUC) >0.7. The variables used in the three models also showed strong correlations at different omics levels and were effective at discriminating between high-FS and low-FS COAD patients (AUC >0.7). CONCLUSIONS: This study identified different DNA methylation (DNAm), lncRNA, and miRNA characteristics between COAD patients with high and low ferroptosis activity. Furthermore, ferroptosis-related multi-omics signatures were established for COAD prognosis and classification. These insights present new opportunities for improving the efficacy of COAD therapy.

Metabolomics on depression: A comparison of clinical and animal research.

BACKGROUND: Depression is a major cause of suicide and mortality worldwide. This study aims to conduct a systematic review to identify metabolic biomarkers and pathways for major depressive disorder (MDD), a prevalent subtype of clinical depression. METHODS: We searched for metabolomics studies on depression published between January 2000 and January 2023 in the PubMed and Web of Science databases. The reported metabolic biomarkers were systematically evaluated and compared. Pathway analysis was implemented using MetaboAnalyst 5.0. RESULTS: We included 26 clinical studies on MDD and 78 metabolomics studies on depressive-like animal models. A total of 55 and 77 high-frequency metabolites were reported consistently in two-thirds of clinical and murine studies, respectively. In the comparison between murine and clinical studies, we identified 9 consistently changed metabolites (tryptophan, tyrosine, phenylalanine, methionine, fumarate, valine, deoxycholic acid, pyruvate, kynurenic acid) in the blood, 1 consistently altered metabolite (indoxyl sulfate) in the urine and 14 disturbed metabolic pathways in both types of studies. These metabolic dysregulations and pathways are mainly implicated in enhanced inflammation, impaired neuroprotection, reduced energy metabolism, increased oxidative stress damage and disturbed apoptosis, laying solid molecular foundations for MDD. LIMITATIONS: Due to unavailability of original data like effect-size results in many metabolomics studies, a meta-analysis cannot be conducted, and confounding factors cannot be fully ruled out. CONCLUSIONS: This systematic review delineated metabolic biomarkers and pathways related to depression in the murine and clinical samples, providing opportunities for early diagnosis of MDD and the development of novel diagnostic targets.

Anomalous origin of the left suprarenal, inferior phrenic arteries and left ovarian artery in a human cadaver.

This report addresses three variants identified within a female cadaver. Specifically, these were an anomalous origin of the right suprarenal artery, an abnormal bilateral ovarian vein branch, and a arterial tortuosity of the left ovarian artery. Indeed, the cadaver evinced abnormal origins in the case of the middle suprarenal artery (MSA), right inferior phrenic artery (IPA), and the renal capsule artery (emanating from the right renal artery). The MSA and IPA shared a common trunk with the inferior suprarenal artery. It was additionally observed that the right ovarian vein anastomoses the branches from the right kidney posterior inferior along with those to the renal fat capsule. Abnormal origin was evident in the case of the left ovarian artery, and arterial tortuosity was apparent in the lower region of the vessels. This report addresses both the clinical import of these variations and their likely causes. In the subdiaphragmatic region, surgical success and prognosis may be impacted by such anomalies; accordingly surgeons must be aware of anatomical variants of the ovarian and suprarenal arteries.

The New Role of HNF1A-NAS1/miR-214/INHBA Signaling Axis in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and one of the leading causes of death worldwide. Seriously threatens human life and health. Previous studies have identified that inhibin ßA (INHBA) could induce tumorgenesis and progression of CRC through the regulation of the TGF-ß/Smad signal axis. The abnormal expression of INHBA is related to the poor prognosis of patients. The aim of this study was to identify the molecular mechanism of HNF1A-AS1 and miR-214 regulating INHBA and carcinogenesis through bioinformatics combined with experiments. METHODS: The expression of HNF1A-AS1, miRNA-214-5p, INHBA in pan-cancer and CRC were investigated in the Cancer Genome Atlas (TCGA). The correlation between HNF1A-AS1 and immune-related genes or miRNAs was explored via the Gene Expression Profiling Interactive Analysis (GEPIA) and volcano plots, respectively. The association between HNF1A-AS1 and differentially expressed miRNAs was constructed by TargetScan. The miRDB, miRWalk, and TargetScan databases were utilized to predict the target genes of hsa-miR-214. The expression of INHBA in tissues and cell lines of CRC was examined by RT-qPCR and western blot assay. RESULTS: The INHBA and HNF1A-AS1 expressions were increased in Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) of the TCGA database. Hsa-miR-214 was relatively less expressed in CRC tissues compared with para-cancer tissues. The expression of HNF1A-AS1 was negatively correlated with hsa-miR-214. INHBA was one of the target genes of hsa-miR-214 based on miRDB, miRWalk, and TargetScan databases. The specific binding sites of INHBA-3'UTR and miR-214-5p were identified by starBase. The expression level of INHBA was positively correlated with the T stage of tumor and negatively correlated with overall survival (OS) and disease-free survival (DFS) in CRC patients. The results of RT-qPCR and western blot indicated that the expression of INHBA in tissues and cell lines in CRC was higher than those in para-carcinoma tissues and normal colon cell lines, respectively. CONCLUSIONS: These findings suggested that HNF1A-AS1 and miRNA-214-5p were key upstream non-coding RNAs of INHBA. The HNF1A-AS1/miR-214/INHBA signal axis plays a significant role in the tumorgenesis and progression of CRC. By interfering with HNF1A-AS1 and INHBA genes on HT29 and SW480 cells, it was found that HNF1A-AS1 and INHBA genes may be important target genes in CRC.

Unraveling the prognostic significance and molecular characteristics of tumor-infiltrating B lymphocytes in clear cell renal cell carcinoma through a comprehensive bioinformatics analysis.

Introduction: Clear cell renal cell carcinoma (ccRCC) is a prevalent subtype of kidney cancer that exhibits a complex tumor microenvironment, which significantly influences tumor progression and immunotherapy response. In recent years, emerging evidence has underscored the involvement of tumor-infiltrating B lymphocytes (TIL-Bs), a crucial component of adaptive immunity, and their roles in ccRCC as compared to other tumors. Therefore, the present study endeavors to systematically explore the prognostic and molecular features of TIL-Bs in ccRCC. Methods: Initially, xCell algorithm was used to predict TIL-Bs in TCGA-KIRC and other ccRCC transcriptomic datasets. The Log-Rank test and Cox regression were applied to explore the relationship of B-cells with ccRCC survival. Then, we used WGCNA method to identify important modules related to TIL-Bs combining Consensus subcluster and scRNA-seq data analysis. To narrow down the prospective biomarkers, a prognostic signature was proposed. Next, we explored the feature of the signature individual genes and the risk-score. Finally, the potential associations of signature with clinical phenotypes and drugs were investigated. Results: Preliminary, we found ccRCC survival was negatively associated with TIL-Bs, which was confirmed by other datasets. Afterwards, ten co-expression modules were identified and a distinct ccRCC cluster was subsequently detected. Moreover, we assessed the transcriptomic alteration of B-cell in ccRCC and a relevant B-cell subtype was also pinpointed. Based on two core modules (brown, red), a 10-gene signature (TNFSF13B, SHARPIN, B3GAT3, IL2RG, TBC1D10C, STAC3, MICB, LAG3, SMIM29, CTLA4) was developed in train set and validated in test sets. These biomarkers were further investigated with regards to their differential expression and correlation with immune characteristics, along with risk-score related mutations and pathways. Lastly, we established a nomogram combined tumor grade and discovered underlying drugs according to their sensitivity response. Discussion: In our research, we elucidated the remarkable association between ccRCC and B-cells. Then, we detected several key gene modules, together with close patient subcluster and B-cell subtype,which could be responsible for the TIL-Bs in ccRCC. Moreover, we proposed a 10-gene signature and investigated its molecular features from multiple perspectives. Overall, understanding the roles of TIL-Bs could aid in the immunotherapeutic approaches for ccRCC, which deserve further research to clarify the implications for patient prognosis and treatment.

A high-field cellular DNP-supported solid-state NMR approach to study proteins with sub-cellular specificity.

Studying the structural aspects of proteins within sub-cellular compartments is of growing interest. Dynamic nuclear polarization supported solid-state NMR (DNP-ssNMR) is uniquely suited to provide such information, but critically lacks the desired sensitivity and resolution. Here we utilize SNAPol-1, a novel biradical, to conduct DNP-ssNMR at high-magnetic fields (800 MHz/527 GHz) inside HeLa cells and isolated cell nuclei electroporated with [13C,15N] labeled ubiquitin. We report that SNAPol-1 passively diffuses and homogenously distributes within whole cells and cell nuclei providing ubiquitin spectra of high sensitivity and remarkably improved spectral resolution. For cell nuclei, physical enrichment facilitates a further 4-fold decrease in measurement time and provides an exclusive structural view of the nuclear ubiquitin pool. Taken together, these advancements enable atomic interrogation of protein conformational plasticity at atomic resolution and with sub-cellular specificity.

Locally advanced rectal cancer with dMMR/MSI-H may be excused from surgery after neoadjuvant anti-PD-1 monotherapy: a multiple-center, cohort study.

Objective: Examine patients with locally advanced rectal cancer (LARC) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) who received neoadjuvant immunotherapy (nIT), and compare the outcomes of those who chose a watch-and-wait (WW) approach after achieving clinical complete response (cCR) or near-cCR with those who underwent surgery and were confirmed as pathological complete response (pCR). Methods: LARC patients with dMMR/MSI-H who received nIT were retrospectively examined. The endpoints were 2-year overall survival (OS), 2-year disease-free survival (DFS), local recurrence (LR), and distant metastasis (DM). The efficacy of programmed cell death protein-1 (PD-1) inhibitor, immune-related adverse events (irAEs), surgery-related adverse events (srAEs), and enterostomy were also recorded. Results: Twenty patients who received a PD-1 inhibitor as initial nIT were examined. Eighteen patients (90%) achieved complete response (CR) after a median of 7 nIT cycles, including 11 with pCR after surgery (pCR group), and 7 chose a WW strategy after evaluation as cCR or near-cCR (WW group). Both groups had median follow-up times of 25.0 months. Neither group had a case of LR or DM, and the 2-year DFS and OS in each group was 100%. The two groups had similar incidences of irAEs (P=0.627). In the pCR group, however, 2 patients (18.2%) had permanent colostomy, 3 (27.3%) had temporary ileostomy, and 2 (18.2%) had srAEs. Conclusion: Neoadjuvant PD-1 blockade had high efficacy and led to a high rate of CR in LARC patients with dMMR/MSI-H. A WW strategy appears to be a safe and reliable option for these patients who achieve cCR or near-cCR after nIT.