Facile Synthesis of Rigid Binuclear Manganese Complexes for Magnetic Resonance Angiography and SLC39A14-Mediated Hepatic Imaging.

Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.

The relationship between the network of non-coding RNAs-molecular targets and N6-methyladenosine modification in tumors of urinary system.

N6-methyladenosine (m6A) methylation, a prevalent eukaryotic post-transcriptional modification, is involved in multiple biological functions, including mediating variable splicing, RNA maturation, transcription, and nuclear export, and also is vital for regulating RNA translation, stability, and cytoplasmic degradation. For example, m6A methylation can regulate pre-miRNA expression by affecting both splicing and maturation. Non-coding RNA (ncRNA), which includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), does not encode proteins but has powerful impacts on transcription and translation. Conversely, ncRNAs may impact m6A methylation by affecting the expression of m6A regulators, including miRNAs targeting mRNA of m6A regulators, or lncRNAs, and circRNAs, acting as scaffolds to regulate transcription of m6A regulatory factors. Dysregulation of m6A methylation is common in urinary tumors, and the regulatory role of ncRNAs is also important for these malignancies. This article provides a systematic review of the role and mechanisms of action of m6A methylation and ncRNAs in urinary tumors.

Light-induced electronic polarization in antiferromagnetic Cr2O3.

In a solid, the electronic subsystem can exhibit incipient order with lower point group symmetry than the crystal lattice. Ultrafast external fields that couple exclusively to electronic order parameters have rarely been investigated, however, despite their potential importance in inducing exotic effects. Here we show that when inversion symmetry is broken by the antiferromagnetic order in Cr2O3, transmitting a linearly polarized light pulse through the crystal gives rise to an in-plane rotational symmetry-breaking (from C3 to C1) via optical rectification. Using interferometric time-resolved second harmonic generation, we show that the ultrafast timescale of the symmetry reduction is indicative of a purely electronic response; the underlying spin and crystal structures remain unaffected. The symmetry-broken state exhibits a dipole moment, and its polar axis can be controlled with the incident light. Our results establish a coherent nonlinear optical protocol by which to break electronic symmetries and produce unconventional electronic effects in solids.

Magnetochiral tunneling in paramagnetic Co1/3NbS2.

Electric currents have the intriguing ability to induce magnetization in nonmagnetic crystals with sufficiently low crystallographic symmetry. Some associated phenomena include the non-linear anomalous Hall effect in polar crystals and the nonreciprocal directional dichroism in chiral crystals when magnetic fields are applied. In this work, we demonstrate that the same underlying physics is also manifested in the electronic tunneling process between the surface of a nonmagnetic chiral material and a magnetized scanning probe. In the paramagnetic but chiral metallic compound Co1/3NbS2, the magnetization induced by the tunneling current is shown to become detectable by its coupling to the magnetization of the tip itself. This results in a contrast across different chiral domains, achieving atomic-scale spatial resolution of structural chirality. To support the proposed mechanism, we used first-principles theory to compute the chirality-dependent current-induced magnetization and Berry curvature in the bulk of the material. Our demonstration of this magnetochiral tunneling effect opens up an avenue for investigating atomic-scale variations in the local crystallographic symmetry and electronic structure across the structural domain boundaries of low-symmetry nonmagnetic crystals.

Emerging strategy for the treatment of urothelial carcinoma: Advances in antibody-drug conjugates combination therapy.

Urothelial carcinoma (UC) is a prevalent malignant tumor involving the urinary system. Although there are various treatment modalities, including surgery, chemotherapy, and immune checkpoint inhibitor (ICI) therapy, some patients experience disease recurrence and metastasis with poor prognosis and dismal long-term survival. Antibody-drug conjugates (ADCs), which combine the targeting ability of antibody drugs with the cytotoxicity of chemotherapeutic drugs, have recently emerged as a prominent research focus in the development of individualized precision cancer therapy. Although ADCs have improved the overall response rate in patients with UC, their effectiveness remains limited. Currently, ADC-based combination therapies, particularly ADC combined with ICIs, have demonstrated promising efficacy. This combination approach has advanced the treatment of UC, exhibiting the potential to become the standard first-line therapy for advanced UC in the future. This article reviewed clinical trials involving ADC-based combination therapy for UC and discussed the possible challenges and future perspectives to provide guidance for the clinical treatment of UC.

Survival outcomes in patients with acute myeloid leukaemia who received subsequent therapy for relapse in QUAZAR AML-001.

In the phase 3 QUAZAR AML-001 trial (NCT01757535) of patients with acute myeloid leukaemia (AML) in remission following intensive chemotherapy (IC) and ineligible for haematopoietic stem cell transplant (HSCT), oral azacitidine (Oral-AZA) maintenance significantly prolonged overall survival (OS) versus placebo. The impact of subsequent treatment following maintenance has not been evaluated. In this post hoc analysis, OS was estimated for patients who received subsequent AML therapy, and by regimen received (IC or lower-intensity therapy). First subsequent therapy (FST) was administered after treatment discontinuation in 134/238 Oral-AZA and 173/234 placebo patients. OS from randomization in patients who received FST after Oral-AZA versus placebo was 17.8 versus 12.9 months (HR: 0.82 [95% CI: 0.64-1.04], median follow-up: 56.7 months); OS from FST was similar between arms. Among patients who received injectable hypomethylating agents as FST, median OS was 8.2 versus 4.9 months in the Oral-AZA versus placebo groups (HR: 0.66 [95% CI: 0.41-1.06]). Forty-eight patients (16/238 Oral-AZA, 32/234 placebo) received HSCT following treatment discontinuation, including six Oral-AZA patients still in first remission; Oral-AZA OS benefit persisted when censoring these patients. Oral-AZA maintenance can prolong AML remission duration without negatively impacting survival outcomes after salvage therapies.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

Potential future changes in soil carbon dynamics in the Ziwuling Forest, China under different climate change scenarios.

Soil carbon (C) cycling processes in terrestrial ecosystems are significantly influenced by global changes, and soil microorganisms play a crucial role in soil organic carbon (SOC) and its feedbacks to climate change. To investigate the potential future changes in soil C dynamics under different scenarios in the Ziwuling Forest region, China, we conducted a soil observation and sampling experiment from April 2021 to July 2022. By utilizing a microbial ecological model (MEND), we aimed to predict the future dynamics of soil C under different scenarios in the area. Our results demonstrate that under the RCP2.6 (Representative Concentration Pathway) scenario, SOC showed a rapid increase, SOC under the RCP2.6 scenario will be significantly higher than those under the RCP4.5 scenario and RCP8.5 scenario in the topsoil and whole soil. Furthermore, the positive correlation between total litter carbon (LC) and SOC under the RCP2.6 scenario highlights the potential role of total litter carbon in driving SOC dynamics. Our study also revealed that the low greenhouse gas (GHG) emission scenario favors the accumulation of SOC in the study area, while the high GHG emission scenario leads to greater soil carbon loss. Overall, these results underscore the importance of considering the impact of climate change, especially global warming, on soil ecosystems in the future. Protecting the soil ecosystem of the Loess Plateau is critical for maintaining soil carbon sinks, preventing soil erosion, and improving and regulating the surrounding environmental climate.

Nucleation Domains in Biomineralization: Biomolecular Sequence and Conformational Features.

Biomolecules play a vital role in the regulation of biomineralization. However, the characteristics of practical nucleation domains are still sketchy. Herein, the effects of the representative biomolecular sequence and conformations on calcium phosphate (Ca-P) nucleation and mineralization are investigated. The results of computer simulations and experiments prove that the line in the arrangement of dual acidic/essential amino acids with a single interval (Bc (Basic) -N (Neutral) -Bc-N-Ac (Acidic)- NN-Ac-N) is most conducive to the nucleation. 2α-helix conformation can best induce Ca-P ion cluster formation and nucleation. "Ac- × × × -Bc" sequences with α-helix are found to be the features of efficient nucleation domains, in which process, molecular recognition plays a non-negligible role. It further indicates that the sequence determines the potential of nucleation/mineralization of biomolecules, and conformation determines the ability of that during functional execution. The findings will guide the synthesis of biomimetic mineralized materials with improved performance for bone repair.

Ferrorotational Selectivity in Ilmenites.

Unlike what happens in conventional ferroics, the ferrorotational (FR) domain manipulation and visualization in FR materials are nontrivial as they are invariant under both space-inversion and time-reversal operations. FR domains have recently been observed by using the linear electrogyration (EG) effect and X-ray diffraction (XRD) diffraction mapping. However, ferrorotational selectivity, such as the selective processing of the FR domains and direct visualization of the FR domains, e.g., under an optical microscope, would be the next step to study the FR domains and their possible applications in technology. Unexpectedly, we discovered that the microscopic FR structural distortions in ilmenite crystals can be directly coupled with macroscopic mechanical rotations in such a way that FR domains can be visualized under an optical microscope after innovative rotational polishing, a combined ion milling with a specific rotational polishing, or a twisting-induced fracturing process. Thus, the FR domains could be a unique medium to register the memory of a rotational mechanical process due to a novel selective coupling between its microscopic structural rotations and an external macroscopic rotation. Analogous to the important enantioselectivity in modern chemistry and the pharmaceutical industry, this newly discovered ferrorotational selectivity opens up opportunities for FR manipulation and new FR functionality-based applications.

Knowledge mapping and current trends of Warburg effect in the field of cancer.

Background: Since abnormal aerobic glycolysis was first identified in cancer cells, many studies have focused on its mechanisms. The purpose of this study was to analyze the global research status of the Warburg effect in cancer using bibliometrics. Methods: Articles published from 01 January 2013 to 31 December 2022 (n=2,067) were retrieved from the Web of Science core collection database and analyzed using VOSviewer and CiteSpace software. Results: Over the past decade, there was an overall increase in the number of annual publications. China was the most productive country with 790 articles, while the United States received the most citations, with 25,657 citations in total. Oncotarget was the most productive and most cited journal, with 99 articles and 4,191 citations, respectively. International cooperation was common, with the USA cooperating most with other countries. Lactate metabolism, citrate production, and non-coding RNAs related to the Warburg effect have received increasing attention in cancer research. These areas may become future research trends. Conclusion: The study findings help summarize the research status and hotspots of the Warburg effect cancer, and will inform subsequent research.

Knowledge mapping and current trends of global research on snoRNA in the field of cancer.

Cancer is a major health hazard for humans. Recent studies have indicated the involvement of small nucleolar RNAs (snoRNAs) in the occurrence and development of cancer and indicated its potential role as a diagnostic/prognostic marker and therapeutic target. The purpose of this study was to use the bibliometrics method to analyze the published literature on this subject. We collected articles pertaining to the field of snoRNA and cancer from the Web of Science Core Collection database. The data were analyzed to identify the research hotspots and frontiers. The number of articles in this field was low in the early period. Chu Liang and Montanaro Lorenzo were the most prolific authors on this subject, while Jiang and Feng were the most frequently cited authors. In China, three institutions published the most articles, namely Wuhan Univ, China Med Univ, and Guangxi Med Univ. The journal with the highest number of articles on this subject was Oncotarget. The country with the most published articles was China. Analysis of keywords and burst words indicated that early studies mainly focused on molecular mechanisms. Available evidence suggests the involvement of snoRNAs in the molecular mechanism of cancer development and their potential role as a diagnostic and prognostic biomarker.

Knowledge-map analysis of bladder cancer immunotherapy.

This study aimed to conduct a bibliometric analysis in the field of bladder cancer (BC) immunotherapy, and explore the research trends, hotspots and frontiers from 2000 to 2022. VOSviewer software was used to analyze the collaborative relationships between authors, institutions, countries/regions, and journals through citation, co-authorship, and co-citation analysis, to identify research hotspots and frontiers in this field. Researchers based in the United States of America have published a total of 627 papers with 27,308 citations. Indeed, the USA ranked first among the top 10 most active countries and showed the most extensive collaboration with other countries. The University of Texas MD Anderson CANC CTR has published 58 articles, making it the top most institution in terms of published articles and active collaborative research. Kamat AM and Lamm DL were the most active and co-cited authors with 28 papers and 980 co-citations, respectively. Chang Yuan and Xu le were the most active collaborative authors with a total link strength of 195. The J UROLOGY was the most active and frequently co-cited journal, with 100 papers and 6,668 co-citations. Studies of BC immunotherapy can be broadly classified into three categories: "basic research", "clinical trial", and "prognosis". Our findings provide an overview of the research priorities and future directions of BC immunotherapy. Tumor microenvironment and immune checkpoint inhibitors (ICIs) of BC, as well as the combination of ICIs with other drugs, may become the main direction of future research.

A Metal-Organic Framework-Incorporated Hydrogel for Delivery of Immunomodulatory Neobavaisoflavone to Promote Cartilage Regeneration in Osteoarthritis.

The treatment of osteoarthritis (OA)-related cartilage defects is a great clinical challenge due to the complex pathogenesis of OA and poor self-repair ability of cartilage tissue. Combining local and long-term anti-inflammatory therapies to promote cartilage repair is an effective method to treat OA. In this study, a zinc-organic framework-incorporated extracellular matrix (ECM)-mimicking hydrogel platform was constructed for the inflammatory microenvironment-responsive delivery of neobavaisoflavone (NBIF) to promote cartilage regeneration in OA. The NBIF was encapsulated in situ in zeolitic imidazolate frameworks (ZIF-8 MOFs). The NBIF@ZIF-8 MOFs were decorated with polydopamine and incorporated into a methacrylate gelatin/hyaluronic acid hybrid network to form the NBIF@ZIF-8/PHG hydrogel. The hydrogel featured excellent cell/tissue affinity, providing a favorable microenvironment for recruiting cells and cytokines to the defect sites. The hydrogel enabled the on-demand NBIF released in response to a weakly acidic microenvironment at the injured joint site to resolve inflammatory responses during the early stages of OA. Consequently, the cooperativity of the loaded NBIF and hydrogel synergistically modulated the immune response and assisted in cartilage defect repair. In summary, the NBIF@ZIF-8/PHG hydrogel delivery platform represents an effective treatment strategy for OA-related cartilage defects and may attract attentions for applications in other inflammatory diseases.

Efficient Osteogenic Activity of PEEK Surfaces Achieved by Femtosecond Laser-Hydroxylation.

Poly(etheretherketone) (PEEK) is regarded as an attractive orthopedic material because of its good biocompatibility and mechanical properties similar to natural bone. The efficient activation methods for the surfaces of PEEK matrix materials have become a hot research topic. In this study, a method using a femtosecond laser (FSL) followed by hydroxylation was developed to achieve efficient bioactivity. It produces microstructures, amorphous carbon, and grafted -OH groups on the PEEK surface to enhance hydrophilicity and surface energy. Both experimental and simulation results show that our modification leads to a superior ability to induce apatite deposition on the PEEK surface. The results also demonstrate that efficient grafting of C-OH through FSL-hydroxylation can effectively enhance cell proliferation and osteogenic differentiation compared to other modifications, thus improving osteogenic activity. Overall, FSL hydroxylation treatment is proved to be a simple, efficient, and environmentally friendly modification method for PEEK activation. It could expand the applications of PEEK in orthopedics, as well as promote the surface modification and structural design of other polymeric biomaterials to enhance bioactivity.

A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling.

Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.

Knowledge mapping and current trends of global research on CRISPR in the field of cancer.

Background: Gene editing tools using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-related systems have revolutionized our understanding of cancer. The purpose of this study was to determine the distribution, collaboration, and direction of cancer research using CRISPR. Methods: Data from the Web of Science (WoS) Core Collection database were collected from 4,408 cancer publications related to CRISPR from 1 January 2013to 31 December 2022. The obtained data were analyzed using VOSviewer software for citation, co-citation, co-authorship, and co-occurrence analysis. Results: The number of annual publications has grown steadily over the past decade worldwide. The United States was shown, by far, to be the leading source of cancer publications, citations, and collaborations involving CRISPR than any other country, followed by China. Li Wei (Jilin University, China), and Harvard Medical School (Boston, MA, United States) were the author and institution with the most publications and active collaborations, respectively. The journal with the most contributions was Nature Communications (n = 147) and the journal with the most citations was Nature (n = 12,111). The research direction of oncogenic molecules, mechanisms, and cancer-related gene editing was indicated based on keyword analysis. Conclusion: The current study has provided a comprehensive overview of cancer research highlights and future trends of CRISPR, combined with a review of CRISPR applications in cancer to summarize and predict research directions and provide guidance to researchers.

Preexisting Depression and Ambulatory Status After Stroke: Florida-Puerto Rico Collaboration to Reduce Stroke Disparities.

OBJECTIVE: Stroke is a global public health burden, and therefore it is critical to identify modifiable risk factors to reduce stroke incidence and improve outcomes. Depression is such a risk factor; however, the association between preexisting depression and stroke outcomes, such as independent ambulation, is not well studied, especially among racial-ethnic minority groups. To address this gap in the literature, effects of preexisting depression on ambulatory status at hospital discharge after stroke were evaluated among individuals participating in the racially and ethnically diverse Florida-Puerto Rico Collaboration to Reduce Stroke Disparities project. METHODS: Data were analyzed from a total of 42,031 ischemic stroke patients, who were independently ambulatory prior to their stroke, after discharge from 84 hospitals between 2014 and 2017. Preexisting depression was confirmed by medical history or antidepressant medication use. Multilevel multivariate logistic regression analyses were used to assess the association of preexisting depression with independent ambulation at hospital discharge. Effects of sex and race-ethnicity on this association were examined. RESULTS: Of 42,031 participants (mean±SD age=70.4±14.2 years; 48% were female; race-ethnicity: 16% Black, 12% Hispanic living in Florida, and 7% Hispanic living in Puerto Rico), 6,379 (15%) had preexisting depression. Compared with participants without depression, those with preexisting depression were older, were more likely to be female and non-Hispanic White, and had a greater burden of vascular risk factors or comorbid conditions. Independent ambulation at hospital discharge was less frequent among women, Black participants, and individuals with vascular risk factors or comorbid conditions. In multivariate models, preexisting depression decreased the likelihood of independent ambulation at discharge (odds ratio=0.88, 95% CI=0.81, 0.97). No interactions were found between preexisting depression and race-ethnicity or sex. CONCLUSIONS: Preexisting depression was independently associated with dependent ambulation at hospital discharge after stroke, regardless of sex and race-ethnicity. Treating depression may contribute to primary stroke prevention and could improve ambulatory status at discharge.