RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy.

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

Novel PLCZ1 mutation caused polyspermy during in vitro fertilization.

ABSTRACT: Failure of oocyte activation, including polyspermy and defects in pronuclear (PN) formation, triggers early embryonic developmental arrest. Many studies have shown that phospholipase C zeta 1 (PLCZ1) mutations cause failure of PN formation following intracytoplasmic sperm injection (ICSI); however, whether PLCZ1 mutation is associated with polyspermy during in vitro fertilization (IVF) remains unknown. Whole-exome sequencing (WES) was performed to identify candidate mutations in couples with primary infertility. Sanger sequencing was used to validate the mutations. Multiple PLCZ1-mutated sperm were injected into human and mouse oocytes to explore whether PN formation was induced. Assisted oocyte activation (AOA) after ICSI was performed to overcome the failure of oocyte activation. We identified three PLCZ1 mutations in three patients who experienced polyspermy during IVF cycles, including a novel missense mutation c.1154C>T, p.R385Q. PN formation failure was observed during the ICSI cycle. However, injection of multiple PLCZ1-mutated sperm induced PN formation, suggesting that the Ca2+ oscillations induced by the sperm exceeded the necessary threshold for PN formation. AOA after ICSI enabled normal fertilization, and all patients achieved successful pregnancies. These findings expand the mutational spectrum of PLCZ1 and suggest an important role for PLCZ1 in terms of blocking polyspermy. Furthermore, this study may benefit genetic diagnoses in cases of abnormal fertilization and provide potential appropriate therapeutic measures for these patients with sperm-derived polyspermy.

Design, synthesis and biological evaluation of bakuchiol derivatives as multi-target agents for the treatment of Alzheimer's disease.

The concept of multi-target-directed ligands offers fresh perspectives for the creation of brand-new Alzheimer's disease medications. To explore their potential as multi-targeted anti-Alzheimer's drugs, eighteen new bakuchiol derivatives were designed, synthesized, and evaluated. The structures of the new compounds were elucidated by IR, NMR, and HRMS. Eighteen compounds were assayed for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in vitro using Ellman's method. It was shown that most of the compounds inhibited AChE and BuChE to varying degrees, but the inhibitory effect on AChE was relatively strong, with fourteen compounds showing inhibition of >50% at the concentration of 200 µM. Among them, compound 3g (IC50 = 32.07 ± 2.00 µM) and compound 3n (IC50 = 34.78 ± 0.34 µM) showed potent AChE inhibitory activities. Molecular docking studies and molecular dynamics simulation showed that compound 3g interacts with key amino acids at the catalytically active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and binds stably to acetylcholinesterase. On the other hand, compounds 3n and 3q significantly reduced the pro-inflammatory cytokines TNF-α and IL-6 released from LPS-induced RAW 264.7 macrophages. Compound 3n possessed both anti-acetylcholinesterase activity and anti-inflammatory properties. Therefore, an in-depth study of compound 3n is expected to be a multi-targeted anti-AD drug.

Aberrant accumulation of ceramides in mitochondria triggers cell death by inducing autophagy in Arabidopsis.

Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.

Mortality among papillary thyroid cancer patients by detection route: a hospital-based retrospective cohort study.

Background: Incidence rates of papillary thyroid cancer (PTC) have increased rapidly, with incidentally detected cancers contributing a large proportion. We aimed to explore the impact of incidental detection on thyroid cancer-specific and competing mortality among PTC patients. Methods: We conducted a retrospective cohort study of PTC patients at a cancer center in Guangzhou. Baseline information on detection route and other covariates were collected between 2010 and 2018, and death outcome was followed up for each patient. Cumulative incidence functions were used to estimate the mortality risk of thyroid cancer and competing risk. Cause-specific hazard models were then utilized to explore the association between detection routes and PTC-specific and competing mortality. Results: Of the 2874 patients included, 2011 (70.0%) were detected incidentally, and the proportion increased from 36.9% in 2011 to 82.3% in 2018. During a median follow-up of 5.6 years, 42 deaths occurred, with 60% of them due to competing causes. The probability of competing mortality at 5 years in the non-incidental group and incidental group was 1.4% and 0.4%, respectively, and PTC-specific mortality in the non-incidental group and incidental group was 1.0% and 0.1%, respectively. After adjusting for covariates, the HRs of incidental detection were 0.13 (95% CI: 0.04-0.46; P = 0.01) and 0.47 (95% CI: 0.20-1.10; P = 0.10) on PTC-specific mortality and competing mortality, respectively. Conclusions: Incidental detection is associated with a lower risk of PTC-specific and competing mortality. Under the context of increasing magnitude of overdiagnosis, incorporation of detection route in clinical decision-making might be helpful to identify patients who might benefit from more extensive or conservative therapeutic strategies.

A moderately thermophilic origin of a novel family of marine group II euryarchaeota from deep ocean.

Marine group II (MGII) is the most abundant planktonic heterotrophic archaea in the ocean. The evolutionary history of MGII archaea is elusive. In this study, 13 new MGII metagenome-assembled genomes were recovered from surface to the hadal zone in Challenger Deep of the Mariana Trench; four of them from the deep ocean represent a novel group. The optimal growth temperature (OGT) of the common ancestor of MGII has been estimated to be at about 60°C and OGTs of MGIIc, MGIIb, and MGIIa at 47°C-50ºC, 37°C-44ºC, and 30°C-37ºC, respectively, suggesting the adaptation of these species to different temperatures during evolution. The estimated OGT range of MGIIc was supported by experimental measurements of cloned ß-galactosidase that showed optimal enzyme activity around 50°C. These results indicate that MGIIc may have originated from a common ancestor that lived in warm or even hot marine environment, such as hydrothermal vents.

The presence of benzene ring activating CoA ligases for aromatics degradation in the ANaerobic MEthanotrophic (ANME) archaea.

Petroleum-source and black carbon-source aromatic compounds are present in the cold seep environments, where ANaerobic MEthanotrophic (ANME) archaea as the dominant microbial community mediates the anaerobic oxidation of methane to produce inorganic and organic carbon. Here, by predicting the aromatics catabolic pathways in ANME metagenome-assembled genomes, we provide genomic and biochemical evidences that ANME have the potential of metabolizing aromatics via the strategy of CoA activation of the benzene ring using phenylacetic acid and benzoate as the substrates. Two ring-activating enzymes phenylacetate-CoA ligase (PaaKANME) and benzoate-CoA ligase (BadAANME) are able to convert phenylacetate to phenylacetyl-CoA and benzoate to benzoyl-CoA in vitro, respectively. They are mesophilic, alkali resistance, and with broad substrate spectra showing different affinity with various substrates. An exploration of the relative gene abundance in ANME genomes and cold seep environments indicates that about 50% of ANME genomes contain PCL genes, and various bacteria and archaea contain PCL and BCL genes. The results provide evidences for the capability of heterotrophic metabolism of aromatic compounds by ANME. This has not only enhanced our understanding of the nutrient range of ANME but also helped to explore the additional ecological and biogeochemical significance of this ubiquitous sedimentary archaea in the carbon flow in the cold seep environments. IMPORTANCE ANaerobic MEthanotrophic (ANME) archaea is the dominant microbial community mediating the anaerobic oxidation of methane in the cold seep environments, where aromatic compounds are present. Then it is hypothesized that ANME may be involved in the metabolism of aromatics. Here, we provide genomic and biochemical evidences for the heterotrophic metabolism of aromatic compounds by ANME, enhancing our understanding of their nutrient range and also shedding light on the ecological and biogeochemical significance of these ubiquitous sedimentary archaea in carbon flow within cold seep environments. Overall, this study offers valuable insights into the metabolic capabilities of ANME and their potential contributions to the global carbon cycle.

IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation.

BACKGROUND AND OBJECTIVES: Up to 50% of patients with myasthenia gravis (MG) without acetylcholine receptor antibodies (AChR-Abs) have antibodies to muscle-specific kinase (MuSK). Most MuSK antibodies (MuSK-Abs) are IgG4 and inhibit agrin-induced MuSK phosphorylation, leading to impaired clustering of AChRs at the developing or mature neuromuscular junction. However, IgG1-3 MuSK-Abs also exist in MuSK-MG patients, and their potential mechanisms have not been explored fully. METHODS: C2C12 myotubes were exposed to MuSK-MG plasma IgG1-3 or IgG4, with or without purified agrin. MuSK, Downstream of Kinase 7 (DOK7), and ßAChR were immunoprecipitated and their phosphorylation levels identified by immunoblotting. Agrin and agrin-independent AChR clusters were measured by immunofluorescence and AChR numbers by binding of 125I-α-bungarotoxin. Transcriptomic analysis was performed on treated myotubes. RESULTS: IgG1-3 MuSK-Abs impaired AChR clustering without inhibiting agrin-induced MuSK phosphorylation. Moreover, the well-established pathway initiated by MuSK through DOK7, resulting in ßAChR phosphorylation, was not impaired by MuSK-IgG1-3 and was agrin-independent. Nevertheless, the AChR clusters did not form, and both the number of AChR microclusters that precede full cluster formation and the myotube surface AChRs were reduced. Transcriptomic analysis did not throw light on the pathways involved. However, the SHP2 inhibitor, NSC-87877, increased the number of microclusters and led to fully formed AChR clusters. DISCUSSION: MuSK-IgG1-3 is pathogenic but seems to act through a noncanonical pathway. Further studies should throw light on the mechanisms involved at the neuromuscular junction.

Self-accelerated DNA walker mediated electrochemical biosensor for rapid and ultrasensitive detection of microRNA.

Herein, we developed a novel three-dimensional (3D) self-accelerated DNA walker (SADW) which progressively expedite walking rate by unlocking the more walking arm continuously in walker process to construct electrochemical biosensor for ultrasensitive detection of microRNA. Particularly, we skillfully introduced a target analogue sequence in the double-loop hairpin, which could be released in the walking process of SADW, then rapidly activating more silenced walking strands to achieve the continuous self-acceleration, resulting in the expedited reaction rate. Surprisingly, the average reaction rate of SADW was quite higher than that of traditional 3D self-circulating DNA walkers (DW) under pretty low target miRNA concentration, which is ascribed to the outstanding acceleration process of the SADW, readily conquering the major predicaments of DW in detecting target with traces concentration: slow reaction rate and low sensitivity. This way, the elaborated SADW is favorably applied in the ultrasensitive and rapid detection of miRNA-21 in tumor cancer cell lysates with a detection limit down to 5.81 aM which was far from lower than the detection limit of DW. This approach develops the novel generation of widespread strategy for the applications in clinic diagnose, biosensing assay, and DNA nanobiotechnology.

Relationship between multi-slice computed tomography features and pathological risk stratification assessment in gastric gastrointestinal stromal tumors.

BACKGROUND: Computed tomography (CT) imaging features are associated with risk stratification of gastric gastrointestinal stromal tumors (GISTs). AIM: To determine the multi-slice CT imaging features for predicting risk stratification in patients with primary gastric GISTs. METHODS: The clinicopathological and CT imaging data for 147 patients with histologically confirmed primary gastric GISTs were retrospectively analyzed. All patients had received dynamic contrast-enhanced CT (CECT) followed by surgical resection. According to the modified National Institutes of Health criteria, 147 lesions were classified into the low malignant potential group (very low and low risk; 101 lesions) and high malignant potential group (medium and high-risk; 46 lesions). The association between malignant potential and CT characteristic features (including tumor location, size, growth pattern, contour, ulceration, cystic degeneration or necrosis, calcification within the tumor, lymphadenopathy, enhancement patterns, unenhanced CT and CECT attenuation value, and enhancement degree) was analyzed using univariate analysis. Multivariate logistic regression analysis was performed to identify significant predictors of high malignant potential. The receiver operating curve (ROC) was used to evaluate the predictive value of tumor size and the multinomial logistic regression model for risk classification. RESULTS: There were 46 patients with high malignant potential and 101 with low-malignant potential gastric GISTs. Univariate analysis showed no significant differences in age, gender, tumor location, calcification, unenhanced CT and CECT attenuation values, and enhancement degree between the two groups (P > 0.05). However, a significant difference was observed in tumor size (3.14 ± 0.94 vs 6.63 ± 3.26 cm, P < 0.001) between the low-grade and high-grade groups. The univariate analysis further revealed that CT imaging features, including tumor contours, lesion growth patterns, ulceration, cystic degeneration or necrosis, lymphadenopathy, and contrast enhancement patterns, were associated with risk stratification (P < 0.05). According to binary logistic regression analysis, tumor size [P < 0.001; odds ratio (OR) = 26.448; 95% confidence interval (CI): 4.854-144.099)], contours (P = 0.028; OR = 7.750; 95%CI: 1.253-47.955), and mixed growth pattern (P = 0.046; OR = 4.740; 95%CI: 1.029-21.828) were independent predictors for risk stratification of gastric GISTs. ROC curve analysis for the multinomial logistic regression model and tumor size to differentiate high-malignant potential from low-malignant potential GISTs achieved a maximum area under the curve of 0.919 (95%CI: 0.863-0.975) and 0.940 (95%CI: 0.893-0.986), respectively. The tumor size cutoff value between the low and high malignant potential groups was 4.05 cm, and the sensitivity and specificity were 93.5% and 84.2%, respectively. CONCLUSION: CT features, including tumor size, growth patterns, and lesion contours, were predictors of malignant potential for primary gastric GISTs.

Patients with MMAF induced by novel biallelic CFAP43 mutations have good fertility outcomes after intracytoplasmic sperm injection.

As a specific type of asthenoteratozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF) is characterized by composite abnormalities, including absent, short, coiled, angulation, and irregular-caliber flagella. Mutations in cilia- and flagella-associated protein 43 ( CFAP43 ) are one of the main causative factors of MMAF established to date. To identify whether there are other CFAP43 mutations related to MMAF and to determine the clinical outcomes of assisted reproductive technology for patients with MMAF harboring different mutations, we recruited and screened 30 MMAF-affected Chinese men using a 22-gene next-generation sequencing panel. After systematic analysis, seven mutations in CFAP43 , including five novel mutations and two previously reported mutations, were identified from four families and related to MMAF in an autosomal recessive pattern. Papanicolaou staining, immunofluorescence, and electronic microscopy further clarified the semen characteristics and abnormal sperm morphologies, including disorganized axonemal and peri-axonemal structures, of the CFAP43 -deficient men. The female partners of two patients were pregnant after undergoing assisted reproductive technology through intracytoplasmic sperm injection, and one of them successfully gave birth to a healthy boy. This study significantly expands the mutant spectrum of CFAP43 , and together with the available information regarding male infertility and MMAF, provides new information for the genetic diagnosis and counseling of MMAF in the future.

High-Efficiency 3D DNA Walker Immobilized by a DNA Tetrahedral Nanostructure for Fast and Ultrasensitive Electrochemical Detection of MiRNA.

Herein, by directly limiting the reaction space, an ingenious three-dimensional (3D) DNA walker (IDW) with high walking efficiency is developed for rapid and sensitive detection of miRNA. Compared with the traditional DNA walker, the IDW immobilized by the DNA tetrahedral nanostructure (DTN) brings stronger kinetic and thermodynamic favorability resulting from its improved local concentration and space confinement effect, accompanied by a quite faster reaction speed and much better walking efficiency. Once traces of target miRNA-21 react with the prelocked IDW, the IDW could be largely activated and walk on the interface of the electrode to trigger the cleavage of H2 with the assistance of Mg2+, resulting in the release of amounts of methylene blue (MB) labeled on H2 from the electrode surface and the obvious decrease of the electrode signal. Impressively, the IDW reveals a conversion efficiency as high as 9.33 × 108 in 30 min with a much fast reaction speed, which is at least five times beyond that of typical DNA walkers. Therefore, the IDW could address the inherent challenges of the traditional DNA walker easily: slow walking speed and low efficiency. Notably, the IDW as a DNA nanomachine was utilized to construct a sensitive sensing platform for rapid miRNA-21 detection with a limit of detection (LOD) of 19.8 aM and realize the highly sensitive assay of biomarker miRNA-21 in the total RNA lysates of cancer cell. The strategy thus helps in the design of a versatile nucleic acid conversion and signal amplification approach for practical applications in the areas of biosensing assay, DNA nanotechnology, and clinical diagnosis.

Emerging roles of m6A RNA modification in cancer therapeutic resistance.

Marvelous advancements have been made in cancer therapies to improve clinical outcomes over the years. However, therapeutic resistance has always been a major difficulty in cancer therapy, with extremely complicated mechanisms remain elusive. N6-methyladenosine (m6A) RNA modification, a hotspot in epigenetics, has gained growing attention as a potential determinant of therapeutic resistance. As the most prevalent RNA modification, m6A is involved in every links of RNA metabolism, including RNA splicing, nuclear export, translation and stability. Three kinds of regulators, "writer" (methyltransferase), "eraser" (demethylase) and "reader" (m6A binding proteins), together orchestrate the dynamic and reversible process of m6A modification. Herein, we primarily reviewed the regulatory mechanisms of m6A in therapeutic resistance, including chemotherapy, targeted therapy, radiotherapy and immunotherapy. Then we discussed the clinical potential of m6A modification to overcome resistance and optimize cancer therapy. Additionally, we proposed existing problems in current research and prospects for future research.

Kill two birds with one stone: Ratiometric sensing of phosphate via a single-component probe with fluorescence-scattering dual-signal response behavior.

Ratiometric fluorescence sensors gain stronger anti-interference ability via self-calibration. Nevertheless, ratiometric analysis of phosphate (Pi) still faces problems such as complicated construction process of dual emission probes and possible interferences from outputting mono-category fluorescent signal. Herein, we propose a "kill two birds with one stone" strategy to address these challenges, by simply introducing a single-component probe, porphyrin paddlewheel framework-3 (PPF-3) nanosheets without modification, encapsulation or complex, to integrate fluorescence (FL)-second-order scattering (SOS) dual-signal for ratiometric detection of Pi. PPF-3 nanosheets are constructed by coordination of Co2+ with 5,10,15,20-tetrakis(4-carboxyl-phenyl)-porphyrin (TCPP) ligands, displaying weak FL and strong SOS, two different and independent signals. In the response system to Pi, Co2+ and TCPP serve as the recognition element and signal unit, respectively. After interacting with Pi, the high affinity for Co2+ makes Pi snatch Co2+ from the PPF-3 nanosheets, causing their structure disassembly (SOS decrease) and TCPP release (FL increase). Finally, the FL-SOS ratiometric platform is successfully employed to access Pi in real water samples. Synchronous collection of FL and SOS from the single-component probe provides a simpler and more efficient way on ratiometric sensor design as well as a new useful technique for monitoring target-induced aggregation and disaggregation behavior.

A novel phenotype of AChR-deficiency syndrome with predominant facial and distal weakness resulting from the inclusion of an evolutionary alternatively-spliced exon in CHRNA1.

Primary acetylcholine receptor deficiency is the most common subtype of congenital myasthenic syndrome, resulting in reduced amount of acetylcholine receptors expressed at the muscle endplate and impaired neuromuscular transmission. AChR deficiency is caused mainly by pathogenic variants in the ε-subunit of the acetylcholine receptor encoded by CHRNE, although pathogenic variants in other subunits are also seen. We report the clinical and molecular features of 13 patients from nine unrelated kinships with acetylcholine receptor deficiency harbouring the CHRNA1 variant NM_001039523.3:c.257G>A (p.Arg86His) in homozygosity or compound heterozygosity. This variant results in the inclusion of an alternatively-spliced evolutionary exon (P3A) that causes expression of a non-functional acetylcholine receptor α-subunit. We compare the clinical findings of this group to the other cases of acetylcholine receptor deficiency within our cohort. We report differences in phenotype, highlighting a predominant pattern of facial and distal weakness in adulthood, predominantly in the upper limbs, which is unusual for acetylcholine receptor deficiency syndromes, and more in keeping with slow-channel syndrome or distal myopathy. Finally, we stress the importance of including alternative exons in variant analysis to increase the probability of achieving a molecular diagnosis.

Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML.

BACKGROUND: Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE: To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN: From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS: At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION: Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

Programmable mismatch-fueled high-efficiency DNA signal amplifier.

Herein, by introducing mismatches, a high-efficiency mismatch-fueled catalytic multiple-arm DNA junction assembly (M-CMDJA) with high-reactivity and a high-threshold is developed as a programmable DNA signal amplifier for rapid detection and ultrasensitive intracellular imaging of miRNA. Compared with traditional nucleic acid signal amplification (NASA) with a perfect complement, the M-CMDJA possesses larger kinetic and thermodynamic favorability owing to the more negative reaction standard free energy (ΔG) as driving force, resulting in much higher efficiency and rates. Once traces of the input initiator react with the mismatched substrate DNA, it could be converted into amounts of output multiple-arm DNA junctions via the M-CMDJA as the functional DNA conversion nanodevice. Impressively, the mismatch-fueled catalytic four-arm DNA junction assembly (M-CFDJA) exhibits high conversion efficiency up to 1.05 × 108 in 30 min, which is almost ten times more than those of conventional methods. Therefore, the M-CMDJA could easily address the challenges of traditional methods: slow rates and low efficiency. In application, the M-CFDJA as a DNA signal amplifier was successfully used to develop a biosensing platform for rapid miRNA detection with a LOD of 6.11 aM and the ultrasensitive intracellular imaging of miRNA, providing a basis for the next-generation of versatile DNA signal amplification methods for ultimate applications in DNA nanobiotechnology, biosensing assay, and clinical diagnoses.

Is there a gap between artificial intelligence applications and priorities in health care and nursing management?

AIM: The article aims to outline a contrast between three priorities for nursing management proposed a decade ago and key features of the following 10 years of developments on artificial intelligence for health care and nursing management. This analysis intends to contribute to update the international debate on bridging the essence of health care and nursing management priorities and the focus of artificial intelligence developers. BACKGROUND: Artificial intelligence research promises innovative approaches to supporting nurses' clinical decision-making and to conduct tasks not related to patient interaction, including administrative activities and patient records. Yet, even though there has been an increase in international research and development of artificial intelligence applications for nursing care during the past 10 years, it is unclear to what extent the priorities of nursing management have been embedded in the devised artificial intelligence solutions. EVALUATION: Starting from three priorities for nursing management identified in 2011 in a special issue of the Journal Nursing Management, we went on to identify recent evidence concerning 10 years of artificial intelligence applications developed to support health care management and nursing activities since then. KEY ISSUE: The article discusses to what extent priorities in health care and nursing management may have to be revised while adopting artificial intelligence applications or, alternatively, to what extent the direction of artificial intelligence developments may need to be revised to contribute to long acknowledged priorities of nursing management. CONCLUSION: We have identified a conceptual gap between both sets of ideas and provide a discussion on the need to bridge that gap, while admitting that there may have been recent field developments still unreported in scientific literature. IMPLICATIONS FOR NURSING MANAGEMENT: Artificial intelligence developers and health care nursing managers need to be more engaged in coordinating the future development of artificial intelligence applications with a renewed set of nursing management priorities.