An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies.

Antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein prevent SARS-CoV-2 infection. However, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from coronavirus disease 2019 (COVID-19) patients and found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2. Mutational analysis revealed that all of the infectivity-enhancing antibodies recognized a specific site on the NTD. Structural analysis demonstrated that all infectivity-enhancing antibodies bound to NTD in a similar manner. The antibodies against this infectivity-enhancing site were detected at high levels in severe patients. Moreover, we identified antibodies against the infectivity-enhancing site in uninfected donors, albeit at a lower frequency. These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Spatial proximity and gene function: a new dimension in prokaryotic gene association network analysis with 3D-GeneNet.

Understanding the biological functions and processes of genes, particularly those not yet characterized, is crucial for advancing molecular biology and identifying therapeutic targets. The hypothesis guiding this study is that the 3D proximity of genes correlates with their functional interactions and relevance in prokaryotes. We introduced 3D-GeneNet, an innovative software tool that utilizes high-throughput sequencing data from chromosome conformation capture techniques and integrates topological metrics to construct gene association networks. Through a series of comparative analyses focused on spatial versus linear distances, we explored various dimensions such as topological structure, functional enrichment levels, distribution patterns of linear distances among gene pairs, and the area under the receiver operating characteristic curve by utilizing model organism Escherichia coli K-12. Furthermore, 3D-GeneNet was shown to maintain good accuracy compared to multiple algorithms (neighbourhood, co-occurrence, coexpression, and fusion) across multiple bacteria, including E. coli, Brucella abortus, and Vibrio cholerae. In addition, the accuracy of 3D-GeneNet's prediction of long-distance gene interactions was identified by bacterial two-hybrid assays on E. coli K-12 MG1655, where 3D-GeneNet not only increased the accuracy of linear genomic distance tripled but also achieved 60% accuracy by running alone. Finally, it can be concluded that the applicability of 3D-GeneNet will extend to various bacterial forms, including Gram-negative, Gram-positive, single-, and multi-chromosomal bacteria through Hi-C sequencing and analysis. Such findings highlight the broad applicability and significant promise of this method in the realm of gene association network. 3D-GeneNet is freely accessible at https://github.com/gaoyuanccc/3D-GeneNet.

Loss of perinuclear theca ACTRT1 causes acrosome detachment and severe male subfertility in mice.

The perinuclear theca (PT) is a cytoskeletal element encapsulating the sperm nucleus; however, the physiological roles of the PT in sperm are largely uncertain. Here, we reveal that ACTRT1, ACTRT2, ACTL7A and ACTL9 proteins interact to form a multimeric complex and localize to the subacrosomal region of spermatids. Furthermore, we engineered Actrt1-knockout (KO) mice to define the functions of ACTRT1. Despite normal sperm count and motility, Actrt1-KO males were severely subfertile owing to a deficiency in fertilization. Loss of ACTRT1 caused a high incidence of malformed heads and detachment of acrosomes from sperm nuclei, caused by loosened acroplaxome structure during spermiogenesis. Furthermore, Actrt1-KO sperm showed reduced ACTL7A and PLCζ protein content as a potential cause of fertilization defects. Moreover, we reveal that ACTRT1 anchors developing acrosomes to the nucleus, likely by interacting with the inner acrosomal membrane protein SPACA1 and the nuclear envelope proteins PARP11 and SPATA46. Loss of ACTRT1 weakened the interaction between ACTL7A and SPACA1. Our study and recent findings of ACTL7A/ACTL9-deficient sperm together reveal that the sperm PT-specific ARP complex mediates the acrosome-nucleus connection.

MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor.

Regulatory T (Treg) cells are important in maintaining self-tolerance and immune homeostasis. The Treg cell transcription factor Foxp3 works in concert with other co-regulatory molecules, including Eos, to determine the transcriptional signature and characteristic suppressive phenotype of Treg cells. Here, we report that the inflammatory cytokine interleukin-6 (IL-6) actively repressed Eos expression through microRNA-17 (miR-17). miR-17 expression increased in Treg cells in the presence of IL-6, and its expression negatively correlated with that of Eos. Treg cell suppressive activity was diminished upon overexpression of miR-17 in vitro and in vivo, which was mitigated upon co-expression of an Eos mutant lacking miR-17 target sites. Also, RNAi of miR-17 resulted in enhanced suppressive activity. Ectopic expression of miR-17 imparted effector-T-cell-like characteristics to Treg cells via the de-repression of genes encoding effector cytokines. Thus, miR-17 provides a potent layer of Treg cell control through targeting Eos and additional Foxp3 co-regulators.

Tektin bundle interacting protein, TEKTIP1, functions to stabilize the tektin bundle and axoneme in mouse sperm flagella.

Tektins are microtubule inner proteins (MIPs) and localize at the inside lumen of doublet microtubules (DMTs) of cilia/flagella. TEKTIP1, a newly identified protein by cryo-electron microscopy (cryo-EM), is proposed to be localized at the center of the tektin bundle and hypothesized to recruit tektins or stabilize the bundle. However, the physiological role of TEKTIP1 is unknown. In this study, we generated Tektip1-knockout (Tektip1-/-) mice and showed that they were male subfertile primarily due to reduced sperm motility. A high percentage of sperm from Tektip1-/- mice showed moderately disorganized axoneme structures and abnormal flagellar waveforms. TEKTIP1 predominately interacted with TEKT3 among tektins. Loss of TEKTIP1 partially disturbed the organization of tektin bundle by mainly affecting the native status of TEKT3 and its interaction with other tektins. Collectively, our study reveals the physiological role and potential molecular mechanism of TEKTIP1 in axonemal structure and sperm motility, highlights the importance of MIPs in stabilizing DMTs, and suggests a potential relevance of TEKTIP1 deficiency to human asthenospermia. Tektip1-/- mice will be an excellent animal model to study the DMT organization of sperm flagella using cryo-EM in future.

PIN3 positively regulates the late initiation of ovule primordia in Arabidopsis thaliana.

Ovule initiation determines the maximum ovule number and has great impact on seed number and yield. However, the regulation of ovule initiation remains largely elusive. We previously reported that most of the ovule primordia initiate asynchronously at floral stage 9 and PINFORMED1 (PIN1) polarization and auxin distribution contributed to this process. Here, we further demonstrate that a small amount of ovule primordia initiate at floral stage 10 when the existing ovules initiated at floral stage 9 start to differentiate. Genetic analysis revealed that the absence of PIN3 function leads to the reduction in pistil size and the lack of late-initiated ovules, suggesting PIN3 promotes the late ovule initiation process and pistil growth. Physiological analysis illustrated that, unlike picloram, exogenous application of NAA can't restore these defective phenotypes, implying that PIN3-mediated polar auxin transport is required for the late ovule initiation and pistil length. qRT-PCR results indicated that the expression of SEEDSTICK (STK) is up-regulated under auxin analogues treatment while is down-regulated in pin3 mutants. Meanwhile, overexpressing STK rescues pin3 phenotypes, suggesting STK participates in PIN3-mediated late ovule initiation possibly by promoting pistil growth. Furthermore, brassinosteroid influences the late ovule initiation through positively regulating PIN3 expression. Collectively, this study demonstrates that PIN3 promotes the late ovule initiation and contributes to the extra ovule number. Our results give important clues for increasing seed number and yield of cruciferous and leguminous crops.

Garnet secondary ion mass spectrometry oxygen isotopes reveal crucial roles of pulsed magmatic fluid and its mixing with meteoric water in lode gold genesis.

SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.

Fast Nano-IR Hyperspectral Imaging Empowered by Large-Dataset-Free Miniaturized Spatial-Spectral Network.

The emerging field of nanoscale infrared (nano-IR) offers label-free molecular contrast, yet its imaging speed is limited by point-by-point traverse acquisition of a three-dimensional (3D) data cube. Here, we develop a spatial-spectral network (SS-Net), a miniaturized deep-learning model, together with compressive sampling to accelerate the nano-IR imaging. The compressive sampling is performed in both the spatial and spectral domains to accelerate the imaging process. The SS-Net is trained to learn the mapping from small nano-IR image patches to the corresponding spectra. With this elaborated mapping strategy, the training can be finished quickly within several minutes using the subsampled data, eliminating the need for a large-labeled dataset of common deep learning methods. We also designed an efficient loss function, which incorporates the image and spectral similarity to enhance the training. We first validate the SS-Net on an open stimulated Raman-scattering dataset; the results exhibit the potential of 10-fold imaging speed improvement with state-of-the-art performance. We then demonstrate the versatility of this approach on atomic force microscopy infrared (AFM-IR) microscopy with 7-fold imaging speed improvement, even on nanoscale Fourier transform infrared (nano-FTIR) microscopy with up to 261.6 folds faster imaging speed. We further showcase the generalization of this method on AFM-force volume-based multiparametric nanoimaging. This method establishes a paradigm for rapid nano-IR imaging, opening new possibilities for cutting-edge research in materials, photonics, and beyond.

Bilateral Production Shield Enabling Highly Efficient Perovskite Photovoltaics.

Enhancing the intrinsic stability of perovskite and through encapsulation to isolate water, oxygen, and UV-induced decomposition are currently common and most effective strategies in perovskite solar cells. Here, the atomic layer deposition process is employed to deposit a nanoscale (≈100 nm), uniform, and dense Al2O3 film on the front side of perovskite devices, effectively isolating them from the erosion caused by water and oxygen in the humid air. Simultaneously, nanoscale (≈100 nm) TiO2 films are also deposited on the glass surface to efficiently filter out the ultraviolet (UV) light in the light source, which induces degradation in perovskite. Ultimately, throughthe collaborative effects of both aspects, the stability of the devices is significantly improved under conditions of humid air and illumination. As a result, after storing the devices in ambient air for 1000 h, the efficiency only declines to 95%, and even after 662 h of UV exposure, the efficiency remains at 88%, far surpassing the performance of comparison devices. These results strongly indicate that the adopted Al2O3 and TiO2 thin films play a significant role in enhancing the stability of perovskite solar cells, demonstrating substantial potential for widespread industrial applications.

Quality Evaluation of Guidelines for the Diagnosis and Treatment of Liver Failure.

OBJECTIVES: This study aimed to systematically assess the methodological quality and key recommendations of the guidelines for the diagnosis and treatment of liver failure (LF), furnishing constructive insights for guideline developers and equipping clinicians with evidence-based information to facilitate informed decision-making. DATA SOURCES: Electronic databases and manual searches from January 2011 to August 2023. STUDY SELECTION: Two reviewers independently screened titles and abstracts, then full texts for eligibility. Fourteen guidelines were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data and checked by two others. Methodological quality of the guidelines was appraised using the Appraisal of Guidelines for Research and Evaluation II tool. Of the 14 guidelines, only the guidelines established by the Society of Critical Care Medicine and the American College of Gastroenterology (2023) achieved an aggregate quality score exceeding 60%, thereby meriting clinical recommendations. It emerged that there remains ample room for enhancement in the quality of the guidelines, particularly within the domains of stakeholder engagement, rigor, and applicability. Furthermore, an in-depth scrutiny of common recommendations and supporting evidence drawn from the 10 adult LF guidelines unveiled several key issues: controversy exists in the recommendation, the absence of supporting evidence and confusing use of evidence for recommendations, and a preference in evidence selection. CONCLUSIONS: There are high differences in methodological quality and recommendations among LF guidelines. Improving these existing problems and controversies will benefit existing clinical practice and will be an effective way for developers to upgrade the guidelines.

Dissection of the Pearl of Csaba pedigree identifies key genomic segments related to early ripening in grape.

Pearl of Csaba (PC) is a valuable backbone parent for early-ripening grapevine (Vitis vinifera) breeding, from which many excellent early ripening varieties have been bred. However, the genetic basis of the stable inheritance of its early ripening trait remains largely unknown. Here, the pedigree, consisting of 40 varieties derived from PC, was re-sequenced for an average depth of ∼30×. Combined with the resequencing data of 24 other late-ripening varieties, 5,795,881 high-quality single nucleotide polymorphisms (SNPs) were identified following a strict filtering pipeline. The population genetic analysis showed that these varieties could be distinguished clearly, and the pedigree was characterized by lower nucleotide diversity and stronger linkage disequilibrium than the non-pedigree varieties. The conserved haplotypes (CHs) transmitted in the pedigree were obtained via identity-by-descent analysis. Subsequently, the key genomic segments were identified based on the combination analysis of haplotypes, selective signatures, known ripening-related quantitative trait loci (QTLs), and transcriptomic data. The results demonstrated that varieties with a superior haplotype, H1, significantly (one-way ANOVA, P < 0.001) exhibited early grapevine berry development. Further analyses indicated that H1 encompassed VIT_16s0039g00720 encoding a folate/biopterin transporter protein (VvFBT) with a missense mutation. VvFBT was specifically and highly expressed during grapevine berry development, particularly at veraison. Exogenous folate treatment advanced the veraison of "Kyoho". This work uncovered core haplotypes and genomic segments related to the early ripening trait of PC and provided an important reference for the molecular breeding of early-ripening grapevine varieties.

Tailoring whispering-gallery fields in optical black hole cavities.

The ability to confine light has great significance in both fundamental science and practical applications. Optical black hole (OBH) cavities show intriguing zero radiation loss and strong field confinement. In this work, we systematically explore the whispering gallery mode (WGM) in a group of generalized OBH cavities, featuring bound states and strong field confinement. The field confinement in generalized OBH cavities is revealed to be enhanced with the increase of index-modulation factors, resulting from the increase of a potential barrier. Furthermore, we reveal the anomalous external resonant modes, exhibiting fascinating field enhancement in the low-index region far beyond the cavity boundary. These anomalous WGMs are attributed to the potential bending effect and above-barrier resonance. Our work may shed light on tailoring WGM fields in gradient-index cavities and find potential applications in light coupling and optical sensing.

Diabetes and aortic dissection: unraveling the role of 3-hydroxybutyrate through mendelian randomization.

BACKGROUND: In observational and experimental studies, diabetes has been reported as a protective factor for aortic dissection. 3-Hydroxybutyrate, a key constituent of ketone bodies, has been found to favor improvements in cardiovascular disease. However, whether the protective effect of diabetes on aortic dissection is mediated by 3-hydroxybutyrate is unclear. We aimed to investigate the causal effects of diabetes on the risk of aortic dissection and the mediating role of 3-hydroxybutyrate in them through two-step Mendelian randomization. MATERIALS AND METHODS: We performed a two-step Mendelian randomization to investigate the causal connections between diabetes, 3-hydroxybutyrate, and aortic dissection and calculate the mediating effect of 3-hydroxybutyrate. Publicly accessible data for Type 1 diabetes, Type 2 diabetes, dissection of aorta and 3-hydroxybutyrate were obtained from genome-wide association studies. The association between Type 1 diabetes and dissection of aorta, the association between Type 2 diabetes and dissection of aorta, and mediation effect of 3-hydroxybutyrate were carried out separately. RESULTS: The IVW method showed that Type 1 diabetes was negatively associated with the risk of aortic dissection (OR 0.912, 95% CI 0.836-0.995), The weighted median, simple mode and weighted mode method showed consistent results. The mediated proportion of 3-hydroxybutyrate on the relationship between Type 1 diabetes and dissection of aorta was 24.80% (95% CI 5.12-44.47%). The IVW method showed that Type 2 diabetes was negatively associated with the risk of aortic dissection (OR 0.763, 95% CI 0.607-0.960), The weighted median, simple mode and weighted mode method showed consistent results. 3-Hydroxybutyrate does not have causal mediation effect on the relationship between Type 2 diabetes and dissection of aorta. CONCLUSION: Mendelian randomization study revealed diabetes as a protective factor for dissection of aorta. The protective effect of type 1 diabetes on aortic dissection was partially mediated by 3-hydroxybutyrate, but type 2 diabetes was not 3-hydroxybutyrate mediated.

Isolation and characterization of a novel Bacillus cereus bacteriophage vBce-DP7.

Foodborne pathogens have become a major concern for public health. Bacillus cereus, a representative foodborne pathogen, is particularly challenging due to its ability to cause food poisoning and its resilient spores that are difficult to completely eradicate. Therefore, it is crucial to develop measures to prevent and control B. cereus. Bacteriophages, which are high specific towards their host strains and cannot infect eukaryotes, have proven to be effective in combating foodborne pathogens and are safe for human use. In this study, we isolated and characterized a novel bacteriophage named vBce-DP7 that specifically targets B. cereus strains belonging to three different sequence types (STs). Phage vBce-DP7 is a lytic one and has a short latent time of only 15 minutes. Moreover, it exhibited a good temperature tolerance, retaining high activity across a broad range of 4 - 55 °C. Additionally, its activity remains unaffected within a wide pH range spanning from 2 - 10. Interestingly, with only 4% genetic similarity with known bacteriophages, vBce-BP7 shows a possible classification on a family level though it shares many similar functional proteins with Salasmaviridae bacteriophages. Taken together, vBce-BP7 demonstrates its significant potential for further exploration in terms of phage diversity and its application in controlling B. cereus.

Contributions of the N-terminal flanking residues of an antigenic peptide from the Japanese cedar pollen allergen Cry j 1 to the T-cell activation by HLA-DP5.

Cry j 1 is a major allergen present in Japanese cedar (Cryptomeria japonica) pollens. Peptides with the core sequence of KVTVAFNQF from Cry j 1 ('pCj1') bind to HLA-DP5 and activate Th2 cells. In this study, we noticed that Ser and Lys at positions -2 and -3, respectively, in the N-terminal flanking (NF) region to pCj1 are conserved well in HLA-DP5-binding allergen peptides. A competitive binding assay showed that the double mutation of Ser(-2) and Lys(-3) to Glu [S(P-2)E/K(P-3)E] in a 13-residue Cry j 1 peptide (NF-pCj1) decreased its affinity for HLA-DP5 by about 2-fold. Similarly, this double mutation reduced, by about 2-fold, the amount of NF-pCj1 presented on the surface of mouse antigen-presenting dendritic cell line 1 (mDC1) cells stably expressing HLA-DP5. We established NF-pCj1-specific and HLA-DP5-restricted CD4+ T-cell clones from HLA-DP5 positive cedar pollinosis (CP) patients, and analyzed their IL-2 production due to the activation of mouse TG40 cells expressing the cloned T-cell receptor by the NF-pCj1-presenting mDC1 cells. The T-cell activation was actually decreased by the S(P-2)E/K(P-3)E mutation, corresponding to the reduction in the peptide presentation by this mutation. In contrast, the affinity of NF-pCj1·HLA-DP5 for the T-cell receptor was not affected by the S(P-2)E/K(P-3)E mutation, as analyzed by surface plasmon resonance. Considering the positional and side-chain differences of these NF residues from previously reported T-cell activating sequences, the mechanisms of enhanced T-cell activation by Ser(-2) and Lys(-3) of NF-pCj1 may be novel.

Azo-Cyanamide Bridged Dinuclear Iron Complexes Exhibiting no Electronic Coupling but Moderate Magnetic Coupling between the two Iron Centers.

To investigate the effect of long-distance organic ligand on electronic coupling between metallic atoms, the mononuclear and dinuclear complexes [Cp(dppe)Fe(apc)] (1), [{Cp(dppe)Fe}2(µ-adpc)] (2), [{CpMe5(dppe)Fe}2(µ-adpc) (3) and their oxidized complexes [Cp(dppe)Fe(apc)][PF6] (1[PF6]), [{Cp(dppe)Fe}2(µ-adpc)][PF6] (2[PF6]2), [{CpMe5(dppe)Fe}2(µ-adpc)][PF6]2 (3[PF6]2) (Cp=1,3-cyclopentadiene, CpMe5=1,2,3,4,5-pentamethylcyclopentadiene, dppe=1,2-bis(diphenylphosphino)ethane), apc-=4-azo(phenylcyanamido)benzene and adpc2-=4,4'-azodi(phenylcyanamido)) were synthesized and characterized by cyclic voltammetry, UV-vis, single-crystal X-ray diffraction and Mössbauer spectra. Electrochemical measurements showed no electronic coupling between the two terminal Fe units, However, the investigation results of the magnetic properties of the two-electron oxidized complexes indicate the presence of moderate antiferromagnetic coupling across 18 Šdistance.

Prevalence and risk factors of fatigue and its association with quality of life among patients with chronic pancreatitis: A cross-sectional study.

BACKGROUND: Fatigue is a debilitating symptom found in various chronic diseases and is associated with more severe symptoms and worse quality of life (QoL). However, this symptom has not been adequately addressed in chronic pancreatitis (CP), and there have been no studies on fatigue in patients with CP. METHODS: This cross-sectional study was conducted at the Changhai Hospital in Shanghai, China. Data on the patients' sociodemographic, disease, and therapeutic characteristics were collected. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. QoL was assessed utilizing the European Organization for the Research and Treatment of Cancer of QoL questionnaire (EORTC-QLQ-C30). Sleep quality, anxiety and depression, and pain was assessed using Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the Brief Pain Inventory, respectively. RESULTS: The prevalence of fatigue among Chinese patients with CP was 35.51 % (87/245). Multivariate analysis showed that steatorrhea (OR = 2.638, 95 % CI: 1.117-6.234), history of smoking (OR = 4.627, 95 % CI: 1.202-17.802), history of endoscopic treatment (OR = 0.419, 95 % CI: 0.185-0.950), depression (OR = 5.924, 95 % CI: 2.462-14.255), and sleep disorder (OR = 6.184, 95 % CI: 2.543-15.034) were influencing factors for the presence of fatigue. The scores for global health and all functional dimensions in the EORTC-QLQ-C30 significantly decreased, whereas the scores for all symptom dimensions significantly increased in patients with fatigue. CONCLUSIONS: This study indicated that Fatigue is a common symptom and has a negative impact on the QoL of patients with CP. Steatorrhea, smoking history, endoscopic treatment, depression, and sleep disorders were associated with fatigue.

Clinical prognostic value of different NPM1 mutations in acute myeloid leukemia patients.

BACKGROUND: Acute myeloid leukemia (AML) patients with various nucleophosmin 1 (NPM1) mutations are controversial in the prognosis. This study aimed to investigate the prognosis of patients according to types of NPM1 mutations (NPM1mut). METHODS: Bone marrow samples of 528 patients newly diagnosed with AML, were collected for morphology, immunology, cytogenetics, and molecular biology examinations. Gene mutations were detected by next-generation sequencing (NGS) technology. RESULTS: About 25.2% of cases exhibited NPM1mut. 83.5% of cases were type A, while type B and D were respectively account for 2.3% and 3.0%. Furthermore, 15 cases of rare types were identified, of which 2 cases have not been reported. Clinical characteristics were similar between patients with A-type NPM1 mutations (NPM1A - type mut) and non-A-type NPM1 mutations (NPM1non - A-type mut). Event-free survival (EFS) was significantly different between patients with low NPM1non - A-type mut variant allele frequency (VAF) and low NPM1A - type mut VAF (median EFS = 3.9 vs. 8.5 months, P = 0.020). The median overall survival (OS) of the NPM1non - A-type mutFLT3-ITDmut group, the NPM1A - type mutFLT3-ITDmut group, the NPM1non - A-type mutFLT3-ITDwt group, and the NPM1A - type mutFLT3-ITDwt group were 3.9, 10.7, 17.3 and 18.8 months, while the median EFS of the corresponding groups was 1.4, 5.0, 7.6 and 9.2 months (P < 0.0001 and P = 0.004, respectively). CONCLUSIONS: No significant difference was observed in OS and EFS between patients with NPM1A - type mut and NPM1non - A-type mut. However, types of NPM1 mutations and the status of FLT3-ITD mutations may jointly have an impact on the prognosis of AML patients.

Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.

Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.