Arabidopsis α-Aurora kinase plays a role in cytokinesis through regulating MAP65-3 association with microtubules at phragmoplast midzone.

The α-Aurora kinase is a crucial regulator of spindle microtubule organization during mitosis in plants. Here, we report a post-mitotic role for α-Aurora in reorganizing the phragmoplast microtubule array. In Arabidopsis thaliana, α-Aurora relocated from spindle poles to the phragmoplast midzone, where it interacted with the microtubule cross-linker MAP65-3. In a hypomorphic α-Aurora mutant, MAP65-3 was detected on spindle microtubules, followed by a diffuse association pattern across the phragmoplast midzone. Simultaneously, phragmoplast microtubules remained belatedly in a solid disk array before transitioning to a ring shape. Microtubules at the leading edge of the matured phragmoplast were often disengaged, accompanied by conspicuous retentions of MAP65-3 at the phragmoplast interior edge. Specifically, α-Aurora phosphorylated two residues towards the C-terminus of MAP65-3. Mutation of these residues to alanines resulted in an increased association of MAP65-3 with microtubules within the phragmoplast. Consequently, the expansion of the phragmoplast was notably slower compared to wild-type cells or cells expressing a phospho-mimetic variant of MAP65-3. Moreover, mimicking phosphorylation reinstated disrupted MAP65-3 behaviors in plants with compromised α-Aurora function. Overall, our findings reveal a mechanism in which α-Aurora facilitates cytokinesis progression through phosphorylation-dependent restriction of MAP65-3 associating with microtubules at the phragmoplast midzone.

The Arabidopsis BUB1/MAD3 family protein BMF3 requires BUB3.3 to recruit CDC20 to kinetochores in spindle assembly checkpoint signaling.

The spindle assembly checkpoint (SAC) ensures faithful chromosome segregation during cell division by monitoring kinetochore-microtubule attachment. Plants produce both sequence-conserved and diverged SAC components, and it has been largely unknown how SAC activation leads to the assembly of these proteins at unattached kinetochores to prevent cells from entering anaphase. In Arabidopsis thaliana, the noncanonical BUB3.3 protein was detected at kinetochores throughout mitosis, unlike MAD1 and the plant-specific BUB1/MAD3 family protein BMF3 that associated with unattached chromosomes only. When BUB3.3 was lost by a genetic mutation, mitotic cells often entered anaphase with misaligned chromosomes and presented lagging chromosomes after they were challenged by low doses of the microtubule depolymerizing agent oryzalin, resulting in the formation of micronuclei. Surprisingly, BUB3.3 was not required for the kinetochore localization of other SAC proteins or vice versa. Instead, BUB3.3 specifically bound to BMF3 through two internal repeat motifs that were not required for BMF3 kinetochore localization. This interaction enabled BMF3 to recruit CDC20, a downstream SAC target, to unattached kinetochores. Taken together, our findings demonstrate that plant SAC utilizes unconventional protein interactions for arresting mitosis, with BUB3.3 directing BMF3's role in CDC20 recruitment, rather than the recruitment of BUB1/MAD3 proteins observed in fungi and animals. This distinct mechanism highlights how plants adapted divergent versions of conserved cell cycle machinery to achieve specialized SAC control.

A unique circulating microRNA pairs signature serves as a superior tool for early diagnosis of pan-cancer.

Cancer remains a major burden globally and the critical role of early diagnosis is self-evident. Although various miRNA-based signatures have been developed in past decades, clinical utilization is limited due to a lack of precise cutoff value. Here, we innovatively developed a signature based on pairwise expression of miRNAs (miRPs) for pan-cancer diagnosis using machine learning approach. We analyzed miRNA spectrum of 15832 patients, who were divided into training, validation, test, and external test sets, with 13 different cancers from 10 cohorts. Five different machine-learning (ML) algorithms (XGBoost, SVM, RandomForest, LASSO, and Logistic) were adopted for signature construction. The best ML algorithm and the optimal number of miRPs included were identified using area under the curve (AUC) and youden index in validation set. The AUC of the best model was compared to previously published 25 signatures. Overall, Random Forest approach including 31 miRPs (31-miRP) was developed, proving highly efficient in cancer diagnosis across different datasets and cancer types (AUC range: 0.980-1.000). Regarding diagnosis of cancers at early stage, 31-miRP also exhibited high capacities, with AUC ranging from 0.961 to 0.998. Moreover, 31-miRP exhibited advantages in differentiating cancers from normal tissues (AUC range: 0.976-0.998) as well as differentiating cancers from corresponding benign lesions. Encouragingly, comparing to previously published 25 different signatures, 31-miRP also demonstrated clear advantages. In conclusion, 31-miRP acts as a powerful model for cancer diagnosis, characterized by high specificity and sensitivity as well as a clear cutoff value, thereby holding potential as a reliable tool for cancer diagnosis at early stage.

Pan-cancer characterization of cell-free immune-related miRNA identified as a robust biomarker for cancer diagnosis.

Minimally invasive testing is essential for early cancer detection, impacting patient survival rates significantly. Our study aimed to establish a pioneering cell-free immune-related miRNAs (cf-IRmiRNAs) signature for early cancer detection. We analyzed circulating miRNA profiles from 15,832 participants, including individuals with 13 types of cancer and control. The data was randomly divided into training, validation, and test sets (7:2:1), with an additional external test set of 684 participants. In the discovery phase, we identified 100 differentially expressed cf-IRmiRNAs between the malignant and non-malignant, retaining 39 using the least absolute shrinkage and selection operator (LASSO) method. Five machine learning algorithms were adopted to construct cf-IRmiRNAs signature, and the diagnostic classifies based on XGBoost algorithm showed the excellent performance for cancer detection in the validation set (AUC: 0.984, CI: 0.980-0.989), determined through 5-fold cross-validation and grid search. Further evaluation in the test and external test sets confirmed the reliability and efficacy of the classifier (AUC: 0.980 to 1.000). The classifier successfully detected early-stage cancers, particularly lung, prostate, and gastric cancers. It also distinguished between benign and malignant tumors. This study represents the largest and most comprehensive pan-cancer analysis on cf-IRmiRNAs, offering a promising non-invasive diagnostic biomarker for early cancer detection and potential impact on clinical practice.

A coadapted KNL1 and spindle assembly checkpoint axis orchestrates precise mitosis in Arabidopsis.

The kinetochore scaffold 1 (KNL1) protein recruits spindle assembly checkpoint (SAC) proteins to ensure accurate chromosome segregation during mitosis. Despite such a conserved function among eukaryotic organisms, its molecular architectures have rapidly evolved so that the functional mode of plant KNL1 is largely unknown. To understand how SAC signaling is regulated at kinetochores, we characterized the function of the KNL1 gene in Arabidopsis thaliana. The KNL1 protein was detected at kinetochores throughout the mitotic cell cycle, and null knl1 mutants were viable and fertile but exhibited severe vegetative and reproductive defects. The mutant cells showed serious impairments of chromosome congression and segregation, that resulted in the formation of micronuclei. In the absence of KNL1, core SAC proteins were no longer detected at the kinetochores, and the SAC was not activated by unattached or misaligned chromosomes. Arabidopsis KNL1 interacted with SAC essential proteins BUB3.3 and BMF3 through specific regions that were not found in known KNL1 proteins of other species, and recruited them independently to kinetochores. Furthermore, we demonstrated that upon ectopic expression, the KNL1 homolog from the dicot tomato was able to functionally substitute KNL1 in A. thaliana, while others from the monocot rice or moss associated with kinetochores but were not functional, as reflected by sequence variations of the kinetochore proteins in different plant lineages. Our results brought insights into understanding the rapid evolution and lineage-specific connection between KNL1 and the SAC signaling molecules.

A comprehensive pan-cancer analysis of prognostic value and potential clinical implications of FTH1 in cancer immunotherapy.

BACKGROUND: Numerous studies have highlighted the crucial value of the heavy chain of ferritin (FTH1) as a key regulator of iron metabolism and a suppressor of ferroptosis, intimately tied to the tumor immune microenvironment (TIME). Nevertheless, the precise impact of FTH1 on cancer immunotherapy remains vague. Our study aims to systematically explore the prognostic significance and immune role of FTH1 in pan-cancers immunotherapy. METHODS: Our study delves into the potential of FTH1 as an immunotherapeutic target within the TIME of various solid cancers. The immune landscape and underlying mechanisms of FTH1 in the TIME were investigated by multiple algorithms and bioinformatics methods. Single-cell sequencing analysis and multiplex immunofluorescence staining techniques are applied to observe FTH1 co-expression on both tumor and immune cells. RESULTS: FTH1 exhibited aberrant expression patterns across multiple cancers, which is strongly correlated with immunotherapy resistance. Patients with high FTH1 expression levels tended to derive less benefit from immunotherapies. Moreover, FTH1 demonstrated a significant correlation with TIME infiltration, immune checkpoint molecules, and immune-related pathways. Notably, FTH1 showed a positive association with macrophage infiltrations, its expression was particularly noteworthy in malignant cells and macrophages. Inhibiting FTH1-related signaling pathways appeared to be a potential strategy to counteract tumor immunotherapy resistance. CONCLUSION: Our comprehensive analyses may offer valuable insights into the role of FTH1 in tumor immunotherapy. The observed correlations pave the way for further functional experiments, fostering an enhanced understanding that could shape future research endeavors.

Synergistic effect of organic matter-floc size-bound water and multifactorial quantitative model of optimal reagent demand in sewage sludge conditioning process prior to dewatering.

The high amount of densely hydrated organic substance present in sewage sludge impedes its filterability, thus restricting sludge disposal. Although chemical conditioning can facilitate filtration, the diverse sludge properties complicate the quantitative control of conditioning process. Investigating how to accurately quantify the optimal reagent demand (ORD) based on the critical physicochemical properties of the target sludge is an effective way to address the current issue. This study focused on the sewage and stockpiled sludge with varying properties, and their ORD under different chemical conditioning. The results showed that organic content, floc size, and bound water synergistically influenced conditioning process. The quantitative models were established between their coupling indicators and ORD, with coupling indicators including the ratio of organic content to floc size, the ratio of flow viscosity to floc size, and the ratio of the product of organic content and bound water to floc size. The linear correlation of the coupling indicator with ORD was higher than that of the traditional single-factor indicator. Furthermore, the inherent filterability of the sludge was somewhat separate from the adjustability of its filtration. A "dual-system" impact model was proposed to characterized the conditioning and filtration processes. These results provide theoretical guidance for the quantitative regulation of conditioning and filtration processes of sludge with complex characteristics.

Identifying critical regions for nitrogen and phosphorus loss management in a large-scale complex basin: The Jialing River.

The determination of critical management areas for nitrogen (N) and phosphorus (P) losses in large-scale basins is critical to reduce costs and improve efficiency. In this study, the spatial and temporal characteristics of the N and P losses in the Jialing River from 2000 to 2019 were calculated based on the Soil and Water Assessment Tool (SWAT) model. The trends were analyzed using the Theil-Sen median analysis and Mann-Kendall test. The Getis-Ord Gi* was used to determine significant coldspot and hotspot regions to identify critical regions and priorities for regional management. The ranges of the annual average unit load losses for N and P in the Jialing River were 1.21-54.53 kg ha-1 and 0.05-1.35 kg ha-1, respectively. The interannual variations in both N and P losses showed decreasing trends, with change rates of 0.327 and 0.003 kg ha-1·a-1 and change magnitudes of 50.96% and 41.05%, respectively. N and P losses were highest in the summer and lowest in the winter. The coldspot regions for N loss were clustered northwest of the upstream Jialing River and north of Fujiang River. The coldspot regions for P loss were clustered in the central, western, and northern areas of the upstream Jialing River. The above regions were found to be not critical for management. The hotspot regions for N loss were clustered in the south of the upstream Jialing River, the central-western and southern areas of the Fujiang River, and the central area of the Qujiang River. The hotspot regions for P loss were clustered in the south-central area of the upstream Jialing River, the southern and northern areas of the middle and downstream Jialing River, the western and southern areas of the Fujiang River, and the southern area of the Qujiang River. The above regions were found to be critical for management. There was a significant difference between the high load area for N and the hotspot regions, while the high load region for P was consistent with the hotspot regions. The coldspot and hotspot regions for N would change locally in spring and winter, and the coldspot and hotspot regions for P would change locally in summer and winter, respectively. Therefore, managers should make specific adjustments in critical regions for different pollutants according to seasonal characteristics when developing management programs.

Large-scale sediment and phosphorus transport in the Three Gorges Reservoir based on a new reservoir operation method.

Change of hydrodynamic conditions is a key factor inducing sedimentation, water eutrophication and algal blooms in the Three Gorges Reservoir (TGR). How to mitigate sedimentation and phosphorus (P) retention by improving hydrodynamic conditions in the Three Gorges Reservoir area (TGRA) is an urgent issue in the study of sediment and water environment. In this study, a Hydrodynamic-Sediment-Water quality model for the whole TGRA is proposed considering sediment and P inputs from numerous tributaries, and a new reservoir operation method namely the tide-type operation method (TTOM) is used to investigate the large-scale sediment and P transport in the TGR based on the model. Results indicate that the TTOM can reduce sedimentation and total phosphorus (TP) retention in the TGR. Compared with the actual operation method (AOM), sediment outflow and sediment export ratio (Eratio) of the TGR increased about 17.13% and 1%-3% in 2015-2017, and sedimentation decreased about 3% under the TTOM. TP retention flux and retention rate (RE) decreased about 13.77% and 2%-4%. The flow velocity (V) and sediment carrying capacity (S*) increased about 40% in the local reach. Larger daily water level fluctuation at dam site is more conducive to reducing sedimentation and TP retention in the TGR. Sediment inputs from the Yangtze River, Jialing River, Wu River and other tributaries account for 59.27%, 11.21%, 3.81% and 25.70% of the total sediment inflow during 2015-2017, and TP inputs were 65.96%, 10.01%, 17.40% and 6.63%. In the paper, an innovative method is proposed to reduce sedimentation and P retention in the TGR under the given hydrodynamic conditions and related quantitative contribution driven by the proposed method is analyzed. The work is favorable for expanding the understanding of the hydrodynamic and nutrition flux changes in the TGR, and provides a new perspective for water environment protection and reasonable operation of large reservoirs.

Recent Research Progress of Surface-Enhanced Raman Scattering Dominated Analysis Strategies in Early Diagnosis of Diseases.

Timely and powerful diagnostic means can achieve better therapeutic effects, reduce disease torment, and improve survival rate. As a powerful non-invasive spectroscopy technology, surface-enhanced Raman scattering (SERS) have testified to be a great potential candidate for extensive early clinical disease diagnosis. In recent years, the introduction of SERS label, combined with other analysis modes or artificial intelligence, and the emergence of miniaturized devices have made SERS technology more advantageous in early diagnosis of diseases. This review focuses on the research progress of SERS dominated analytical strategies in the field of early disease diagnosis in the past five years. The main content includes the application of label-free SERS detection; the construction of label SERS methodologies for various disease markers; SERS dominated multimode early disease diagnosis strategies; integration of SERS and artificial intelligence; portable Raman equipment and SERS imaging; and opportunities and trends for SERS diagnostic technology in the future.

Continuous metabolic syndrome severity score and the risk of CVD and all-cause mortality.

BACKGROUND: The dualistic diagnostic criteria for metabolic syndrome overlooked the severity of metabolic syndrome, and the relationships between the severity of metabolic syndrome and adverse health conditions are poorly characterized. We therefore aimed to investigate the associations of metabolic syndrome severity with incident cardiovascular disease (CVD)/all-cause mortality. METHODS: A total of 116,772 participants from the Kailuan study were followed up biennially between 2006 and 2018. The severity of metabolic syndrome was evaluated using a continuous metabolic syndrome severity score (MetS score). Cox proportional hazards model was used to examine the association between MetS score and the risk of CVD and all-cause mortality. Restricted cubic spline analyses were performed to explore the dose-response associations. RESULTS: We found that the risk of CVD and all-cause mortality increased consistently with the MetS score. In the multivariable-adjusted model, the hazard ratios of CVD and all-cause mortality were 2.05 (95% CI 1.86-2.25) and 1.45 (95% CI 1.35-1.56), respectively, in those subjects>75th percentile compared with those <25th percentile. Additionally, a J-shaped dose-response relationship was found between MetS score and the risk of all-cause mortality (pnonlinearity <.001), while a linear relationship between MetS score and the risk of CVD was observed in this study (pnonlinearity  = .737). CONCLUSIONS: This study suggests significant dose-response relationships between MetS score and the risk of CVD/mortality. Subjects without metabolic syndrome but with a relatively high MetS score should raise their awareness and pay more attention to the possible increased risk of CVD events.

[Tempo-spatial and Retention Analysis of Total Phosphorus in the Three Gorges Reservoir].

Phosphorus, as a limiting and vital macronutrient in water, circulates mainly with sediment through rivers. The construction and operation of large reservoirs can have a profound impact on the characteristics of phosphorus transportation and transformation. Based on measured hydrological and water quality data during 2008-2016 in the Three Gorges Reservoir (TGR), a statistical model of total phosphorus (TP) flux and sediment load in different periods was established. The formula of TP flux was established by analyzing the interpolation of unmeasured TP concentration, tempo-spatial characteristics, flux variation, and the retention effect of TP in the TGR. The results indicated that taking no account of the effects of TP inflows of tributaries, annual TP concentration in the TGR varied between 0.196 mg·L-1 and 0.290 mg·L-1 during 2008-2012, and inner-annual changes in TP concentration presented an "M" type with two obvious peaks. TP concentration decreased slowly from upstream to downstream of the TGR, and increased significantly from Cuntan to Qingxichang in some years. The average annual TP flux and retention rate of the TGR were 82300 t and 49.76% during 2008-2012, respectively. During 2013-2016, the average annual TP flux and retention rate decreased significantly, to about 47900 t and 12.03%, respectively.

Brassinosteroids regulate root meristem development by mediating BIN2-UPB1 module in Arabidopsis.

Plant steroid hormones brassinosteroids (BRs) regulate plant growth and development at many levels. While negative regulatory factors that inhibit development and are counteracted by BRs exist in the root meristem, these factors have not been characterized. The functions of UPB1 transcription factor in BR-regulated root growth have not been established, although its role in regulating root are well documented. Here, we found that BIN2 interacts with and phosphorylates the UPB1 transcription factor consequently promoting UPB1 stability and transcriptional activity. Genetic analysis revealed that UPB1 deficiency could partially recover the short-root phenotype of BR-deficient mutants. Expression of a mutated UPB1S37AS41A protein lacking a conserved BIN2 phosphorylation sites can rescue shorter root phenotype of bin2-1 mutant. In addition, UPB1 was repressed by BES1 at the transcriptional level. The paclobutrazol-resistant protein family (PRE2/3) interacts with UPB1 and inhibits its transcriptional activity to promote root meristem development, and BIN2-mediated phosphorylation of UPB1 suppresses its interaction with PRE2/3, and subsequently impairing root meristem development. Taken together, our data elucidate a molecular mechanism by which BR promotes root growth via inhibiting BIN2-UPB1 module.

Involvement of Lhcb6 and Lhcb5 in Photosynthesis Regulation in Physcomitrella patens Response to Abiotic Stress.

There are a number of highly conserved photosystem II light-harvesting antenna proteins in moss whose functions are unclear. Here, we investigated the involvement of chlorophyll-binding proteins, Lhcb6 and Lhcb5, in light-harvesting and photosynthesis regulation in Physcomitrella patens. Lhcb6 or Lhcb5 knock-out resulted in a disordered thylakoid arrangement, a decrease in the number of grana membranes, and an increase in the number of starch granule. The absence of Lhcb6 or Lhcb5 did not noticeably alter the electron transport rates. However, the non-photochemical quenching activity in the lhcb5 mutant was dramatically reduced when compared to wild-type or lhcb6 plants under abiotic stress. Lhcb5 plants were more sensitive to photo-inhibition, while lhcb6 plants showed little difference compared to the wild-type plants under high-light stress. Moreover, both mutants showed a growth malformation phenotype with reduced chlorophyll content in the gametophyte. These results suggested that Lhcb6 or Lhcb5 played a unique role in plant development, thylakoid organization, and photoprotection of PSII in Physcomitrella, especially when exposed to high light or osmotic environments.

Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways.

Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke.

[Academic misconduct of graduates and the credit education].

Nowadays the phenomenon of academic misconduct (such as plagiarism, fabrication, falsification, etc.) is very frequent. The reasons for academic misconduct are involved in the problems in graduate education system, social environment and students themselves. Therefore, colleges and universities should place great emphasis on constructing a healthy school environment and academic atmosphere for failure tolerance with the help of high-tech modern means. It also needs to improve the academic supervision and evaluation system, strengthen the punishments for academic misconduct and enhance the mentor's exemplary role in education. The eventual goal for our education is to obtain innovative talents who are integrity, respect science and truth, and are good samples for academic performances.