Repetitive traumatic brain injury-induced complement C1-related inflammation impairs long-term hippocampal neurogenesis.

JOURNAL/nrgr/04.03/01300535-202503000-00027/figure1/v/2024-06-17T092413Z/r/image-tiff Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus, leading to long-term cognitive impairment. However, the mechanism underlying this neurogenesis impairment remains unknown. In this study, we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury. Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development, delayed neuronal maturation, and reduced the complexity of neuronal dendrites and spines. Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval. Moreover, following repetitive traumatic brain injury, neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased, C1q binding protein levels were decreased, and canonical Wnt/ß-catenin signaling was downregulated. An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function. These findings suggest that repetitive traumatic brain injury-induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

Phosphorus and sulfur co-doped nickel molybdate with rich-oxygen vacancies for efficient water splitting.

The rational design of high-performance electrocatalysts is essential for promoting the industrialization of electrocatalytic water-splitting technology. Herein, phosphorus and sulfur co-doped nickel molybdate with rich-oxygen vacancies (P, S-NiMoO4) was prepared as an efficient bifunctional self-supporting water-splitting catalyst from the perspective of enhancing the conductivity and optimizing the electronic configurations. The incorporation of P, S and oxygen vacancies greatly enhances the conductivity and charge-transfer efficiency of NiMoO4. Additionally, P and S can serve as proton carriers and electron acceptors to enhance the catalytic activity by accelerating proton activation and high-valent metal generation in the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). As expected, P, S-NiMoO4 demonstrates efficient bifunctional catalytic activity with an overpotential of only 31/206 mV at 10 mA cm-2 for HER/OER in 1 M KOH. Meantime, the electrolyzer assembled with P, S-NiMoO4 as electrodes requires a voltage of only 1.55 V to achieve a water-splitting current density of 50 mA cm-2 along with good stability over 110 h. This work puts forward a novel approach based on elemental doping and vacancy engineering for the design of effective and enduring catalysts for water splitting.

Temporal variation characteristics in the association between climate and vegetation in Northwest China.

Northwest China has undergone notable alterations in climate and vegetation growth in recent decades. Nevertheless, uncertainties persist concerning the response of different vegetation types to climate change and the underlying mechanisms. This study utilized the Normalized Difference Vegetation Index (NDVI) and three sets of meteorological data to investigate the interannual variations in the association between vegetation and climate (specifically precipitation and temperature) from 1982 to 2015. Several conclusions were drawn. (1) RNDVI-GP (relationship between Growing Season NDVI and precipitation) decreased significantly across all vegetation, while RNDVI-GT (relationship between Growing Season NDVI and temperature) showed an insignificant increase. (2) Trends of RNDVI-GP and RNDVI-GT exhibited great variations across various types of vegetation, with forests displaying notable downward trends in both indices. The grassland exhibited a declining trend in RNDVI-GP but an insignificant increase in RNDVI-GT, while no significant temporal changes in RNDVI-GP or RNDVI-GT were observed in the barren land. (3) The fluctuations in RNDVI-GP and RNDVI-GT closely aligned with variations in drought conditions. Specifically, in regions characterized by VPD (vapor pressure deficit) trends less than 0.02 hpa/yr, which are predominantly grasslands, a rise in SWV (soil water volume) tended to cause a reduction in RNDVI-GP but an increase in RNDVI-GT. However, a more negative trend in SWV was associated with a more negative trend in both RNDVI-GP and RNDVI-GT when the VPD trend exceeded 0.02 hPa/yr, primarily in forests. Our results underscore the variability in the relationship between climate change and vegetation across different vegetation types, as well as the role of drought in modulating these associations.

Poly[[{µ2-5-[(di-methyl-amino)(thioxo)meth-oxy]benzene-1,3-di-carboxyl-ato-κ4 O 1,O 1':O 3,O 3'}(µ2-4,4'-di-pyridyl-amine-κ2 N 4:N 4')cobalt(II)] di-methyl-formamide hemisolvate monohydrate].

In the crystal structure of the title compound, {[Co(C11H9NSO5)(C10H9N3)]0.5C3H7NO·H2O} n or {[Co(dmtb)(dpa)]·0.5DMF·H2O} n (dmtb2- = 5-[(di-meth-yl-amino)-thioxometh-oxy]-1,3-benzene-dicarboxyl-ate and dpa = 4,4'-di-pyridyl-amine), an assembly of periodic [Co(C11H9NSO5)(C10H9N3)] n layers extending parallel to the bc plane is present. Each layer is constituted by distorted [CoO4N2] octa-hedra, which are connected through the µ 2-coordination modes of both dmtb2- and dpa ligands. Occupationally disordered water and di-meth-yl-formamide (DMF) solvent mol-ecules are located in the voids of the network to which they are connected through hydrogen-bonding inter-actions.

A human autoimmune organoid model reveals IL-7 function in coeliac disease.

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury1-4. Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8+ T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity.

p-d Orbital Hybridization Induced by Asymmetrical FeSn Dual Atom Sites Promotes the Oxygen Reduction Reaction.

With more flexible active sites and intermetal interaction, dual-atom catalysts (DACs) have emerged as a new frontier in various electrocatalytic reactions. Constructing a typical p-d orbital hybridization between p-block and d-block metal atoms may bring new avenues for manipulating the electronic properties and thus boosting the electrocatalytic activities. Herein, we report a distinctive heteronuclear dual-metal atom catalyst with asymmetrical FeSn dual atom sites embedded on a two-dimensional C2N nanosheet (FeSn-C2N), which displays excellent oxygen reduction reaction (ORR) performance with a half-wave potential of 0.914 V in an alkaline electrolyte. Theoretical calculations further unveil the powerful p-d orbital hybridization between p-block stannum and d-block ferrum in FeSn dual atom sites, which triggers electron delocalization and lowers the energy barrier of *OH protonation, consequently enhancing the ORR activity. In addition, the FeSn-C2N-based Zn-air battery provides a high maximum power density (265.5 mW cm-2) and a high specific capacity (754.6 mA h g-1). Consequently, this work validates the immense potential of p-d orbital hybridization along dual-metal atom catalysts and provides new perception into the logical design of heteronuclear DACs.

Kaiser score diagnosis of breast MRI lesions: Factors associated with false-negative and false-positive results.

PURPOSE: We sought factors associated with false-negative and false-positive results in the diagnosis of breast lesions using the Kaiser score (KS) on breast magnetic resonance imaging (MRI). METHODS: We retrospectively analyzed 1058 patients with 1058 breast lesions who underwent preoperative breast MRI with successful histopathologic results. Two radiologists assessed each lesion according to KS criteria, and clinicopathologic features and MRI findings were analyzed. Multivariate regression analysis was conducted to identify factors associated with false-negative and false-positive KS results. RESULTS: Of the 1058 lesions, 859 were malignant and 199 were benign. Particularly high misdiagnosis rates were observed for intraductal papilloma, inflammatory lesion, and mucinous carcinoma. For breast cancer, KS yielded 821 (95.6 %) true-positive and 38 (4.4 %) false-negative results. Multivariate analysis showed that smaller lesion size (≤1 cm) (OR, 3.698; 95 %CI, 1.430-9.567; p = 0.007), absence of ipsilateral breast hypervascularity (OR, 3.029; 95 %CI, 1.370-6.693; p = 0.006), and presence of hyperintensity on T2WI (OR, 2.405; 95 %CI, 1.121-5.162; p = 0.024) were significantly associated with false-negative breast cancer results. For benign lesions, KS yielded 141 (70.9 %) true-negative and 58 (29.1 %) false-positive results. Multivariate regression analysis revealed that non-mass enhancement lesions (OR, 4.660; 95 %CI, 2.018-10.762; p＜0.001), moderate/high background parenchymal enhancement (OR, 2.402; 95 %CI, 1.180-4.892; p = 0.016), and the presence of hyperintensity on T2WI (OR, 2.986; 95 %CI, 1.386-6.433; p = 0.005) were significantly associated with false-positive KS results. CONCLUSION: Several clinicopathologic and MRI features influence the accuracy of KS diagnosis. Understanding these factors may facilitate appropriate use of KS and guide alternative diagnostic approaches, ultimately improving diagnostic accuracy in the evaluation of breast lesions.

Pim-1 kinase protects the liver from ischemia reperfusion injury by regulating dynamics-related protein 1.

Hepatic ischemia-reperfusion (IR) injury significantly impacts liver transplantation success, yet current treatments remain inadequate. This study explores the role of Proto-oncogene serine/threonine-protein kinase (Pim-1) in liver IR, an area previously unexplored. Utilizing a mouse liver IR in vivo model and a MIHA cell hypoxia-reoxygenation in vitro model, we observed that Pim-1 expression increases following IR, inversely correlating with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Increased Pim-1 expression stabilizes mitochondrial membranes by modifying Drp1 phosphorylation, reducing mitochondrial fission and apoptosis, thereby mitigating liver damage. Additionally, we discovered that elevated Pim-1 expression is dependent on the trimethylation of histone H3 lysine 9 during liver IR. These findings underscore the importance and potential clinical application of targeting Pim-1 in treating hepatic IR, presenting a novel therapeutic avenue.

Hybrid ant colony-based inter-cluster routing protocol for FANET.

This study addresses the challenges in large-scale unmanned aerial vehicle (UAV) clusters, specifically the scalability issues and limitations of using reactive routing protocols for inter-cluster routing. These traditional methods place an excessive burden on cluster heads and struggle to adapt to frequently changing topologies, leading to decreased network performance. To solve these problems, we propose an innovative inter-cluster routing protocol (ICRP), which is based on a hybrid ant colony algorithm. During the route establishment phase, ICRP uses this algorithm to identify the optimal relay node. This approach is inspired by the foraging behavior of Physarum polycephalum, combining factors such as the number of hops from the source node, the load condition of the node, and its weight in the pheromone calculation. In the route maintenance phase, ICRP uses a predictive repair and contraction mechanism to dynamically maintain routes, accommodating the high mobility of UAVs. Comparative simulations in OMNeT + + showed that this protocol surpasses ad-hoc on-demand distance vector (AODV), fuzzy-logic-assisted-AODV, and Enhanced-Ant-AODV routing protocols in packet delivery rate and end-to-end transmission delay. Furthermore, it showed superior adaptation to network environments with high-speed node mobility.

Hypertriglyceridemia, Hypercholesterolemia, Body Mass Index, and the Risk of Acute Pancreatitis.

OBJECTIVE: The purpose of this work was to check the connection between parameters of lipid profile and body mass index (BMI) in relation to the occurrence of acute pancreatitis within a sample of adults from northern China. METHODOLOGY: A total of 123,214 participants from the Kailuan Group were incorporated into this prospective study. The subjects were categorized into quartiles on the basis of their initial levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). On the basis of BMI classification, the individuals in the study were divided into three distinct groups: normal weight, overweight, and obese. The data were analyzed to explore the correlation between lipid profile and BMI with acute pancreatitis. RESULTS: Over a period of 12.59 ± 0.98 years, during the median follow-up duration, a total of 410 new patients with acute pancreatitis were recorded. The occurrence rate and total occurrence of acute pancreatitis demonstrated an upward trend in correlation with elevated levels of TG, TC, and BMI. Following adjustment for multiple variables, it was observed that individuals in the fourth quartile of TG and TC levels demonstrated the highest likelihood of developing acute pancreatitis. Furthermore, our analysis revealed that a proportion of 19.29% of the correlation between BMI and the likelihood of experiencing acute pancreatitis can be attributed to the influence of elevated TG levels, whereas 12.69% of the association was mediated by higher TC. CONCLUSIONS: We found that hypertriglyceridemia, hypercholesterolemia, and obesity were risk factors for acute pancreatitis, especially in young and middle-aged men.TG and TC were the mediating factors between BMI and the risk of acute pancreatitis.

[Comparison on Environmental Benefits of Municipal Solid Waste Management in Suzhou Before and After Classification].

In order to systematically understand the urban environmental benefit improvement of municipal solid waste （MSW） classification, based on the disposal data of MSW before and after the MSW classification in Suzhou from 2017 to 2021, the environmental impact potential （EIP） of the MSW collection-transportation-disposal process was calculated, and the environmental benefits of the MSW integrated management in Suzhou to 2035 were predicted. After the MSW classification in Suzhou at the end of 2019, the EIP （in terms of PET2000, the same below） of the per unit weight of MSW was reduced by 18.38% from 2.34×10-13 t-1 in 2017 to 1.91×10-13 t-1 in 2021. The environmental benefits of the MSW integrated management could be improved by classification. Based on the Suzhou MSW removal and transportation situation in 2021, different classification and disposal scenarios were established to calculate. It was found that after the classification effect showed gradient improvement, and the disposal capacity matched accordingly, the environmental benefits of MSW were further improved. Under the planning disposal capacity scenario of "zero waste to landfill", the EIP and the total carbon emissions of per unit weight of MSW should be reduced by 23.96% and 30.73%, respectively, compared with the actual situation in 2021. Based on the linear model of population and economic development level of Suzhou, it is expected that the annual production of MSW in Suzhou will be increased to 6.965 million tons in 2035. Under the background of continuous improvement of MSW classification and continuous optimization of city appearance and environment in Suzhou, based on the status quo of terminal disposal capacity in Suzhou, the EIP of per unit weight of MSW after improving the efficiency of classification by 2035 was predicted to be 1.54×10-13 t-1, the total EIP would be 1.05×10-6, and the total carbon emissions would increase to 3.80 million tons. Under the ideal scenario of expanding the scale of waste disposal, "zero landfill" of raw MSW, and full resource utilization of food waste, the EIP of per unit weight of MSW in 2035 was predicted to be 1.28×10-13 t-1, and the total EIP and the total carbon emissions would be 8.69×10-7 and 3.23 million tons, respectively, which was approximately 5.65% and 1.23% less than the actual scenario in 2021, respectively. The EIP and carbon emissions of MSW integrated management could be controlled better by the coordinated promotion of classified collection and transportation and quality disposal.

Alcoholic Liver Disease in China: A Disease Influenced by Complex Social Factors That Should Not Be Neglected.

Alcoholic liver disease (ALD) encompasses liver damage caused by chronic, excessive alcohol consumption. It manifests initially as marked hepatocellular steatosis and can progress to steatohepatitis, liver fibrosis, and cirrhosis. With China's rapid economic growth, coupled with a complex social background and the influence of a deleterious wine culture, the number of patients with ALD in China has increased significantly; the disease has become a social and health problem that cannot be ignored. In this review, we briefly described the social factors affecting ALD in China and elaborated on differences between alcoholic and other liver diseases in terms of complications (e.g., cirrhosis, upper gastrointestinal bleeding, hepatic encephalopathy, hepatocellular carcinoma, addiction, and other extrahepatic diseases). We also emphasized that ALD was more dangerous and difficult to treat than other liver diseases due to its complications, and that precise and effective treatment measures were lacking. In addition, we considered new ideas and treatment methods that may be generated in the future.

Benzoate glycosides from Gentiana scabra Bge. and their lipid-lowering activity.

Seven undescribed benzoate glycosides (1-7) and five known ones (8-12) were isolated from the rhizomes of Gentiana scabra Bge. Their structures were characterized by comprehensive NMR and MS spectroscopic data analysis. The lipid-lowering effects of these compounds were evaluated by measuring the triglyceride (TG) contents and intracellular lipid droplets (LDs) in oleic acid (OA)-treated HepG2 cells. The results showed that compounds 1, 5, 7, and 11 significantly reduced the TG content at 20 µM, and the Bodipy staining displayed that OA enhanced the levels of LDs in the cell, while these compounds reversed the lipid accumulation caused by OA. These findings provide a basis for further development and utilization of G. scabra as a natural source of potential lipid-lowering agents.

Connectome gradient dysfunction contributes to white matter hyperintensity-related cognitive decline.

BACKGROUND: Although white matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary-to-transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether connectome gradient structure is altered as WMH progresses and how this alteration is associated with WMH-related cognitive decline remain unknown. METHODS: A total of 758 WMH individuals completed cognitive assessment and resting-state functional MRI (rs-fMRI). The functional connectome gradient was reconstructed based on rs-fMRI by using a gradient decomposition framework. Interrelations among the spatial distribution of WMH, functional gradient measures, and specific cognitive domains were explored. RESULTS: As the WMH volume increased, the executive function (r = -0.135, p = 0.001) and information-processing speed (r = -0.224, p = 0.001) became poorer, the gradient range (r = -0.099, p = 0.006), and variance (r = -0.121, p < 0.001) of the primary-to-transmodal gradient reduced. A narrower gradient range (r = 0.131, p = 0.001) and a smaller gradient variance (r = 0.136, p = 0.001) corresponded to a poorer executive function. In particular, the relationship between the frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary-to-transmodal gradient. CONCLUSIONS: These findings indicated that WMH volume, the primary-to-transmodal gradient, and cognition were interrelated. The detrimental effect of the frontal/occipital WMH on executive function was partly mediated by the decreased differentiation of the connectivity pattern between the primary and transmodal areas.

[Modern understanding of uric acid metabolism disorders and progress in traditional Chinese medicine prevention and treatment].

The abnormal production and/or excretion of uric acid can lead to a disorder in uric acid metabolism, resulting in hyperuricemia, uric acid nephropathy, gouty arthritis, and other diseases related to uric acid metabolism disorder. The clinical incidence of these diseases is increasing year after year, posing a significant threat to public health. In the past, hyperuricemia and gouty arthritis were often considered different diseases, with uric acid nephropathy being a complication of hyperuricemia. However, recent research has challenged this perspective, suggesting that hyperuricemia, uric acid nephropathy, and gouty arthritis are different stages of the same disease, with urate deposition as the common pathological feature. This article offered a comprehensive overview of the current understanding of hyperuricemia, uric acid nephropathy, and gouty arthritis in both traditional Chinese medicine(TCM) and western medicine. It delved into the most up-to-date insights into the involvement of urate deposition in the pathogenesis of uric acid metabolism disorders and highlighted the dominant role of TCM in the prevention and treatment of uric acid metabolism disorders, so as to provide a reference for effective intervention strategies and drug development in uric acid metabolism disorder-related diseases.

Investigation of Babesia spp. and Theileria spp. in ticks from Western China and identification of a novel genotype of Babesia caballi.

Babesia spp. and Theileria spp. are tick-borne protozoan parasites with veterinary importance. In China, epidemiological and genetic investigations on many Babesia and Theileria species were still absent in many areas and many tick species. From Aug 2021 to May 2023, 645 ticks were collected from the body surface of domestic animals (camels, goats, sheep, and cattle) using tweezers in seven counties in three provinces including Xinjiang (Qitai, Mulei, Hutubi, and Shihezi counties), Chongqing (Youyang and Yunyang counties), and Qinghai (Huangzhong county). Three tick species were morphologically and molecularly identified (334 Hyalomma asiaticum from Xinjiang, 245 Rhipicephalus microplus from Chongqing, and 66 Haemaphysalis qinghaiensis from Qinghai). A total of three Babesia species and two Theileria species were detected targeting the 18S gene. The COI and cytb sequences were also recovered from Babesia strains for further identification. In R. microplus from Chongqing, Babesia bigemina, the agent of bovine babesiosis, was detected. Notably, in H. asiaticum ticks from Xinjiang, a putative novel genotype of Babesia caballi was identified (0.90%, 3/334), whose COI and cytb genes have as low as 85.82% and 90.64-90.91% nucleotide identities to currently available sequences. It is noteworthy whether the sequence differences of its cytb contribute to the drug resistance of this variant due to the involvement of cytb in the drug resistance of Babesia. In addition, Theileria orientalis and Theileria annulata were detected in R. microplus from Chongqing (12.20%, 31/245) and H. asiaticum from Xinjiang (1.50%, 5/334), respectively. These results suggest that these protozoan parasites may be circulating in domestic animals in these areas. The pathogenicity of the novel genotype of B. caballi also warrants further investigation.

Potent synergy and sustained bactericidal activity of polymyxins combined with Gram-positive only class of antibiotics versus four Gram-negative bacteria.

BACKGROUND: Gram-negative bacteria (GNB) are becoming increasingly resistant to a wide variety of antibiotics. There are currently limited treatments for GNB, and the combination of antibiotics with complementary mechanisms has been reported to be a feasible strategy for treating GNB infection. The inability to cross the GNB outer membrane (OM) is an important reason that a broad spectrum of Gram-positive only class of antibiotics (GPOAs) is lacking. Polymyxins may help GPOAs to permeate by disrupting OM of GNB. OBJECTIVE: To identify what kind of GPOAs can be aided to broaden their anti-GNB spectrum by polymyxins, we systematically investigated the synergy of eight GPOAs in combination with colistin (COL) and polymyxin B (PMB) against GNB in vitro. METHODS: The synergistic effect of COL or PMB and GPOAs combinations against GNB reference strains and clinical isolates were determined by checkerboard tests. The killing kinetics of the combinations were assessed using time-kill assays. RESULTS: In the checkerboard tests, polymyxins-GPOAs combinations exert synergistic effects characterized by species and strain specificity. The synergistic interactions on P. aeruginosa strains are significantly lower than those on strains of A. baumannii, K. pneumoniae and E. coli. Among all the combinations, COL has shown the best synergistic effect in combination with dalbavancin (DAL) or oritavancin (ORI) versus almost all of the strains tested, with FICIs from 0.16 to 0.50 and 0.13 to < 0.28, respectively. In addition, the time-kill assays demonstrated that COL/DAL and COL/ORI had sustained bactericidal activity. CONCLUSIONS: Our results indicated that polymyxins could help GPOAs to permeate the OM of specific GNB, thus showed synergistic effects and bactericidal effects in the in vitro assays. In vivo combination studies should be further conducted to validate the results of this study.

Molecular insights into degron recognition by CRL5ASB7 ubiquitin ligase.

The ankyrin (ANK) SOCS box (ASB) family, encompassing ASB1-18, is the largest group of substrate receptors of cullin 5 Ring E3 ubiquitin ligase. Nonetheless, the mechanism of substrate recognition by ASB family proteins has remained largely elusive. Here we present the crystal structure of ASB7-Elongin B-Elongin C ternary complex bound to a conserved helical degron. ASB7 employs its ANK3-6 to form an extended groove, effectively interacting with the internal α-helix-degron through a network of side-chain-mediated electrostatic and hydrophobic interactions. Our structural findings, combined with biochemical and cellular analyses, identify the key residues of the degron motif and ASB7 required for their recognition. This will facilitate the identification of additional physiological substrates of ASB7 by providing a defined degron motif for screening. Furthermore, the structural insights provide a basis for the rational design of compounds that can specifically target ASB7 by disrupting its interaction with its cognate degron.

Exploring Pattern of Relapse in Pediatric Patients with Acute Lymphocytic Leukemia and Acute Myeloid Leukemia Undergoing Stem Cell Transplant Using Machine Learning Methods.

Background. Leukemic relapse remains the primary cause of treatment failure and death after allogeneic hematopoietic stem cell transplant. Changes in post-transplant donor chimerism have been identified as a predictor of relapse. A better predictive model of relapse incorporating donor chimerism has the potential to improve leukemia-free survival by allowing earlier initiation of post-transplant treatment on individual patients. We explored the use of machine learning, a suite of analytical methods focusing on pattern recognition, to improve post-transplant relapse prediction. Methods. Using a cohort of 63 pediatric patients with acute lymphocytic leukemia (ALL) and 46 patients with acute myeloid leukemia (AML) who underwent stem cell transplant at a single institution, we built predictive models of leukemic relapse with both pre-transplant and post-transplant patient variables (specifically lineage-specific chimerism) using the random forest classifier. Local Interpretable Model-Agnostic Explanations, an interpretable machine learning tool was used to confirm our random forest classification result. Results. Our analysis showed that a random forest model using these hyperparameter values achieved 85% accuracy, 85% sensitivity, 89% specificity for ALL, while for AML 81% accuracy, 75% sensitivity, and 100% specificity at predicting relapses within 24 months post-HSCT in cross validation. The Local Interpretable Model-Agnostic Explanations tool was able to confirm many variables that the random forest classifier identified as important for the relapse prediction. Conclusions. Machine learning methods can reveal the interaction of different risk factors of post-transplant leukemic relapse and robust predictions can be obtained even with a modest clinical dataset. The random forest classifier distinguished different important predictive factors between ALL and AML in our relapse models, consistent with previous knowledge, lending increased confidence to adopting machine learning prediction to clinical management.

Dissecting the Superior Drivers for the Simultaneous Improvement of Fiber Quality and Yield Under Drought Stress Via Genome-Wide Artificial Introgressions of Gossypium barbadense into Gossypium hirsutum.

Global water scarcity and extreme weather intensify drought stress, significantly reducing cotton yield and quality worldwide. Drought treatments are conducted using a population of chromosome segment substitution lines generated from E22 (G. hirsutum) and 3-79 (G. barbadense) as parental lines either show superior yields or fiber quality under both control and drought conditions. Fourteen datasets, covering 4 yields and 4 quality traits, are compiled and assessed for drought resistance using the drought resistance coefficient (DRC) and membership function value of drought resistance (MFVD). Genome-wide association studies, linkage analysis, and bulked segregant analysis are combined to analyze the DR-related QTL. A total of 121 significant QTL are identified by DRC and MFVD of the 8 traits. CRISPR/Cas9 and virus-induced gene silencing techniques verified DRR1 and DRT1 as pivotal genes in regulating drought resistant of cotton, with hap3-79 exhibiting greater drought resistance than hapE22 concerning DRR1 and DRT1. Moreover, 14 markers with superior yield and fiber quality are selected for drought treatment. This study offers valuable insights into yield and fiber quality variations between G. hirsutum and G. barbadense amid drought, providing crucial theoretical and technological backing for developing cotton varieties resilient to drought, with high yield and superior fiber quality.