Stabilizing axin leads to optic nerve hypoplasia in a mouse model of autism.

Autism spectrum disorder (ASD) is a group of neurodevelopment disorders characterized by deficits in social interaction and communication, and repetitive or stereotyped behavior. Autistic children are more likely to have vision problems, and ASD is unusually common among blind people. However, the mechanisms behind the vision disorders in autism are unclear. Stabilizing WNT-targeted scaffold protein Axin2 by XAV939 during embryonic development causes overproduction of cortical neurons and leads to autistic-like behaviors in mice. In this study, we investigated the relationship between vision abnormality and autism using an XAV939-induced mouse model of autism. We found that the mice receiving XAV939 had decreased amplitude of bright light-adaptive ERG. The amplitudes and latency of flash visual evoked potential recorded from XAV939-treated mice were lower and longer, respectively than in the control mice, suggesting that XAV939 inhibits visual signal processing and conductance. Anatomically, the diameters of RGC axons were reduced when Axin2 was stabilized during the development, and the optic fibers had defective myelin sheaths and reduced oligodendrocytes. The results suggest that the WNT signaling pathway is crucial for optic nerve development. This study provides experimental evidence that conditions interfering with brain development may also lead to visual problems, which in turn might exaggerate the autistic features in humans.

The mechanism of static postural control in the impact of lower limb muscle strength asymmetry on gait performance in the elderly.

Background: Abnormal gait is prevalent among the elderly population, leading to reduced physical activity, increased risk of falls, and the potential development of dementia and disabilities, thus degrading the quality of life in later years. Numerous studies have highlighted the crucial roles of lower limb muscle strength asymmetry and static postural control in gait, and the reciprocal influence of lower limb muscle strength asymmetry on static postural control. However, research exploring the interrelationship between lower limb muscle strength asymmetry, static postural control, and gait performance has been limited. Methods: A total of 55 elderly participants aged 60 to 75 years were recruited. Isokinetic muscle strength testing was used to assess bilateral knee extension strength, and asymmetry values were calculated. Participants with asymmetry greater than 15% were categorized as the Asymmetry Group (AG), while those with asymmetry less than 15% were classified in the Symmetry Group (SG). Gait parameters were measured using a plantar pressure gait analysis system to evaluate gait performance, and static postural control was assessed through comfortable and narrow stance tests. Results: First, participants in the AG demonstrated inferior gait performance, characterized by slower gait speed, longer stance time and percentage of stance time in gait, and smaller swing time and percentage of swing time in gait. Spatial-temporal gait parameters of the weaker limb tended to be abnormal. Second, static postural control indices were higher in AG compared to SG in all aspects except for the area of ellipse during the comfortable stance with eyes open test. Third, abnormal gait parameters were associated with static postural control. Conclusion: Firstly, elderly individuals with lower limb muscle strength asymmetry are prone to abnormal gait, with the weaker limb exhibiting poorer gait performance. Secondly, lower limb muscle strength asymmetry contributes to diminished static postural control in the elderly. Thirdly, the mechanism underlying abnormal gait in the elderly due to lower limb muscle strength asymmetry may be linked to a decline in static postural control.

Corrosion Properties and Passive Film Interface of Inconel 718 in NaNO3 Solution for Laser-Assisted Electrochemical Machining.

Laser-assisted electrochemical machining (ECM) is an ideal manufacturing method for Inconel 718 (IN718) because of the method's high efficiency and good surface quality, and the basis for and key to laser-assisted ECM is its anodic electrochemical dissolution behavior. In this study, IN718 in a 10 wt % NaNO3 solution was subjected to innovative electrochemical testing and laser-assisted ECM experiments to investigate its corrosion properties and the passive film characteristics formed on its surface. The passivation-related behaviors and structures of the passive film were investigated based on open-circuit potentials, dynamic polarization, potentiostatic polarization, and electrochemical impedance spectroscopy. It was found that there was obvious active-passive-transpassive transition behavior, and the structure of the passive film in laser-assisted ECM exhibited pores and defects, resulting in weak corrosion resistance, compared with IN718 under ECM without laser irradiation. The chemical composition of the passive film was obtained by X-ray photoelectron spectroscopy. The results showed that the passive film was composed mainly of a mixture of NiO, Ni(OH)2, Cr2O3, CrO3, Fe2O3, α-Fe2O3, α-FeOOH, Nb2O5, NbO, MoO3, MoO2, and TiO2. The passive film formed by laser-assisted ECM was rich in NiO and TiO2 and lacked Cr2O3 and MoO3, which validated its pores and defect structures. A corresponding schematic model was also proposed to characterize the interface structure between the IN718 substrate and the passive film. Laser-assisted ECM tests were performed under different current densities and machining times, and the corrosion morphology of IN718 was identified. Corrosion pits and a loose product layer appeared on the machined surface at low current densities, and the dissolution mechanism was pitting. The quantity and depth of the corrosion pits dispersed on the machined surface clearly decreased as the current density increased. Finally, a quantitative corrosion model was established to characterize the dissolution behavior of IN718 in NaNO3 solution during laser-assisted ECM.

A new strategy to construct MOF-on-MOF derivatives for the removal of tetracycline hydrochloride from water by activation of peroxymonosulfate.

A MOF-on-MOF composite derivative material named ZIF-67@Ce-MOF-600 was designed and synthesized. The preparation of ZIF-67@Ce-MOF-600 was optimized from the aspects of the ratio of metal and ligand, heat-treatment temperature. It was demonstrated by XRD, FT-IR, SEM-EDS and TEM. The optimum conditions for the activation of PMS by ZIF-67@Ce-MOF-600 for the degradation of tetracycline (TC) were investigated by adjusting the catalyst dosage, TC, pH, peoxymonosulfate (PMS) concentration, and different kinds of water, co-existing anions and pollution. Under optimal conditions (20 mg catalysts and 50 mg PMS added) in 100 mL of tetracyclines (TC) solvent (20 mg TC/L), the removal rate could reach up to 99.2% and after five cycles was 70.5%. The EPR results indicated the presence of free radicals and non-free radical, among which free radicals intended to play a major role in the degradation process. Its possible degradation pathways and attack sites were analyzed by liquid-phase mass spectrometry and DFT analysis.

N-terminal truncated phospholipase A1 accessory protein PlaS from Serratia marcescens alleviates inhibitory on host cell growth and enhances PlaA1 enzymatic activity.

Phospholipase A1 (PLA1) is a kind of specific phospholipid hydrolase widely used in food, medical, textile. However, limitations in its expression and enzymatic activity have prompted the investigation of the phospholipase-assisting protein PlaS. In this study, we elucidate the role of PlaS in enhancing the expression and activity of PlaA1 through N-terminal truncation. Our research demonstrates that truncating the N-terminal region of PlaS effectively overcomes its inhibitory effect on host cells, resulting in improved cell growth and increased protein solubility of the protein. The yeast two-hybrid assay confirms the interaction between PlaA1 and N-terminal truncated PlaS (∆N27 PlaS), highlighting their binding capabilities. Furthermore, in vitro studies using Biacore analysis reveal a concentration-dependent and specific binding between PlaA1 and ∆N27 PlaS, exhibiting high affinity. Molecular docking analysis provides insights into the hydrogen bond interactions between ∆N27 PlaS and PlaA1, identifying key amino acid residues crucial for their binding. Finally, the enzyme activity of PLA1 was boost to 8.4 U/mL by orthogonal test. Study significantly contributes to the understanding of the interaction mechanism between PlaS and PlaA1, offering potential strategies for enhancing PlaA1 activity through protein engineering approaches.

Metabolic inflexibility promotes mitochondrial health during liver regeneration.

Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial ß-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.

Development and application of a cycleave dual-probe fluorescence quantitative PCR method for simultaneous detection of Mycoplasma gallisepticum ts-11 vaccine strain and non-ts-11 strains.

An attenuated vaccine against the Mycoplasma gallisepticum ts-11 strain has become an effective prevention and control method against MG infection. However, the ts-11 strain is usually difficult to distinguish from the non-ts-11 strain (including field isolates and other vaccine strains (F and 6/85)). Therefore, it is critical to establish a rapid and effective method to distinguish ts-11 strains from non-ts-11 strains. The gene sequences of the ts-11 strain (CP044225.1) and the non-ts-11 strain (including the wild-type (CP006916.3), 6/85 (CP044224.1), and F strains (NC_017503.1) were used to construct a conserved region containing a single point mutation in the potC gene in the ts-11 strain, after which a primer-probe combination method was designed. The primer-probe method was able to accurately and efficiently identify the ts-11 and non-ts-11 strains with minimum detection limits of 2.43 copies/µL and 1.65 copies/µL, respectively. Moreover, it could simultaneously distinguish the ts-11 strain from a non-ts-11 strain, and amplifications of avian influenza virus, infectious bronchitis virus, Newcastle disease virus, fowl adenovirus, infectious laryngotracheitis virus, infectious bursal disease virus, chicken anemia virus, Marek's disease virus, Mycoplasma synoviae, and Ornithobacter rhinotracheale were negative. The detection of clinical samples revealed that the established dual-probe fluorescence quantitative PCR method could be used to screen for mixed and single infections of the ts-11 strain and non-ts-11 strains effectively, with lower variation coefficients for intra- and interbatch repetition. The established cycleave dual-probe fluorescence quantitative PCR method showed good specificity, sensitivity, and repeatability and provides powerful technical support for the rapid and efficient differential diagnosis of the MG ts-11 strain from non-ts-11 strains.

De novo and salvage purine synthesis pathways across tissues and tumors.

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

Liver cancer initiation requires translational activation by an oncofetal regulon involving LIN28 proteins.

It is unknown which post-transcriptional regulatory mechanisms are required for oncogenic competence. Here, we show that the LIN28 family of RNA-binding proteins (RBPs), which facilitate post-transcriptional RNA metabolism within ribonucleoprotein networks, are essential for the initiation of diverse oncotypes of hepatocellular carcinoma (HCC). In HCC models driven by NRASG12V/Tp53, CTNNB1/YAP/Tp53, or AKT/Tp53, mice without Lin28a and Lin28b were markedly impaired in cancer initiation. We biochemically defined an oncofetal regulon of 15 factors connected to Lin28 through direct mRNA and protein interactions. Interestingly, all were RBPs and only 1 of 15 is a Let-7 target. Polysome profiling and reporter assays showed that LIN28B directly increased the translation of 8 of these 15 RBPs. As expected, overexpression of LIN28B and IGFBP1-3 were able to genetically rescue cancer initiation. Using this platform to probe components downstream of LIN28, we found that 8 target RBPs were able to restore NRASG12V/Tp53 cancer formation in Lin28a/b deficient mice. Furthermore, these LIN28B targets promote cancer initiation through an increase in protein synthesis. LIN28B, central to an RNP regulon that increases translation of RBPs, is important for tumor initiation in the liver.

PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.

Comparison of proximal and distal laparoscopic ureteroureterostomy for complete duplex kidneys in children.

OBJECTIVE: To compare efficacy of proximal and distal laparoscopic ureteroureterostomy (UU) for complete duplex kidneys in children. METHODS: Patients who underwent laparoscopic UU for complete duplex kidneys between December 2016 and July 2022 were reviewed retrospectively. 71 patients who had normal lower pole moiety without vesicoureteral reflux (VUR) were recruited. All of them underwent ultrasound, voiding cystourethrography (VCUG), renal scintigraphy, and magnetic resonance urography preoperatively. Proximal laparoscopic UU was performed in 35 patients and distal laparoscopic UU in 36 patients. Double J stents were placed in normal lower pole moieties. Clinical data, including general information, diagnosis, surgical management, imaging characteristics, clinical symptoms and postoperative complications (classified according to the modified Clavien-Dindo classification), and length of stay were recorded. Measurement date comparisons between groups were performed by t test, counting date were analyzed by chi-square test. RESULTS: The study consisted of 71 patients (56 females and 15 males) with complete duplex kidneys (41 in left kidney and 30 in right kidney). The patients' mean age was 34 m (range 3-161 m) and follow-up ranged from 25 to 81 m. No significant difference was found in age and follow-up time between the two groups. Laparoscopic UU was performed in all patients successfully. The operation time of the two groups was 108.42 ± 26.95 min for distal UU vs 121.46 ± 35.15 min for proximal UU(p = 0.14). No significant difference in postoperative complications was seen between the two groups (22.2% vs 31.4%, p = 0.345). However, in terms of the grading of postoperative complications, the proximal UU group had a higher grade (3 of them had a grade of IV) and more serious complications. CONCLUSIONS: There was no significant difference in the overall incidence of complications between distal and proximal UU. Compared with proximal laparoscopic UU, distal laparoscopic UU is easier to perform with less injury to the peripheral tissues. Postoperative complications of proximal UU are more serious and more difficult to manage. We recommend complete duplex kidney ureteral reconstruction with distal UU.

Relationship between different clinical characteristics and pericoronary adipose tissue attenuation values quantified from coronary computed tomographic angiography (CCTA) in patients without coronary heart disease (CHD).

Background: Pericoronary adipose tissue (PCAT) is a sensor of vascular inflammation. Elevated PCAT attenuation values indicate the presence of coronary inflammation in patients. However, it is unclear which clinical characteristics are associated with increased PCAT attenuation values in patients without coronary heart disease (CHD). The study aims to investigate the relationship between increased PCAT attenuation values and clinical characteristics of patients without CHD. Methods: We recruited 785 eligible patients without CHD who underwent coronary computed tomographic angiography (CCTA). Clinical data were recorded for each patient, and PCAT attenuation values for the left anterior descending branch (LADPCAT), left circumflex branch (LCXPCAT), and right coronary artery (RCAPCAT) were quantified by CCTA using fully automated software. Univariate and multivariate analyses were performed to identify the associations between different clinical characteristics and elevated LADPCAT, LCXPCAT, and RCAPCAT. Results: Univariate analysis showed body mass index (BMI) to be positively associated with LADPCAT (rs=0.109), LCXPCAT (rs=0.076), and RCAPCAT (rs=0.083). Moreover, the duration of smoking, and drinking was positively associated with LADPCAT (rs=0.099, 0.165). Hyperlipidemia was positively associated with LADPCAT (rs=0.089) and RCAPCAT (rs=0.334), while statin use was negatively associated with RCAPCAT (rs=-0.145). Multivariate analysis showed that the significant determinants of LADPCAT were BMI (ß=0.359, P=0.001), duration of smoking (ß=2.612, P=0.002), drinking (ß=4.106, P<0.001), and hyperlipidemia (ß=1.664, P=0.027). LCXPCAT was associated with BMI (ß=0.218, P=0.024), while RCAPCAT was associated with hyperlipidemia (ß=6.110, P<0.001) and statin use (ß=-3.338, P<0.001). Conclusions: In patients without CHD, the PCAT attenuation values measured using CCTA were associated with various clinical characteristics. LADPCAT was associated with BMI, smoking duration, drinking, and hyperlipidemia. On the other hand, LCXPCAT was associated with BMI, while RCAPCAT was associated with hyperlipidemia and statin use.

Association between Pericoronary Fat Attenuation Index Values and Plaque Composition Volume Fraction Measured by Coronary Computed Tomography Angiography.

RATIONALE AND OBJECTIVES: The pericoronary fat attenuation index (FAI) values around plaques may reveal the relationship between periplaque vascular inflammation and different plaque component volume fractions. We aimed to evaluate the potential associations between periplaque FAI values and plaque component volume fractions. MATERIALS AND METHODS: 496 patients (1078 lesions) with coronary artery disease, who underwent computed tomography angiography (CCTA) between September 2022 and August 2023, were analyzed retrospectively. Each lesion was characterized and the plaque component volume fractions and periplaque FAI values were measured. Multiple linear regression, weighted quantile sum (WQS) regression, and quantile g-computation (Qgcomp) were used to explore the relationship between plaque component volume fractions and the risk of elevated periplaque FAI values. RESULTS: After adjusting for clinical characteristics, multiple linear regression identified that lipid components volume fraction (ß = 0.162, P < 0.001) were independent risk factors for elevated periplaque FAI values whereas calcified components volume fraction (ß = -0.066, P = 0.025) were independent protective factors. The WQS regression models indicated an increase in the overall confounding effect of the adjusted lipid indices and plaque composition volume fraction on the risk of elevated periplaque FAI values (P = 0.004). Qgcomp analysis indicated lipid component volume fraction and calcified component volume fraction was positively and negatively correlated with elevated plaque FAI values, respectively (all P < 0.05). CONCLUSIONS: Periplaque FAI values quantified by CCTA were strongly correlated with lipid and calcification component volume fractions.

Factors of children's allocation behavior: peer relationship and resource quantity as the main determinants.

This study investigated the resource allocation of Chinese sixth-graders and the role of peer relationship in different resource conditions (N = 132, Mage = 11. 35 years, SD = 0.60). We designed the resource quantity as a between-group variable, with one group participating in a resource-limited experiment and another group in a resource-abundant experiment. Both groups of children allocated token resources to three types of peers relationships: good friends, disliked individuals, and strangers. Based on our experimental hypotheses, we presupposed three experimental outcomes: selfish allocation, equal allocation, and altruistic allocation. To analyze the data, we employed multivariate unordered regression analysis and performed two rounds of regression analyses using both selfish and altruistic allocations as reference categories to enhance the statistical power of regression model. Our results reveal that the resource quantity had a significant hindering effect on children's allocation behaviors, as the amount of available resources for allocation increased, so did their willingness to allocate selfishly. It was also found that an increase in resources led to a decrease in the proportion of children allocating equally. Nonetheless, the results still revealed generalized peer relationship preferences: children tended to allocate more resources to friends than to individuals they disliked. But when faced with disliked individuals, they were relatively more likely to allocate equally. Finally, we observed the proportion of equal allocation and discussed the similar impact of inequality aversion, different allocation contexts, and children's theory of mind on equitable allocation among sixth-graders.

The impact of road environments on rural periodic market travel satisfaction: a heterogeneity analysis of travel modes.

Introduction: Travel satisfaction as experienced by rural residents is closely related to personal physical and mental health, as well as rural economic conditions. An improved rural road environment can be expected to enhance villagers' satisfaction with regards to visits to markets, but to date this has not been established empirically. Methods: In this study, a questionnaire was designed to obtain local residents' evaluations of road environment characteristics for periodic market travel. And we use an Oprobit regression model and Importance-Performance Map Analysis (IPMA) to explore the heterogeneity of the 14 key elements of the "home-to-market" road environment impact on villagers' satisfaction under different modes of travel. Results: The results of the study reveal that villagers expressed dissatisfaction with the current lack of sidewalks and non-motorized paths, and except for road traffic disturbances and road deterioration, which did not significantly affect mode of travel, other factors proved significant. Significantly, bus services are associated with a significant positive effect on walking, non-motorized and bus travel satisfaction, while distance travel also affects walking, non-motorized and motorized travel satisfaction. It is worth noting that greening and service facilities negatively affect motorized travel satisfaction. In summary, road width, sidewalks, bus service, and road deterioration, are among the elements most in need of urgent improvement for all modes of travel. Discussion: The characteristics of the road environment that influence satisfaction with travel to the periodic market vary by travel mode, and this study is hoped to provide data support and optimization recommendations for the improvement of the rural road environment in China and other countries.

Self-assembly of a unique triangle-like tungstovanadate containing pentagonal {(WO7)W3(SnR)2} cluster.

In aqueous solution, a novel triangle-like tungstovanadate estertin derivative K10H10.5[(W4O15(H2O)2){(SnCH2CH2COO)2(V0.75W10.75/V0.25O39)}{{(SnCH2CH2COO)2(µ-OH)}2(SnCH2CH2COO)(VW10O37)}2]·31H2O ((SnR)8-V3W35, R = CH2CH2COO) was assembled by a conventional synthetic method. (SnR)8-V3W35 is composed of one [VW11O39]7- ({VW11}) and two [VW10O37]9- ({VW10}) units connected by eight [Sn(CH2)2COO]2+ groups and a {W4O19} cluster. Interestingly, there exists a pentagonal bipyramid WO7 polyhedral center surrounded by two SnCO5 and three WO6 octahedra, forming a pentagonal {(WO7)W3(SnR)2} cluster in this polyoxometalate (POM), which is also the first example of a pentagonal structure formed by transition metals (TMs) and main group organometals in the POM family. Furthermore, the structure of this organic-inorganic hybrid POM also exhibits the largest number of organotin groups introduced into the POM system. It was characterized with various physico-chemical and spectroscopic methods, including X-ray single crystal and powder diffraction analysis, 119Sn and 51V NMR, IR, thermal gravimetric analysis (TGA), etc. In addition, the catalytic activity of (SnR)8-V3W35 as a mimic of peroxidase was evaluated using o-phenylenediamine (OPD) as a peroxidase substrate. The major factors influencing the oxidation reaction such as pH, the dosage of (SnR)8-V3W35, and concentrations of OPD and H2O2 were mainly studied. (SnR)8-V3W35 exhibits good peroxidase-like catalytic activity. From another perspective, the successful acquisition of (SnR)8-V3W35 further proves the instability and easy reassembly characteristics of TM-sandwich-type tungstovanadates, which also provides a new assembly strategy for synthesizing POM-estertin derivatives.

Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation.

The urokinase-type plasminogen activator receptor (uPAR) emerges as a key target for anti-metastasis owing to its pivotal role in facilitating the invasive and migratory processes of cancer cells. Recently, we identified the uPAR-targeting anti-metastatic ability of diltiazem (22), a commonly used antihypertensive agent. Fine-tuning the chemical structures of known hits represents a vital branch of drug development. To develop novel anti-metastatic drugs, we performed an interface-driven structural evolution strategy on 22. The uPAR-targeting and anti-cancer abilities of this antihypertensive drug wereidentified by us recently. Based on in silico strategy, including extensive molecular dynamics (MD) simulations, hierarchical binding free energy predictions, and ADMET profilings, we designed, synthesized, and identified three new diltiazem derivatives (221-8, 221-57, and 221-68) as uPAR inhibitors. Indeed, all of these three derivatives exhibited uPAR-depending inhibitory activity against PC-3 cell line invasion at micromolar level. Particularly, derivatives 221-68 and 221-8 showed enhanced uPAR-dependent inhibitory activity against the tumor cell invasion compared to the original compound. Microsecond timesclae MD simulations demonstrated the optimized moiety of 221-68 and 221-8 forming more comprehensive interactions with the uPAR, highlighting the reasonability of our strategy. This work introduces three novel uPAR inhibitors, which not only pave the way for the development of effective anti-metastatic therapeutics, but also emphasize the efficacy and robustness of an in silico-based lead compound optimization strategy in drug design.

C2c: Predicting Micro-C from Hi-C.

MOTIVATION: High-resolution Hi-C data, capable of detecting chromatin features below the level of Topologically Associating Domains (TADs), significantly enhance our understanding of gene regulation. Micro-C, a variant of Hi-C incorporating a micrococcal nuclease (MNase) digestion step to examine interactions between nucleosome pairs, has been developed to overcome the resolution limitations of Hi-C. However, Micro-C experiments pose greater technical challenges compared to Hi-C, owing to the need for precise MNase digestion control and higher-resolution sequencing. Therefore, developing computational methods to derive Micro-C data from existing Hi-C datasets could lead to better usage of a large amount of existing Hi-C data in the scientific community and cost savings. RESULTS: We developed C2c ("high" or upper case C to "micro" or lower case c), a computational tool based on a residual neural network to learn the mapping between Hi-C and Micro-C contact matrices and then predict Micro-C contact matrices based on Hi-C contact matrices. Our evaluation results show that the predicted Micro-C contact matrices reveal more chromatin loops than the input Hi-C contact matrices, and more of the loops detected from predicted Micro-C match the promoter-enhancer interactions. Furthermore, we found that the mutual loops from real and predicted Micro-C better match the ChIA-PET data compared to Hi-C and real Micro-C loops, and the predicted Micro-C leads to more TAD-boundaries detected compared to the Hi-C data. The website URL of C2c can be found in the Data Availability Statement.

Quantitative evaluation of CTP derived time-density alterations versus CTP for collateral status prediction with stroke.

BACKGROUND AND OBJECTIVES: Collateral status is a pivotal determinant of clinical outcomes in acute ischemic stroke (AIS); however, its evaluation can be challenging. We investigated the predictive value of CT perfusion (CTP) derived time and density alterations versus CTP for collateral status prediction in AIS. METHODS: Consecutive patients with anterior circulation occlusion within 24 h were retrospectively included. Time-density curves of the CTP specified ischemic core, penumbra, and the corresponding contralateral unaffected brain were obtained. The collateral status was dichotomised into robust (4-5 scores) and poor (0-3 scores) using multiphase collateral scoring, as described by Menon et al.. Receiver operating characteristic curves and multivariable regression analysis were performed to assess the predictive ability of CTP-designated tissue time and density alterations, CTP for robust collaterals, and favourable outcomes (mRS score of 0-2 at 90 days). RESULTS: One-hundred patients (median age, 68 years; interquartile range, 57-80 years; 61 men) were included. A smaller ischemic core, shorter peak time delay, lower peak density decrease, lower cerebral blood volume ratio, and cerebral blood flow ratio in the CTP specified ischemic core were significantly associated with robust collaterals (PFDR ≤ 0.004). The peak time delay demonstrated the highest diagnostic value (AUC, 0.74; P < 0.001) with 66.7 % sensitivity and 73.7 % specificity. Furthermore, the peak time delay of less than 8.5 s was an independent predictor of robust collaterals and favourable clinical outcomes. CONCLUSIONS: Robust collateral status was significantly associated with the peak time delay in the ischemic core. It is a promising image marker for predicting collateral status and functional outcomes in AIS.

Continuous 3D Myocardial Motion Tracking via Echocardiography.

Myocardial motion tracking stands as an essential clinical tool in the prevention and detection of cardiovascular diseases (CVDs), the foremost cause of death globally. However, current techniques suffer from incomplete and inaccurate motion estimation of the myocardium in both spatial and temporal dimensions, hindering the early identification of myocardial dysfunction. To address these challenges, this paper introduces the Neural Cardiac Motion Field (NeuralCMF). NeuralCMF leverages implicit neural representation (INR) to model the 3D structure and the comprehensive 6D forward/backward motion of the heart. This method surpasses pixel-wise limitations by offering the capability to continuously query the precise shape and motion of the myocardium at any specific point throughout the cardiac cycle, enhancing the detailed analysis of cardiac dynamics beyond traditional speckle tracking. Notably, NeuralCMF operates without the need for paired datasets, and its optimization is self-supervised through the physics knowledge priors in both space and time dimensions, ensuring compatibility with both 2D and 3D echocardiogram video inputs. Experimental validations across three representative datasets support the robustness and innovative nature of the NeuralCMF, marking significant advantages over existing state-of-the-art methods in cardiac imaging and motion tracking. Code is available at: https://njuvision.github.io/NeuralCMF.