FFCM-MRF: An accurate and generalizable cerebrovascular segmentation pipeline for humans and rhesus monkeys based on TOF-MRA.

PURPOSE: Cerebrovascular segmentation and quantification of vascular morphological features in humans and rhesus monkeys are essential for prevention, diagnosis, and treatment of brain diseases. However, current automated whole-brain vessel segmentation methods are often not generalizable to independent datasets, limiting their usefulness in real-world environments with their heterogeneity in participants, scanners, and species. MATERIALS AND METHODS: In this study, we proposed an automated, accurate and generalizable segmentation method for magnetic resonance angiography images called FFCM-MRF. This method integrated fast fuzzy c-means clustering and Markov random field optimization by vessel shape priors and spatial constraints. We used a total of 123 human and 44 macaque MRA images scanned at 1.5 T, 3 T, and 7 T MRI from 9 datasets to develop and validate the method. RESULTS: FFCM-MRF achieved average Dice similarity coefficients ranging from 69.16 % to 89.63 % across multiple independent datasets, with improvements ranging from 3.24 % to 7.3 % compared to state-of-the-art methods. Quantitative analysis showed that FFCM-MRF can accurately segment major arteries in the Circle of Willis at the base of the brain and small distal pial arteries while effectively reducing noise. Test-retest analysis showed that the model yielded high vascular volume and diameter reliability. CONCLUSIONS: Our results have demonstrated that FFCM-MRF is highly accurate and reliable and largely independent of variations in field strength, scanner platforms, acquisition parameters, and species. The macaque MRA data and user-friendly open-source toolbox are freely available at OpenNeuro and GitHub to facilitate studies of imaging biomarkers for cerebrovascular and neurodegenerative diseases.

The efficacy and safety of sacubitril/valsartan compared with ACEI/ARB in the treatment of heart failure following acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

Purpose: To systematically assess the efficacy and safety of sacubitril/valsartan (SV) by comparison with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for the treatment of heart failure caused by acute myocardial infarction (HF-AMI) based on current randomized controlled trials (RCTs). Methods: Several electronic databases were searched up to 27 May 2023. Primary endpoints were the efficacy including the left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), N-terminal pro-B type natriuretic peptide (NT-proBNP) and 6-min walk test (6MWT) and secondary endpoints were the safety including the major adverse cardiovascular event (MACE) and adverse reaction (AE). Results: A total of 14 RCTs were included and all patients were from China. Among included 1,991 patients, 997 patients received SVs and 994 patients received ACEIs/ARBs. The pooled results demonstrated that patients in the SV group showed significantly better efficacy representing as increased LVEF [weighted mean difference (WMD): 4.43%, 95% confidence interval (CI): 2.84%-6.02%, p < 0.001] and 6MWT (WMD: 30.84 m, 95% CI: 25.65 m-36.03 m, p < 0.001) and decreased LVEDD (WMD: -3.24 mm, 95% CI: -4.96 mm ∼ -1.52 mm, p < 0.001) and NT-proBNP (WMD: -188.12 pg/mL, 95% CI: -246.75 pg/mL ∼ 129.49 pg/mL, p < 0.001), which was also verified by subgroup analysis based on the history of percutaneous coronary intervention (PCI). Besides, the SV group showed significantly lower incidence rate of MACE [relative risk (RR): 0.60, 95% CI: 0.47-0.75, p < 0.001] and patients receiving SVs in the non-PCI group also showed lower incidence of AE (RR: 0.38, 95% CI: 0.20-0.71, p = 0.002). Conclusion: For the treatment of HF-AMI, SV is more effective and safer than ACEI/ARB based on current evidence, but more high-quality RCTs are still needed to verify above findings.

Mapping blood traits to structural organization of the brain in rhesus monkeys.

Hematological and biochemical blood traits have been linked to brain structural characteristics in humans. However, the relationship between these two domains has not been systematically explored in nonhuman primates, which are crucial animal models for understanding the mechanisms of brain function and developing therapeutics for various disorders. Here we investigated the associations between hematological/biochemical parameters and the brain's gray matter volume and white matter integrity derived from T1-weighted and diffusion magnetic resonance imaging in 36 healthy macaques. We found that intersubject variations in basophil count and hemoglobin levels correlated with gray matter volumes in the anterior cingulum, prefrontal cortex, and putamen. Through interactions between these key elements, the blood parameters' covariation network was linked with that of the brain structures, forming overarching networks connecting blood traits with structural brain features. These networks exhibited hierarchical small-world architecture, indicating highly effective interactions between their constituent elements. In addition, different subnetworks of the brain areas or fiber tracts tended to correlate with unique groups of blood indices, revealing previously unknown brain structural organization. These results provide a quantitative characterization of the interactions between blood parameters and brain structures in macaques and may increase the understanding of the body-brain relationship and the pathogenesis of relevant disorders.

MonkeyTrail: A scalable video-based method for tracking macaque movement trajectory in daily living cages.

Behavioral analysis of macaques provides important experimental evidence in the field of neuroscience. In recent years, video-based automatic animal behavior analysis has received widespread attention. However, methods capable of extracting and analyzing daily movement trajectories of macaques in their daily living cages remain underdeveloped, with previous approaches usually requiring specific environments to reduce interference from occlusion or environmental change. Here, we introduce a novel method, called MonkeyTrail, which satisfies the above requirements by frequently generating virtual empty backgrounds and using background subtraction to accurately obtain the foreground of moving animals. The empty background is generated by combining the frame difference method (FDM) and deep learning-based model (YOLOv5). The entire setup can be operated with low-cost hardware and can be applied to the daily living environments of individually caged macaques. To test MonkeyTrail performance, we labeled a dataset containing >8 000 video frames with the bounding boxes of macaques under various conditions as ground-truth. Results showed that the tracking accuracy and stability of MonkeyTrail exceeded that of two deep learning-based methods (YOLOv5 and Single-Shot MultiBox Detector), traditional frame difference method, and naïve background subtraction method. Using MonkeyTrail to analyze long-term surveillance video recordings, we successfully assessed changes in animal behavior in terms of movement amount and spatial preference. Thus, these findings demonstrate that MonkeyTrail enables low-cost, large-scale daily behavioral analysis of macaques.

Promoting Cas9 degradation reduces mosaic mutations in non-human primate embryos.

CRISPR-Cas9 is a powerful new tool for genome editing, but this technique creates mosaic mutations that affect the efficiency and precision of its ability to edit the genome. Reducing mosaic mutations is particularly important for gene therapy and precision genome editing. Although the mechanisms underlying the CRSIPR/Cas9-mediated mosaic mutations remain elusive, the prolonged expression and activity of Cas9 in embryos could contribute to mosaicism in DNA mutations. Here we report that tagging Cas9 with ubiquitin-proteasomal degradation signals can facilitate the degradation of Cas9 in non-human primate embryos. Using embryo-splitting approach, we found that shortening the half-life of Cas9 in fertilized zygotes reduces mosaic mutations and increases its ability to modify genomes in non-human primate embryos. Also, injection of modified Cas9 in one-cell embryos leads to live monkeys with the targeted gene modifications. Our findings suggest that modifying Cas9 activity can be an effective strategy to enhance precision genome editing.

Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain.

Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and >15 years of age to examine the expression of Parkin, PINK1, and α-synuclein, which are known to cause PD via loss- or gain-of-function mechanisms. We found that α-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of α-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant α-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD.

Early Parkinson's disease symptoms in α-synuclein transgenic monkeys.

Parkinson's disease (PD) is an age-dependent neurodegenerative disease that can be caused by genetic mutations in α-synuclein (α-syn) or duplication of wild-type α-syn; PD is characterized by the deposition of α-syn aggregates, indicating a gain of toxicity from accumulation of α-syn. Although the major neuropathologic feature of PD is the degeneration of dopaminergic (DA) neurons in the substantia nigra, non-motor symptoms including anxiety, cognitive defect and sleep disorder precede the onset of motor impairment, and many clinical symptoms of PD are not caused by degeneration of DA neurons. Non-human primate models of PD are important for revealing the early pathology in PD and identifying effective treatments. We established transgenic PD rhesus monkeys that express mutant α-syn (A53T). Six transgenic A53T monkeys were produced via lentiviral vector expressing A53T in fertilized monkey eggs and subsequent embryo transfer to surrogates. Transgenic A53T is expressed in the monkey brain and causes age-dependent non-motor symptoms, including cognitive defects and anxiety phenotype, without detectable sleeping disorders. The transgenic α-syn monkeys demonstrate the specific early symptoms caused by mutant α-syn and provide insight into treatment of early PD.

[Changes of agroecosystem services value under effects of land consolidation].

This paper quantitatively described the changes of agroecosystem functions before (2003) and after (2007) the implementation of Gaolong land consolidation project in Hechuan of Chongqing. Engineering design and shadow price were integrated to quantify the effects of the project on the functions, and cost-benefit analysis was used to further explain the economic meanings of the functions, and to analyze the changes of the agroecosystem services value under effects of the project. Compared with that before the land consolidation, the agroecosystem services value after the land consolidation was somewhat improved, with the largest increment of nutrient cycling function and the smallest change of soil conservation function. In the implementation of the project, the changes of the agroecosystem services value induced by farmland water conservancy, field road building, and land-leveling engineering mainly manifested in the change of disturbance function. From the 7th to 35th year after the project, the cost benefit would have a rapid increase, and tended to be stable after then, giving a weak ecological pressure and little services value loss, and benefiting the improvement of regional ecological environment.