Immunomodulation Pathogenesis and Treatment of Bone Nonunion.

Fractures and bone nonunion commonly require surgical intervention. Serious outcomes of non-healing in the late stages of fracture place a significant financial burden on society and families. Bone nonunion occurs when a fracture stops healing, for many reasons, and leads to a variety of bad outcomes. Numerous factors, including biomechanics and immunology, are involved in the complicated mechanisms of bone nonunion. The immune-inflammatory response plays a significant part in the emergence of bone nonunion, and the occurrence, control, and remission of inflammation in the bone healing process have a significant influence on the ultimate success of bone tissue repair. In the bone microenvironment, immune cells and associated cytokines control bone repair, which is significantly influenced by macrophages, T cells, and fibroblast growth factor. To limit acute inflammation and  balance osteogenesis and osteoblastogenesis for tissue repair and regeneration, immune cells and various cytokines in the local microenvironment must be precisely regulated. As a bad complication of late-stage fractures, bone nonunion has a significant effect on patients' quality of life and socioeconomic development. Therefore, in-depth research on its pathogenesis and treatment methods has important clinical value. To provide more precise, focused therapeutic options for the treatment of bone nonunion, we discuss the regulatory roles of the key immune cells engaged in bone healing within the microenvironment during bone healing and their effect on osteogenesis.

Phenome-wide association study and precision medicine of cardiovascular diseases in the post-COVID-19 era.

SARS-CoV-2 infection causes injuries of not only the lungs but also the heart and endothelial cells in vasculature of multiple organs, and induces systemic inflammation and immune over-reactions, which makes COVID-19 a disease phenome that simultaneously affects multiple systems. Cardiovascular diseases (CVD) are intrinsic risk and causative factors for severe COVID-19 comorbidities and death. The wide-spread infection and reinfection of SARS-CoV-2 variants and the long-COVID may become a new common threat to human health and propose unprecedented impact on the risk factors, pathophysiology, and pharmacology of many diseases including CVD for a long time. COVID-19 has highlighted the urgent demand for precision medicine which needs new knowledge network to innovate disease taxonomy for more precise diagnosis, therapy, and prevention of disease. A deeper understanding of CVD in the setting of COVID-19 phenome requires a paradigm shift from the current phenotypic study that focuses on the virus or individual symptoms to phenomics of COVID-19 that addresses the inter-connectedness of clinical phenotypes, i.e., clinical phenome. Here, we summarize the CVD manifestations in the full clinical spectrum of COVID-19, and the phenome-wide association study of CVD interrelated to COVID-19. We discuss the underlying biology for CVD in the COVID-19 phenome and the concept of precision medicine with new phenomic taxonomy that addresses the overall pathophysiological responses of the body to the SARS-CoV-2 infection. We also briefly discuss the unique taxonomy of disease as Zheng-hou patterns in traditional Chinese medicine, and their potential implications in precision medicine of CVD in the post-COVID-19 era.

Research Progress on the Pathogenesis of Knee Osteoarthritis.

Knee osteoarthritis (KOA) is a chronic joint bone disease characterized by inflammatory destruction and hyperplasia of bone. Its main clinical symptoms are joint mobility difficulties and pain, severe cases can lead to limb paralysis, which poses major pressure to the quality of life and mental health of patients, but also brings serious economic burden to society. The occurrence and development of KOA is influenced by many factors, including systemic factors and local factors. The joint biomechanical changes caused by aging, trauma and obesity, abnormal bone metabolism caused by metabolic syndrome, the effects of cytokines and related enzymes, genetic and biochemical abnormalities caused by plasma adiponectin, etc. all directly or indirectly lead to the occurrence of KOA. However, there is little literature that systematically and comprehensively integrates macro- and microscopic KOA pathogenesis. Therefore, it is necessary to comprehensively and systematically summarize the pathogenesis of KOA in order to provide a better theoretical basis for clinical treatment.

Abnormal Gray Matter Structural Covariance Networks in Children With Bilateral Cerebral Palsy.

Bilateral cerebral palsy (BCP) is a common movement disorder in children, which often results in lifelong motor disability. One main symptom of BCP is the limitation of hand function in everyday activities. However, the neuroanatomical basis of this prominent hand impairment is yet to discover. Recent advances mainly focus on the lesions of BCP, but the views on the atypical development of cortical parcellations are extremely lacking. Here, in our study, neuroimaging with network analysis was employed to evaluate the changes of structural covariance networks (SCNs) in BCP children. We aimed to elucidate the alteration of SCNs based on cortical thickness (CT), and to reveal the relationship of CT and hand function in the participants with BCP. SCNs were constructed using covariance between regional CT, which was acquired from T1-weighted images of 19 children with BCP and 19 demographically matched healthy controls (HCs). Compared with HCs, BCP children showed increased CT in several regions involving the bilateral areas (lateral occipital, lingual, and fusiform) and right areas (cuneus, pericalcarine, inferior temporal, middle temporal, superior temporal, and insula). Decreased CT was found in the left superior temporal and right superior parietal cortices. Global network analyses revealed significantly decreased normalized clustering and small-worldness in the BCP network. The area under the curve (AUC) of global network measures varied slightly between the BCP and HC networks. The resistance of the both SCNs to the target and random attack showed no significant difference. Also, the BCP foci (right superior temporal and subtemporal cortex) showed a significantly negative correlation between the CT and manual ability. In this work, we identified the CT-based SCNs changes in children with BCP. The abnormal topological organization of SCNs was revealed, indicating abnormal CT, incongruous development of structural wiring, destructive nodal profiles of betweenness, and moved hub distribution in BCP children. This may provide a neuroanatomical hallmark of BCP in the developing brain. Therefore, our results may not only reflect neurodevelopmental aberrations but also compensatory mechanisms.

Treatment response prediction of rehabilitation program in children with cerebral palsy using radiomics strategy: protocol for a multicenter prospective cohort study in west China.

BACKGROUND: Cerebral palsy (CP) is a major cause of chronic childhood disability worldwide, causing activity limitation as well as impairments in sensation, cognition, and communication. Leveraging biomarkers to establish individualized predictions of future treatment responses will be of great value. We aim to develop and validate a model that can be used to predict the individualized treatment response in Children with CP. METHODS: A multicenter prospective cohort study will be conducted in 4 hospitals in west China. One hundred and thirty children with CP will be recruited and undergo clinical assessment using the Peabody Developmental Motor Scales, Manual Ability Classification System (MACS), Hand Assessment for Infants (HAI), Assisting Hand Assessment (AHA), and Gross Motor Function Classification System (GMFCS). The data collected will include MRI image, clinical status, and socioeconomic status. The clinical information and MRI features extracted using radiomics strategy will be combined for exploratory analysis. The accuracy, sensitivity, and specificity of the model will be assessed using multiple modeling methodologies. Internal and external validation will be used to evaluate the performance of the radiomics model. DISCUSSION: We hypothesized that the findings from this study could provide a critical step towards the prediction of treatment response in children with CP, which could also complement other biomarkers in the development of precision medicine approaches for this severe disorder. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT02979743).

Isolated periventricular pseudocysts do not affect white matter microstructure development in neonatal stage: A retrospective case-control diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Periventricular pseudocysts (PVPCs) are cystic cavities originating from the germinal matrix. The effects of PVPCs on the development of white matter (WM) in neonates remain unclear. This study aimed to characterise WM microstructural variations in neonates with PVPCs with and without additional abnormities on MRI. MATERIALS AND METHODS: Neonates with PVPCs and controls with no MRI abnormalities were retrospectively enrolled. Test subjects were divided into groups 1 (isolated PVPCs) and 2 (PVPCs with additional MRI abnormalities). The PVPC MRI features collected included lateralisation, locularity, anatomic location, and the maximum anteroposterior diameter. Diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were compared between the PVPC and control groups using tract-based spatial statistics. RESULTS: Thirty-eight neonates with PVPCs and 60 controls were enrolled. Groups 1 and 2 contained 15 and 23 subjects, respectively. The additional MRI findings in group 2 included intracranial haemorrhage, punctate WM lesions, hypoxic-ischaemic encephalopathy, and acute cerebral infarction. No significant differences were found in PVPC MRI features between the 2 test groups. Compared to controls, no significant changes in DTI metrics were observed in group 1 neonates; whereas extensive WM regions with decreased FA, increased RD, and unchanged/increased AD were found in group 2. CONCLUSIONS: Isolated PVPCs are not independently correlated with WM microstructural variations in neonates. This result provides further evidence for supporting the benign outcome of fetuses with isolated PVPCs.

Urban-rural-specific trend in prevalence of general and central obesity, and association with hypertension in Chinese adults, aged 18-65 years.

BACKGROUND: China has the largest obese population in the world, and the prevalence of central obesity is increasing dramatically in China. Moreover, the rapid economic growth of China in recent decades has led to rapid urbanization in rural China. However, studies comparing the prevalence trends of different types of obesity and the association of obesity with hypertension between urban and rural areas in China are very scarce, and most studies have focused only on the difference in the prevalence of overweight and general obesity or hypertension among rural and urban populations. Therefore, the focus of this study was to examine the shifts in the overall distribution of the prevalence of different types of obesity and to estimate the risk of hypertension in different types of obesity among urban and rural adults aged 18-65 years. METHODS: Seven iterations of the China Health and Nutrition Survey (CHNS), conducted in 1993, 1997, 2000, 2004, 2006, 2009 and 2011, were used in this study. A total of 53,636 participants aged 18-65 years were included. Obesity was classified into three types based on body mass index (BMI) and waist circumference (WC). A log-binomial model was constructed to estimate the prevalence ratio (PR) of hypertension with three types of obesity. RESULTS: The age-standardized prevalence of central obesity only, general obesity only, and both central and general obesity increased from 15.8, 0.2 and 2.9% in 1993 to 30.3, 0.9 and 10.3% in 2011, respectively. The prevalence of central obesity only (urban vs. rural: 20.8% vs. 13.4% in 1993, 29.6% vs. 30.6% in 2011) and both central and general obesity (urban vs. rural: 3.5% vs. 2.5% in 1993, 10.0% vs. 10.6% in 2011) in rural adults exceeded that in urban adults in 2011. Participants with both central and general obesity had the highest risk for incident hypertension compared with those with normal body measurements (adjusted PR, urban: 2.30 (95% CI, 2.01-2.63), rural: 2.50 (95% CI, 2.25-2.77)). CONCLUSIONS: Both WC and BMI should be considered measures of obesity and targeted in hypertension prevention. More attention should be paid to the incidence of central obesity in adults in rural China.

Chromosome mapping, molecular cloning and expression analysis of a novel gene response for leaf width in rice.

Genetic analysis revealed that narrow leaf, small panicle, thin and slender stems as well as low fertility rate of an Indica rice variety were recessive traits and controlled by a single gene. Applying map-based cloning strategy, a novel narrow leaf gene, which was named nal11 was delimited to an interval of 58.3 kb between the InDel markers N10 and InD5016. There are 9 genes in the mapping interval, and only a heat shock DNAJ protein encode gene (Os07g09450) has a specific G to T SNP, which was occurred at the last base of the second exon of Os07g09450 in ZYX. 5' and 3' RACE result shown that there were two transcripts in NAL11, and the SNP in nal11 leads to a variable shear of mRNA. In addition, this type of mRNA alternative splicing together with a stop codon closely followed the SNP which caused termination of translation destroyed the DNAJ domain of nal11's product. These results suggested that the heat shock DNAJ gene was most likely to be the candidate gene of nal11. The results of RT-PCR and real-time PCR further verified that the SNP in the ZYX-nal11 gene affects mRNA splicing pattern. Phenotype of ZYX may be caused by a statistically significant reduction in the total number of small veins in leaf, size and number of small vascular bundles and cells in stems, similar to several previous reported mutations. The basic molecular information we provide here will be useful for further investigations of the physiological function of the heat shock DNAJ gene, which will be helpful in better understanding the role of the DNAJ family in regulation of plant type traits such as leaf width of rice.

Quantitative trait loci identification and meta-analysis for rice panicle-related traits.

Rice yield is a complex trait controlled by quantitative trait loci (QTLs). In the past three decades, thousands of QTLs for rice yield traits have been detected, but only a very small percentage has been cloned to date, as identifying the QTL genes requires a substantial investment of time and money. Meta-analysis provides a simple, reliable, and economical method for integrating information from multiple QTL studies across various environmental and genetic backgrounds, detecting consistent QTLs powerfully and estimating their genetic positions precisely. In this study, we aimed to locate consistent QTL regions associated with rice panicle traits by applying a genome-wide QTL meta-analysis approach. We first conducted a QTL analysis of 5 rice panicle traits using 172 plants in 2011 and 138 plants in 2012 from an F2 population derived from a cross between Nipponbare and H71D rice cultivators. A total of 54 QTLs were detected, and these were combined with 1085 QTLs collected from 82 previous studies to perform a meta-analysis using BioMercator v4.2. The integration of 82 maps resulted in a consensus map with 6970 markers and a total map length of 1823.1 centimorgan (cM), on which 837 QTLs were projected. These QTLs were then integrated into 87 meta-quantitative trait loci (MQTLs) by meta-analysis, and the 95 % confidence intervals (CI) of them were smaller than the mean value of the original QTLs. Also, 30 MQTLs covered 47 of the 54 QTLs detected from the cross between Nipponbare and H71D in this study. Among them, the two major and stable QTLs, spp10.1 and sd10.1, were found to be included in MQTL10.4. The three other major QTLs, pl3.1, sb2.1, and sb10.1, were included in MQTL3.3, MQTL2.2, and MQTL10.3, respectively. A total of 21 of the 87 MQTLs' phenotypic variation were >20 %. In total, 24 candidate genes were found in 15 MQTLs that spanned physical intervals <0.2 Mb, including genes that have been cloned previously, e.g., EP3, LP, MIP1, HTD1, DSH1, and OsPNH1. However, it would be beneficial to identify a greater number of candidate genes from these MQTLs. Mining new genes that modulate yield and its related traits would assist researchers to better understand the relevant molecular mechanisms. The MQTLs found in this study that have small physical and genetic intervals are useful not only for marker-assisted selection and pyramiding, but they also provide important information of rice yield and related gene mining for future research.