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Despite a strong genetic component, only a few genes have been identified in congenital heart diseases (CHDs). We introduced systems analyses to uncover the hidden organization on biological networks of mutations in CHDs and leveraged network analysis to integrate the protein interactome, patient exomes, and single-cell transcriptomes of the developing heart. We identified a CHD network regulating heart development and observed that a sub-network also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHDs and neurodevelopmental conditions. At a small scale, we experimentally verified uncharacterized cardiac functions of several proteins. At a global scale, our study revealed developmental dynamics of the network and observed its association with the hypoplastic left heart syndrome (HLHS), which was further supported by the dysregulation of the network in HLHS endothelial cells. Overall, our work identified previously uncharacterized CHD factors and provided a generalizable framework applicable to studying many other complex diseases. A record of this paper's Transparent Peer Review process is included in the supplemental information.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

AbstractCongenital heart diseases (CHD) are a class of birth defects affecting ∼1% of live births. These conditions are hallmarked by extreme genetic heterogeneity, and therefore, despite a strong genetic component, only a very handful of at-risk loci in CHD have been identified. We herein introduced systems analyses to uncover the hidden organization on biological networks of genomic mutations in CHD, and leveraged network analysis techniques to integrate the human interactome, large-scale patient exomes, the fetal heart spatial transcriptomes, and single-cell transcriptomes of clinical samples. We identified a highly connected network in CHD where most of the member proteins had previously uncharacterized functions in regulating fetal heart development. While genes on the network displayed strong enrichment for heart-specific functions, a sub-group, active specifically at early developmental stages, also regulates fetal brain development, thereby providing mechanistic insights into the clinical comorbidities between CHD and neurodevelopmental conditions. At a small scale, we experimentally verified previously uncharacterized cardiac functions of several novel proteins employing cellular assays and gene editing techniques. At a global scale, our study revealed developmental dynamics of the identified CHD network and observed the strongest enrichment for pathogenic mutations in the network specific to hypoplastic left heart syndrome (HLHS). Our single-cell transcriptome analysis further identified pervasive dysregulation of the network in cardiac endothelial cells and the conduction system in the HLHS left ventricle. Taken together, our systems analyses identified novel factors in CHD, revealed key molecular mechanisms in HLHS, and provides a generalizable framework readily applicable to studying many other complex diseases.

【Objective】 Soil temperature affects crop growth and biogeochemical processes in terrestrial systems, and understanding its variation is hence important to evaluate the impact of global warming on agricultural production and soil gas emissions. The aim of this paper is to analyze the change in soil temperature over the past 50 years at Wudaogou Hydrological Station in Anhui province, China. 【Method】 The analysis was based on data measured from 1971 to 2020. Monthly average temperature at different soil depths from 0 to 320 cm, as well as their relationship with ambient air temperature was analyzed, using linear trend estimation, M-K test and Morlet wavelet method. 【Result】 ①The temperature at different soil layers has changed. Except in the period from June to September, soil temperature in other months has been in increase, with the largest increase seen in March and the least increase in October. Temperature in the depths of 0~160 cm has been increasing, with the increasing rate decreasing along the soil depth. In contrast, the temperature at the depth of 320cm has been dropping. ②The wavelet analysis showed two dominant periods in the monthly-average temperature: 3~6, 8~12 a, and a further period of 15~25 a. ③The M-K mutation test showed that the temperature at depths from 0 to 320 cm had undergone abrupt changes in 2012, 2017, 2016, 2019 and 1972. ④The temperature at different soil depths was correlated with ambient air temperature differently, with the temperature in the depths of 0~80 cm being more sensitive to air temperature. No correlation was found between the air temperature and soil temperature at the depth of 320 cm. 【Conclusion】 The monthly average temperature at different soil layers has been in increase over the past centuries, likely due to global warming, though the increasing rate and its correlation with air temperature varied with soil depth.

We investigated the effect of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) on lymphocytes and white blood cells of patients with malignant tumors. After PEG-rhG-CSF treatment, the count of lymphocytes increased in 66 cases, remained unchanged in 2 cases, and decreased in 20 cases. The difference in lymphocyte count before and after treatment was statistically significant (P < 0.001). White blood cell changes were positively correlated with lymphocyte changes (r = 0.36, P = 0.001). In the subgroup with increased white blood cells (n = 80), there were 62 cases with increased lymphocytes, 1 case with unchanged lymphocytes, and 17 cases with decreased lymphocytes after PEG-rhG-CSF treatment. There was significant difference in the count of lymphocytes and white blood cells (P < 0.001). In the subgroup with 6 mg of PEG-rhG-CSF (n = 66) and the subgroup with 3 mg of PEG-rhG-CSF (n = 22), the changes of white blood cell and lymphocyte counts before and after treatment were statistically significant (P < 0.001). The two were positively correlated in the 6 mg PEG-rhG-CSF subgroup, with correlation coefficient r = 0.34 (P = 0.002). PEG-rhG-CSF can increase the count of lymphocytes and white blood cells in patients with malignant tumors, and the increase of lymphocytes is positively correlated with the increase of white blood cells.

Bone grafting is crucial for bone regeneration. Recent studies have proposed the use of calcium citrate (CC) as a potential graft material. Notably, citrate does not inhibit hydroxyapatite (HAp) formation at specific calcium-to-citrate molar ratios. Octacalcium phosphate (OCP)/gelatine (Gel) composites, which are commonly produced from porcine Gel, are valued for their biodegradability and bone replacement capability. This study introduces fish Gel as an alternative to porcine Gel because of its wide acceptance and eco-friendliness. This is the first study to examine the interaction effects between two osteogenic materials, OCP/CC, and the influence of different gelatine matrix components on HAp formation in an SBF. Samples with varying CC contents were immersed in an SBF for 7 d and analysed using various techniques, confirming that high CC doses prevent HAp formation, whereas lower doses facilitate it. Notably, small-sized OCP/CC/porcine Gel composites exhibit a high HAp generation rate. Porcine Gel composites form denser HAp clusters, whereas fish Gel composites form larger spherical HAps. This suggests that lower CC doses not only avoid inhibiting HAp formation but also enhance it with the OCP/Gel composite. Compared with porcine Gel, fish Gel composites show less nucleation but an increased crystal growth for HAp. [ABSTRACT FROM AUTHOR]