Though cardiovascular diseases (CVDs) and gastrointestinal disorders (GIDs) are different diseases associated with different organs, they are highly correlated clinically. Importantly, in Traditional Chinese Medicine (TCM), similar treatment strategies have been applied in both diseases. However, the etiological mechanisms underlying them remain unclear. Here, an integrated systems pharmacology approach is presented for illustrating the molecular correlations between CVDs and GIDs. Firstly, we identified pairs of genes that are associated with CVDs and GIDs and found that these genes are functionally related. Then, the association between 115 heart meridian (HM) herbs and 163 stomach meridian (SM) herbs and their combination application in Chinese patent medicine was investigated, implying that both CVDs and GIDs can be treated by the same strategy. Exemplified by a classical formula Sanhe Decoration (SHD) treating chronic gastritis, we applied systems-based analysis to introduce a drug-target-pathway-organ network that clarifies mechanisms of different diseases being treated by the same strategy. The results indicate that SHD regulated several pathological processes involved in both CVDs and GIDs. We experimentally confirmed the predictions implied by the effect of SHD for myocardial ischemia. The systems pharmacology suggests a novel integrated strategy for rational drug development for complex associated diseases.Over the past decade, there has been a marked increase in our understanding that there are higher prevalence rates of gastrointestinal disease (GIDs) in patients with cardiovascular disease (CVDs) 1,2 with similar dysfunctional phenotypes, such as rib pain, stomach pain, nausea and vomiting. However, the underlying co-occurrence mechanisms of CVDs and GIDs are unclear, thereby hampering development of drugs for both diseases in humans 3 . In modern Western medicine, usually, it has been observed that cardiovascular diseases have an etiological relationship with gastrointestinal disorders. Several studies have reported that the risk of cardiovascular disease in patients with gastrointestinal disease appears to be far greater than in the general population 4 . Moreover, some gastrointestinal disorders may increase patients' risk of cardiovascular disease as well. For example, patients with chronic gastrointestinal ischemia have an increased CVDs' risk and excess mortality 5 . Furthermore, the pathophysiological mechanisms between the two organs would supply realistic treatment for CVDs and GIDs 6 . For example, Iranian traditional physicians have introduced several remedies for heart-stomach association ailments in a previous study 7 . In addition, novel studies demonstrated the close relationship between gastroesophageal reflux disease (GERD) and the development of atrial fibrillation (AF), notably, acid-suppressive therapy is an effective strategy for the management of AF and may help to minimize the use of anti-arrhythmic agents 8,9 .

This perspective aims to provide a global view on polypharmacology, which is the foundation of the next paradigm in drug discovery.

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A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference for bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid (RA)-induced differentiation. To accommodate this elevated energy demand, RA signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. Disrupting mitochondrial respiration significantly blocked spermatogonial differentiation. Inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway also repressed the formation of c-Kit + differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon RA-induced differentiation, with both RNAseq and quantitative proteomic analyses. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration that is required for spermatogonial proliferation and differentiation.

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future.

Improvement in growth and fatness traits are the main objectives in pig all breeding programs. Tenth rib backfat thickness (10RIBBFT) and days to 100 kg (D100), which are good predictors of carcass lean content and growth rate, respectively, are economically important traits and also main breeding target traits in pigs. To investigate the genetic mechanisms of 10RIBBFT and D100 of pigs, we sampled 1,137 and 888 pigs from 2 Yorkshire populations of American and British origin, respectively, and conducted genome-wide association study (GWAS) through combined analysis and meta-analysis, to identify SNPs associated with 10RIBBFT and D100. A total of 11 and 7 significant SNPs were identified by combined analysis for 10RIBBFT and D100, respectively. And in meta-analysis, 8 and 7 significant SNPs were identified for 10RIBBFT and D100, respectively. Among them, 6 and 5 common significant SNPs in two analysis results were, respectively, identified associated with 10RIBBFT and D100, and correspondingly explained 2.09% and 0.52% of the additive genetic variance of 10RIBBFT and D100. Further bioinformatics analysis revealed 10 genes harboring or close to these common significant SNPs, 5 for 10RIBBFT and 5 for D100. In particular, Gene Ontology analysis highlighted 6 genes, PCK1, ANGPTL3, EEF1A2, TNFAIP8L3, PITX2, and PLA2G12, as promising candidate genes relevant with backfat thickness and growth. PCK1, ANGPTL3, EEF1A2, and TNFAIP8L3 could influence backfat thickness through phospholipid transport, regulation of lipid metabolic process through the glycerophospholipid biosynthesis and metabolism pathway, the metabolism of lipids and lipoproteins pathway. PITX2 has a crucial role in skeletal muscle tissue development and animal organ morphogenesis, and PLA2G12A plays a role in the lipid catabolic and phospholipid catabolic processes, which both are involved in the body weight pathway. All these candidate genes could directly or indirectly influence fat production and growth in Yorkshire pigs. Our findings provide novel insights into the genetic basis of growth and fatness traits in pigs. The candidate genes for D100 and 10RIBBFT are worthy of further investigation.

Specific DNA mutations underlying several genetic defects associated with embryo loss or reduced calf survivability have been identified in dairy cattle, and a convenient and cost-effective platform is required for their routine screening. We developed Kompetitive allele-specific PCR (KASP) assays for discrimination of the wild-type alleles from the associated defective alleles at each of 8 common genetic defects in Holstein cattle, involving 5 SNP [HH1, HH3, HH4, bovine leukocyte adhesion deficiency (BLAD), and complex vertebral malformation (CVM)] and 3 insertion or deletion mutations [HH5, haplotype for cholesterol deficiency (HCD), and brachyspina (BS)]. A total of 390 cows from a Chinese Holstein herd were genotyped and the carriers identified at 7 of these 8 loci (except HH4), with the highest carrier frequencies found for CVM (10.5%) and HH1 (10.0%), followed by HH3 (2.6%), BS (2.1%), HCD (1.3%), HH5 (0.8%), and BLAD (0.5%). Surprisingly, 102 cows (26.2%) carried at least 1 of the 7 defective alleles. Our results demonstrate that these KASP assays are simple, rapid, and reliable for the detection of multiple genetic defects. The high carrier frequency of these genetic defects indicates an urgent need for routine molecular testing to eliminate the deleterious alleles from Chinese Holstein cattle.

LATERAL ORGAN BOUNDARIES DOMAIN (LBD) proteins, a family of plant-specific transcription factors harboring a conserved Lateral Organ Boundaries (LOB) domain, are regulators of plant organ development. Recent studies haveunraveled additional pivotal roles of the LBD protein family beyond defining lateral organ boundaries, such as pollen development and nitrogen metabolism. The structural basis for the molecular network of LBD-dependent processes remains to be deciphered. Here, we solved the first structure of the homodimeric LOB domain of Ramosa2 from wheat (TtRa2LD) to 1.9 Å resolution. Our crystal structure reveals structural features shared with other zinc-finger transcriptional factors, as well as some features unique to LBD proteins. Formation of the TtRa2LD homodimer relied on hydrophobic interactions of its coiled-coil motifs. Several specific motifs/domains of the LBD protein were also involved in maintaining its overall conformation. The intricate assembly within and between the monomers determined the precise spatial configuration of the two zinc fingers that recognize palindromic DNA sequences. Biochemical, molecular modeling, and small-angle X-ray scattering experiments indicated that dimerization is important for cooperative DNA binding and discrimination of palindromic DNA through a molecular calipers mechanism. Along with previously published data, this study enables us to establish an atomic-scale mechanistic model for LBD proteins as transcriptional regulators in plants.