Heterogeneous Family Research Articles

Distinct Proteomic Profiling of Plasma Extracellular Vesicles from Moderate-to-Severe Atopic Dermatitis Patients.

BackgroundAtopic dermatitis (AD) is a chronic, inflammatory cutaneous disorder characterized by a T helper 2 (Th2) immune response phenotype. Extracellular vesicles (EVs) are a heterogeneous family of cell-derived membranous structures, which transport cellular components such as DNA and proteins, and are involved in multiple physiological and pathological processes. Increasing evidence has shown that EVs secretion took part in the pathogenesis of AD. However, the proteomic studies of plasma-derived EVs in AD patients have not been reported.ObjectiveIn this study, we investigated the diversity of plasma EVs collected from AD patients and healthy individuals and suggested that the candidates for uniquely or differentially expressed proteins in plasma EVs could be a diagnostic marker in AD.MethodsThe plasma EVs were collected from 12 patients with moderate-to-severe AD and 13 healthy subjects. Proteomic analysis was performed by using a comprehensive nanoLC‑MS/MS method.ResultsProteomic analysis revealed that a total of 1478 proteins in plasma EVs were found to be common proteins in AD, whereas a total of 1597 proteins in plasma EVs were found to be common proteins in HC. Eighty-six proteins in plasma EVs showed more than 2.5-fold up-regulation, while a total of 225 proteins in plasma EVs showed less than 1/2.5-fold down-regulation with a significant difference (p < 0.05) among AD compared with HC. The candidates for differentially expressed proteins in plasma EVs have been described as a connectivity PPI network related to several KEGG pathways, including pathways in platelet activation, complement, and so on.ConclusionSLP-76 tyrosine phosphoprotein (SLP76) involved in platelet activation may significantly contribute to the pathogenesis of AD. We will further verify the role of SLP67 in AD via animal and cell experiments to provide a promising therapeutic or diagnostic target.

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Simple SummaryThe advent of DNA massive sequencing technologies has allowed for the first time an extensive look into the heterogeneous spectrum of genes and mutations underpinning myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). In this review, we wish to explore the most recent advances and the rationale for the potential therapeutic interest of three main actors in myelo-leukemic transformation: transcription factors that govern myeloid differentiation; RNA splicing factors, which ensure proper mRNA maturation and whose mutations increase R-loops formation; and deubiquitinating enzymes, which contribute to genome stability in hematopoietic stem cells (HSCs).Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.

Ultra-High-Density QTL Marker Mapping for Seedling Photomorphogenesis Mediating Arabidopsis Establishment in Southern Patagonia.

Arabidopsis thaliana shows a wide range of genetic and trait variation among wild accessions. Because of its unparalleled biological and genomic resources, Arabidopsis has a high potential for the identification of genes underlying ecologically important complex traits, thus providing new insights on genome evolution. Previous research suggested that distinct light responses were crucial for Arabidopsis establishment in a peculiar ecological niche of southern Patagonia. The aim of this study was to explore the genetic basis of contrasting light-associated physiological traits that may have mediated the rapid adaptation to this new environment. From a biparental cross between the photomorphogenic contrasting accessions Patagonia (Pat) and Columbia (Col-0), we generated a novel recombinant inbred line (RIL) population, which was entirely next-generation sequenced to achieve ultra-high-density saturating molecular markers resulting in supreme mapping sensitivity. We validated the quality of the RIL population by quantitative trait loci (QTL) mapping for seedling de-etiolation, finding seven QTLs for hypocotyl length in the dark and continuous blue light (Bc), continuous red light (Rc), and continuous far-red light (FRc). The most relevant QTLs, Rc1 and Bc1, were mapped close together to chromosome V; the former for Rc and Rc/dark, and the latter for Bc, FRc, and dark treatments. The additive effects of both QTLs were confirmed by independent heterogeneous inbred families (HIFs), and we explored TZP and ABA1 as potential candidate genes for Rc1 and Bc1QTLs, respectively. We conclude that the Pat × Col-0 RIL population is a valuable novel genetic resource to explore other adaptive traits in Arabidopsis.

HNRNPH1 Is a Novel Regulator Of Cellular Proliferation and Disease Progression in Chronic Myeloid Leukemia.

RNA binding proteins act as essential modulators in cancers by regulating biological cellular processes. Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), as a key member of the heterogeneous nuclear ribonucleoproteins family, is frequently upregulated in multiple cancer cells and involved in tumorigenesis. However, the function of HNRNPH1 in chronic myeloid leukemia (CML) remains unclear. In the present study, we revealed that HNRNPH1 expression level was upregulated in CML patients and cell lines. Moreover, the higher level of HNRNPH1 was correlated with disease progression of CML. In vivo and in vitro experiments showed that knockdown of HNRNPH1 inhibited cell proliferation and promoted cell apoptosis in CML cells. Importantly, knockdown of HNRNPH1 in CML cells enhanced sensitivity to imatinib. Mechanically, HNRNPH1 could bind to the mRNA of PTPN6 and negatively regulated its expression. PTPN6 mediated the regulation between HNRNPH1 and PI3K/AKT activation. Furthermore, the HNRNPH1–PTPN6–PI3K/AKT axis played a critical role in CML tumorigenesis and development. The present study first investigated the deregulated HNRNPH1–PTPN6–PI3K/AKT axis moderated cell growth and apoptosis in CML cells, whereby targeting this pathway may be a therapeutic CML treatment.

Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives.

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.

Consumption inequality across heterogeneous families

What does preference heterogeneity imply for consumption inequality? This paper studies the link from wage to consumption inequality within a lifecycle model of consumption and family labor supply. Its distinctive feature is that households have general heterogeneous preferences over consumption and labor supply. The paper shows identification of the joint distribution of unobserved household preferences separately from the observed distributions of incomes and outcomes. Estimation on data from the Panel Study of Income Dynamics in the US reveals substantial unexplained heterogeneity in consumption preferences but little unexplained heterogeneity in labor supply preferences. Preference heterogeneity accounts for about a third of consumption inequality in recent years and implies, on average, lower partial insurance of wage shocks compared to recent studies in the literature.

The Sulfation Code of Tauopathies: Heparan Sulfate Proteoglycans in the Prion Like Spread of Tau Pathology.

Tauopathies are a heterogenous family of progressive neurodegenerative diseases defined by the appearance of proteinaceous lesions within the brain composed of abnormally folded species of Microtubule Associated Protein Tau (tau). Alzheimer’s Disease (AD), the most common tauopathy, is the leading cause of cognitive decline among the elderly and is responsible for more than half of all cases of senile dementia worldwide. The characteristic pathology of many tauopathies—AD included—presents as Neurofibrillary Tangles (NFTs), insoluble inclusions found within the neurons of the central nervous system composed primarily of tau protein arranged into Paired Helical Fibrils (PHFs). The spatial extent of this pathology evolves in a remarkably consistent pattern over the course of disease progression. Among the leading hypotheses which seek to explain the stereotypical progression of tauopathies is the prion model, which proposes that the spread of tau pathology is mediated by the transmission of self-propagating tau conformers between cells in a fashion analogous to the mechanism of communicable prion diseases. Protein-glycan interactions between tau and Heparan Sulfate Proteoglycans (HSPGs) have been implicated as a key facilitator in each stage of the prion-like propagation of tau pathology, from the initial secretion of intracellular tau protein into the extracellular matrix, to the uptake of pathogenic tau seeds by cells, and the self-assembly of tau into higher order aggregates. In this review we outline the biochemical basis of the tau-HS interaction and discuss our current understanding of the mechanisms by which these interactions contribute to the propagation of tau pathology in tauopathies, with a particular focus on AD.

Fossil record of Celastraceae: evaluation and potential use in molecular calibrations

Background: Celastraceae is a morphologically heterogeneous family. For this reason, the inclusion of some taxa within this group is controversial. Recently this problem has become significant since its fossil record is recognized as an important source of information for evolutionary studies, especially those using molecular clocks which require a robust, reliable fossil record.&#x0D; Questions: What are the most reliable fossil records of Celastraceae? What morphological characters are used to assign fossils in the family?&#x0D; Study site and dates: Compilation of records contained in paleontological databases, and paleobotanical literature, covering publications from 1869 to 2018.&#x0D; Methods: Published information on the Celastraceae fossil record was compiled and analyzed using the most recent classification system and specialized literature on the family.&#x0D; Results: A total of 168 fossil records were examined, of which nine are proposed for use as molecular clock calibration points. Each specimen has a description based on a character set used for its identification, a photograph and/or illustration, their geological age is well supported, their geographic origin is known, and the specimens are in accredited home institutions with publicly accessible collections.&#x0D; Conclusions: The identification and establishment of relationships between fossil and extant taxa have important limitations that depend on the critical interpretation of morphology in a phylogenetic context. Therefore, it is essential to incorporate only those morphological studies in Celastraceae that help clarify its fossil record.

Expression pattern of matrix metalloproteinases-2 and -9 and their tissue inhibitors in patients with chronic inflammatory demyelinating polyneuropathy

Matrix metalloproteinases (MMPs) are a heterogeneous family of endopeptidases that play a role in many physiological functions, including the immune response. An imbalance between the activity of MMPs and their physiological tissue inhibitors (TIMPs) has been proposed in the pathophysiology of different autoimmune disorders. We aimed to assess the plasmatic levels of MMP-2, MMP-9, and their inhibitors TIMP-1 and -2 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Twenty patients with CIDP and 20 age- and sex-matched healthy controls were enrolled. Plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by the enzyme-linked immunosorbent assay. CIDP subjects had higher MMP-9 concentrations along with TIMP-1 downregulation when compared to controls, with the consequent increase in the MMP-9/TIMP-1 ratio (p<0.000002 for all measures). Conversely, the concentration of MMP-2 was lower in the CIDP group (p<0.01) without changes in the TIMP-2 concentration. The MMP-2/TIMP-2 ratio was decreased in the patients' group (p<0.02). We provide first preliminary evidence that the plasmatic pattern of MMPs and TIMPs is markedly altered in patients with CIDP. Future studies are needed to assess the potential usefulness of these new biomarkers in the clinical setting.

Venturing Motives and Venturing Types in Entrepreneurial Families: A Corporate Entrepreneurship Perspective

Current research suggests that entrepreneurship in the family business context is mainly induced by top-down firm-level activity. We propose that entrepreneurial activity is also initiated autonomously as a bottom-up process by individual members or a group of individual members of an entrepreneurial family (EF). Building on 63 interviews with EF members involved in 39 venturing cases, we reveal a set of unique motives driving the venturing activity and show how these motives are intertwined with six heterogeneous family venture types. We also emphasize how positioning (i.e., inside or outside of family firms’ boundaries), family support, emotional attachment, and transgenerational intention vary among the different venture types.

Validation of functional polymorphisms affecting maize plant height by unoccupied aerial systems discovers novel temporal phenotypes.

Plant height (PHT) in maize (Zea mays L.) has been scrutinized genetically and phenotypically due to relationship with other agronomically valuable traits (e.g., yield). Heritable variation of PHT is determined by many discovered quantitative trait loci; however, phenotypic effects of such loci often lack validation across environments and genetic backgrounds, especially in the hybrid state grown by farmers rather than the inbred state more often used by geneticists. A previous genome-wide association study using a topcrossed hybrid diversity panel identified two novel quantitative trait variants controlling both PHT and grain yield. Here, heterogeneous inbred families demonstrated that these two loci, characterized by two single nucleotide polymorphisms (SNPs), cause phenotypic variation in inbred lines, but that size of these effects were variable across four different genetic backgrounds, ranging from 1 to 10 cm. Weekly unoccupied aerial system flights demonstrated the two SNPs had larger effects, varying from 10 to 25 cm, in early growth while effects decreased toward the end of the season. These results show that allelic effect sizes of economically valuable loci are both dynamic in temporal growth and dynamic across genetic backgrounds, resulting in informative phenotypic variability overlooked following traditional phenotyping methods. Public genotyping data show recent favorable allele selection in elite temperate germplasm with little change across tropical backgrounds. As these loci remain rarer in tropical germplasm, with effects most visible early in growth, they are useful for breeding and selection to expand the genetic basis of maize.

Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms?

Simple SummaryNeuroendocrine neoplasms are highly heterogeneous tumors in terms of primary origin, molecular landscape, clinical presentation and behavior. To date, several drugs have been approved and many ongoing trials are testing new agents or new combinations. In this work we aim to provide a comprehensive review of approved agents and promising novel drugs in clinical development for the treatment of neuroendocrine neoplasms. Our manuscript could be a useful review and guidance for neuroendocrine neoplasms-dedicated clinicians.Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.

Bioinformatics Identification of Green Tea Anticancer Properties: a Network-Based Approach

Background and objectives: Promising anticancer properties are associated with the consumption of green tea. On the other hand, lung cancer has been showing to possess the highest number of death compared to other types of cancer. The aim of this study was to understand the mechanisms by which green tea shows this effect; bioinformatics study of proteome profile could be essential. For this reason, the proteomics analysis of human lung adenocarcinoma A-549 cells treated with green tea extract was chosen for protein-protein interaction (PPI) network analysis. Methods: Cytoscape v.3.8.2 and its applications analyzed a number of 14 differentially expressed proteins (DEPs) from green tea treatment experiment as two networks. The biological annotations and action type exploration of the hub-bottlenecks of the PPI network were then carried out. Results. The investigation indicated that among 14 queries DEPs, HNRNPA2B1, PCBP1, and HNRNPC may show substantial role. Moreover, HSPA8 was the top hub-bottleneck and half of the central protein groups were enriched with heterogeneous nuclear ribonucleoproteins complex family (HNRNPs). Conclusion. The anticancer bioinformatics study of green tea suggests a complex nature for green tea. This finding urges complementary evaluations to validate whether green tea is applicable as an anticancer agent in medicine.

Establishment of an Academic Tissue Microarray Platform as a Tool for Soft Tissue Sarcoma Research.

Soft tissue sarcoma (STS) is a heterogeneous family of rare mesenchymal tumors, characterized by histopathological and molecular diversity. Tissue microarray (TMA) is a tool that allows performing research in orphan diseases in a more efficient and cost-effective way. TMAs are paraffin blocks consisting of multiple small representative tissue cores from biological samples, for example, from multiple donors, diverse sites of disease, or multiple different diseases. In 2015, we began constructing TMAs using archival tumor material from STS patients. Specimens were well annotated in terms of histopathological diagnosis, treatment, and clinical follow-up of the tissue donors. Each TMA block contains duplicate or triplicate 1.0–1.5 mm tissue cores from representative tumor areas selected by sarcoma pathologists. The construction of TMAs was performed with TMA Grand Master (3DHistech). So far, we have established disease-specific TMAs from 7 STS subtypes: gastrointestinal stromal tumor (72 cases included in the array), alveolar soft part sarcoma (n = 12 + 47), clear cell sarcoma (n = 22 + 32), leiomyosarcoma (n = 55), liposarcoma (n = 42), inflammatory myofibroblastic tumor (n = 12 + 21), and alveolar rhabdomyosarcoma (n = 24). We also constructed a multisarcoma TMA covering a representative number of important histopathological subtypes on arrays for screening purposes, namely, angiosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxoid liposarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma, with 7–11 individual cases per subtype. We are currently expanding the list of TMAs with additional sarcoma entities, considering the heterogeneity of this family of tumors. Our extensive STS TMA platform is suitable for rapid and cost-effective morphological, immunohistochemical, and molecular characterization of the tumor as well as for the identification of potential novel diagnostic markers and drug targets. It is readily available for collaborative projects with research partners.

Fine mapping identifies NAD-ME1 as a candidate underlying a major locus controlling temporal variation in primary and specialized metabolism in Arabidopsis.

Plant metabolism is modulated by a complex interplay between internal signals and external cues. A major goal of all quantitative metabolomic studies is to clone the underlying genes to understand the mechanistic basis of this variation. Using fine-scale genetic mapping, in this work we report the identification and initial characterization of NAD-DEPENDENT MALIC ENZYME 1 (NAD-ME1) as the candidate gene underlying the pleiotropic network Met.II.15 quantitative trait locus controlling variation in plant metabolism and circadian clock outputs in the Bay×Sha Arabidopsis population. Transcript abundance and promoter analysis in NAD-ME1Bay-0 and NAD-ME1Sha alleles confirmed allele-specific expression that appears to be due a polymorphism disrupting a putative circadian cis-element binding site. Analysis of transfer DNA insertion lines and heterogeneous inbred families showed that transcript variation of the NAD-ME1 gene led to temporal shifts of tricarboxylic acid cycle intermediates, glucosinolate (GSL) accumulation, and altered regulation of several GSL biosynthesis pathway genes. Untargeted metabolomic analyses revealed complex regulatory networks of NAD-ME1 dependent upon the daytime. The mutant led to shifts in plant primary metabolites, cell wall components, isoprenoids, fatty acids, and plant immunity phytochemicals, among others. Our findings suggest that NAD-ME1 may act as a key gene to coordinate plant primary and secondary metabolism in a time-dependent manner.

The cost of clean energy transition in rural China: Evidence based on marginal treatment effects

The clean energy transition in residential sector in rural China is of great significance for climate change mitigation. Using rural household survey from 2005 to 2008, we estimate the marginal treatment effects of using gas on energy expenses in rural China based on the generalized Roy model. Generally, using gas increases the rural household expense on fuel by 65%–80% on average. Essential heterogeneity are proved across different households. The households with lower income, lower educational attainment, smaller floor space are less willing to use gas as their main fuel. The policy-relevant treatment effects show that the household expenses on fuel would increase by at least 80% if the popularity of gas doubled, which might worsen the financial condition of poor families. The policy simulation results imply more flexible rural energy policies should be concerned for heterogeneous families.

Transient receptor potential (TRP) channels in human colorectal cancer: evidence and perspectives.

Colorectal cancer (CRC) is one of the leading causes of death in the civilized world. Transient receptor potential channels (TRPs) are a heterogeneous family of cation channels that play an important role in gastrointestinal physiology. TRPs have been linked with carcinogenesis in the colon and their role as potential therapeutic targets and prognostic biomarkers is under investigation.

Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors.

Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.

Somatostatin-Dopamine Chimeric Molecules in Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) are a widely heterogeneous family of neoplasms arising from neuroendocrine cells, which are interspersed throughout the body. Despite NENs are relatively rare, their incidence and prevalence are constantly increasing probably due to the improvement in earlier diagnosis and patients’ management. When surgery is not curative, particularly for patients with metastatic disease, several medical options are available. Somatostatin analogues (SSA) are the first-line medical therapy for well-differentiated NENs. Interestingly, the heterodimerization of somatostatin receptors (SSTs) with dopamine receptors (DRs) has been discovered in NENs. This phenomenon results in hybrid receptors with enhanced functional activity. On these bases, chimeric molecules embracing somatostatin and dopamine features have been recently developed. The aim of this review is to provide a comprehensive overview of the available preclinical and clinical data regarding chimeric somatostatin-dopamine agonists as a new class of “magic bullet” in the therapy of NENs.

Mapping quantitative trait loci and predicting candidate genes for leaf angle in maize

Leaf angle of maize is a fundamental determinant of plant architecture and an important trait influencing photosynthetic efficiency and crop yields. To broaden our understanding of the genetic mechanisms of leaf angle formation, we constructed a F3:4 recombinant inbred lines (RIL) population to map QTL for leaf angle. The RIL was derived from a cross between a model inbred line (B73) with expanded leaf architecture and an elite inbred line (Zheng58) with compact leaf architecture. A sum of eight QTL were detected on chromosome 1, 2, 3, 4 and 8. Single QTL explained 4.3 to 14.2% of the leaf angle variance. Additionally, some important QTL were confirmed through a heterogeneous inbred family (HIF) approach. Furthermore, twenty-four candidate genes for leaf angle were predicted through whole-genome re-sequencing and expression analysis in qLA02-01and qLA08-01 regions. These results will be helpful to elucidate the genetic mechanism of leaf angle formation in maize and benefit to clone the favorable allele for leaf angle. Besides, this will be helpful to develop the novel maize varieties with ideal plant architecture through marker-assisted selection.