Tissue-specific O-GlcNAcylation profiling identifies substrates in translational machinery in Drosophila mushroom body contributing to olfactory learning.

O-GlcNAcylation is a dynamic post-translational modification that diversifies the proteome. Its dysregulation is associated with neurological disorders that impair cognitive function, and yet identification of phenotype-relevant candidate substrates in a brain-region specific manner remains unfeasible. By combining an O-GlcNAc binding activity derived from Clostridium perfringens OGA (CpOGA) with TurboID proximity labeling in Drosophila, we developed an O-GlcNAcylation profiling tool that translates O-GlcNAc modification into biotin conjugation for tissue-specific candidate substrates enrichment. We mapped the O-GlcNAc interactome in major brain regions of Drosophila and found that components of the translational machinery, particularly ribosomal subunits, were abundantly O-GlcNAcylated in the mushroom body of Drosophila brain. Hypo-O-GlcNAcylation induced by ectopic expression of active CpOGA in the mushroom body decreased local translational activity, leading to olfactory learning deficits that could be rescued by dMyc overexpression-induced increase of protein synthesis. Our study provides a useful tool for future dissection of tissue-specific functions of O-GlcNAcylation in Drosophila, and suggests a possibility that O-GlcNAcylation impacts cognitive function via regulating regional translational activity in the brain.

Newly synthesized proteins often receive further chemical modifications that change their structure and role in the cell. O-GlcNAcylation, for instance, consists in a certain type of sugar molecule being added onto dedicated protein segments. It is required for the central nervous system to develop and work properly; in fact, several neurological disorders such as Alzheimer's, Parkinson's or Huntington's disease are linked to disruptions in O-GlcNAcylation. However, scientists are currently lacking approaches that would allow them to reliably identify which proteins require O-GlcNAcylation in specific regions of the brain to ensure proper cognitive health. To address this gap, Yu et al. developed a profiling tool that allowed them to probe O-GlcNAcylation protein targets in different tissues of fruit flies. Their approach relies on genetically manipulating the animals so that a certain brain area overproduces two enzymes that work in tandem; the first binds specifically to O-GlcNAcylated proteins, which allows the second to add a small 'biotin' tag to them. Tagged proteins can then be captured and identified. Using this tool helped Yu et al. map out which proteins go through O-GlcNAcylation in various brain regions. This revealed, for example, that in the mushroom body ­ the 'learning center' of the fly brain ­ O-GlcNAcylation occurred predominantly in the protein-building machinery. To investigate the role of O-GlcNAcylation in protein synthesis and learning, Yu et al. used an approach that allowed them to decrease the levels of O-GlcNAcylation in the mushroom body. This resulted in reduced local protein production and the flies performing poorly in olfactory learning tasks. However, artificially increasing protein synthesis reversed these deficits. Overall, the work by Yu et al. provides a useful tool for studying the tissue-specific effects of O-GlcNAcylation in fruit flies, and its role in learning. Further studies should explore how this process may be linked to cognitive function by altering protein synthesis in the brain.

Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming.

Human health is facing a host of new threats linked to unbalanced diets, including high-sugar diet (HSD), which contributes to the development of both metabolic and behavioral disorders. Studies have shown that diet-induced metabolic dysfunctions can be transmitted to multiple generations of offspring and exert long-lasting health burden. Meanwhile, whether and how diet-induced behavioral abnormalities can be transmitted to the offspring remains largely unclear. Here, we showed that ancestral HSD exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila. These behavioral deficits were transmitted through the maternal germline and companied by the enhancement of H3K27me3 modifications. PCL-PRC2 complex, a major driver of H3K27 trimethylation, was upregulated by ancestral HSD exposure, and disrupting its activity eliminated the transgenerational inheritance of sweet sensitivity and feeding behavior deficits. Elevated H3K27me3 inhibited the expression of a transcriptional factor Cad and suppressed sweet sensitivity of the sweet-sensing gustatory neurons, reshaping the sweet perception and feeding behavior of the offspring. Taken together, we uncovered a novel molecular mechanism underlying behavioral abnormalities spanning multiple generations of offspring upon ancestral HSD exposure, which would contribute to the further understanding of long-term health risk of unbalanced diet.

A patent and literature review of CDK12 inhibitors.

INTRODUCTION: Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine protein kinases and is associated with cyclin K to exert its biological functions, including regulating gene transcription, mRNA processing, and translation. Increasing evidences demonstrate the importance of CDK12 in various human cancers, illustrating its potential as both biomarker and therapeutic target. In addition, CDK12 is also a promising target for the treatment of myotonic dystrophy type 1. Efforts have been taken to discover small molecule inhibitors to validate this important therapeutic target. AREAS COVERED: This review covers the patented CDK12 inhibitors from 2016 to present, as well as these from peer-reviewed literature. It provides the reader an update of the discovery strategies, chemical structures, and molecular profiling of all available CDK12 inhibitors. EXPERT OPINION: CDK12 inhibitors with various mechanism of actions have been discovered, and it is a great set of tools to evaluate the therapeutic potential of CDK12 in different disease models. CDK12 inhibitors have shown promising results in myotonic dystrophy type 1 mouse model and several preclinical cancer models either as single agent or combination with other anti-cancer agents. Its therapeutic value awaits more rigorous preclinical testing and further clinical investigation.

Functional reciprocity of proteins involved in mitosis and endocytosis.

Mitosis and endocytosis are two fundamental cellular processes essential for maintaining a eukaryotic life. Mitosis partitions duplicated chromatin enveloped in the nuclear membrane into two new cells, whereas endocytosis takes in extracellular substances through membrane invagination. These two processes are spatiotemporally separated and seemingly unrelated. However, recent studies have uncovered that endocytic proteins have moonlighting functions in mitosis, and mitotic complexes manifest additional roles in endocytosis. In this review, we summarize important proteins or protein complexes that participate in both processes, compare their mechanism of action, and discuss the rationale behind this multifunctionality. We also speculate on the possible origin of the functional reciprocity from an evolutionary perspective.

Receptor for advanced glycation end-product rs1800624 polymorphism contributes to increase breast cancer risk: Evidence from a meta-analysis.

BACKGROUND: Although several studies have identified an association between the receptor for advanced glycation end-product (RAGE) rs1800624 polymorphism and breast cancer, the results have been conflicting. Therefore, we conducted a meta-analysis to assess the relationship between the RAGE rs1800624 polymorphism and breast cancer risk. METHODS: Studies were searched in the PubMed, Web of Science, Embase, Wanfang Med Online, and China National Knowledge Infrastructure databases until September 20, 2019 to identify all potential literature on this association. Fixed-effect or random-effect models were used to calculate odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Subgroup and sensitivity analyses and tests for publication bias were also performed. RESULTS: Five eligible studies involving 2823 subjects (1410 patients and 1413 healthy controls) were included in the current meta-analysis. The pooled analysis indicated a positive correlation between the RAGE rs1800624 polymorphism and the risk of breast cancer in a homozygous genetic model (OR = 1.423, 95% CI = 1.043-1.941, P = .026). Ethnicity-based subgroup analysis demonstrated that RAGE rs1800624 polymorphism may increase the risk of breast cancer in the Asian population in homozygous model (OR = 1.661, 95% CI = 1.178-2.342, P = .004). CONCLUSION: The RAGE rs1800624 polymorphism may increase the risk of breast cancer in the homozygous genetic model, especially in Asian populations. Large-scale and well-designed studies are needed in different populations to further evaluate the role of the RAGE polymorphism in breast cancer.

Association of the IL-1B rs1143623 Polymorphism and Cancer Risk: A Meta-Analysis.

Aim: To derive a more precise association between the interleukin-1 beta (IL-1B) gene polymorphism rs1143623 and cancer risk. Methods: Published case-control studies up to November 5, 2019, that met all inclusion criteria were identified using PubMed, Web of Science, and EMBASE. Odds ratios and 95% confidence intervals were calculated to estimate the strength of associations using multiple genetic models. Sensitivity analyses and publication biases were also performed. Results: Nine articles covering 11 case-control studies, with 4801 cases and 6116 controls, were included in this meta-analysis. No significant association between the IL-1B rs1143623 polymorphism and cancer risk was observed under the homozygous, heterozygous, dominant, recessive, or allelic genetic models (all p > 0.05). Subgroup analysis by ethnicity indicated that the IL-1B rs1143623 polymorphism may decrease the risk of cancer in Asians under the heterozygous and dominant genetic models (both p < 0.05). Sensitivity analyses showed that none of the individual studies significantly affected the overall results. No significant publication biases were detected in this meta-analysis. Conclusion: Our results suggest that there is no significant association between the IL-1B rs1143623 polymorphism and cancer risk in the overall human population, but that it may provide a protective affect among Asians.

The Kinase Activity of Drosophila BubR1 Is Required for Insulin Signaling-Dependent Stem Cell Maintenance.

As a core component of the mitotic checkpoint complex, BubR1 has a modular organization of molecular functions, with KEN box and other motifs at the N terminus inhibiting the anaphase-promoting complex/cyclosome, and a kinase domain at the C terminus, whose function remains unsettled, especially at organismal levels. We generate knock-in BubR1 mutations in the Drosophila genome to separately disrupt the KEN box and the kinase domain. All of the mutants are homozygously viable and fertile and show no defects in mitotic progression. The mutants without kinase activity have an increased lifespan and phenotypic changes associated with attenuated insulin signaling, including reduced InR on the cell membrane, weakened PI3K and AKT activity, and elevated expression of dFoxO targets. The BubR1 kinase-dead mutants have a reduced cap cell number in female germaria, which can be rescued by expressing a constitutively active InR. We conclude that one major physiological role of BubR1 kinase in Drosophila is to modulate insulin signaling.

Anomalous effect of the aging degree on the ionic permeability of silica shells.

We present a systematic study on the ionic permeability and protective ability of silica shells with different aging degrees by using the acid etching of silica-coated iron oxide nanoparticles as the model reaction. Contradictory to common impressions, we found that the ionic permeability of silica shells increased rather than decreased with the increasing aging degree. This trend may be explained by the chemical nature of the sol-gel silica shell that affects the wettability and, thereby, the transportation of water molecules and hydrated ions. Our study provides novel insights into the protective ability of sol-gel derived silica, which enables us to design thin but low-permeability shells for the stability of inner nanoparticles under harsh conditions without scarifying the performance of core-shell nanostructures.

Multidisciplinary team for the diagnosis and treatment of 2 cases of primary intestinal yolk sac tumor.

Extragonadal primary yolk sac tumor of the intestinal tract origin is exceedingly rare. Through a multiple disciplinary team, the diagnosis and treatment of primary intestinal yolk sac tumor were further defined. We report 2 such cases with detailed histologic and immunohistochemical analysis. The two patients were a 7-year-old girl and a 29-year-old woman. Both of them preoperatively had an elevated serum alpha fetoprotein (AFP) level (≥ 1,210 ng/mL). The tumors are located in the intestine and imaging examination indicated the rectum as the primary site. Grossly the mass was grey-white and crisp texture. Microscopic examination featured reticular, microcystic, macrocystic, papillary, solid, and some glandular patterns. Immunohistochemically, tumor cells of both cases were positive for SALL4, AFP, pan-cytokeratin (AE1/AE3), and glypican-3. Simultaneously, a stain for EMA, OCT4, CD30, HCG, vimentin and CK20 were negative in all 2 neoplasms. The features of morphology, immunohistochemistry, laboratory examinations and imaging studies consist of the diagnosis of primary yolk sac tumor of the intestine.