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Manmade high-performance polymers are typically non-biodegradable and derived from petroleum feedstock through energy intensive processes involving toxic solvents and byproducts. While engineered microbes have been used for renewable production of many small molecules, direct microbial synthesis of high-performance polymeric materials remains a major challenge. Here we engineer microbial production of megadalton muscle titin polymers yielding high-performance fibers that not only recapture highly desirable properties of natural titin (i.e., high damping capacity and mechanical recovery) but also exhibit high strength, toughness, and damping energy — outperforming many synthetic and natural polymers. Structural analyses and molecular modeling suggest these properties derive from unique inter-chain crystallization of folded immunoglobulin-like domains that resists inter-chain slippage while permitting intra-chain unfolding. These fibers have potential applications in areas from biomedicine to textiles, and the developed approach, coupled with the structure-function insights, promises to accelerate further innovation in microbial production of high-performance materials., Here, the authors engineer microbial production of muscle titin fibers with highly desirable mechanical properties and provide structural analyses that explain the molecular mechanisms underlying high performance of this polymer with potential uses in biomedicine and textile industries, among others.

Increasing crop production is necessary to feed the world's expanding population, and crop breeders often utilize genetic variations to improve crop yield and quality. However, the narrow diversity of the wheat D genome seriously restricts its selective breeding. A practical solution is to exploit the genomic variations of Aegilops tauschii via introgression. Here, we established a rapid introgression platform for transferring the overall genetic variations of A. tauschii to elite wheats, thereby enriching the wheat germplasm pool. To accelerate the process, we assembled four new reference genomes, resequenced 278 accessions of A. tauschii and constructed the variation landscape of this wheat progenitor species. Genome comparisons highlighted diverse functional genes or novel haplotypes with potential applications in wheat improvement. We constructed the core germplasm of A. tauschii, including 85 accessions covering more than 99% of the species' overall genetic variations. This was crossed with elite wheat cultivars to generate an A. tauschii-wheat synthetic octoploid wheat (A-WSOW) pool. Laboratory and field analysis with two examples of the introgression lines confirmed its great potential for wheat breeding. Our high-quality reference genomes, genomic variation landscape of A. tauschii and the A-WSOW pool provide valuable resources to facilitate gene discovery and breeding in wheat.

Docosahexaenoic acid (DHA) has been studied for many years owing to its protective effect on the decline in brain function. DHA intake reduces the risk of Alzheimer's disease (AD) and decreases amyloid deposition; however, the underlying molecular mechanism has not been completed elucidated. In this study, the effect of DHA on the cognitive function of amyloid precursor protein (APP)/PS1 in wild-type mice and its related mechanism were investigated. Results from the Morris water maze test showed that DHA improved learning and memory function in mice. Moreover, DHA reduced neuronal damage in mice brains, as determined using Nissl staining. Unsaturated fatty acid levels in the brain of mice increased (p < 0.01) after DHA administration and saturated fatty acid levels decreased (p < 0.01). The deposition of amyloid-beta (Aβ) plaques and tau protein neurofibrillary tangles was significantly inhibited. The mechanism of action of DHA was attributed to the upregulation of the expression of β-secretase (BACE)2, which competed with BACE1 to cleave APP, thus decreasing the production of extracellular Aβ fragments (p < 0.01). The expression level of insulin-degrading enzyme was not significantly different. The expression of N-methyl-D-aspartate receptors was further downregulated and the phosphorylation of glycogen synthase kinase-3β and tau protein was inhibited (p < 0.01). These data indicated that DHA could protect cognitive function in mice by reducing Aβ plaque formation and decreasing tau phosphorylation levels.

The expression of microRNA‑383 (miR‑383) is downregulated in a variety of tumor tissues, and it exhibits antiproliferative activity in non‑small cell lung cancer cells. In the present study, an association between the downregulation of miR‑383 expression and the deletion of chr8p22 in patients with lung adenocarcinoma was identified. The promoting effect of miR‑383 on cisplatin sensitivity was verified both in vivo and in vitro. Additionally, it was revealed that the expression of RNA binding motif protein 24 (RBM24) protein was regulated by and negatively correlated with miR‑383 expression. Ectopic expression of RBM24 or inhibition of miR‑383 decreased the chemosensitivity of parental A549 cells, whereas knockdown of RBM24 in cisplatin‑resistant A549 cells increased chemosensitivity. Mechanistically, miR‑383 interfered with the activation of nuclear factor κB (NF‑κB) signaling through repression of RBM24‑mediated phosphorylation of Rel‑like domain‑containing protein A and inhibitor α of NF‑κB. Taken together, the downregulation of miR‑383 induced RBM24 expression, which was mediated through the activation of NF‑κB signaling, to contribute to chemotherapy resistance in lung adenocarcinoma cells. The results of the present study highlight potential therapeutic targets for the clinical reversal of the chemotherapy resistance in lung adenocarcinoma.

Aegilops tauschii, the wild progenitor of wheat D-genome and a valuable germplasm for wheat improvement, has a wide natural distribution from eastern Turkey to China. However, the phylogenetic relationship and dispersion history of Ae. tauschii in China has not been scientifically clarified. In this study, we genotyped 208 accessions (with 104 in China) using ddRAD sequencing and 55K SNP array, and classified the population into six sublineages. Three possible spreading routes or events were identified, resulting in specific distribution patterns, with four sublineages found in Xinjiang, one in Qinghai, two in Shaanxi and one in Henan. We also established the correlation of SNP-based, karyotype-based and spike-morphology-based techniques to demonstrate the internal classification of Ae. tauschii, and developed consensus dataset with 1245 putative accessions by merging data previously published. Our analysis suggested that eight inter-lineage accessions could be assigned to the putative Lineage 3 and these accessions would help to conserve the genetic diversity of the species. By developing the consensus phylogenetic relationships of Ae. tauschii, our work validated the hypothesis on the dispersal history of Ae. tauschii in China, and contributed to the efficient and comprehensive germplasm-mining of the species.

Background Cold-inducible RNA binding protein (CIRP) is a newly discovered proto-oncogene. In this study, we investigated the role of CIRP in the progression of non-small cell lung cancer (NSCLC) using patient tissue samples, cultured cell lines and animal lung cancer models. Methods Tissue arrays, IHC and HE staining, immunoblotting, and qRT-PCR were used to detect the indicated gene expression; plasmid and siRNA transfections as well as viral infection were used to manipulate gene expression; cell proliferation assay, cell cycle analysis, cell migration and invasion analysis, soft agar colony formation assay, tail intravenous injection and subcutaneous inoculation of animal models were performed to study the role of CIRP in NSCLC cells; Gene expression microarray was used to select the underlying pathways; and RNA immunoprecipitation assay, biotin pull-down assay, immunopurification assay, mRNA decay analyses and luciferase reporter assay were performed to elucidate the mechanisms. The log-rank (Mantel-Cox) test, independent sample T-test, nonparametric Mann-Whitney test, Spearman rank test and two-tailed independent sample T-test were used accordingly in our study. Results Our data showed that CIRP was highly expressed in NSCLC tissue, and its level was negatively correlated with the prognosis of NSCLC patients. By manipulating CIRP expression in A549, H460, H1299, and H1650 cell lines, we demonstrated that CIRP overexpression promoted the transition of G1/G0 phase to S phase and the formation of an enhanced malignant phenotype of NSCLC, reflected by increased proliferation, enhanced invasion/metastasis and greater tumorigenic capabilities both in vitro and in vivo. Transcriptome sequencing further demonstrated that CIRP acted on the cell cycle, DNA replication and Wnt signaling pathway to exert its pro-oncogenic action. Mechanistically, CIRP directly bound to the 3′- and 5′-UTRs of CTNNB1 mRNA, leading to enhanced stability and translation of CTNNB1 mRNA and promoting IRES-mediated protein synthesis, respectively. Eventually, the increased CTNNB1 protein levels mediated excessive activation of the Wnt/β-catenin signaling pathway and its downstream targets C-myc, COX-2, CCND1, MMP7, VEGFA and CD44. Conclusion Our results support CIRP as a candidate oncogene in NSCLC and a potential target for NSCLC therapy.

Introduction: Proteolysis – targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

In the aerial plant organs, cuticular wax forms a hydrophobic layer that can protect cells from dehydration, repel pathogen attacks, and prevent organ fusion during development. The MIXTA gene encodes an MYB-like transcription factor, which is associated with epicuticular wax biosynthesis to increase the wax load on the surface of leaves. In this study, the AmMIXTA-homologous gene EgMIXTA1 was functionally characterized in the Eustoma grandiflorum. EgMIXTA1 was ubiquitously, but highly, expressed in leaves and buds. We identified the Eustoma MIXTA homolog and developed the plants for overexpression. EgMIXTA1-overexpressing plants had more wax crystal deposition on the leaf surface compared to wild-type and considerably more overall cuticular wax. In the leaves of the overexpression line, the cuticular transpiration occurred more slowly than in those of non-transgenic plants. Analysis of gene expression indicated that several genes, such as EgCER3, EgCER6, EgCER10, EgKCS1, EgKCR1, and EgCYP77A6, which are known to be involved in wax biosynthesis, were induced by EgMIXTA1-overexpression lines. Expression of another gene, WAX INDUCER1/SHINE1, encoding a transcription factor that stimulates the production of cutin, was also significantly higher in the overexpressors than in wild-type. However, the expression of a lipid-related gene, EgABCG12, did not change relative to the wild-type. These results suggest that EgMIXTA1 is involved in the biosynthesis of cuticular waxes.

Nasopharyngeal carcinoma (NPC) is the most common cancer with high metastatic potential that occurs in the epithelial cells of the nasopharynx. Distant metastases are the primary cause for treatment failure and mortality of NPC patients. However, the underlying mechanism responsible for the initiation of tumour cell dissemination and tumour metastasis in NPC is not well understood. Here, we demonstrated that epidermal growth factor receptor (EGFR) was highly expressed in tumour tissues of NPC patients with distant metastases and was associated with a decrease in reactive oxygen species (ROS). We also revealed that extracellular vesicles (EVs) transfer occurred from highly to poorly metastatic NPC cells, mediating cell–cell communication and enhancing the metastatic potential of poorly metastatic NPC cells. Further experiments indicated that EVs derived from highly metastatic NPC cells induced the up‐regulation of EGFR and down‐regulation of ROS in low metastatic NPC cells. Mechanistically, EGFR‐rich EVs‐mediated EGFR overexpression down‐regulated intracellular ROS levels through the PI3K/AKT pathway, thus promoting the metastatic potential of poorly metastatic NPC cells. Strikingly, treatment with EVs secreted from highly metastatic NPC cells was significantly associated with rapid NPC progression and shorter survival in xenografted mice. These findings not only improve our understanding of EVs‐mediated NPC metastatic mechanism but also have important implications for the detection and treatment of NPC patients accompanied by aberrant EGFR‐rich EVs transmission.

Multidrug resistance is a major obstacle to the effective treatment of esophageal carcinoma. It occurs more readily in hypoxia and acidosis microenvironment. TTLL6 is one of Tubulin tyrosine ligase-like family members. In this study, the effect of TTLL6 on the regulation of cisplatin (CDDP) sensitivity was evaluated in CDDP-resistant esophageal carcinoma (EC) cells both in vitro and in vivo. In hypoxia/acidosis condition, overexpression of TTLL6 in EC109/CDDP cells significantly lowered the IC50 of CDDP and increased the CDDP-induced apoptosis; while knockdown of TTLL6 expression in EC109/CDDP cells exhibited the opposite effects. Further study showed that, mechanistically, TTLL6 was inversely correlated with ERBB2 and TOPOIIA, and positively correlated with apoptosis-associated factor Caspase 9. Furthermore, animal model confirmed that TTLL6 negatively regulated the growth of xenograft tumor after chemotherapy. Alternated expression of TTLL6 also regulated the expression of ERBB2, TOPOIIA and Caspase 9 in EC109/CDDP cells in vivo. In conclusion, our results suggest that TTLL6 could reverse the drug resistant of EC109/CDDP cells, it might provide a potential treatment strategy for the clinical reversing the chemotherapy resistance.

Summary Many animals, including humans, have evolved to live and move in groups. In humans, disrupted social interactions are a fundamental feature of many psychiatric disorders. However, we know little about how genes regulate social behavior. Zebrafish may serve as a powerful model to explore this question. By comparing the behavior of wild-type fish with 90 mutant lines, we show that mutations of genes associated with human psychiatric disorders can alter the collective behavior of adult zebrafish. We identify three categories of behavioral variation across mutants: “scattered,” in which fish show reduced cohesion; “coordinated,” in which fish swim more in aligned schools; and “huddled,” in which fish form dense but disordered groups. Changes in individual interaction rules can explain these differences. This work demonstrates how emergent patterns in animal groups can be altered by genetic changes in individuals and establishes a framework for understanding the fundamentals of social information processing., Graphical Abstract, Highlights • Genes linked to human psychiatric disorders can alter zebrafish collective behavior • Differences from wild-type lead to “scattered,” “coordinated,” and “huddled” behavior • Changes in individual interaction rules can explain emergent group level patterns, Biological Sciences; Genetics; Behavior Genetics; Behavioral Neuroscience

Diabetic nephropathy (DN) is characterized by sterile inflammation with continuous injury and loss of renal inherent parenchyma cells. Podocyte is an essential early injury target in DN. The injury and loss of podocytes are closely associated with proteinuria, the early symptom of renal injury in DN. However, the exact mechanism for podocyte injury and death in DN remains ambiguous. In this study we investigated whether pyroptosis, a newly discovered cell death pathway was involved in DN. Diabetic mice were generated by high-fat diet/STZ injections. We showed that the expression levels of caspase-11 and cleavage of gasdermin D (GSDMD-N) in podocytes were significantly elevated, accompanied by reduced expression of podocyte makers nephrin and podocin, loss and fusion in podocyte foot processes, increased inflammatory cytokines NF-κB, IL-1β, and IL-18, macrophage infiltration, glomerular matrix expansion and increased urinary albumin to creatinine ratio (UACR). All these changes in diabetic mice were blunted by knockout of caspase-11 or GSDMD. Cultured human and mouse podocytes were treated with high glucose (30 mM), which significantly increased the expression levels of caspase-11 or caspase-4 (the homolog of caspase-11 in human), GSDMD-N, NF-κB, IL-1β, and IL-18, and decreased the expression of nephrin and podocin. Either caspase-4 or GSDMD knockdown by siRNA significantly blunted these changes. In summary, our results demonstrate that caspase-11/4 and GSDMD-mediated pyroptosis is activated and involved in podocyte loss under hyperglycemia condition and the development of DN.

Repair of DNA double-strand breaks (DSBs) requires eviction of the histones around DNA breaks to allow the loading of numerous repair and checkpoint proteins. However, the mechanism and regulation of this process remain poorly understood. Here, we show that histone H2B ubiquitination (uH2B) promotes histone eviction at DSBs independent of resection or ATP-dependent chromatin remodelers. Cells lacking uH2B or its E3 ubiquitin ligase Bre1 exhibit hyper-resection due to the loss of H3K79 methylation that recruits Rad9, a known negative regulator of resection. Unexpectedly, despite excessive single-strand DNA being produced, bre1Δ cells show defective RPA and Rad51 recruitment and impaired repair by homologous recombination and response to DNA damage. The HR defect in bre1Δ cells correlates with impaired histone loss at DSBs and can be largely rescued by depletion of CAF-1, a histone chaperone depositing histones H3-H4. Overexpression of Rad51 stimulates histone eviction and partially suppresses the recombination defects of bre1Δ mutant. Thus, we propose that Bre1 mediated-uH2B promotes DSB repair through facilitating histone eviction and subsequent loading of repair proteins.

Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection-induced inflammatory responses are largely responsible for the death of novel coronavirus disease 2019 (COVID-19) patients. However, the mechanism by which SARS-CoV-2 triggers inflammatory responses remains unclear. Here, we aimed to explore the regulatory role of SARS-CoV-2 spike protein in infected cells and attempted to elucidate the molecular mechanism of SARS-CoV-2-induced inflammation. Methods SARS-CoV-2 spike pseudovirions (SCV-2-S) were generated using the spike-expressing virus packaging system. Western blot, mCherry-GFP-LC3 labeling, immunofluorescence, and RNA-seq were performed to examine the regulatory mechanism of SCV-2-S in autophagic response. The effects of SCV-2-S on apoptosis were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Western blot, and flow cytometry analysis. Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the mechanism of SCV-2-S in inflammatory responses. Results Angiotensin-converting enzyme 2 (ACE2)-mediated SCV-2-S infection induced autophagy and apoptosis in human bronchial epithelial and microvascular endothelial cells. Mechanistically, SCV-2-S inhibited the PI3K/AKT/mTOR pathway by upregulating intracellular reactive oxygen species (ROS) levels, thus promoting the autophagic response. Ultimately, SCV-2-S-induced autophagy triggered inflammatory responses and apoptosis in infected cells. These findings not only improve our understanding of the mechanism underlying SARS-CoV-2 infection-induced pathogenic inflammation but also have important implications for developing anti-inflammatory therapies, such as ROS and autophagy inhibitors, for COVID-19 patients.

DNA double-strand breaks (DSBs) are among the most deleterious type of DNA lesions threatening genome integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are two major pathways to repair DSBs. HR requires a homologous template to direct DNA repair, and is generally recognized as a high-fidelity pathway. In contrast, NHEJ directly seals broken ends, but the repair product is often accompanied by sequence alterations. The choice of repair pathways is strictly controlled by the cell cycle. The occurrence of HR is restricted to late S to G2 phases while NHEJ operates predominantly in G1 phase, although it can act throughout most of the cell cycle. Deregulation of repair pathway choice can result in genotoxic consequences associated with cancers. How the cell cycle regulates the choice of HR and NHEJ has been extensively studied in the past decade. In this review, we will focus on the current progresses on how HR is controlled by the cell cycle in both Saccharomyces cerevisiae and mammals. Particular attention will be given to how cyclin-dependent kinases modulate DSB end resection, DNA damage checkpoint signaling, repair and processing of recombination intermediates. In addition, we will discuss recent findings on how HR is repressed in G1 and M phases by the cell cycle.

As an inflammatory factor, IL‐25 has been studied in variouscancers, but it is rarely reported in cancer chemotherapy resistance. Major vault protein (MVP), as a gene associated with lung multidrug resistance, is associated with multiple chemotherapy resistances of lung cancer. However, the relationship between IL‐25 and MVP in lung cancer cells has not been studied. In this study, we found that both IL‐25 and MVP were elevated expressed in cisplatin‐resistant lung adenocarcinoma cell line (A549/CDDP). Silencing of IL‐25 resulted in down‐regulation of MVP expression and reduced cisplatin tolerance of A549/CDDP cells. Overexpression of IL‐25 resulted in increase of MVP expression and the cisplatin tolerance in A549 cells. In addition, we found that the extracellular IL‐25 could stimulate the expression of MVP and activate the NF‐κB signaling pathway. Further, animal models also confirmed that IL‐25 reduced the sensitivity of xenografts to chemotherapy. Taken together, we believe that the up‐regulation of IL‐25 induces MVP expression contributing to chemotherapy resistances of lung cancer cells. Our findings suggest that interference the expression of IL‐25 might be potential treatment strategies for the clinical reversing the chemotherapy resistance.

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N1 -hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC50 = 0.074 μm against HeLa nuclear extract) and showed higher inhibitory activity than the positive control SAHA (IC50 = 0.131 μm), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.

The wide application of neonicotinoid insecticides in soil may affect soil microbial community, yet the information is limited. This study first reports the effects of thiamethoxam and dinotefuranon on soil microbial community. Soil from a forest land was collected and spiked with different nominal levels (0.02 mg kg−1, 0.2 mg kg−1 and 2.0 mg kg−1) of thiamethoxam and dinotefuran, respectively, and cultivated for 112 days. During the study, concentrations of the two neonicotinoids and their potential degradation products were monitored by LC-MS/MS. At day 112, the soils were analyzed for genetic profile by high-throughput sequencing and carbon metabolic profile by Biolog-ECO plate. The results showed that thiamethoxam and dinotefuran were both attenuated during the study with rate constants being 0.008–0.017 d−1 and 0.024–0.032 d−1, respectively, and biodegradation played an important role. As compared to the blank control, the exposure to the studied two neonicotinoids changed the microbial community, and the changes were influenced by both the type of neonicotinoid and the level of exposure. As compared to the blank control, the relative abundances of phyla Gemmatimonadetes and OD1 decreased under most exposed conditions, while the relative abundances of Chloroflexi and Nitrospirae increased under most exposed conditions. The community transition changed the functional potential, particularly carbon metabolism (mostly decreased) and nitrogen metabolism (mostly increased). As compared to the blank control, the utilization of total 31 carbon sources (including six categories) was increased under low exposure to thiamethoxam, but was decreased under all other exposed conditions. Low exposure to dinotefuran stimulated the utilization of three categories of carbon sources (amines, carbohydrates and phenolic compounds). Low exposure to both neonicotinoids increased the community diversity, while middle and high exposure to both neonicotinoids decreased the community diversity. These findings provide new insights into the effects of neonicotinoids on microbial community in soil.

Collective behaviors of groups of animals, such as schooling and shoaling of fish, are central to species survival, but genes that regulate these activities are not known. Here we parsed collective behavior of groups of adult zebrafish using computer vision and unsupervised machine learning into a set of highly reproducible, unitary, several hundred millisecond states and transitions, which together can account for the entirety of relative positions and postures of groups of fish. Using CRISPR-Cas9 we then targeted for knockout 35 genes associated with autism and schizophrenia. We found mutations in three genes had distinctive effects on the amount of time spent in the specific states or transitions between states. Mutation inimmp2l(inner mitochondrial membrane peptidase 2-like gene) enhances states of cohesion, so increases shoaling; mutation in in the Nav1.1 sodium channel,scn1lab+/− causes the fish to remain scattered without evident social interaction; and mutation in the adrenergic receptor,adra1aa−/−, keeps fish close together and retards transitions between states, leaving fish motionless for long periods. Motor and visual functions seemed relatively well-preserved. This work shows that the behaviors of fish engaged in collective activities are built from a set of stereotypical states. Single gene mutations can alter propensities to collective actions by changing the proportion of time spent in these states or the tendency to transition between states. This provides an approach to begin dissection of the molecular pathways used to generate and guide collective actions of groups of animals.

2-Nitrobenzyl isocyanide is reported as a universal convertible isocyanide with extensive applicability in both Ugi four-component reaction (Ugi-4CR) and Ugi-tetrazole reaction. The cleavage of this isocyanide from 17examples in both acidic and basic conditions is presented. Additionally, this isocyanide has various handling and synthetic advantages, as it is easy to prepare, odorless, stable, and easy to handle as a solid.

Progressive loss of cardiac cardiomyocytes is involved in pathogenesis of heart failure. Inflammation is considered as a major risk factor that triggers cardiomyocytes apoptosis or induces cellular damage. Proinflammatory cytokines such as TNFα can directly activate cell apoptosis or promote oxidant production that damages cellular structure eventually. We investigated TNFα mediated apoptosis in cultured rat primary cardiomyocytes. Annexin V/PI staining and apoptosis biomarker expression were used to examine cardiomyocytes cell apoptosis response. We also identified key microRNA that plays a regulatory role in this pathway with genetic and biochemical approaches. Apoptosis Inducing Factor (AIF) expression was found to be upregulated with 10μg/ml or 50μg/ml TNFα stimulation for 24h, which was associated with apoptotic index. Subsequently, miR-186 was identified as direct regulator of AIF in TNFα mediated cardiomyocytes apoptosis from microRNA expression profiling. miR-186 level was downregulated with TNFα treatment that was correlated with AIF induction. Last, in the rescue experiment, miR-186 mimic protected cardiomyocytes against TNFα mediated apoptosis. Collectively, the results suggest TNFα-induced AIF upregulation contributes to apoptosis in rat primary cardiomyocytes through regulating miR-186 expression, which implies miR-186 could be a potential therapeutic target for preventing inflammation associated cardiac damage.

Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L-phenylglycine-containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L-phenylglycine-containing branched cap group could not change the isoform selectivity of PXD101 dramatically.

Recently, more evidence of polygenicity and pleiotropy has been found in genome-wide association (GWA) studies of complex psychiatric diseases (e.g., schizophrenia), where multiple interacting genetic variants may affect multiple phenotypic traits simultaneously. In this work, we propose a new sparse collaborative group-ridge low-rank regression model (sCGRLR) to study the pleiotropic effects of a group of genetic variants on multiple imaging-derived quantitative traits (i.e., endophenotype). In the method, we enforce sparse and low-rank regularizations to reduce the number of features and then construct an effective gene or gene-set based statistic test to evaluate the significance of selected features. We show the advantage of our method with other gene-set pleiotropy analysis methods and other sparse multivariate regression methods in terms of type I error and power on simulated data. Finally, we demonstrate its application to real data analysis on the study of schizophrenia.