Journals
2018 EN
Marina E. Borisova · Andrea Voigt · Maxim A. X. Tollenaere
+9 more
Ultraviolet (UV) light radiation induces the formation of bulky photoproducts in the DNA that globally affect transcription and splicing. However, the signaling pathways and mechanisms that link UV-light-induced DNA damage to changes in RNA metabolism remain poorly understood. Here we employ quantitative phosphoproteomics and protein kinase inhibition to provide a systems view on protein phosphorylation patterns induced by UV light and uncover the dependencies of phosphorylation events on the canonical DNA damage signaling by ATM/ATR and the p38 MAP kinase pathway. We identify RNA-binding proteins as primary substrates and 14-3-3 as direct readers of p38-MK2-dependent phosphorylation induced by UV light. Mechanistically, we show that MK2 phosphorylates the RNA-binding subunit of the NELF complex NELFE on Serine 115. NELFE phosphorylation promotes the recruitment of 14-3-3 and rapid dissociation of the NELF complex from chromatin, which is accompanied by RNA polymerase II elongation.
Journals
2018 EN
Kimmo Palin · Esa Pitkänen · Mikko Turunen
+37 more
Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
Journals
2018 EN
Amrita Sahu · Hikaru Mamiya · Sunita N. Shinde
+13 more
While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the “anti-aging” protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.
Journals
2018 EN
Lorillee Tallorin · Jialei Wang · Woojoo E. Kim
+8 more
The discovery of peptide substrates for enzymes with exclusive, selective activities is a central goal in chemical biology. In this paper, we develop a hybrid computational and biochemical method to rapidly optimize peptides for specific, orthogonal biochemical functions. The method is an iterative machine learning process by which experimental data is deposited into a mathematical algorithm that selects potential peptide substrates to be tested experimentally. Once tested, the algorithm uses the experimental data to refine future selections. This process is repeated until a suitable set of de novo peptide substrates are discovered. We employed this technology to discover orthogonal peptide substrates for 4’-phosphopantetheinyl transferase, an enzyme class that covalently modifies proteins. In this manner, we have demonstrated that machine learning can be leveraged to guide peptide optimization for specific biochemical functions not immediately accessible by biological screening techniques, such as phage display and random mutagenesis.
Journals
2018 EN
Satyam Mukherjee · Yun Huang · Julia Neidhardt
+2 more
Debate over the impact of team composition on the outcome of a contest has attracted sports enthusiasts and sports scientists for years. A commonly held belief regarding team success is the superstar effect; that is, including more talent improves the performance of a team 1 . However, studies of team sports have suggested that previous relations and shared experiences among team members improve the mutual understanding of individual habits, techniques and abilities and therefore enhance team coordination and strategy 2-9 . We explored the impact of within-team relationships on the outcome of competition between sports teams. Relations among teammates consist of two aspects: qualitative and quantitative. While quantitative aspects measure the number of times two teammates collaborated, qualitative aspects focus on 'prior shared success'; that is, whether teamwork succeeded or failed. We examined the association between qualitative team interactions and the probability of winning using historical records from professional sports-basketball in the National Basketball Association, football in the English Premier League, cricket in the Indian Premier League and baseball in Major League Baseball-and the multiplayer online battle game Defense of the Ancients 2. Our results show that prior shared success between team members significantly improves the odds of the team winning in all sports beyond the talents of individuals.
Journals
2018 EN
Fangjie Zhu · Lucas Farnung · Eevi Kaasinen
+9 more
Nucleosomes cover most of the genome and are thought to be displaced by transcription factors in regions that direct gene expression. However, the modes of interaction between transcription factors and nucleosomal DNA remain largely unknown. Here we systematically explore interactions between the nucleosome and 220 transcription factors representing diverse structural families. Consistent with earlier observations, we find that the majority of the studied transcription factors have less access to nucleosomal DNA than to free DNA. The motifs recovered from transcription factors bound to nucleosomal and free DNA are generally similar. However, steric hindrance and scaffolding by the nucleosome result in specific positioning and orientation of the motifs. Many transcription factors preferentially bind close to the end of nucleosomal DNA, or to periodic positions on the solvent-exposed side of the DNA. In addition, several transcription factors usually bind to nucleosomal DNA in a particular orientation. Some transcription factors specifically interact with DNA located at the dyad position at which only one DNA gyre is wound, whereas other transcription factors prefer sites spanning two DNA gyres and bind specifically to each of them. Our work reveals notable differences in the binding of transcription factors to free and nucleosomal DNA, and uncovers a diverse interaction landscape between transcription factors and the nucleosome.
Journals
2018 EN
Peng Jiang · Shengqing Gu · Deng Pan
+12 more
Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.
Journals
2018 EN
Nitin Jain · Satyam Vergish · Jitendra P. Khurana
The circadian clock in plants is the intrinsic rhythmic expression of thousands of genes in a 24 h period, which is set by the day-night cycles in the environment. The study of the circadian clock often requires expression profiling of genes over a large number of samples for which RT-qPCR is invariably used. Reliability of the results depends largely on the house-keeping genes, which serve as control and thus should be chosen carefully to prevent erroneous results. In this study, ten house-keeping genes were chosen from rice for stability analysis with 48 tissue samples harvested from plants subjected to diurnal/circadian cycles. Although, all the genes were found to be stable, however, six of them showed cyclic expression patterns and caused major changes in the expression profiles of the target genes when used to normalize their expression data, thereby making them poor candidates for diurnal/circadian studies. In conclusion, reference genes need to be selected for diurnal/circadian studies with extra caution as more than 80% of transcriptome in plants undergoes cycling, which remains undetected by the gene stability assessment software and can severely affect the RT-qPCR based gene expression profiling. The geometric mean of two or more most stable reference genes is hence recommended for diurnal/circadian studies in plants.
Journals
2018 EN
Sravya Tekumalla · Yogesh Nandigam · Nitish Bibhanshu
+4 more
Magnesium has been trending of late in automobile, aerospace, defense, sports, electronic and biomedical sectors as it offers an advantage in light-weighting. In aluminum, titanium, and steel dominated aerospace and defense sectors, applications of Mg were banned/restricted until recently due to perceived easy ignition and inability to self-extinguish immediately. Strength is generally inversely related to ductility, weak texture and unrelated to ignition resistance, making it challenging to optimize all four concurrently in a material. We address this challenge by designing a low density (~1.76 g.cm −3 ) in-situ Mg nanocomposite. It is a resultant of a sequence of in-situ reactions during melt processing and extrusion. The in-situ formed Y 2 O 3 nanoparticles exhibit coherency with matrix and lead to development of large amount of elastic and plastic strain fields around them. These nanoparticles and secondary phases (Mg 2 Ca and Mg 2 Y) are responsible for the nanocomposite’s high tensile strength (~343 MPa). A weak texture mediated tensile ductility of 30% and compressive failure strain of 44% is observed. Further, the ignition temperature increased to 1045 °C (near the boiling point of Mg) due to the formation of protective surficial oxide layers aided by the presence of insulating Y 2 O 3 nanoparticles, rendering the nanocomposite outperform other traditional commercial Mg-based materials.
Journals
2018 EN
Prosenjit Ghosh · K. Prasanna · Yogaraj Banerjee
+4 more
The Cretaceous greenhouse climate was accompanied by major changes in Earth’s hydrological cycle, but seasonally resolved hydroclimatic reconstructions for this anomalously warm period are rare. We measured the δ 18 O and CO 2 clumped isotope Δ 47 of the seasonal growth bands in carbonate shells of the mollusc Villorita cyprinoides (Black Clam) growing in the Cochin estuary, in southern India. These tandem records accurately reconstruct seasonal changes in sea surface temperature (SST) and seawater δ 18 O, allowing us to document freshwater discharge into the estuary, and make inferences about rainfall amount. The same analytical approach was applied to well-preserved fossil remains of the Cretaceous (Early Maastrichtian) mollusc Phygraea (Phygraea) vesicularis from the nearby Kallankuruchchi Formation in the Cauvery Basin of southern India. The palaeoenvironmental record shows that, unlike present-day India, where summer rainfall predominates, most rainfall in Cretaceous India occurred in winter. During the Early Maastrichtian, the Indian plate was positioned at ~30°S latitude, where present-day rainfall and storm activity is also concentrated in winter. The good match of the Cretaceous climate and present-day climate at ~30°S suggests that the large-scale atmospheric circulation and seasonal hydroclimate patterns were similar to, although probably more intense than, those at present.