Deep learning modeling m6A deposition reveals the importance of downstream cis-element sequences.

The N6-methyladenosine (m6A) modification is deposited to nascent transcripts on chromatin, but its site-specificity mechanism is mostly unknown. Here we model the m6A deposition to pre-mRNA by iM6A (intelligent m6A), a deep learning method, demonstrating that the site-specific m6A methylation is primarily determined by the flanking nucleotide sequences. iM6A accurately models the m6A deposition (AUROC = 0.99) and uncovers surprisingly that the cis-elements regulating the m6A deposition preferentially reside within the 50 nt downstream of the m6A sites. The m6A enhancers mostly include part of the RRACH motif and the m6A silencers generally contain CG/GT/CT motifs. Our finding is supported by both independent experimental validations and evolutionary conservation. Moreover, our work provides evidences that mutations resulting in synonymous codons can affect the m6A deposition and the TGA stop codon favors m6A deposition nearby. Our iM6A deep learning modeling enables fast paced biological discovery which would be cost-prohibitive and unpractical with traditional experimental approaches, and uncovers a key cis-regulatory mechanism for m6A site-specific deposition

Allosteric collaboration between elongation factor G and the ribosomal L1 stalk directs tRNA movements during translation

Determining the mechanism by which transfer RNAs (tRNAs) rapidly and precisely transit through the ribosomal A, P and E sites during translation remains a major goal in the study of protein synthesis. Here, we report the real-time dynamics of the L1 stalk, a structural element of the large ribosomal subunit that is implicated in directing tRNA movements during translation. Within pre-translocation ribosomal complexes, the L1 stalk exists in a dynamic equilibrium between open and closed conformations. Binding of elongation factor G (EF-G) shifts this equilibrium towards the closed conformation through one of at least two distinct kinetic mechanisms, where the identity of the P-site tRNA dictates the kinetic route that is taken. Within post-translocation complexes, L1 stalk dynamics are dependent on the presence and identity of the E-site tRNA. Collectively, our data demonstrate that EF-G and the L1 stalk allosterically collaborate to direct tRNA translocation from the P to the E sites, and suggest a model for the release of E-site tRNA

Impact of late spring Siberian snow on summer rainfall in South-Central China

Located in the Yangtze River Valley and surrounded by mountains, South-Central China (SCC) frequently suffered from natural disasters such as torrential precipitation, landslide and debris flow. Here we provide corroborative evidence for a link between the late spring (May) snow water equivalent (SWE) over Siberia and the summer (July–August, abbr. JA) rainfall in SCC. We show that, in May, anomalously low SWE over Siberia is robustly related to a large warming from the surface to the mid-troposphere, and to a stationary Rossby wave train from Siberia eastward toward the North Atlantic. On the one hand, over the North Atlantic there exhibits a tripole pattern response of sea surface temperature anomalies in May. It persists to some extent in JA and in turn triggers a wave train propagating downstream across Eurasia and along the Asian jet, as the so-called Silk Road pattern (SRP). On the other hand, over northern Siberia the drier soil occurs in JA, accompanied by an overlying anomalous anticyclone through the positive feedback. This anomalous anticyclone favors the tropospheric cooling over southern Siberia, and the meridional (northward) displacement of the Asian jet (JMD) due to the change in the meridional temperature gradient. The combination of the SRP and the JMD facilitates less water vapor transport from the tropical oceans and anomalous descending motion over SCC, and thus suppresses the precipitation. These findings indicate that May Siberian SWE can be exploited for seasonal predictability of SCC precipitation.acceptedVersio

The Atlantic Multidecadal Variability phase-dependence of teleconnection between the North Atlantic Oscillation in February and the Tibetan Plateau in March

The Tibetan Plateau (TP), referred to as the “Asian water tower,” contains one of the largest land ice masses on Earth. The local glacier shrinkage and frozen-water storage are strongly affected by variations in surface air temperature over the TP (TPSAT), especially in springtime. This study reveals that the relationship between the February North Atlantic Oscillation (NAO) and March TPSAT is unstable with time and regulated by the phase of the Atlantic multidecadal variability (AMV). The significant out-of-phase connection occurs only during the warm phase of AMV (AMV+). The results show that during the AMV+, the negative phase of the NAO persists from February to March, and is accompanied by a quasi-stationary Rossby wave train trapped along a northward-shifted subtropical westerly jet stream across Eurasia, inducing an anomalous adiabatic descent that warms the TP. However, during the cold phase of the AMV, the negative NAO cannot persist into March. The Rossby wave train propagates along the well-separated polar and subtropical westerly jets, and the NAO–TPSAT connection is broken. Further investigation suggests that the enhanced synoptic eddy and low-frequency flow (SELF) interaction over the North Atlantic in February and March during the AMV+, caused by the southward-shifted storm track, helps maintain the NAO pattern via positive eddy feedback. This study provides a new detailed perspective on the decadal variability of the North Atlantic–TP connection in late winter to early spring.publishedVersio

Robust nonparametric quantification of clustering density of molecules in single-molecule localization microscopy

We report a robust nonparametric descriptor,&nbsp;J&prime;(r), for quantifying the density of clustering molecules in single-molecule localization microscopy.&nbsp;J&prime;(r), based on nearest neighbor distribution functions, does not require any parameter as an input for analyzing point patterns. We show that&nbsp;J&prime;(r) displays a valley shape in the presence of clusters of molecules, and the characteristics of the valley reliably report the clustering features in the data. Most importantly, the position of the&nbsp;J&prime;(r) valley () depends exclusively on the density of clustering molecules (&rho;c). Therefore, it is ideal for direct estimation of the clustering density of molecules in single-molecule localization microscopy. As an example, this descriptor was applied to estimate the clustering density of&nbsp;ptsG&nbsp;mRNA in&nbsp;E. coli&nbsp;bacteria.</p

Graphical models for inferring single molecule dynamics

The recent explosion of experimental techniques in single molecule biophysics has generated a variety of novel time series data requiring equally novel computational tools for analysis and inference. This article describes in general terms how graphical modeling may be used to learn from biophysical time series data using the variational Bayesian expectation maximization algorithm (VBEM). The discussion is illustrated by the example of single-molecule fluorescence resonance energy transfer (smFRET) versus time data, where the smFRET time series is modeled as a hidden Markov model (HMM) with Gaussian observables. A detailed description of smFRET is provided as well. The VBEM algorithm returns the model’s evidence and an approximating posterior parameter distribution given the data. The former provides a metric for model selection via maximum evidence (ME), and the latter a description of the model’s parameters learned from the data. ME/VBEM provide several advantages over the more commonly used approach of maximum likelihood (ML) optimized by the expectation maximization (EM) algorithm, the most important being a natural form of model selection and a well-posed (non-divergent) optimization problem. The results demonstrate the utility of graphical modeling for inference of dynamic processes in single molecule biophysics