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Currently indexing 101,433 bioRxiv papers from 428,488 authors.

Most tweeted bioRxiv papers, last 7 days

Results 1 through 20 out of 386


1: Fitting quantum machine learning potentials to experimental free energy data: Predicting tautomer ratios in solution

Marcus Wieder, Josh Fass et al.

35 tweets (posted 25 Oct 2020) biophysics

The computation of tautomer rations of druglike molecules is enormously important in computer-aided drug discovery, as over a quarter of all approved drugs can populate multiple tautomeric species in solution. Unfortunately, accurate calculations of aqueous tautomer ratios\---|the degree to which these species must be penalized in order to correctly account for tautomers in modeling binding for computer-aided drug discovery\---|is surprisingly difficult. While quantum chemical approaches to computing aqueous tautomer ratios using continuum solvent models and rigid-rotor harmonic-oscillator thermochemistry are currently state of the art, these methods are still surprisingly inaccurate despite their enormous computational expense. Here, we show that a major source of this inaccuracy lies in the breakdown of the standard approach to accounting for quantum chemical thermochemistry using rigid rotor harmonic oscillator (RRHO) approximations, which are frustrated by the complex conformational landscape introduced by the migration of double bonds, creation of stereocenters, and introduction of multiple conformations separated by low energetic barriers induced by migration of a single proton. Using quantum machine learning (QML) methods that allow us to compute potential energies with quantum chemical accuracy at a fraction of the cost, we show how rigorous alchemical free energy calculations can be used to compute tautomer ratios in vacuum free from the limitations introduced by RRHO approximations. Furthermore, since the parameters of QML methods are tunable, we show how we can train these models to correct limitations in the underlying learned quantum chemical potential energy surface using free energies, enabling these methods to learn to generalize tautomer free energies across a broader range of predictions. ### Competing Interest Statement The authors have declared no competing interest.


2: Multiple sequential prediction errors during reward processing in the human brain

Colin W Hoy, Sheila C Steiner et al.

33 tweets (posted 21 Oct 2020) neuroscience

Recent developments in reinforcement learning, cognitive control, and systems neuroscience highlight the complimentary roles in learning of valenced reward prediction errors (RPEs) and non-valenced salience prediction errors (PEs) driven by the magnitude of surprise. A core debate in reward learning focuses on whether valenced and non-valenced PEs can be isolated in the human electroencephalogram (EEG). Here, we combine behavioral modeling and single-trial EEG regression revealing a sequence of valenced and non-valenced...


3: No evidence of coronaviruses or other potentially zoonotic viruses in Sunda pangolins (Manis javanica) entering the wildlife trade via Malaysia.

Jimmy Lee, Tom Hughes et al.

32 tweets (posted 19 Jun 2020) molecular biology

The legal and illegal trade in wildlife for food, medicine and other products is a globally significant threat to biodiversity that is also responsible for the emergence of pathogens that threaten human and livestock health and our global economy. Trade in wildlife likely played a role in the origin of COVID-19, and viruses closely related to SARS-CoV-2 have been identified in bats and pangolins, both traded widely. To investigate the possible role of pangolins as a source of potential zoonoses, we collected throat and ...


4: Many but not all lineage-specific genes can be explained by homology detection failure

Caroline M. Weisman, Andrew W. Murray et al.

31 tweets (posted 28 Feb 2020) evolutionary biology

Genes for which homologs can be detected only in a limited group of evolutionarily related species, called "lineage-specific genes," are pervasive: essentially every lineage has them, and they often comprise a sizable fraction of the group's total genes. Lineage-specific genes are often interpreted as "novel" genes, representing genetic novelty born anew within that lineage. Here, we develop a simple method to test an alternative null hypothesis: that lineage-specific genes do have homologs outside of the lineage that, ...


5: Mapping-based genome size estimation

Boas Pucker

31 tweets (posted 13 Apr 2019) genomics

While the size of chromosomes can be measured under a microscope, the size of genomes cannot be measured precisely. Biochemical methods and k-mer distribution-based approaches allow only estimations. An alternative approach to predict the genome size based on high contiguity assemblies and short read mappings is presented here and optimized on Arabidopsis thaliana and Beta vulgaris. Brachypodium distachyon, Solanum lycopersicum, Vitis vinifera, and Zea mays were also analyzed to demonstrate the broad applicability of th...


6: Power and limits of selection genome scans on temporal data from a selfing population

Miguel Navascués, Arnaud Becheler et al.

30 tweets (posted 08 May 2020) evolutionary biology

Tracking genetic changes of populations through time allows a more direct study of the evolutionary processes acting on the population than a single contemporary sample. Several statistical methods have been developed to characterize the demography and selection from temporal population genetic data. However, these methods are usually developed under the assumption of outcrossing reproduction and might not be applicable when there is substantial selfing in the population. Here, we focus on a method to detect loci under ...


7: Dynamic targeting enables domain-general inhibitory control over action and thought by the prefrontal cortex.

Dace Apšvalka, Catarina S. Ferreira et al.

29 tweets (posted 23 Oct 2020) neuroscience

Successful self-control requires the ability to stop unwanted actions or thoughts. Stopping is regarded as a central function of inhibitory control, a mechanism enabling the suppression of diverse mental content, and strongly associated with the prefrontal cortex. A domain-general inhibitory control capacity, however, would require the region or regions implementing it to dynamically shift top-down inhibitory connectivity to diverse target regions in the brain. Here we show that stopping unwanted thoughts and stopping u...


8: Single-nucleus and spatial transcriptomics of archival pancreatic cancer reveals multi-compartment reprogramming after neoadjuvant treatment

William L Hwang, Karthik A. Jagadeesh et al.

25 tweets (posted 25 Aug 2020) genomics

Pancreatic ductal adenocarcinoma (PDAC) remains a treatment-refractory disease. Characterizing PDAC by mRNA profiling remains particularly challenging. Previously identified bulk expression subtypes were influenced by contaminating stroma and have not yet informed clinical management, whereas single cell RNA-seq (scRNA-seq) of fresh tumors under-represented key cell types. Here, we developed a robust single-nucleus RNA-seq (snRNA-seq) technique for frozen archival PDAC specimens and used it to study both untreated tumor...


9: Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer

Srivatsan Raghavan, Peter S. Winter et al.

25 tweets (posted 25 Aug 2020) cancer biology

In pancreatic ductal adenocarcinoma (PDAC), the basal-like and classical transcriptional subtypes are associated with differential chemotherapy sensitivity and patient survival. These phenotypes have been defined using bulk transcriptional profiling, which can mask underlying cellular heterogeneity and the biologic mechanisms that distinguish these subtypes. Furthermore, few studies have interrogated metastases, which are the cause of mortality in most patients with this highly lethal disease. Using single-cell RNA-sequ...


10: Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies

Jaewon J. Lee, Vincent Bernard et al.

25 tweets (posted 29 Jul 2020) cancer biology

Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployed ex vivo preclinical platforms, such as patient-derived organoids (PDOs) remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human pr...


11: Spontaneous Cell Fusions as a Mechanism of Parasexual Recombination in Tumor Cell Populations

Daria Miroshnychenko, Etienne Baratchart et al.

19 tweets (posted 10 Mar 2020) cancer biology

Initiation and progression of cancers reflect the underlying process of somatic evolution, which follows a Darwinian logic, i.e ., diversification of heritable phenotypes provides a substrate for natural selection, resulting in the outgrowth of the most fit subpopulations. Although somatic evolution can tap into multiple sources of diversification, it is assumed to lack access to (para)sexual recombination – a key diversification mechanism throughout all strata of life. Based on observations of spontaneous fusions invol...


12: Molecular architecture of the developing mouse brain

Gioele La Manno, Kimberly Siletti et al.

18 tweets (posted 03 Jul 2020) developmental biology

The mammalian brain develops through a complex interplay of spatial cues generated by diffusible morphogens, cell-cell interactions, and intrinsic genetic programs that result in the generation of likely more than a thousand distinct cell types. Therefore, a complete understanding of mammalian brain development requires systematic mapping of cell states covering the entire relevant spatiotemporal range. Here we report a comprehensive single-cell transcriptome atlas of mouse brain development spanning from gastrulation t...


13: Single source of pangolin CoVs with a near identical Spike RBD to SARS-CoV-2

Yujia Alina Chan, Shing Hei Zhan

17 tweets (posted 07 Jul 2020) genomics

Multiple publications have independently described pangolin CoV genomes from the same batch of smuggled pangolins confiscated in Guangdong province in March, 2019. We analyzed the three metagenomic datasets that sampled this batch of pangolins and found that the two complete pangolin CoV genomes, GD_1 by Xiao et al. Nature and MP789 by Liu et al. PLoS Pathogens, were both built primarily using the 2019 dataset first described by Liu et al. Viruses. Other publications, such as Zhang et al. Current Biology and Lam et al. ...


14: Elephant Genomes Elucidate Disease Defenses and Other Traits

Marc Tollis, Elliot Ferris et al.

14 tweets (posted 31 May 2020) evolutionary biology

Disease susceptibility and resistance comprise important factors in conservation, particularly in elephants. To determine genetic mechanisms underlying disease resistance and other unique elephant traits, we estimated 862 and 1,017 potential regulatory elements in Asian and African elephants, respectively. These elements are significantly enriched in both species with differentially expressed genes involved in immunity pathways, including tumor-necrosis factor which plays a role in the response to elephant endotheliotro...


15: Time scale separation of information processing between sensory and associative regions

Pierpaolo Sorrentino, Giovanni Rabuffo et al.

14 tweets (posted 24 Oct 2020) neuroscience

Stimulus perception is assumed to involve the (fast) detection of sensory inputs and their (slower) integration. The capacity of the brain to quickly adapt, at all times, to unexpected stimuli suggests that the interplay between the slow and fast processes happens at short timescales. We hypothesised that, even during resting-state, the flow of information across the brain regions should evolve quickly, but not homogeneously in time. Here we used high temporal-resolution Magnetoencephalography (MEG) signals to estimate ...


16: Misoprostol Treatment Prevents Hypoxia-Induced Cardiac Dysfunction, Aberrant Cardiomyocyte Mitochondrial Dynamics and Permeability Transition Through Bnip3 Phosphorylation

Matthew D Martens, Nivedita Seshadri et al.

14 tweets (posted 10 Oct 2020) cell biology

Systemic hypoxia, a major complication associated with reduced gestational time, affects more 60% of preterm infants and is a known driver of hypoxia-induced Bcl-2-like 19kDa-interacting protein 3 (Bnip3) expression in the neonatal heart. At the level of the cardiomyocyte, Bnip3 activity plays a prominent role in the evolution of necrotic cell death, disrupting subcellular calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests both a cardioprotective role for protein k...


17: The mechanism of motor inhibition by microtubule-associated proteins

Luke S Ferro, Lisa Eshun-Wilson et al.

13 tweets (posted 23 Oct 2020) biophysics

Microtubule (MT)-associated proteins (MAPs) regulate intracellular transport by selectively recruiting or excluding kinesin and dynein motors from MTs. We used single-molecule and cryo-electron imaging to determine the mechanism of MAP-motor interactions in vitro. Unexpectedly, we found that the regulatory role of a MAP cannot be predicted based on whether it overlaps with the motor binding site or forms liquid condensates on the MT. Although the MT binding domain (MTBD) of MAP7 overlaps with the kinesin-1 binding site,...


18: Atlas of tissue-specific and tissue-preferential gene expression in ecologically and economically significant conifer Pinus sylvestris

Sandra Cervantes, Jaana Vuosku et al.

11 tweets (posted 23 Oct 2020) genomics

Background: Despite their ecological and economical importance, conifers still have limited genomic resources, mainly due to the large size and complexity of their genomes. In addition, several of the available genomic resources lack complete structural and functional annotation. Transcriptomic resources have been commonly used to compensate for these deficiencies, though for most conifer species the currently available transcriptomes are limited to a small number of tissues, or capture only a fraction of the genes pres...


19: A 'Naturalistic Neuroimaging Database' for understanding the brain using ecological stimuli

Sarah Aliko, Jiawen Huang et al.

10 tweets (posted 25 May 2020) neuroscience

Neuroimaging has advanced our understanding of human psychology using reductionist stimuli that often do not resemble information the brain naturally encounters. It has improved our understanding of the network organization of the brain mostly through analyses of 'resting-state' data for which the functions of networks cannot be verifiably labelled. We make a 'Naturalistic Neuroimaging Database' (NNDb v1.0) publically available to allow for a more complete understanding of the brain under more ecological conditions duri...


20: Spatially-specific working memory activity in the human superior colliculus

Masih Rahmati, Kevin DeSimone et al.

10 tweets (posted 18 Jun 2020) neuroscience

Theoretically, working memory (WM) representations are encoded by population activity of neurons with distributed tuning across the stored feature. Here, we leverage computational neuroimaging approaches to map the topographic organization of human superior colliculus (SC) and model how population activity in SC encodes WM representations. We first modeled receptive field properties of voxels in SC, deriving a detailed topographic organization resembling that of the primate SC. Neural activity within male and female hum...