Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 73,081 bioRxiv papers from 318,277 authors.
Most tweeted bioRxiv papers, last 7 days
732 results found. For more information, click each entry to expand.
15 tweets microbiology
Prokaryote genomes exhibit a wide range of GC contents and codon usages, both resulting from an interaction between mutational bias and natural selection. In order to investigate the basis underlying specific codon changes, we performed a comprehensive analysis of 29-different prokaryote families. The analysis of core-gene sets with increasing ancestries in each family lineage revealed that the codon usages became progressively more adapted to the tRNA pools. While, as previously reported, highly-expressed genes presented the more optimized codon usage, the singletons contained the less selectively-favored codons. Results showed that usually codons with the highest translational adaptation were preferentially enriched. In agreement with previous reports, a C-bias in 2- to 3-fold codons, and a U-bias in 4-fold codons occurred in all families, irrespective of the global genomic-GC content. Furthermore, the U-biases suggested that U3-mRNA U34-tRNA interactions were responsible for a prominent codon optimization in both the more ancestral core and the highly expressed genes. A comparative analysis of sequences that encode conserved-(cr) or variable-(vr) translated products, with each one being under high- (HEP) and low- (LEP) expression levels, demonstrated that the efficiency was more relevant (by a factor of 2) than accuracy to modelling codon usage. Finally, analysis of the third position of codons (GC3) revealed that, in genomes of global GC contents higher than 35-40%, selection favored a GC3 increase; whereas in genomes with very low-GC contents, a decrease in GC3 occurred. A comprehensive final model is presented where all patterns of codon usage variations are condensed in five distinct behavioral groups.
15 tweets biochemistry
RNAs interact with networks of proteins to form complexes (RNPs) that govern many biological processes, but these networks are currently impossible to examine in a comprehensive way. We developed a live-cell chemical probing strategy for mapping protein interaction networks in any RNA with single-nucleotide resolution. This RNP-MaP strategy (RNP network analysis by mutational profiling) simultaneously detects binding by and cooperative interactions involving multiple proteins with single RNA molecules. RNP-MaP revealed that two structurally related, but sequence-divergent noncoding RNAs, RNase P and RMRP, share nearly identical RNP networks and, further, that protein interaction network hubs identify function-critical sites in these RNAs. RNP-MaP identified numerous protein interaction networks within the XIST long noncoding RNA that are conserved between mouse and human RNAs and distinguished communities of proteins that network together on XIST. RNP-MaP data show that the Xist E region is densely networked by protein interactions and that PTBP1, MATR3, and TIA1 proteins each interface with the XIST E region via two distinct interaction modes; and we find that the XIST E region is sufficient to mediate RNA foci formation in cells. RNP-MaP will enable discovery and mechanistic analysis of protein interaction networks across any RNA in cells.
15 tweets neuroscience
Abstract Development generates a vast number of neuron types and classes. When and how neuronal differentiation end is poorly understood. Here, we show that Drosophila olfactory sensory neurons (OSNs) matures during a critical period and reveal that the differentiation termination mechanism is similar to the mammalian odorant receptor (OR) choice mechanism. Our initial experiments showed that initiation of Drosophila OR expression required heterochromatin opening and a H3K9me3 demethylase, Kdm4b . Further genetic studies demonstrated that Lsd1 and su(var)3-9 , similar to mouse, were required to balance heterochromatin in order to stabilize OR expression. Expression analysis further showed that Lsd1, su(var)3-9 increased and Kdm4b decreased during the first two days after eclosion. We further showed that environment changes during the period, but not after, caused permanent transformed Lsd1, su(var)3-9 and Kdm4b expression and altered OR gene regulation. Results that together suggest the last step in OSN terminal differentiation to be a gene regulatory critical period.
15 tweets biochemistry
Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import activity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient. cGAMP influences anion influx through VRAC, indicating it is likely a direct substrate of the channel. Activation or inhibition of the channel modulates cGAMP transport. The LRRC8A:C channel also transports other 2'3'-cyclic dinucleotides, including the investigational new cancer therapeutic ADU-S100. Furthermore, we demonstrate that the LRRC8A-containing channel is the dominant cGAMP importer in primary human vasculature cells, indicating that modulation of this channel represents a promising strategy to boost therapeutic STING signaling in tumor vasculature.
15 tweets cancer biology
Linde A Miles, Robert L. Bowman, Tiffany R Merlinsky, Isabelle S Csete, Aik Ooi, Robert Durruthy-Durruthy, Michael Bowman, Christopher Famulare, Minal A Patel, Pedro Mendez, Chrysanthi Ainali, Mani Manivannan, Sombeet Sahu, Aaron D Goldberg, Kelly Bolton, Ahmet ZEHIR, Raajit Rampal, Martin P Carroll, Sara E Meyer, Aaron D. Viny, Ross L. Levine
Myeloid malignancies, including acute myeloid leukemia (AML), arise from the proliferation and expansion of hematopoietic stem and progenitor cells which acquire somatic mutations. Bulk molecular profiling studies on patient samples have suggested that somatic mutations are obtained in a step-wise fashion, where mutant genes with high variant allele frequencies (VAFs) are proposed to occur early in disease development and mutations with lower VAFs are thought to be acquired later in disease progression 1-3. Although bulk sequencing informs leukemia biology and prognostication, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity and clone size, or offer definitive evidence of mutational order. To elucidate the clonal framework of myeloid malignancies, we performed single cell mutational profiling on 146 samples from 123 patients. We found AML is most commonly comprised of a small number of dominant clones, which in many cases harbor co-occurring mutations in epigenetic regulators. Conversely, mutations in signaling genes often occur more than once in distinct subclones consistent with increasing clonal diversity. We also used these data to map the clonal trajectory of each patient and found that specific mutation combinations (FLT3-ITD + NPM1c) synergize to promote clonal expansion and dominance. We combined cell surface protein expression with single cell mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our studies of clonal architecture at a single cell level provide novel insights into the pathogenesis of myeloid transformation and how clonal complexity contributes to disease progression.
14 tweets molecular biology
The TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum. Most known biomolecular condensates are sphere-like, but TIS granules have a mesh-like morphology. Through in vivo and in vitro reconstitution experiments we discovered that this shape is generated by extensive intermolecular RNA-RNA interactions. They are mostly accomplished by mRNAs with large unstructured regions in their 3′UTRs that we call intrinsically disordered regions (IDRs). As AU-rich RNA is a potent chaperone that suppresses protein aggregation and is overrepresented in mRNAs with IDRs, our data suggests that TIS granules concentrate mRNAs that assist protein folding. In addition, the proximity of translating mRNAs in TIS granule networks may enable co-translational protein complex formation.
14 tweets systems biology
Motivation: Emerging phenomena in developmental biology and tissue engineering are the result of feedbacks between gene expression and cell biomechanics. In that context, in silico experiments are a powerful tool to understand fundamental mechanisms and to formulate and test hypotheses. Results: Here we present TiFoSi, a computational tool to simulate the cellular dynamics of planar epithelia. TiFoSi allows to model feedbacks between cellular mechanics and gene expression (either in a deterministic or a stochastic way), the interaction between different cell populations, the custom design of the cell cycle and cleavage properties, the protein number partitioning upon cell division, and the modeling of cell communication (juxtacrine and paracrine signalling). TiFoSi fills a niche in the field of software solutions to simulate the mechanobiology of epithelia because of its functionalities, computational efficiency, and its user-friendly approach to design in silico experiments using XML configuration files.
14 tweets biophysics
Nuclei are constantly under external stress - be it during migration through tight constrictions or compressive pressure by the actin cap - and the mechanical properties of nuclei govern their subsequent deformations. Both altered mechanical properties of nuclei and abnormal nuclear morphologies are hallmarks of a variety of disease states. Little work, however, has been done to link specific changes in nuclear shape to external forces. Here, we utilize a combined atomic force microscope and light sheet microscope (AFM-LS) to show SKOV3 nuclei exhibit a two-regime force response that correlates with changes in nuclear volume and surface area, allowing us to develop an empirical model of nuclear deformation. Our technique further decouples the roles of chromatin and lamin A/C in compression, showing they separately resist changes in nuclear volume and surface area respectively; this insight was not previously accessible by Hertzian analysis. A two-material finite element model supports our conclusions. We also observed that chromatin decompaction leads to lower nuclear curvature under compression, which is important for maintaining nuclear compartmentalization and function. The demonstrated link between specific types of nuclear morphological change and applied force will allow researchers to better understand the stress on nuclei throughout various biological processes.
13 tweets neuroscience
Hebbian plasticity, a mechanism believed to be the substrate of learning and memory, detects and further enhances correlated neural activity. Because this constitutes an unstable positive feedback loop, it requires additional homeostatic control. Computational work suggests that in recurrent networks, the homeostatic mechanisms observed in experiments are too slow to compensate instabilities arising from Hebbian plasticity and need to be complemented by rapid compensatory processes. We suggest presynaptic inhibition as a candidate that rapidly provides stability by compensating recurrent excitation induced by Hebbian changes. Presynaptic inhibition is mediated by presynaptic GABA receptors that effectively and reversibly attenuate transmitter release. Activation of these receptors can be triggered by excess network activity, hence providing a stabilising negative feedback loop that weakens recurrent interactions on sub-second timescales. We study the stabilising effect of presynaptic inhibition in a recurrent networks, in which presynaptic inhibition is implemented as a multiplicative reduction of recurrent synaptic weights in response to increasing inhibitory activity. We show that networks with presynaptic inhibition display a gradual increase of firing rates with growing excitatory weights, in contrast to traditional excitatory-inhibitory networks. This alleviates the positive feedback loop between Hebbian plasticity and network activity and thereby allows homeostasis to act on timescales similar to those observed in experiments. Our results generalise to spiking networks with a biophysically more detailed implementation of the presynaptic inhibition mechanism. In conclusion, presynaptic inhibition provides a powerful compensatory mechanism that rapidly reduces effective recurrent interactions and thereby stabilises Hebbian learning.
13 tweets cell biology
While feedback loops are essential for robustness in signaling systems, they make discerning the role of individual components challenging. Here we introduce temperature as a powerful perturbation method for uncoupling enzymatic processes, by exposing the differential sensitivity of limiting reactions to temperature due to their activation energies. Using this method, we study the sensitivity to temperature of different cell cycle events of early fly embryos. While the subdivision of cell cycle steps is conserved across a wide range of temperatures (5-35?C), the transition into prometaphase exhibits the most sensitivity, arguing that it has a different mechanism of regulation. Using a biosensor, we quantify the activity of Cdk1 and show that the activation of Cdk1 drives entry into prometaphase but is not required for earlier events. In fact, chromosome condensation can still occur when Cdk1 is inhibited pharmacologically. These results demonstrate that different kinases are rate-limiting for different steps of mitosis.
12 tweets microbiology
Most motile bacteria are propelled by rigid, helical, flagellar filaments and display distinct swimming patterns to explore their favorable environments. Escherichia coli cells have a reversible rotary motor at the base of each filament. They exhibit a run-tumble swimming pattern, driven by switching of rotatory direction which causes polymorphic flagellar transformation. Here we report a novel swimming mode in E. coli ATCC10798, which is one of the original K-12 clones. High-speed tracking of single ATCC10798 cells showed forward and backward swimming with an average turning angle of 150 degrees. The flagellar helicity remained right-handed with a 1.3 μm pitch and 0.14 μm helix radius, which is assumed to be a curly type, regardless of motor switching; the flagella of ATCC10798 did not show polymorphic transformation. The torque and rotational switching of the motor was almost identical to the E. coli W3110 strain, which is a derivative of K-12 and a wild-type for chemotaxis. The single point mutation of N87K in FliC, one of the filament subunits, is critical to the change in flagellar morphology and swimming pattern, and lack of flagellar polymorphism. E. coli cells expressing FliC(N87K) sensed ascending a chemotactic gradient in liquid but did not form rings on a semi-solid surface. Based on these findings, we propose a flagellar polymorphism-dependent migration mechanism in structured environments.
12 tweets neuroscience
One important neural hallmark of working memory is persistent elevated delay-period activity in frontal and parietal cortex. In human fMRI, delay-period BOLD activity in frontal and parietal cortex increases monotonically with memory load and asymptotes at an individual's capacity. Previous work has demonstrated that frontal and parietal delay-period activity correlates with the decline in behavioral memory precision observed with increasing memory load. However, because memory precision can be influenced by a variety of factors, it remains unclear what cognitive processes underlie persistent activity in frontal and parietal cortex. Recent psychophysical work has shown that attractor dynamics bias memory representations toward a few stable representations and reduce the effects of internal noise. From this perspective, imprecision in memory results from both drift towards stable attractor states and random diffusion. Here we asked whether delay-period BOLD activity in frontal and parietal cortex might be explained, in part, by these attractor dynamics. We analyzed data from an existing experiment in which subjects performed delayed recall for line orientation, at different loads, during fMRI scanning. We modeled subjects' behavior using a discrete attractor model, and calculated within-subject correlation between frontal and parietal delay-period activity and estimated sources of memory error (drift and diffusion). We found that although increases in frontal and parietal activity were associated with increases in both diffusion and drift, diffusion explained the most variance in frontal and parietal delay-period activity. In comparison, a subsequent whole-brain regression analysis showed that drift rather than diffusion explained the most variance in delay-period activity in lateral occipital cortex. These results provide a new interpretation for the function of frontal, parietal, and occipital delay-period activity in working memory.
12 tweets genetics
People in the Americas represent a diverse group of populations with varying degrees of admixture among African, European, and Amerindigenous ancestries. In the United States, many populations with non-European ancestry remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genome-wide genotype data from the Hispanic Community Health Study/Study of Latinos, we find that Amerindigenous ancestry has increased over time across Hispanic/Latino populations, particularly in Mexican Americans where Amerindigenous ancestry increased by an average of ~20% over the 50-year period spanning 1940s-1990s. We find similar patterns across American cities, and replicate our observations in an independent sample of Mexican Americans. These dynamic ancestry patterns are a result of a complex interaction of several population and cultural factors, including strong ancestry-related assortative mating and subtle shifts in migration with differences in subcontinental Amerindigenous ancestry over time. These factors have shaped patterns of genetic variation, including an increase in runs of homozygosity in Amerindigenous ancestral tracts, and also influenced the genetic architecture of complex traits within the Mexican American population. We show for height, a trait correlated with ancestry, polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within Hispanics/Latinos that may influence biomedical traits, demonstrating a crucial need to improve our understanding of the genetic diversity of admixed populations.
12 tweets genomics
Autism typically presents with a highly heterogeneous set of features, including frequent comorbidity with intellectual disability (ID). The overlap between these two phenotypes has confounded the accurate diagnosis and discovery of genetic factors associated with autism. We analyzed genetic variants in 2,290 individuals with autism from the Simons Simplex Collection (SSC) who have either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity. We found that individuals who carried variants in a set of 173 reported autism-associated genes showed decreased IQ (p=5.49×10-6) and increased autism severity (p=0.013) compared with individuals without such variants. A subset of autism-associated genes also showed strong evidence for ID comorbidity in published case reports. We also found that individuals with high-functioning autism (IQ>100) had lower frequencies of CNVs (p=0.065) and LGD variants (p=0.021) compared with individuals who manifested both autism and ID (IQ<70). These data indicated that de novo LGD variants conferred a 1.53-fold higher risk (p=0.035) towards comorbid ID, while LGD mutations specifically disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID. Furthermore, de novo LGD variants in individuals with high-functioning autism were more likely to disrupt genes with little functional relevance towards neurodevelopment, as demonstrated by evidence from pathogenicity metrics, expression patterns in the developing brain, and mouse model phenotypes. Overall, our data suggest that de novo pathogenic variants disrupting genes associated with autism contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.
12 tweets genomics
RNA editing is an epitranscriptomic modification of emerging relevance to disease development and manifestations. ADAR1, which resides on human chromosome 1q21, is an RNA editor whose over-expression, either by interferon (IFN) induction or through gene amplification, is associated with increased editing and poor outcomes in Multiple Myeloma (MM). Here we explored the role of ADAR1 in the context of MM progression, by focusing on a group of 23 patients in the MMRF CoMMpass Study for which RNAseq and WES datasets exist for matched pre-and post-relapse samples. Our analysis reveals an acquisition of new DNA mutations on disease progression at specific loci surrounding the sites of ADAR associated (A-to-I) RNA editing. These analyses suggest that the RNA editing enzyme ADAR1 can function as a DNA mutator during Multiple Myeloma (MM) progression. These data imply that guide-targeted RNA editing has the capacity to generate specific mutational signatures at predetermined locations. More generally, these data suggest that a dual role of RNA editor and DNA mutator might be shared by other deaminases, such as APOBECs, so that DNA mutation might be the result of collateral damage on the genome by an editing enzyme whose primary job is to re-code the cognate transcript toward specific functional outcomes.
12 tweets molecular biology
CRISPR-Cas9 deletion (CRISPR-del) is the leading approach for eliminating DNA from mammalian cells and underpins a variety of genome-editing applications. Target DNA, defined by a pair of double strand breaks (DSBs), is removed during non-homologous end-joining (NHEJ). However, the low efficiency of CRISPR-del results in laborious experiments and false negative results. Using an endogenous reporter system, we demonstrate that temporary inhibition of DNA-dependent protein kinase (DNA-PK) - an early step in NHEJ - yields up to 17-fold increase in DNA deletion. This is observed across diverse cell lines, gene delivery methods, commercial inhibitors and guide RNAs, including those that otherwise display negligible activity. Importantly, the method is compatible with pooled functional screens employing lentivirally-delivered guide RNAs. Thus, delaying the kinetics of NHEJ relative to DSB formation is a simple and effective means of enhancing CRISPR-deletion.
12 tweets neuroscience
Fear is maximally adaptive when the response level rapidly scales to the degree of threat. Using a behavioral procedure consisting of danger, uncertainty and safety cues, we have found rapid scaling of fear (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of rapid fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions. NAcc-lesioned rats showed general impairment in scaling fear to degree of threat, as well as impairment in a specific component of scaling: rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. Rats were trained to the point of discrimination, and the NAcc was green-light illuminated during cue or control periods. NAcc-halorhodopsin rats receiving light illumination during cue presentation were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling of fear to degree of threat, and a specific role in one component of scaling: rapid discrimination of uncertain threat and safety.
11 tweets neuroscience
The demand for affordable tools for recording extracellular activity and successfully isolating single units from different brain preparations has pushed researchers and companies to invest in developing and fabricating new recording devices. However, depending on the brain region of interest, experimental question or type of preparations, different devices are required thus adding substantial financial burden to laboratories. We have developed a simple and affordable tetrode-based device that allows interchangeable extracellular recordings of neural activity between in vivo and ex vivo preparations and can be easily implemented in all wet-bench laboratories. Spontaneous activity from several putative single neurons could be easily recorded and isolated by lowering the device into ex vivo cerebellum brain slices. The same device was also used in vivo , lowered into primary auditory cortex of adult anesthetized transgenic mice expressing channelrhodopsin in cortical neurons. Acoustic stimulation of the contralateral ear or direct laser optogenetic stimulation successfully evoked cortical activity at the recording site. Several isolated putative single neurons presented time-locked activity response to the different stimuli. In summary, we developed an affordable, versatile and modular device to facilitate tetrode extracellular recordings interchangeably between in vivo anaesthetized animals and ex vivo brain slice recordings.
11 tweets neuroscience
Federico Scala, Dmitry Kobak, Matteo Bernabucci, Yves Bernaerts, Cathryn René Cadwell, Jesus Ramon Castro, Leonard Hartmanis, Xiaolong Jiang, Sophie Laturnus, Elanine Miranda, Shalaka Mulherkar, Zheng Huan Tan, Zizhen Yao, Hongkui Zeng, Rickard Sandberg, Philipp Berens, Andreas Savas Tolias
Cortical neurons exhibit astounding diversity in gene expression as well as in morphological and electrophysiological properties. Most existing neural taxonomies are based on either transcriptomic or morpho-electric criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells. Here we used Patch-seq to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of over 1300 neurons in adult mouse motor cortex, providing a comprehensive morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (Vip, Pvalb, Sst, etc.) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well-separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neural types in the neocortex do not always form discrete entities. Instead, neurons follow a hierarchy consisting of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.
11 tweets microbiology
Although many bacterial cell division factors have been uncovered over the years, evidence from recent studies points to the existence of yet to be discovered factors involved in cell division regulation. Thus, it is important to identify factors and conditions that regulate cell division to obtain a better understanding of this fundamental biological process. We recently reported that in the Gram-positive organisms Bacillus subtilis and Staphylococcus aureus , increased production of YpsA resulted in cell division inhibition. In this study, we isolated spontaneous suppressor mutations to uncover critical residues of YpsA and the pathways through which YpsA may exert its function. Using this technique, we were able to isolate four unique intragenic suppressor mutations in ypsA (E55D, P79L, R111P, G132E) that rendered the mutated YpsA non-toxic upon overproduction. We also isolated an extragenic suppressor mutation in yfhS, a gene that encodes a protein of unknown function. Subsequent analysis confirmed that cells lacking yfhS were unable to undergo filamentation in response to YpsA overproduction. We also serendipitously discovered that YfhS may play a role in cell size regulation.
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