Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of next- and third-generation RNA-Seq data reveals the structures of alternative transcription units in bacterial genomes

Alternative transcription units (ATUs) are dynamically encoded under different conditions or environmental stimuli in bacterial genomes, and genome-scale identification of ATUs is essential for studying the emergence of human diseases caused by bacterial organisms. However, it is unrealistic to identify all ATUs using experimental techniques, due to the complexity and dynamic nature of ATUs. Here we present the first-of-its-kind computational framework, named SeqATU, for genome-scale ATU prediction based on next-generation RNA-Seq data. The framework utilizes a convex quadratic programming model to seek an optimum expression combination of all of the to-be-identified ATUs. The predicted ATUs in E. coli reached a precision of 0.77/0.74 and a recall of 0.75/0.76 in the two RNA-Sequencing datasets compared with the benchmarked ATUs from third-generation RNA-Seq data. We believe that the ATUs identified by SeqATU can provide fundamental knowledge to guide the reconstruction of transcriptional regulatory networks in bacterial genomes.
Learning attention-controllable border-ownership for objectness inference and binding

Human visual systems can parse a scene composed of novel objects and infer their surfaces and occlusion relationships without relying on object-specific shapes or textures. Perceptual grouping can bind together spatially disjoint entities to unite them as one object even when the object is entirely novel, and bind other perceptual properties like color and texture to that object using object-based attention. Border-ownership assignment, the assignment of perceived occlusion boundaries to specific perceived surfaces, is an intermediate representation in the mammalian visual system that facilitates this perceptual grouping. Since objects in a scene can be entirely novel, inferring border ownership requires integrating global figural information, while dynamically postulating what the figure is, a chicken-and egg process that is complicated further by missing or conflicting local evidence regarding the presence of boundaries. Based on neuroscience observations, we introduce a model – the cloned Markov random field (CMRF)– that can learn attention-controllable representations for border-ownership. Higher-order contour representations that distinguish border-ownerships emerge as part of learning in this model. When tested with a cluttered scene of novel 2D objects with noisy contour-only evidence, the CMRF model is able to perceptually group them, despite clutter and missing edges. Moreover, the CMRF is able to use occlusion cues to bind disconnected surface elements of novel objects into coherent objects, and able to use top-down attention to assign border ownership to overlapping objects. Our work is a step towards dynamic binding of surface elements into objects, a capability that is crucial for intelligent agents to interact with the world and to form entity-based abstractions.
Identification of Discriminative Gene-level and Protein-level Features Associated with Gain-of-Function and Loss-of-Function Mutations

Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms as they may result in markedly different clinical phenotypes. Here, we generated the first extensive database of all currently known germline GOF and LOF pathogenic mutations by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF mutations by applying machine learning and statistical analyses to identify discriminative features. We found that GOF mutations were enriched in essential genes, autosomal dominant inheritance, protein binding and interaction domains, whereas LOF mutations were enriched in singleton genes, protein-truncating variants, and protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a comprehensive set of annotated features, and downloading up-to-date versions (https://itanlab.shinyapps.io/goflof/). These results could ultimately improve our understanding of how mutations affect gene/protein function thereby guiding future treatment options.
Developmental emergence of two-stage nonlinear synaptic integration in cerebellar interneurons

Synaptic transmission, connectivity, and dendritic morphology mature in parallel during brain development and are often disrupted in neurodevelopmental disorders. Yet how these changes influence the neuronal computations necessary for normal brain function are not well understood. To identify cellular mechanisms underlying the maturation of synaptic integration in interneurons, we combined patch-clamp recordings of excitatory inputs in cerebellar stellate cells (SCs), 3D-reconstruction of SC morphology with excitatory synapse location, and biophysical modeling. We found that, during development, synaptic strength was homogeneously reduced along the somato-dendritic axis, but that dendritic integration was always sublinear. However, dendritic branching increased without changes in synapse density, leading to a substantial gain in distal inputs. Thus, changes in synapse distribution, rather than dendrite cable properties, are the dominant mechanism underlying the maturation of neuronal computation. These mechanisms favor the emergence of a spatially compartmentalized two-stage integration model promoting location-dependent integration within dendritic subunits.
The effect of root exudates on the transcriptome of rhizosphere Pseudomonas spp

Plants live in association with microorganisms that positively influence plant development, vigor, and fitness in response to pathogens and abiotic stressors. The bulk of the plant microbiome is concentrated belowground at the plant root-soil interface. Plant roots secrete carbon-rich rhizodeposits containing primary and secondary low molecular-weight metabolites, lysates, and mucilages. These exudates provide nutrients for soil microorganisms and modulate their affinity to host plants, but molecular details of this process are largely unresolved. We addressed this gap by focusing on the molecular dialogue between eight well-characterized beneficial strains of the Pseudomonas fluorescens group and Brachypodium distachyon, a model for economically important food, feed, forage, and biomass crops of the grass family. We collected and analyzed root exudates of B. distachyon and demonstrated the presence of multiple carbohydrates, amino acids, organic acids and phenolic compounds. The subsequent screening of bacteria by Biolog Phenotype MicroArrays revealed that many of these metabolites provide carbon and energy for the Pseudomonas strains. RNA-seq profiling of bacterial cultures amended with root exudates revealed changes in the expression of genes encoding numerous catabolic and anabolic enzymes, transporters, transcriptional regulators, stress response, and conserved hypothetical proteins. Almost half of the differentially expressed genes mapped to the variable part of the strains’ pangenome, reflecting the importance of the variable gene content in the adaptation of P. fluorescens to the rhizosphere lifestyle. Our results collectively reveal the diversity of cellular pathways and physiological responses underlying the establishment of mutualistic interactions between these beneficial rhizobacteria and their plant hosts.
Aberrant Dynamic Functional Connectivity of Default Mode Network in Schizophrenia and Links to Symptom Severity

Background Schizophrenia affects around 1% of the global population. Functional connectivity extracted from resting-state functional magnetic resonance imaging (rs-fMRI) has previously been used to study schizophrenia and has great potential to provide novel insights into the disorder. Some studies have shown abnormal functional connectivity in the default mode network of individuals with schizophrenia, and more recent studies have shown abnormal dynamic functional connectivity (dFC) in individuals with schizophrenia. However, DMN dFC and the link between abnormal DMN dFC and symptom severity have not been well characterized. Method Resting-state fMRI data from subjects with schizophrenia (SZ) and healthy controls (HC) across two datasets were analyzed independently. We captured seven maximally independent subnodes in the DMN by applying group independent component analysis and estimated dFC between subnode time courses using a sliding window approach. A clustering method separated the dFCs into five reoccurring brain states. A feature selection method modeled the difference between SZs and HCs using the state-specific FC features. Finally, we used the transition probability of a hidden Markov model to characterize the link between symptom severity and dFC in SZ subjects. Results We found decreases in the connectivity of the anterior cingulate cortex (ACC) and increases in the connectivity between the precuneus (PCu) and the posterior cingulate cortex (PCC) (i.e., PCu/PCC) of SZ subjects. In SZ, the transition probability from a state with weaker PCu/PCC and stronger ACC connectivity to a state with stronger PCu/PCC and weaker ACC connectivity increased with symptom severity. Conclusions To our knowledge, this was the first study to investigate DMN dFC and its link to schizophrenia symptom severity. We identified reproducible neural states in a data-driven manner and demonstrated that the strength of connectivity within those states differed between SZs and HCs. Additionally, we identified a relationship between SZ symptom severity and the dynamics of DMN functional connectivity. We validated our results across two datasets. These results support the potential of dFC for use as a biomarker of schizophrenia and shed new light upon the relationship between schizophrenia and DMN dynamics.
Biosynthesis of Steroidal Alkaloids Are Coordinately Regulated and Differ Among Tomatoes in the Red-Fruited Clade

We quantitatively profiled and genotyped two tomato populations representing diversity in the red-fruited clade to address the lack of knowledge regarding the chemical diversity, concentration, and genetic architecture controlling tomato steroidal alkaloids. We grew 107 genetically diverse fresh market, processing, land-race, and wild tomatoes in multiple environments. Nine steroidal alkaloids were quantified using ultra-high performance liquid chromatography tandem mass spectrometry. The diversity panel and a biparental population segregating for high alpha-tomatine, were genotyped to identify and validate quantitative trait loci (QTL) associated with steroidal alkaloids. Land-races and wild material exhibited higher alkaloid concentrations and more chemical diversity. Average total content of steroidal alkaloids, often dominated by lycoperoside F/G/esculeoside A, ranged from 1.9 to 23.3 mg/100 g fresh weight across accessions. Land-race and wild cherry accessions distinctly clustered based on elevated early or late steroidal alkaloid concentrations. Significant correlations were observed among early and late steroidal alkaloids in a species-dependent manner. A QTL controlling multiple, early steroidal alkaloid pathway intermediates on chromosome 3 was identified by genome wide association (GWAS) and validated in a backcross population. Tomato steroidal alkaloids are diverse in the red-fruited tomato clade and their biosynthesis is regulated in a coordinated manner.
Binding and activation of serotonergic G-protein coupled receptors by the multimodal antidepressant vortioxetine

G-protein coupled receptors are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor, but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5? Studying vortioxetine, an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of vortioxetine binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare to available experimental data. We are able to rationalize the differential mode of action of vortioxetine at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation suggesting that interaction with helix 5 does not necessarily require a hydrogen bond as previously suggested. The results extend our current understanding of agonist and antagonist action at GPCRs.
rdrugtrajectory: An R Package for the Analysis of Drug Prescriptions in Electronic Health Care Records

Primary care electronic health care records are rich with patient and clinical information. Studying electronic health care records has resulted in marked improvements to national health care processes and patient-care decision making, and is a powerful supplementary source of data for drug discovery effort. We present the R package rdrugtrajectory, designed to yield demographic and patient-level characteristics of drug prescriptions in the UK Clinical Practice Research Datalink dataset. The package operates over Clinical Practice Research Datalink Gold clinical, referral and therapy datasets and includes features such as first drug prescriptions analysis, cohort-wide prescription information, cumulative drug prescription events, the longitudinal trajectory of drug prescriptions, and a survival analysis timeline builder to identify risks related to drug prescription switching. The rdrugtrajectory package has been made freely available via the GitHub repository.
Novel functional sequences uncovered through a bovine multiassembly graph

Significance Most sequence variant analyses rely on a linear reference genome that is assumed to lack millions of bases that occur in the genomes of other individuals. To quantify the extent and functional relevance of such missing bases, we integrate six genome assemblies from cattle and related species into a pangenome. This allows us to uncover more than 70 million bases that are not included in the Bos taurus reference genome. Through complementary bioinformatics, genomics, and transcriptomics methods, we discover putative genes from nonreference sequences that are differentially expressed and thousands of polymorphic sites that were unused so far. Our work provides a computational framework, broadly applicable to many species, to make a so-far neglected source of genomic variation amenable to genetic investigations. Many genomic analyses start by aligning sequencing reads to a linear reference genome. However, linear reference genomes are imperfect, lacking millions of bases of unknown relevance and are unable to reflect the genetic diversity of populations. This makes reference-guided methods susceptible to reference-allele bias. To overcome such limitations, we build a pangenome from six reference-quality assemblies from taurine and indicine cattle as well as yak. The pangenome contains an additional 70,329,827 bases compared to the Bos taurus reference genome. Our multiassembly approach reveals 30 and 10.1 million bases private to yak and indicine cattle, respectively, and between 3.3 and 4.4 million bases unique to each taurine assembly. Utilizing transcriptomes from 56 cattle, we show that these nonreference sequences encode transcripts that hitherto remained undetected from the B. taurus reference genome. We uncover genes, primarily encoding proteins contributing to immune response and pathogen-mediated immunomodulation, differentially expressed between Mycobacterium bovis–infected and noninfected cattle that are also undetectable in the B. taurus reference genome. Using whole-genome sequencing data of cattle from five breeds, we show that reads which were previously misaligned against the Bos taurus reference genome now align accurately to the pangenome sequences. This enables us to discover 83,250 polymorphic sites that segregate within and between breeds of cattle and capture genetic differentiation across breeds. Our work makes a so-far unused source of variation amenable to genetic investigations and provides methods and a framework for establishing and exploiting a more diverse reference genome.
Simultaneous association of grip effort with snack food items does not change preferences

Effort is typically considered aversive such that rewards requiring less effort are preferred over identical value rewards that require greater effort, commonly referred to as “effort discounting”. Although effort has been repeatedly shown to be weighed as a cost, there are indications to suggest that under some conditions it may increase preferences. An example for how effort affects preferences is the ‘contrast effect’ were items that follow effort production gain value. In the current study we examined whether the association of grip effort with snack food items would change preferences. In four experiments, we first identified each participant’s individual preferences of snack food items and subjective maximal grip force. We then associated different effort levels with items of similar preference. Finally, we tested for changes in preferences following the effort association. Across the four studies, effort association had no effect on preferences. Using Bayesian analyses, we conclude that simultaneous association of effort does not change preferences in our studies and call for a replication effort of previous findings.
The adhesion capability of Staphylococcus aureus cells is heterogeneously distributed over the cell envelope

Understanding and controlling microbial adhesion is an important biomedical problem. However, many properties of the adhesion process of bacteria are still unknown, for example the distribution of adhesive strength over the cell wall. While a patchy colloid model for adhesion has been developed recently for Gram-negative Escherichia coli cells, a comparable model for Grampositive cells is unknown. Here, we use single-cell force spectroscopy to measure the adhesion of Staphylococcus aureus at different positions on tailored surfaces. We find heterogeneous adhesion profiles with varying degrees of intensity. By comparing these results to simulations, we find that locally increased adhesion can be explained by several distinct spots of high adhesion capabilities, similar to the patchy colloid model. Only for the underlying profile without local adhesive spots simple geometric considerations are insufficient. Rather, strong angle-dependent molecule-substratum interactions are necessary to explain the bathtub-like adhesion profiles seen for Staphylococcus aureus on a sinusoidal surface. We discuss implications of our results for the development of new materials and the design and analysis of future studies.
Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Accurate chromosome segregation during cell division requires amphitelic chromosome attachment to the spindle apparatus. It is ensured by the combined activity of the Spindle Assembly Checkpoint (SAC) [1], a signaling mechanism that delays anaphase onset in response to unattached chromosomes, and an error correction mechanism that eliminates syntelic attachments [2]. The SAC becomes active when Mps1 kinase sequentially phosphorylates the kinetochore protein Spc105/KNL1 and the signaling proteins that Spc105/KNL1 recruits enabling the production of the Mitotic Checkpoint Complex (MCC) [3-8]. The error correction mechanism is regulated by the Aurora B kinase, but Aurora B also promotes SAC signaling via indirect mechanisms [9-12]. Here we present evidence that Aurora B kinase activity directly promotes MCC production by working downstream of Mps1 in budding yeast and human cells. Using the ectopic SAC activation (eSAC) system, we find that the conditional dimerization of Aurora B in budding yeast, and an Aurora B recruitment domain in HeLa cells, with either Bub1 or Mad1, but not the ‘MELT’ motifs in Spc105/KNL1, leads to ectopic MCC production and mitotic arrest [13-16]. Importantly, this requires the ability of Bub1 to recruit both Mad1 and Cdc20. These and other data show that Aurora B cooperates with Bub1 to promote MCC production, but only after Mps1 licenses Bub1 recruitment to the kinetochore. This direct involvement of Aurora B in SAC signaling likely enables SAC signaling to continue after Mps1 activity in the kinetochore is lowered.
The elevational ascent and spread of invasive annual grass dominance in the Great Basin, USA

Aim In the western US, sagebrush (Artemisia spp.) and salt desert shrublands are rapidly transitioning to communities dominated by exotic annual grasses, a novel and often self-reinforcing state that threatens the economic sustainability and conservation value of rangelands. Climate change is predicted to directly and indirectly favor annual grasses, potentially pushing transitions to annual grass dominance into higher elevations and north-facing aspects. We sought to quantify the expansion of annual grass-dominated vegetation communities along topographic gradients over the past several decades. Location Our analysis focused on rangelands among three ecoregions in the Great Basin of the western US, where several species of exotic annual grasses are widespread among shrub and perennial grass-dominated vegetation communities. Methods We used recently developed remote sensing-based rangeland vegetation data to produce yearly maps of annual grass-dominated vegetation communities spanning the period 1990–2020. With these maps, we quantified the rate of spread and characterized changes in the topographic distribution (i.e., elevation and aspect) of areas transitioning to annual grass dominance. Results We documented more than an eight-fold increase in annual grass-dominated area (to >77,000 km2) occurring at an average rate of >2,300 km2 yr-1. In 2020, annual grasses dominated one fifth (19.8%) of Great Basin rangelands. This rapid expansion is associated with a broadening of the topographic niche, with widespread movement into higher elevations and north-facing aspects. Main conclusions Accelerated, strategic intervention is critically needed to conserve the fragile band of rangelands being compressed between annual grassland transitions at lower elevations and woodland expansion at higher elevations.