scCODA is a Bayesian model for compositional single-cell data analysis

Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA (https://github.com/theislab/scCODA), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.

New End-Stopped Complex Cell Model Applicable in Convolutional Neural Networks

This article is dedicated to modeling the end-stopped neuron. This type of neuron gives the maximum response at the end of the line and is used to refine the edge. The article provides an overview of different models of end-stopped neurons. I have proposed a simpler and more accurate model of an end-stopped neuron based on the use of Gabor filters in antiphase. For this purpose, the models of simple and complex cells whose output is used in the proposed model are also described. Simple cells are based on the use of a Gabor filter, the parameters of which are also described in this article. The proposed model has shown its effectiveness.

A new class of cell wall-recycling L,D-carboxypeptidase determines β-lactam susceptibility and morphogenesis in Acinetobacter baumannii

The hospital-acquired pathogen Acinetobacter baumannii possesses a complex cell envelope that is key to its multidrug resistance and virulence. The bacterium, however, lacks many canonical enzymes that build the envelope in model organisms. Instead, A. baumannii contains a number of poorly annotated proteins that may allow alternative mechanisms of envelope biogenesis. We demonstrated previously that one of these unusual proteins, ElsL, is required for cell elongation and for withstanding antibiotics that attack the septal cell wall. Curiously, ElsL is composed of a leaderless YkuD-family domain usually found in secreted, cell-wall-modifying L,D-transpeptidases (LDTs). Here, we show that, rather than being an LDT, ElsL is actually a new class of cytoplasmic L,D-carboxypeptidase (LDC) that provides a critical step in cell-wall recycling previously thought to be missing from A. baumannii. Absence of ElsL impairs cell wall integrity, elongation, and intrinsic resistance due to buildup of murein tetrapeptide precursors, toxicity of which is bypassed by preventing muropeptide recycling. Multiple pathways in the cell become sites of vulnerability when ElsL is inactivated, including L,D-crosslink formation, cell division, and outer membrane lipid homoeostasis, reflecting its pleiotropic influence on cell envelope physiology. We thus reveal a novel class of cell-wall-recycling LDC critical to growth and homeostasis of A. baumannii and likely many other bacteria.

A framework for evaluating edited cell libraries created by massively parallel genome engineering

Genome engineering methodologies are transforming biological research and discovery. Approaches based on CRISPR technology have been broadly adopted and there is growing interest in the generation of massively parallel edited cell libraries. Comparing the libraries generated by these varying approaches is challenging and researchers lack a common framework for defining and assessing the characteristics of these libraries. Here we describe a framework for evaluating massively parallel libraries of edited genomes based on established methods for sampling complex populations. We define specific attributes and metrics that are informative for describing a complex cell library and provide examples for estimating these values. We also connect this analysis to generic phenotyping approaches, using either pooled (typically via a selection assay) or isolate (often referred to as screening) phenotyping approaches. We approach this from the context of creating massively parallel, precisely edited libraries with one edit per cell, though the approach holds for other types of modifications, including libraries containing multiple edits per cell (combinatorial editing). This framework is a critical component for evaluating and comparing new technologies as well as understanding how a massively parallel edited cell library will perform in a given phenotyping approach.

The spatial transcriptomic landscape of the healing intestine following damage

The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics (ST) to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we used our resource to map transcriptomics modules associated with human diseases demonstrating that ST can be used to inform clinical practice. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.

Composition and function of the C1b/C1f region in the ciliary central apparatus

Motile cilia are ultrastructurally complex cell organelles with the ability to actively move. The highly conserved central apparatus of motile 9 × 2 + 2 cilia is composed of two microtubules and several large microtubule-bound projections, including the C1b/C1f supercomplex. The composition and function of C1b/C1f subunits has only recently started to emerge. We show that in the model ciliate Tetrahymena thermophila, C1b/C1f contains several evolutionarily conserved proteins: Spef2A, Cfap69, Cfap246/LRGUK, Adgb/androglobin, and a ciliate-specific protein Tt170/TTHERM_00205170. Deletion of genes encoding either Spef2A or Cfap69 led to a loss of the entire C1b projection and resulted in an abnormal vortex motion of cilia. Loss of either Cfap246 or Adgb caused only minor alterations in ciliary motility. Comparative analyses of wild-type and C1b-deficient mutant ciliomes revealed that the levels of subunits forming the adjacent C2b projection but not C1d projection are greatly reduced, indicating that C1b stabilizes C2b. Moreover, the levels of several IFT and BBS proteins, HSP70, and enzymes that catalyze the final steps of the glycolytic pathway: enolase ENO1 and pyruvate kinase PYK1, are also reduced in the C1b-less mutants.

Neuron-Oligodendrocyte Interactions in the Structure and Integrity of Axons

The myelination of axons by oligodendrocytes is a highly complex cell-to-cell interaction. Oligodendrocytes and axons have a reciprocal signaling relationship in which oligodendrocytes receive cues from axons that direct their myelination, and oligodendrocytes subsequently shape axonal structure and conduction. Oligodendrocytes are necessary for the maturation of excitatory domains on the axon including nodes of Ranvier, help buffer potassium, and support neuronal energy metabolism. Disruption of the oligodendrocyte-axon unit in traumatic injuries, Alzheimer’s disease and demyelinating diseases such as multiple sclerosis results in axonal dysfunction and can culminate in neurodegeneration. In this review, we discuss the mechanisms by which demyelination and loss of oligodendrocytes compromise axons. We highlight the intra-axonal cascades initiated by demyelination that can result in irreversible axonal damage. Both the restoration of oligodendrocyte myelination or neuroprotective therapies targeting these intra-axonal cascades are likely to have therapeutic potential in disorders in which oligodendrocyte support of axons is disrupted.