A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.

Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined.

Mapping hormone-regulated cell-cell interaction networks in the human breast at single-cell resolution.

The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy regulates breast development and modifies cancer risk. How these hormones impact each cell type in the breast remains poorly understood because they act indirectly through paracrine networks. Using single-cell analysis of premenopausal breast tissue, we reveal a network of coordinated transcriptional programs representing the tissue-level response to changing hormone levels.

CloudPred: Predicting Patient Phenotypes From Single-cell RNA-seq.

Single-cell RNA sequencing (scRNA-seq) has the potential to provide powerful, high-resolution signatures to inform disease prognosis and precision medicine. This paper takes an important first step towards this goal by developing an interpretable machine learning algorithm, CloudPred, to predict individuals' disease phenotypes from their scRNA-seq data. Predicting phenotype from scRNA-seq is challenging for standard machine learning methods-the number of cells measured can vary by orders of magnitude across individuals and the cell populations are also highly heterogeneous.

Bimodal function of chromatin remodeler in neural crest induction and Wnt-dependent emigration.

During gastrulation, neural crest cells are specified at the neural plate border, as characterized by expression. Using single-cell RNA sequencing coupled with high-resolution hybridization to identify novel transcriptional regulators, we show that chromatin remodeler is highly expressed prior to specification and maintained in migrating chick neural crest cells. Temporally controlled CRISPR-Cas9-mediated knockouts uncovered two distinct functions of in neural crest development.

Highly multiplexed single-cell RNA-seq by DNA oligonucleotide tagging of cellular proteins.

We describe a universal sample multiplexing method for single-cell RNA sequencing in which fixed cells are chemically labeled by attaching identifying DNA oligonucleotides to cellular proteins. Analysis of a 96-plex perturbation experiment revealed changes in cell population structure and transcriptional states that cannot be discerned from bulk measurements, establishing an efficient method for surveying cell populations from large experiments or clinical samples with the depth and resolution of single-cell RNA sequencing.

Integrated measurement of intracellular proteins and transcripts in single cells.

Biological function arises from the interplay of proteins, transcripts, and metabolites. An ongoing revolution in miniaturization technologies has created tools to analyze any one of these species in single cells, thus resolving the heterogeneity of tissues previously invisible to bulk measurements. An emerging frontier is single cell multi-omics, which is the measurement of multiple classes of analytes from single cells.

Diffusion as a Ruler: Modeling Kinesin Diffusion as a Length Sensor for Intraflagellar Transport.

An important question in cell biology is whether cells are able to measure size, either whole cell size or organelle size. Perhaps cells have an internal chemical representation of size that can be used to precisely regulate growth, or perhaps size is just an accident that emerges due to constraint of nutrients. The eukaryotic flagellum is an ideal model for studying size sensing and control because its linear geometry makes it essentially one-dimensional, greatly simplifying mathematical modeling.

Adult Neurogenesis Is Sustained by Symmetric Self-Renewal and Differentiation.

Somatic stem cells have been identified in multiple adult tissues. Whether self-renewal occurs symmetrically or asymmetrically is key to understanding long-term stem cell maintenance and generation of progeny for cell replacement. In the adult mouse brain, neural stem cells (NSCs) (B1 cells) are retained in the walls of the lateral ventricles (ventricular-subventricular zone [V-SVZ]).

Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch.

Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis.

patterning of pluripotent stem cell-derived intestine recapitulates human development.

The intestine plays a central role in digestion, nutrient absorption and metabolism, with individual regions of the intestine having distinct functional roles. Many examples of region-specific gene expression in the adult intestine are known, but how intestinal regional identity is established during development is a largely unresolved issue. Here, we have identified several genes that are expressed in a region-specific manner in the developing human intestine.

Signaling Boundary Conditions Drive Self-Organization of Human "Gastruloids".

Morphogenesis requires tissues to sense and respond to their geometry. In this issue of Developmental Cell, Etoc et al. (2016) show that a confined colony of human embryonic stem cells can spontaneously sense its boundary, generating a self-organized TGF-β signaling gradient that patterns it into a tissue resembling a gastrulating embryo.

SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells.

The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs).

Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors.

The Notch protein is one of the most mechanistically direct transmembrane receptors-the intracellular domain contains a transcriptional regulator that is released from the membrane when engagement of the cognate extracellular ligand induces intramembrane proteolysis. We find that chimeric forms of Notch, in which both the extracellular sensor module and the intracellular transcriptional module are replaced with heterologous protein domains, can serve as a general platform for generating novel cell-cell contact signaling pathways. Synthetic Notch (synNotch) pathways can drive user-defined functional responses in diverse mammalian cell types.

Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo.

Human intestinal organoids (HIOs) are a tissue culture model in which small intestine-like tissue is generated from pluripotent stem cells. By carrying out unsupervised hierarchical clustering of RNA-sequencing data, we demonstrate that HIOs most closely resemble human fetal intestine. We observed that genes involved in digestive tract development are enriched in both fetal intestine and HIOs compared to adult tissue, whereas genes related to digestive function and Paneth cell host defense are expressed at higher levels in adult intestine.

A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity.

Developing tissues contain motile populations of cells that can self-organize into spatially ordered tissues based on differences in their interfacial surface energies. However, it is unclear how self-organization by this mechanism remains robust when interfacial energies become heterogeneous in either time or space. The ducts and acini of the human mammary gland are prototypical heterogeneous and dynamic tissues comprising two concentrically arranged cell types.

The rational parameterization theorem for multisite post-translational modification systems.

Post-translational modification of proteins plays a central role in cellular regulation but its study has been hampered by the exponential increase in substrate modification forms ("modforms") with increasing numbers of sites. We consider here biochemical networks arising from post-translational modification under mass-action kinetics, allowing for multiple substrates, having different types of modification (phosphorylation, methylation, acetylation, etc.) on multiple sites, acted upon by multiple forward and reverse enzymes (in total number L), using general enzymatic mechanisms.

Unlimited multistability in multisite phosphorylation systems.

Reversible phosphorylation on serine, threonine and tyrosine is the most widely studied posttranslational modification of proteins. The number of phosphorylated sites on a protein (n) shows a significant increase from prokaryotes, with n /= 150 sites. Multisite phosphorylation has many roles and site conservation indicates that increasing numbers of sites cannot be due merely to promiscuous phosphorylation.

Influence of common orthodontic appliances on the diagnostic quality of cranial magnetic resonance images.

Introduction: The aim of this study was to evaluate cranial magnetic resonance (MR) image distortion caused by various orthodontic brackets.

Methods: Ten subjects received 5 consecutive cranial MR scans. A control scan was conducted with Essix trays (GAC International, Bohemia, NY) fitted over the maxillary and mandibular teeth.

Programming with models: modularity and abstraction provide powerful capabilities for systems biology.

Mathematical models are increasingly used to understand how phenotypes emerge from systems of molecular interactions. However, their current construction as monolithic sets of equations presents a fundamental barrier to progress. Overcoming this requires modularity, enabling sub-systems to be specified independently and combined incrementally, and abstraction, enabling generic properties of biological processes to be specified independently of specific instances.

Extended pedal imaging via modifications of the traditional forefoot axial radiographic study: teaching new tricks to an old dog? an initial report with case presentations.

Background: The plain film forefoot axial radiographic view is a specialized view in podiatric imaging. In everyday office practice, an axial orthoposer is used, and the study is nonweightbearing. Largely useless for imaging functional pathology, the forefoot axial view's main use centers around imaging of the plantar metatarsal heads and the hallucal sesamoid complex.

An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types.

Azygos vein dialysis catheter placement using the translumbar approach in a patient with inferior vena cava occlusion.

We describe percutaneous, translumbar placement of a 14-Fr dialysis catheter into an ascending lumbar vein to achieve tip position in an enlarged azygos vein. The patient had thrombosis of all traditional vascular sites, as well as the inferior vena cava. This catheter functioned well for 7 months before fatal catheter-related infection developed.

The health care philosophy that nearly destroyed Medicare in Canada in a single decade.

Background: In 1989, governments in Canada perceived an economic crisis in health care funding and commissioned two economists, Drs. Barer and Stoddart, to review policies. They indicated that major costs were caused by physicians and recommended cutting physician training and hospital facilities.