The rockefeller university

Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into microniches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.

The future of medicine is discussed in the context of epigenetic influences during the entire life course and the lived experiences of each person, avoiding as much as possible the "medicalization" of the individual and taking a more humanistic view. The reciprocal communication between brain and body via the neuroendocrine, autonomic, metabolic and immune systems and the plasticity of brain architecture provide the basis for devising better "top down" interventions that engage the whole person in working towards his or her welfare. The life course perspective emphasizes the importance of intervening early in life to prevent adverse early life experiences, including the effects of poverty, that can have lifelong consequences, referred to as "biological embedding". In the spirit of integrative, humanistic medicine, treatments that "open windows of plasticity" allow targeted behavioral interventions to redirect brain and body functions and behavior in healthier directions. Policies of government and the private sector, particularly at the local, community level, can create a supporting environment for such interventions. See "Common Ground for Health: Personalized, Precision and Social Medicine McEwen & Getz (C) 2017 Published by Elsevier Inc.

Patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) exhibit variable vulnerability to infections by mycobacteria and other intramacrophagic bacteria (e.g., Salmonella and Klebsiella) and fungi (e.g., Histoplasma, Candida, Paracoccidioides, Coccidioides, and Cryptococcus). The hallmark of MSMD is the inherited impaired production of interferon gamma (IFN-gamma) or the lack of response to it. Mutations in the interleukin (IL)-12 receptor subunit beta 1 (IL12RB1) gene accounts for 38% of cases of MSMD. Most IL12RB1 pathogenic allele mutations, including ten known stop-gain variants, cause IL-12R beta 1 complete deficiency (immunodeficiency-30, IMD30) by knocking out receptor cell-surface expression. IL12RB1 loss-of-function genotypes impair both IL-12 and IL-23 responses. Here, we assess the health effects of a rare, novel IL12RB1 stop-gain homozygous genotype with paradoxical IL-12R beta 1 cell-surface expression. We appraise four MSMD children from three unrelated Brazilian kindreds by clinical consultation, medical records, and genetic and immunologic studies. The clinical spectrum narrowed down to Bacillus Calmette-Guerin (BCG) vaccine-related suppurative adenitis in all patients with one death, and recrudescence in two, histoplasmosis, and recurrence in one patient, extraintestinal salmonellosis in one child, and cutaneous vasculitis in another. In three patients, we established the homozygous Trp7Ter predicted loss-of-function inherited genotype and inferred it from the heterozygote parents of the fourth case. The Trp7Ter mutation maps to the predicted IL-12R beta 1 N-terminal signal peptide sequence. BCG- or phytohemagglutinin-blasts from the three patients have reduced cell-surface expression of IL-12R beta 1 with impaired production of IFN-gamma and IL-17A. Screening of 227 unrelated healthy subjects from the same geographic region revealed one heterozygous genotype (allele frequency 0.0022) vs. one in over 841,883 public genome/exomes. We also show that the carriers bear European ancestry-informative alleles and share the extended CACCAGTCCGG IL12RB1 haplotype that occurs worldwide with a frequency of 8.4%. We conclude that the novel IL12RB1 N-terminal signal peptide stop-gain loss-of-function homozygous genotype confers IL-12R beta 1 deficiency with varying severity and early-onset age through diminished cell-surface expression of an impaired IL-12R beta 1 polypeptide. We firmly recommend attending to warning signs of IMD30 in children who are HIV-1 negative with a history of adverse effects to the BCG vaccine and presenting with recurrent Histoplasma spp. and extraintestinal Salmonella spp. infections.

Human red blood cells (RBCs) are normally phagocytized by macrophages of splenic and hepatic sinusoids at 120 days of age. The destruction of RBCs is ultimately controlled by antagonist effects of phosphatidylserine (PS) and CD47 on the phagocytic activity of macrophages. In this work, we introduce a conceptual model that explains RBC lifespan as a consequence of the dynamics of these molecules. Specifically, we suggest that PS and CD47 define a molecular algorithm that sets the timing of RBC phagocytosis. We show that significant changes in RBC lifespan described in the literature can be explained as alternative outcomes of this algorithm when it is executed in different conditions of oxygen availability. The theoretical model introduced here provides a unified framework to understand a variety of empirical observations regarding RBC biology. It also highlights the role of RBC lifespan as a key element of RBC homeostasis.

Zebra finches (Taeniopygia guttata) learn to produce songs in a manner reminiscent of spoken language development in humans. One candidate gene implicated in influencing learning is the N-methyl-D-aspartate (NMDA) subtype 2B glutamate receptor (NR2B). Consistent with this idea, NR2B levels are high in the song learning nucleus LMAN (lateral magnocellular nucleus of the anterior nidopallium) during juvenile vocal learning, and decreases to low levels in adults after learning is complete and the song becomes more stereotyped. To test for the role of NR2B in generating song plasticity, we manipulated NR2B expression in LMAN of adult male zebra finches by increasing its protein levels to those found in juvenile birds, using a lentivirus containing the full-length coding sequence of the human NR2B subunit. We found that increased NR2B expression in adult LMAN induced increases in song sequence diversity and slower song tempo more similar to juvenile songs, but also increased syllable repetitions similar to stuttering. We did not observe these effects in control birds with overexpression of NR2B outside of LMAN or with the green fluorescent protein (GFP) in LMAN. Our results suggest that low NR2B subunit expression in adult LMAN is important in conserving features of stereotyped adult courtship song.

A multifunctional chlorin platform appended with four short polyethylene glycols and a carboxylate-linker allows rapid conjugation to biotargeting motifs such as proteins and oligonucleotides. The stability and photophysical properties of the chlorin enable development of diagnostics, imaging, molecular tracking, and theranostics.

BACKGROUND Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-alpha/beta immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. METHODS We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. RESULTS We found that TLR3-and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-alpha/beta and IFN-alpha/beta-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-alpha did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3-or IFN-alpha/beta-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children. (C) 2017 by the American College of Cardiology Foundation.

Within cells, nanostructures are often organized using local assembly rules that produce long-range order(1,2). Because these rules can take into account the cell's current structure and state, they can enable complexes, organelles or cytoskeletal structures to assemble around existing cellular components to form architectures(3-6). Although many methods for self-assembling biomolecular nanostructures have been developed(7-11), few can be programmed to assemble structures whose form depends on the identity and organization of structures already present in the environment. Here, we demonstrate that DNA nanotubes can grow to connect pairs of molecular landmarks with different separation distances and relative orientations. DNA tile nanotubes nucleate at these landmarks and grow while their free ends diffuse. The nanotubes can then join end to end to form stable connections, with unconnected nanotubes selectively melted away. Connections form between landmark pairs separated by 1-10 mu m in more than 75% of cases and can span a surface or three dimensions. This point-to-point assembly process illustrates how self-assembly kinetics can be designed to produce structures with a desired physical property rather than a specific shape.

Translational profiling methodologies enable the systematic characterization of cell types in complex tissues, such as the mammalian brain, where neuronal isolation is exceptionally difficult. Here, we report a versatile strategy for profiling CNS cell types in a spatiotemporally restricted fashion by engineering a Cre-dependent adeno-associated virus expressing an EGFP-tagged ribosomal protein (AAV-FLEXEGFPL10a) to access translating mRNAs by translating ribosome affinity purification (TRAP). We demonstrate the utility of this AAV to target a variety of genetically and anatomically defined neural populations expressing Cre recombinase and illustrate the ability of this viralTRAP(vTRAP) approach to recapitulate the molecular profiles obtained by bacTRAP in corticothalamic neurons across multiple serotypes. Furthermore, spatially restricting adeno-associated virus (AAV) injections enabled the elucidation of regional differences in gene expression within this cell type. Altogether, these results establish the broad applicability of the vTRAP strategy for the molecular dissection of any CNS or peripheral cell type that can be engineered to express Cre.

The static electric polarization of a holographic field theory dual to the Einstein-Maxwell theory in the background of AdS(4) with a Reissner-Nordstrom (AdS-RN) black hole is investigated. We prove that the holographic polarization is a meromorphic functions in complex momentum plane and locate analytically the asymptotic distribution of the poles along two straight lines parallel to the imaginary axis for a large momentum magnitude. The results are compared with the numerical result on Friedel-like poles of the same holographic model reported in the literature and with the momentum singularities of the one-loop polarization in weak-coupling spinor QED(3) and scalar QED(3) with the similarities and differences discussed.