A gene regulatory network armature for T lymphocyte specification

Choice of a T lymphoid fate by hematopoietic progenitor cells depends on sustained Notch–Delta signaling combined with tightly regulated activities of multiple transcription factors. To dissect the regulatory network connections that mediate this process, we have used high-resolution analysis of regulatory gene expression trajectories from the beginning to the end of specification, tests of the short-term Notch dependence of these gene expression changes, and analyses of the effects of overexpression of two essential transcription factors, namely PU.1 and GATA-3. Quantitative expression measurements of >50 transcription factor and marker genes have been used to derive the principal components of regulatory change through which T cell precursors progress from primitive multipotency to T lineage commitment. Our analyses reveal separate contributions of Notch signaling, GATA-3 activity, and down-regulation of PU.1. Using BioTapestry (www.BioTapestry.org), the results have been assembled into a draft gene regulatory network for the specification of T cell precursors and the choice of T as opposed to myeloid/dendritic or mast-cell fates. This network also accommodates effects of E proteins and mutual repression circuits of Gfi1 against Egr-2 and of TCF-1 against PU.1 as proposed elsewhere, but requires additional functions that remain unidentified. Distinctive features of this network structure include the intense dose dependence of GATA-3 effects, the gene-specific modulation of PU.1 activity based on Notch activity, the lack of direct opposition between PU.1 and GATA-3, and the need for a distinct, late-acting repressive function or functions to extinguish stem and progenitor-derived regulatory gene expression

Remodeling of biological tissue: Mechanically induced reorientation of a transversely isotropic chain network

A new class of micromechanically motivated chain network models for soft biological tissues is presented. On the microlevel, it is based on the statistics of long chain molecules. A wormlike chain model is applied to capture the behavior of the collagen microfibrils. On the macrolevel, the network of collagen chains is represented by a transversely isotropic eight chain unit cell introducing one characteristic material axis. Biomechanically induced remodeling is captured by allowing for a continuous reorientation of the predominant unit cell axis driven by a biomechanical stimulus. To this end, we adopt the gradual alignment of the unit cell axis with the direction of maximum principal strain. The evolution of the unit cell axis' orientation is governed by a first-order rate equation. For the temporal discretization of the remodeling rate equation, we suggest an exponential update scheme of Euler-Rodrigues type. For the spatial discretization, a finite element strategy is applied which introduces the current individual cell orientation as an internal variable on the integration point level. Selected model problems are analyzed to illustrate the basic features of the new model. Finally, the presented approach is applied to the biomechanically relevant boundary value problem of an in vitro engineered functional tendon construct.Comment: LaTeX2e, 19 pages, 9 figure

Transcription factor expression dynamics of early T-lymphocyte specification and commitment

Mammalian T lymphocytes are a prototype for development from adult pluripotent stem cells. While T-cell specification is driven by Notch signaling, T-lineage commitment is only finalized after prolonged Notch activation. However, no T-lineage specific regulatory factor has been reported that mediates commitment. We used a gene-discovery approach to identify additional candidate T-lineage transcription factors and characterized expression of > 100 regulatory genes in early T-cell precursors using realtime RT-PCR. These regulatory genes were also monitored in multilineage precursors as they entered T-cell or non-T-cell pathways in vitro; in non-T cells ex vivo; and in later T-cell developmental stages after lineage commitment. At least three major expression patterns were observed. Transcription factors in the largest group are expressed at relatively stable levels throughout T-lineage specification as a legacy from prethymic precursors, with some continuing while others are downregulated after commitment. Another group is highly expressed in the earliest stages only, and is downregulated before or during commitment. Genes in a third group undergo upregulation at one of three distinct transitions, suggesting a positive regulatory cascade. However, the transcription factors induced during commitment are not T-lineage specific. Different members of the same transcription factor family can follow opposite trajectories during specification and commitment, while factors co-expressed early can be expressed in divergent patterns in later T-cell development. Some factors reveal new regulatory distinctions between αβ and γδ T-lineage differentiation. These results show that T-cell identity has an essentially complex regulatory basis and provide a detailed framework for regulatory network modeling of T-cell specification

Protein intake and risk of frailty among older women in the Nurses' Health Study

Background: There is evidence that an overall healthy diet is associated with lower risk of frailty. However, the effect of diet composition, specifically the role of protein intake on frailty, is mostly unclear. The aim of this study was to evaluate the intake of protein, including total, plant, animal, and dairy protein, in relation to frailty incidence in a large cohort of older women. Methods: We analysed data from 85 871 women aged ≥60 participating in the Nurses' Health Study. Intake of protein was measured nine times during follow-up from 1980 until 2010. Frailty was defined as having at least three of the following five criteria from the Fatigue, Resistance, Ambulation, Illnesses and Loss of Weight (FRAIL) scale: fatigue, low strength, reduced aerobic capacity, having ≥5 illnesses, and weight loss of ≥5%. The occurrence of frailty was assessed every 4 years from 1992 up to 2014. Results: During follow-up, we identified 13 279 incident cases of frailty. Women with a higher intake of plant protein had a lower risk of developing frailty after adjustment for all relevant confounders [relative risks across quintiles of consumption: 1.00, 0.94, 0.89, 0.86, and 0.86; P-trend < 0.001]. In contrast, those with a higher intake of animal protein intake had a higher risk of frailty [relative risks across quintiles of consumption: 1.00, 0.98, 0.99, 1.00, and 1.07; P-trend 0.04]. The intake of total and dairy protein showed no significant association with frailty in the full model. Substituting 5% of energy from plant protein intake at the expense of animal protein, dairy protein, or non-dairy animal protein was associated with 38% (29%, 47%), 32% (21%, 42%), and 42% (33%, 50%) reduced risk of frailty. Conclusions: A higher intake of plant protein, but not animal or dairy protein, was associated with a lower risk of frailty. Substitution of plant protein for animal protein, especially non-dairy animal protein, was associated with lower risk of frailty. Keywords: Diet; Elderly; Frailty; Protei

Evaluation of deformity and hand function in cerebral palsy patients

<p>Abstract</p> <p>Background</p> <p>A cross-sectional study was performed to describe the upper limb deformity and function in cerebral palsy patients and to determine the correlation of deformity, spasticity, motor control, and sensation to hand function in the said population.</p> <p>Materials and methods</p> <p>Thirty patients satisfying our inclusion criteria underwent physical, sensory, and functional assessment using a standard protocol. Physical assessment included documentation of the degree of spasticity, deformity and muscle control. Sensation was tested using static two-point discrimination test and stereognosis test. Melbourne Assessment of the Unilateral Upper Limb Function Test (MAULF), Functional Hand Grip Test (FHGT), and Functional Independence Measure for children (WeeFIM) were used to evaluate hand function. Deformity, spasticity, motor control, and sensation were analyzed for correlation with hand function using Pearson Correlation analysis. A p-value of less than 0.05 was considered statistically significant.</p> <p>Results</p> <p>Functional deficits of the hand increased with increasing severity of deformity and spasticity. Tetraplegics were most affected by spasticity, deformity, poor motor control, sensory and functional deficits. Triplegics, followed by diplegics had more functional upper limbs in terms of the MAULF and FHGT scores. Unilaterally affected patients (triplegics and hemiplegics) scored better in performance of activities of daily living. The MAULF and FHGT had a stronger correlation to deformity, spasticity and motor control compared to the WeeFIM.</p> <p>Conclusion</p> <p>The degree of deformity, spasticity, sensory deficit, and motor control affected the hand function of a cerebral palsy patient significantly. The MAULF and FHGT more accurately represents hand function deficit in cerebral palsy patients.</p

Data on the histological and immune cell response in the popliteal lymph node in mice following exposure to metal particles and ions

AbstractHip implants containing cobalt–chromium (CoCr) have been used for over 80 years. In patients with metal-on-metal (MoM) hip implants, it has been suggested that wear debris particles may contribute to metal sensitization in some individuals, leading to adverse reactions. This article presents data from a study in which the popliteal lymph node assay (PLNA) was used to assess immune responses in mice treated with chromium-oxide (Cr2O3) particles, metal salts (CoCl2, CrCl3, and NiCl2) or Cr2O3 particles with metal salts (“A preliminary evaluation of immune stimulation following exposure to metal particles and ions using the mouse popliteal lymph node assay” (B.E. Tvermoes, K.M. Unice, B. Winans, M. Kovochich, E.S. Fung, W.V. Christian, E. Donovan, B.L. Finley, B.L. Kimber, I. Kimber, D.J. Paustenbach, 2016) [1]). Data are presented on (1) the chemical characterization of TiO2 particles (used as a particle control), (2) clinical observations in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (3) PLN weight and weight index (WI) in mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (4) histological changes in PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, (5) percentages of immune cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts, and (6) percentages of proliferating cells in the PLNs of mice treated with Cr2O3 particles, metal salts or Cr2O3 particles with metal salts

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants &lt;8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Evidence of Associations Between Feto-Maternal Vitamin D Status, Cord Parathyroid Hormone and Bone-Specific Alkaline Phosphatase, and Newborn Whole Body Bone Mineral Content

In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status (25(OH)D), parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose of the present study was to investigate the relationships between maternal and cord 25(OH)D, PTH, BALP, and WBBMC in newborns in a multiethnic population in Oakland, California and to evaluate the predictive value of the biochemical indices as indicators of WBBMC. Maternal and cord blood were collected from 80 mother-infant pairs and infant WBBMC was measured by dual energy X-ray absorptiometry 8–21 days post-birth. Cord PTH and BALP were each inversely correlated with infant WBBMC (r = −0.28, p = 0.01 and r = −0.26, p = 0.02) and with cord 25(OH)D (r = −0.24, p = 0.03 and r = −0.34, p = 0.002), while cord 25(OH)D and unadjusted or weight-adjusted WBBMC were not significantly correlated with one other. In multivariate regression modeling, infant WBBMC was most strongly predicted by infant weight (p < 0.0001), while either PTH or BALP contributed modestly but significantly to the model (p = 0.006 and p = 0.03 respectively). Cord 25(OH)D was not a significant predictor of infant WBBMC. This study provides evidence of associations between feto-maternal 25(OH)D, cord PTH and BALP, and early infant WBBMC, though neither feto-maternal 25(OH)D nor the measured biochemical indices were suitable indicators of WBBMC