The Role of Developmental Timing Regulators in Progenitor Proliferation and Cell Fate Specification During Mammalian Neurogenesis

Developmental timing is a key aspect of tissue and organ formation in which distinct cell types are generated through a series of steps from common progenitors. These progenitors undergo specific changes in gene expression that signifies both a distinct progenitor type and developmental time point that thereby specifies a particular cell fate at that stage of development. The nervous system is an important setting for understanding developmental timing because different cell types are produced in a certain order and the switch from stem cells to progenitors requires precise timing and regulation. Notable examples of such regulatory molecules include the RNA-binding protein LIN28, and its downstream target, miRNA let-7. Although LIN28 is known to regulate both cell fate and tissue growth, and at times to promote an undifferentiated state, thus far a unified understanding of LIN28’s biological role at the cellular level has not been attained. Here I address LIN28’s activity in mammalian postnatal neurogenesis. Constitutive expression of LIN28 in cells derived from the subventricular zone of the mouse caused several distinct effects: (1) the number of differentiated neurons was dramatically reduced while the relative abundance of two neuronal sub-types was significantly altered; (2) the population of proliferating neural progenitors in the SVZ was reduced while the proportion of neuroblasts was increased, (3) neuro-blast exit from the SVZ increased, and (4) the number of astrocytes was reduced while occasionally causing them to appear early. Thus, LIN28 acts at a post-stem cell/pre-differentiation step, and its continuous expression caused a precocious, not a reiterative phenotype, as is seen in other experimental systems. I made use of a circular RNA sponge that effectively inhibits let-7 activity to address the degree to which LIN28’s effects are due to its inhibition of let-7. Moreover, since LIN41 contributes to a subset of LIN28’s function in C. elegans, I explored whether LIN41 played a role in mammalian neurogenesis. I found that although LIN28 has a multifaceted role in the number and types of cells produced during postnatal neurogenesis, it appears that its action through let-7 accounts for only a fraction of these effects

Recruitment Market Trend Analysis with Sequential Latent Variable Models

Recruitment market analysis provides valuable understanding of industry-specific economic growth and plays an important role for both employers and job seekers. With the rapid development of online recruitment services, massive recruitment data have been accumulated and enable a new paradigm for recruitment market analysis. However, traditional methods for recruitment market analysis largely rely on the knowledge of domain experts and classic statistical models, which are usually too general to model large-scale dynamic recruitment data, and have difficulties to capture the fine-grained market trends. To this end, in this paper, we propose a new research paradigm for recruitment market analysis by leveraging unsupervised learning techniques for automatically discovering recruitment market trends based on large-scale recruitment data. Specifically, we develop a novel sequential latent variable model, named MTLVM, which is designed for capturing the sequential dependencies of corporate recruitment states and is able to automatically learn the latent recruitment topics within a Bayesian generative framework. In particular, to capture the variability of recruitment topics over time, we design hierarchical dirichlet processes for MTLVM. These processes allow to dynamically generate the evolving recruitment topics. Finally, we implement a prototype system to empirically evaluate our approach based on real-world recruitment data in China. Indeed, by visualizing the results from MTLVM, we can successfully reveal many interesting findings, such as the popularity of LBS related jobs reached the peak in the 2nd half of 2014, and decreased in 2015.Comment: 11 pages, 30 figure, SIGKDD 201

Emergence of heterogeneity and political organization in information exchange networks

We present a simple model of the emergence of the division of labor and the development of a system of resource subsidy from an agent-based model of directed resource production with variable degrees of trust between the agents. The model has three distinct phases, corresponding to different forms of societal organization: disconnected (independent agents), homogeneous cooperative (collective state), and inhomogeneous cooperative (collective state with a leader). Our results indicate that such levels of organization arise generically as a collective effect from interacting agent dynamics, and may have applications in a variety of systems including social insects and microbial communities.Comment: 10 pages, 6 figure

Binding-incompetent adenovirus facilitates molecular conjugate-mediated gene transfer by the receptor-mediated endocytosis pathway

Molecular conjugate vectors may be constructed that accomplish high efficiency gene transfer by the receptor-mediated endocytosis pathway. In order to mediate escape from lysosomal degradation, we have incorporated adenoviruses into the functional design of the conjugate. In doing so, however, we have introduced an additional ligand, which can bind to receptors on the cell surface, undermining the potential for cell specific targeting. To overcome this, we have treated the adenovirus with a monoclonal anti-fiber antibody, which renders the virus incapable of binding to its receptor. The result is a multi-functional molecular conjugate vector, which has preserved its binding specificity while at the same time being capable of preventing lysosomal degradation of endosome-internalized conjugate-DNA complexes. This finding indicates that adenoviral binding is not a prerequisite for adenoviral-mediated endosome disruption

Multispeckle diffusing-wave spectroscopy: a tool to study slow relaxation and time-dependent dynamics

A multispeckle technique for efficiently measuring correctly ensemble-averaged intensity autocorrelation functions of scattered light from non-ergodic and/or non-stationary systems is described. The method employs a CCD camera as a multispeckle light detector and a computer-based correlator, and permits the simultaneous calculation of up to 500 correlation functions, where each correlation function is started at a different time. The correlation functions are calculated in real time and are referenced to a unique starting time. The multispeckle nature of the CCD camera detector means that a true ensemble average is calculated; no time averaging is necessary. The technique thus provides a "snapshot" of the dynamics, making it particularly useful for non-stationary systems where the dynamics are changing with time. Delay times spanning the range from 1 ms to 1000 s are readily achieved with this method. The technique is demonstrated in the multiple scattering limit where diffusing-wave spectroscopy theory applies. The technique can also be combined with a recently-developed two-cell technique that can measure faster decay times. The combined technique can measure delay times from 10 ns to 1000 s. The method is peculiarly well suited for studying aging processes in soft glassy materials, which exhibit both short and long relaxation times, non-ergodic dynamics, and slowly-evolving transient behavior.Comment: 11 pages 13 figures Accepted in Review of Scientific Instrument (june 02

Excessive gas exchange impairment during exercise in a subject with a history of bronchopulmonary dysplasia and high altitude pulmonary edema

A 27-year-old male subject (V(O2 max)), 92% predicted) with a history of bronchopulmonary dysplasia (BPD) and a clinically documented case of high altitude pulmonary edema (HAPE) was examined at rest and during exercise. Pulmonary function testing revealed a normal forced vital capacity (FVC, 98.1% predicted) and diffusion capacity for carbon monoxide (D(L(CO)), 91.2% predicted), but significant airway obstruction at rest [forced expiratory volume in 1 sec (FEV(1)), 66.5% predicted; forced expiratory flow at 50% of vital capacity (FEF(50)), 34.3% predicted; and FEV(1) /FVC 56.5%] that was not reversible with an inhaled bronchodilator. Gas exchange worsened from rest to exercise, with the alveolar to arterial P(O2) difference (AaD(O2)) increasing from 0 at rest to 41 mmHg at maximal normoxic exercise (VO(2) = 41.4 mL/kg/min) and from 11 to 31 mmHg at maximal hypoxic exercise (VO(2) = 21.9 mL/kg/min). Arterial P(O2) decreased to 67.8 and 29.9 mmHg at maximal normoxic and hypoxic exercise, respectively. These data indicate that our subject with a history of BPD is prone to a greater degree of exercise-induced arterial hypoxemia for a given VO(2) and F(I(O2)) than healthy age-matched controls, which may increase the subject's susceptibility to high altitude illness

Petrogenesis of a late-stage calc-alkaline granite in a giant S-type batholith: geochronology and Sr–Nd–Pb isotopes from the Nomatsaus granite (Donkerhoek batholith), Namibia

The late-tectonic 511.4 ± 0.6 Ma-old Nomatsaus intrusion (Donkerhoek batholith, Damara orogen, Namibia) consists of moderately peraluminous, magnesian, calc-alkalic to calcic granites similar to I-type granites worldwide. Major and trace-element variations and LREE and HREE concentrations in evolved rocks imply that the fractionated mineral assemblage includes biotite, Fe–Ti oxides, zircon, plagioclase and monazite. Increasing K2O abundance with increasing SiO2 suggests accumulation of K-feldspar; compatible with a small positive Eu anomaly in the most evolved rocks. In comparison with experimental data, the Nomatsaus granite was likely generated from meta-igneous sources of possibly dacitic composition that melted under water-undersaturated conditions (X H2O: 0.25–0.50) and at temperatures between 800 and 850 °C, compatible with the zircon and monazite saturation temperatures of 812 and 852 °C, respectively. The Nomatsaus granite has moderately radiogenic initial 87Sr/86Sr ratios (0.7067–0.7082), relatively radiogenic initial εNd values (− 2.9 to − 4.8) and moderately evolved Pb isotope ratios. Although initial Sr and Nd isotopic compositions of the granite do not vary with SiO2 or MgO contents, fSm/Nd and initial εNd values are negatively correlated indicating limited assimilation of crustal components during monazite-dominated fractional crystallization. The preferred petrogenetic model for the generation of the Nomatsaus granite involves a continent–continent collisional setting with stacking of crustal slices that in combination with high radioactive heat production rates heated the thickened crust, leading to the medium-P/high-T environment characteristic of the southern Central Zone of the Damara orogen. Such a setting promoted partial melting of metasedimentary sources during the initial stages of crustal heating, followed by the partial melting of meta-igneous rocks at mid-crustal levels at higher P–T conditions and relatively late in the orogenic evolution

Anatomy, morphology and evolution of the patella in squamate lizards and tuatara (Sphenodon punctatus)

The patella (kneecap) is the largest and best-known of the sesamoid bones, postulated to confer biomechanical advantages including increasing joint leverage and reinforcing the tendon against compression. It has evolved several times independently in amniotes, but despite apparently widespread occurrence in lizards, the patella remains poorly characterised in this group and is, as yet, completely undescribed in their nearest extant relative Sphenodon (Rhynchocephalia). Through radiography, osteological and fossil studies we examined patellar presence in diverse lizard and lepidosauromorph taxa, and using computed tomography, dissection and histology we investigated in greater depth the anatomy and morphology of the patella in 16 lizard species and 19 Sphenodon specimens. We have found the first unambiguous evidence of a mineralised patella in Sphenodon, which appears similar to the patella of lizards and shares several gross and microscopic anatomical features. Although there may be a common mature morphology, the squamate patella exhibits a great deal of variability in development (whether from a cartilage anlage or not, and in the number of mineralised centres) and composition (bone, mineralised cartilage or fibrotendinous tissue). Unlike in mammals and birds, the patella in certain lizards and Sphenodon appears to be a polymorphic trait. We have also explored the evolution of the patella through ancestral state reconstruction, finding that the patella is ancestral for lizards and possibly Lepidosauria as a whole. Clear evidence of the patella in rhynchocephalian or stem lepidosaurian fossil taxa would clarify the evolutionary origin(s) of the patella, but due to the small size of this bone and the opportunity for degradation or loss we could not definitively conclude presence or absence in the fossils examined. The pattern of evolution in lepidosaurs is unclear but our data suggest that the emergence of this sesamoid may be related to the evolution of secondary ossification centres and/or changes in knee joint conformation, where enhancement of extensor muscle leverage would be more beneficial.Sophie Regnault, Marc E. H. Jones, Andrew A. Pitsillides, John R. Hutchinso

Solitary fibrous tumor of the orbit—two cases and a review of the literature

Solitary fibrous tumors of the orbit (SFT) are mesenchymal lesions that can develop either as malignant or benign neoplasias. We describe the histological features leading to the diagnosis in two females and review the current literature. Diagnosis of SFT only can be performed by histological examination, since clinical signs and radiological features are not specific enough. Even a malignant or benign course cannot be predicted, since clinical and radiological features do not correlate with histological signs of malignancy and vice versa. Radical resection is the treatment of choice, since no other treatment option has been proven to be efficien