Miracle-dz/UniFAR-FTUs huggingface dataset:
cAMP perturbs inter‐sertoli tight junction permeability barrier in vitro via its effect on proteasome‐sensitive ubiquitination of occludin

Throughout spermatogenesis, inter‐Sertoli tight junctions (TJs) that constitute the blood‐testis barrier must be disassembled and reassembled to permit the timely movement of preleptotene and leptotene spermatocytes from the basal to the adluminal compartment of the seminiferous epithelium. However, the mechanism and the participating molecules that regulate the bioavailability of TJ proteins are entirely unknown. Using Sertoli cell culture, it was shown that there was an increase in occludin level, concomitant with a reduction of an E3 ubiquitin ligase, Itch, at the time when inter‐Sertoli TJs were assembled. By co‐immunoprecipitation, occludin was shown to associate with Itch at the TJs. A novel interaction between Itch and UBC4 (an ubiquitin‐conjugating enzyme) was identified. When TJs were disrupted by dibutyryl‐cAMP (db‐cAMP), an increase in protein levels of Itch and UBC4 along with a significant reduction in endogenous occludin was detected. These results seemingly suggest that the interaction of Itch and UBC4 on occludin is potentially involved in regulating Sertoli TJ dynamics. Addition of a proteasome inhibitor, MG‐132, into Sertoli cells cultured with db‐cAMP blocked the db‐cAMP‐induced occludin loss in vitro. Accumulations of ubiquitin‐conjugated and Itch‐conjugated occludin were detected in Sertoli cells cultured in the presence of both MG‐132 and db‐cAMP. These results suggest that MG‐132 prevented db‐cAMP‐induced TJ disruption by altering the rate of occludin degradation. Taken collectively, the results reported herein support the notion that db‐cAMP‐induced TJ disruption was mediated by an induction of Itch protein expression, which in turn triggered the ubiquitination of occludin resulting in TJ disruption. © 2004 Wiley‐Liss, Inc.
Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes

ABSTRACT The pathogenic drivers of sporadic and familial motor neuron disease (MND), such amyotrophic lateral sclerosis (ALS), are unknown. MND impairs the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology have remained elusive. The cytosolic and peripheral nucleoporin Ranbp2 is a crucial regulator of the Ran GTPase cycle and of the proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1 motoneurons causes ALS syndromes with hypoactivity followed by hindlimb paralysis, respiratory distress and, ultimately, death. These phenotypes are accompanied by: a decline in the nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve; a reduction in the g-ratios of sciatic and phrenic nerves; and hypertrophy of motoneurons. Furthermore, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors importin β and exportin 1, respectively, Ran GTPase and histone deacetylase 4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor Cxcr4, its antagonizing ligands Cxcl12 and Cxcl14, and effector, latent and activated Stat3 all undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation as a result of Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post-transcriptional downregulation of metalloproteinase 28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase 28 signaling, and proteostasis of substrates that are crucial to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes. Summary: Loss of Ranbp2 in spinal motoneurons drives ALS syndromes in mice and Ranbp2 functions in nucleocytoplasmic trafficking, proteostasis and chemokine signaling uncover novel therapeutic targets and mechanisms for motoneuron disease.
Generation of osteoclasts from hemopoietic cells and a multipotential cell line in vitro

Osteoclasts are the cells that resorb bone. It is generally presumed, on the basis of indirect experiments, that they are derived from the hemopoietic stem cell. However, this origin has never been established. We have developed an assay for osteoclastic differentiation in which bone marrow cells are incubated in liquid culture on slices of cortical bone. The bone slices are inspected in the scanning electron microscope after incubation for the presence of excavations, which are characteristic of osteoclastic activity. We have now incubated bone marrow cells at low density, or a factor‐dependent mouse hemopoietic cell line (FDCP‐mix A4) with 1,25 dihydroxyvitamin D3 (a hormone which we have previously found induces osteoclastic differentiation) with and without murine bone marrow stromal cells, or with and without 3T3 cells, on bone slices. Neither the bone marrow cells nor the bone marrow stromal cells alone developed osteoclastic function even in the presence of 1,25 dihydroxyvitamin D3. However, extensive excavation of the bone surface was observed, only in the presence of 1,25 dihydroxy‐vitamin D3, on bone slices on which bone marrow stromal cells were cocultured with low‐density bone marrow cells or the hemopoietic cell line. Similar results were obtained when the bone marrow stromal cells were killed by glutaraldehyde fixation; 3T3 cells were unable to substitute for stromal cells. These results are strong evidence that osteoclasts derive from the hemopoietic stem cell and suggest that although mature osteoclasts possess neither receptors for nor responsiveness to 1,25 dihydroxyvitamin D3, the hormone induces osteoclastic function through a direct effect on hemopoietic cells rather than through some accessory cell in the bone marrow stroma. The failure of 3T3 cells, which enable differentiation of other hemopoietic progeny from this cell line, to induce osteoclastic differentiation suggests that bone marrow stroma possesses additional characteristics distinct from those that induce differentiation of other hemopoietic cells that are specifically required for osteoclastic differentiation.
Pharmacological Characterization of YM598, a Selective Endothelin-A Receptor Antagonist

The binding affinities of YM598, a novel endothelin-A (ETA) receptor antagonist, for native human ETA receptors expressed in human coronary artery smooth muscle cells and endothelin-B (ETB) subtypes in the human melanoma cell line SKMel- 28 were compared with those of atrasentan and bosentan. The in vivo ETA receptor antagonist activities of YM598 and atrasentan were also evaluated in pithed rats. The inhibitory dissociation constant values of YM598, atrasentan and bosentan were 0.772, 0.0551 and 4.75 nM, respectively, for native human ETA receptors, and 143, 4.80 and 40.9 nM, respectively, for native human ETB subtypes. The calculated selectivity ratios of YM598, atrasentan and bosentan for ETA versus ETB receptors were 222, 136 and 13.0, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner, after both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but those of both agents were comparable when orally administered. These results suggest that YM598 has a high selectivity for native human ETA receptors against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist, with regard to pharmacological bioavailability in rats.
Novel Plant Virus-Based Vaccine Induces Protective Cytotoxic T-Lymphocyte-Mediated Antiviral Immunity through Dendritic Cell Maturation

ABSTRACT Currently used vaccines protect mainly through the production of neutralizing antibodies. However, antibodies confer little or no protection for a majority of chronic viral infections that require active involvement of cytotoxic T lymphocytes (CTLs). Virus-like particles (VLPs) have been shown to be efficient inducers of cell-mediated immune responses, but administration of an adjuvant is generally required. We recently reported the generation of a novel VLP system exploiting the self-assembly property of the papaya mosaic virus (PapMV) coat protein. We show here that uptake of PapMV-like particles by murine splenic dendritic cells (DCs) in vivo leads to their maturation, suggesting that they possess intrinsic adjuvant-like properties. DCs pulsed with PapMV-like particles displaying the lymphocytic choriomeningitis virus (LCMV) p33 immunodominant CTL epitope (PapMV-p33) efficiently process and cross-present the viral epitope to p33-specific transgenic T cells. Importantly, the CTL epitope is also properly processed and presented in vivo, since immunization of p33-specific T-cell receptor transgenic mice with PapMV-p33 induces the activation of large numbers of specific CTLs. C57BL/6 mice immunized with PapMV-p33 VLPs in the absence of adjuvant develop p33-specific effector CTLs that rapidly expand following LCMV challenge and protect vaccinated mice against LCMV infection in a dose-dependent manner. These results demonstrate the efficiency of this novel plant virus-based vaccination platform in inducing DC maturation leading to protective CTL responses.
Repeated On-Chip Interconnect Analysis and Evaluation of Delay, Power, and Bandwidth Metrics under Different Design Goals

As semiconductor process technologies scale down, interconnect planning presents ever-greater challenges to designers. In this paper, we analyze, evaluate and compare various metrics with optimized wire configurations in the contexts of different design criteria: delay minimization, delay-power minimization and delay2-power minimization. We show how various design criteria influence interconnect performance: (1) the optimal inverter to wire capacitance ratio depends only on the technology and design goal, not on wire pitch, (2) at min-pitch, the width pitch ratios of wire for different objective functions are different: the ratio is 0.52 for minimizing delay, 0.31 for minimizing delay2-power product and 0.21 for minimizing delay-power product, (3) the quantitative delay-energy trade-offs for the three objective functions are: the delay-power product reduces power by 67% with a cost of 40% larger delay, while the delay2-power product reduces power by 50% with a cost of 10% larger delay, which implies that delay2-power product results a decent power saving with little cost on speed and (4) the quantitative results of the impact of wire pitch on wire performance are derived. Particularly at 70nm technology node, for bandwidth, the optimal pitch is at min-pitch, while for power, the optimal pitch is 2.35x the min-pitch, and for bandwidth over power, the optimal pitch is 1.76x min-pitch
Single scattering in refractive media with triangle mesh boundaries

Light scattering in refractive media is an important optical phenomenon for computer graphics. While recent research has focused on multiple scattering, there has been less work on accurate solutions for single or low-order scattering. Refraction through a complex boundary allows a single external source to be visible in multiple directions internally with different strengths; these are hard to find with existing techniques. This paper presents techniques to quickly find paths that connect points inside and outside a medium while obeying the laws of refraction. We introduce: a half-vector based formulation to support the most common geometric representation, triangles with interpolated normals; hierarchical pruning to scale to triangular meshes; and, both a solver with strong accuracy guarantees, and a faster method that is empirically accurate. A GPU version achieves interactive frame rates in several examples.
"Forbidden games:" post-traumatic child's play.

Abstract This paper traces the historical and anthropological background of espiritismo and its importance as a folk belief system in mainland Hispanic populations. Pertinent literature is reviewed. Results of a study of the frequency in which psychiatric populations of Puerto Rican and other Hispanic children are involved in the belief system are included. Areas for continued research are outlined.
Nearly-linear time algorithms for graph partitioning, graph sparsification, and solving linear systems

We present algorithms for solving symmetric, diagonally-dominant linear systems to accuracy ε in time linear in their number of non-zeros and log (κf (A) ε), where κf (A) is the condition number of the matrix defining the linear system. Our algorithm applies the preconditioned Chebyshev iteration with preconditioners designed using nearly-linear time algorithms for graph sparsification and graph partitioning.
Broken Symmetries in a Location-Invariant Word Recognition Network

We studied the feedforward network proposed by Dandurand et al. (2010), which maps location-specific letter inputs to location-invariant word outputs, probing the hidden layer to determine the nature of the code. Hidden patterns for words were densely distributed, and K-means clustering on single letter patterns produced evidence that the network had formed semi-location-invariant letter representations during training. The possible confound with superseding bigram representations was ruled out, and linear regressions showed that any word pattern was well approximated by a linear combination of its constituent letter patterns. Emulating this code using overlapping holographic representations (Plate, 1995) uncovered a surprisingly acute and useful correspondence with the network, stemming from a broken symmetry in the connection weight matrix and related to the group-invariance theorem (Minsky & Papert, 1969). These results also explain how the network can reproduce relative and transposition priming effects found in humans.
A Transient Transit Signature Associated with the Young Star RIK-210

We find transient transit-like dimming events within the K2 time series photometry of the young star RIK-210 in the Upper Scorpius OB association. These dimming events are variable in depth, duration, and morphology. High spatial resolution imaging revealed that the star is single and radial velocity monitoring indicated that the dimming events cannot be due to an eclipsing stellar or brown dwarf companion. Archival and follow-up photometry suggest the dimming events are transient in nature. The variable morphology of the dimming events suggests they are not due to a single spherical body. The ingress of each dimming event is always shallower than egress, as one would expect for an orbiting body with a leading tail. The dimming events are periodic and synchronous with the stellar rotation. However, we argue it is unlikely the dimming events could be attributed to anything on the stellar surface based on the observed depths and durations. Variable obscuration by a protoplanetary disk is unlikely on the basis that the star is not actively accreting and lacks the infrared excess associated with an inner disk. Rather, we explore the possibilities that the dimming events are due to magnetospheric clouds, a transiting protoplanet surrounded by circumplanetary dust and debris, eccentric orbiting bodies undergoing periodic tidal disruption, or an extended field of dust or debris near the corotation radius.
Simulating Spatial Reasoning Using ACT-R

We present an ACT-R model of spatial reasoning based on the SRM model (Spatial Reasoning by Models). This model maps spatial working memory to a two-dimensional array and uses a spatial focus to place objects in the array, manipulate the position of objects, and inspect the array to find spatial relations that are not given in the premises. Since the SRM explains many experimental findings only on a qualitative level, we implemented it into an ACT-R model. Not only does the model show some well-known effects in spatial reasoning and offers a good insight into the processes in the SRM model, but in addition it also allows us to predict reasoning times. The Model is accessible through a Java interface, which can be found and run from the following website http://www.informatik. uni-freiburg.de/~srm.
Hybrid Analog–Digital Precoding Revisited Under Realistic RF Modeling

In this letter, we revisit hybrid analog-digital precoding systems with emphasis on the modeling of their radio-frequency (RF) losses, to realistically evaluate their benefits in 5G system implementations. We focus on fully-connected analog beamforming networks (FC-ABFNs) and on discrete Fourier transform implementations, and decompose these as a bank of commonly used RF components. We then model their losses based on their S-parameters. Our results reveal that the performance and energy efficiency of hybrid precoding systems are severely affected once these, commonly ignored, losses are considered in the overall design. In this context, we also show that hybrid precoder designs similar to Butler matrices are capable of providing better performances than FC-ABFN for systems with a large number of RF chains.
Human Cancer Biology Microrna Expression Differentiates Histology and Predicts Survival of Lung Cancer Clinical Cancer Research Authors' Affiliations: Divisions of 1 Cancer Epidemiology and Genetics and 2 Cancer Treatment and Diagnosis

Purpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non–small cell lung cancer. Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics. Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (P global < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2-to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ. Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. The two most common histologic subtypes of non–small cell lung cancer (NSCLC) are squamous cell carcinomas (SQ) and adenocarcinomas, mainly derived from epithelial cells that line the larger airways and the peripheral small airways, respectively (1). Demographic and etiologic characteristics of adenocarcinoma and SQ have been described in refs. (2, 3), and inherited predisposition to distinct histologic types has been identified in refs. (4, 5). Mutations in the RAS proto-oncogene (6) and epidermal growth factor receptor (7) have been mostly found in lung adenocarcinoma, and are typically mutually exclusive (8). Although these and other differences are documented, the precise molecular features that characterize and distinguish the two histologies are largely unknown. Consequently, treatment across NSCLC lesions is similar and shows comparable poor efficacy. A refined understanding of the underlying histologic distinctions may help elucidate histology-specific patterns that can be exploited therapeutically and may improve the …
An Empirical Investigation into the Assimilation of Open Source Server Software

In recent years, open source software (OSS) has become widely known and adopted in practice. In academic literature, an increasing number of studies on the adoption of OSS have been published to investigate which factors influence its adoption. However, most of these studies have an exploratory nature, and empirical support based on a large-scale quantitative study is still missing. To address this issue, we present the results of a large-scale quantitative study investigating the factors that influence the assimilation of open source server software (OSSS) by organizations. OSSS refers to open source software products such as operating systems, web servers and mail servers. We developed a conceptual model that describes the factors influencing the assimilation of OSSS. We gathered data from 210 Belgian organizations and analyzed it using PLS to test this conceptual model. The proposed model was able to explain a large proportion of the variance in the dependent variable in the model. Surprisingly, we have found no support for the influence of several widely claimed advantages of OSSS. Our findings further show that the assimilation of OSSS is predominantly influenced by the availability of internal and external knowledge of OSSS.
Expression in Pichia pastoris and characterization by circular dichroism and NMR of rhodostomin

Rhodostomin (Rho) is a snake venom protein isolated from Calloselasma rhodostoma. Rho is a disintegrin that inhibits platelet aggregation by blocking the binding of fibrinogen to the integrin αIIbβ3 of platelets. Rho produced in Escherichia coli inhibited platelet aggregation with a KI value of 263 nM. Although functional, Rho produced in E. coli is misfolded based on our 2D and 3D NMR studies. In order to correct the folding problem, Rho was expressed in Pichia pastoris. The recombinant Rho expressed in P. pastoris inhibited platelet aggregation with a resulting KI value of 70 nM. This is the same potency as that of native Rho. CD analysis showed that the secondary structures of Rho are pH‐independent and contain 3.5–7.9% α‐helix, 48.2–50.5% β‐structures, and 42.3–47% coil. The sequential assignment and structure analysis of Rho were obtained using 2D and 3D 15N‐edited NMR spectra. These results provide the first direct evidence that highly disulfide‐bonded disintegrin can be expressed in P. pastoris with the correct fold. This evidence may serve as the basis for exploring the structure and function relationships as well as the dynamics of disintegrin and its variants. Proteins 2001;43:499–508. © 2001 Wiley‐Liss, Inc.