Miracle-dz/UniFAR-FTUs huggingface dataset:
Cell death and the development of limb form and skeletal pattern in normal and wingless (ws) chick embryos.

The wingless condition resulting from the action of the sex-linked wingless ( ws ) gene arises from the precocious appearance of cell death in the anterior necrotic zone (ANZ) of the forelimb-bud at stage 19 (3 days) and its progressive extension beyond its normal area during stages 20–23. A similar though less pronounced effect occurs in the hindlimb-bud. Although some wingless hindlimb-buds are normal, others are affected by the precocious appearance of cell death in the ANZ. The ws wingless mutant resembles the different wingless mutant investigated by Zwilling (1956) in that the apical ectodermal ridge (AER) is absent in most ws wing-buds. AER absence could be due to ws mesenchymal cell death interfering with the production of apical ectodermal maintenance factor (AEMF), which Zwilling claims is necessary to maintain the AER which plays an essential role in inducing limb outgrowth. Wingless mutant phenotypes range from birds with rudimentary wings and normal legs through a modal type with forelimbs absent and hindlimbs normal to wingless and legless forms showing a high degree of expressivity. Individual wingless embryos vary in the degree to which the precocious ANZ appearing at 3 days is extended into the limb-bud and the wide range of wingless phenotypic expression is attributed to this variation. Electron microscopic and histochemical analysis of the cell death process in wingless wing-buds revealed the presence of both isolated dead cells and macrophages, which contained intense acid phosphatase activity. These findings are interpreted as showing that isolated dead cells are ingested by neighbouring mesenchymal cells which thus become transformed into macrophages, first ingesting and then digesting further dead cells. A study was made of the origin of the anomalous hindlimb condition, including absence or reduction of the tibia and digits, characteristic of severely affected wingless embryos. Autoradiographic analysis of the pattern of 35SO4 uptake revealed that at stage 24/5 (4½ days) wingless hindlimb-buds which were smaller than normal had a normal prospective fibula region, but that the prospective tibia region was small or absent. Thus the effect of a precocious hindlimb ANZ at stages 19–22 is to reduce or delete the pre-axial prospective tibia at stage 24/5.
Accurate Measurement of the Effects of All Amino-Acid Mutations on Influenza Hemagglutinin

Influenza genes evolve mostly via point mutations, and so knowing the effect of every amino-acid mutation provides information about evolutionary paths available to the virus. We and others have combined high-throughput mutagenesis with deep sequencing to estimate the effects of large numbers of mutations to influenza genes. However, these measurements have suffered from substantial experimental noise due to a variety of technical problems, the most prominent of which is bottlenecking during the generation of mutant viruses from plasmids. Here we describe advances that ameliorate these problems, enabling us to measure with greatly improved accuracy and reproducibility the effects of all amino-acid mutations to an H1 influenza hemagglutinin on viral replication in cell culture. The largest improvements come from using a helper virus to reduce bottlenecks when generating viruses from plasmids. Our measurements confirm at much higher resolution the results of previous studies suggesting that antigenic sites on the globular head of hemagglutinin are highly tolerant of mutations. We also show that other regions of hemagglutinin—including the stalk epitopes targeted by broadly neutralizing antibodies—have a much lower inherent capacity to tolerate point mutations. The ability to accurately measure the effects of all influenza mutations should enhance efforts to understand and predict viral evolution.
Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Significance Targeting oncogenic ROS1 fusion proteins with crizotinib has shown promising clinical outcomes in non-small cell lung cancer (NSCLC) patients, but emergence of resistance to therapy has been reported. By profiling the activity of clinically viable ROS1/anaplastic lymphoma kinase (ALK) inhibitors, we discovered that the Food and Drug Administration (FDA)-approved inhibitor cabozantinib potently inhibits native ROS1 and the crizotinib-resistant ROS1G2032R mutant, suggesting potential utility for treatment of ROS1-rearranged lung cancer. Notably, cabozantinib is ineffective against the closely related ALK kinase. Molecular modeling shows specific structural differences between the kinase domains of ROS1 and ALK that explain selective binding of cabozantinib to ROS1. These findings reveal limitations pertaining to the widely presumed inhibitory reciprocity of ROS1 and ALK inhibitors and may facilitate rational design of new ROS1-selective inhibitors. Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib’s dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure–function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.
DISTRIBUTION AND RELATIONSHIPS OF HEAVY METALS IN THE GIANT CLAM (TRIDACNA MAXIMA) ANDASSOCIATED SEDIMENTS FROM DIFFERENT SITES IN THE EGYPTIAN RED SEA COAST

The giant clam (Tridacna maxima) and sediments have been collected from clean and contaminated coastal sites of the Egyptian Red Sea. Selected samples of the giant clam shells and the associated surface sediments were analyzed for Fe, Mn, Zn, Cu, Pb, Ni and Cd. Significant spatial differences in metal concentrations in Tridacna maxima and sediments were identified. Copper and lead are greatly enriched in the giant clam shells, which is related to their physiological function. Cd content is higher in Tridacna maxima than in sediments, because of the easy substitution between Cd and Ca. The levels of most metals in the giant clam shells and sediments were higher in the anthropogenic sites than in the uncontaminated sites. Generally, metal variations reflect natural conditions and human activity. Moreover, there are no clear relationships between concentrations of heavy metals in the giant clam shells and those in sediments.
GPS Ambiguity Resolution and Validation: Methodologies, Trends and Issues

Resolving the GPS carrier-phase ambiguities has been a continuing challenge for sub -centimeter-level highprecision GPS positioning. Once the integer ambiguities are fixed correctly, the carrie r-phase observations are conceptually turned into sub-centimeter-level high-precision range measurements making it possible to attain high-precision positioning solutions. Consequently, this topic has been a rich source of GPS -research over the last decade. A brief review of the previous work on ambiguity resolution and validation which has been carried out by many research groups from all over the world is presented in this paper. For a general understanding of these contributions, we have classified the ambiguity resolution techniques in terms of their characteristics. Current research trends and issues in ambiguity resolution and validation are described and a bibliography of representative papers is provided.
Reliability-Driven Scheduling of Periodic Tasks in Heterogeneous Real-Time Systems

In this paper we comprehensively investigated the issue of reliability-driven real-time scheduling for periodic tasks in heterogeneous systems. First, we built a reliability model in which the concept of reliability cost is introduced in the context of heterogeneous realtime systems. Next, we proposed a novel reliability- driven scheduling algorithm (referred to as Repars) for periodic tasks in heterogeneous systems. Third, after extending the reliability model to meet the needs of our fault-tolerant scheme, we developed a fault-tolerant scheduling algorithm or Refine. Refine aims to enhance system reliability while being able to tolerate one-processor failures in heterogeneous real-time systems. Experimental results showed that Repars is superior to RMFF in terms of both schedulability and reliability. When compared with Repars, Refine significantly reduced the reliability cost by up to 34% with graceful degradation in schedulability.
Mutagenesis and Functional Studies with Succinate Dehydrogenase Inhibitors in the Wheat Pathogen Mycosphaerella graminicola

A range of novel carboxamide fungicides, inhibitors of the succinate dehydrogenase enzyme (SDH, EC 1.3.5.1) is currently being introduced to the crop protection market. The aim of this study was to explore the impact of structurally distinct carboxamides on target site resistance development and to assess possible impact on fitness. We used a UV mutagenesis approach in Mycosphaerella graminicola, a key pathogen of wheat to compare the nature, frequencies and impact of target mutations towards five subclasses of carboxamides. From this screen we identified 27 amino acid substitutions occurring at 18 different positions on the 3 subunits constituting the ubiquinone binding (Qp) site of the enzyme. The nature of substitutions and cross resistance profiles indicated significant differences in the binding interaction to the enzyme across the different inhibitors. Pharmacophore elucidation followed by docking studies in a tridimensional SDH model allowed us to propose rational hypotheses explaining some of the differential behaviors for the first time. Interestingly all the characterized substitutions had a negative impact on enzyme efficiency, however very low levels of enzyme activity appeared to be sufficient for cell survival. In order to explore the impact of mutations on pathogen fitness in vivo and in planta, homologous recombinants were generated for a selection of mutation types. In vivo, in contrast to previous studies performed in yeast and other organisms, SDH mutations did not result in a major increase of reactive oxygen species levels and did not display any significant fitness penalty. However, a number of Qp site mutations affecting enzyme efficiency were shown to have a biological impact in planta. Using the combined approaches described here, we have significantly improved our understanding of possible resistance mechanisms to carboxamides and performed preliminary fitness penalty assessment in an economically important plant pathogen years ahead of possible resistance development in the field.
MULTIPLE LOGICS WITHIN ORGANIZATIONS : AN INTEGRATIVE

Scholars are increasingly exploring the nature of organizational hybridity, introducing novel insights but also raising questions about definitions and internal dynamics. In this paper, we address these questions. To do so, we first develop a framework of organizational hybridity that distinguishes hybrids based on the incompatibility and centrality of multiple logics. Our framework suggests different types of hybrids experience alternative opportunities and challenges. Second, we integrate varied empirical studies into a model of internal organizational dynamics. Our model describes how outcomes depend on the differentiation and integration of multiple logics within hybrids. Taken together, this framework and model extend our understanding of hybridity, while also provoking future research on this prevalent and enduring feature of organizations.
Adiponectin Inhibits Tumor Necrosis Factor-&agr;–Induced Vascular Inflammatory Response via Caveolin-Mediated Ceramidase Recruitment and Activation

Rationale: Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered. Objective: The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin’s vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling. Methods and Results: Adiponectin significantly reduced tumor necrosis factor (TNF)&agr;–induced intercellular adhesion molecule-1 expression and attenuated TNF&agr;-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin–induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNF&agr;-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNF&agr;-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo. Conclusions: These results demonstrate for the first time that adiponectin inhibits TNF&agr;-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
Electroacupuncture Suppresses the NF-κB Signaling Pathway by Upregulating Cylindromatosis to Alleviate Inflammatory Injury in Cerebral Ischemia/Reperfusion Rats

Electroacupuncture (EA) may reduce inflammatory injury by inhibiting nuclear factor-kappa B (NF-κB) signaling pathway activation after ischemic stroke. Thus, we explored temporal and spatial expression of cylindromatosis (CYLD), a negative feedback inhibitor of the NF-κB signaling pathway, to learn whether CYLD is essential for EA and reduction of inflammatory injury after focal cerebral ischemia/reperfusion. A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats and CYLD gene interference was used to investigate a potential role of neuroprotection. Rats were treated with EA (1 mA, 20 Hz for 5 min, 2 Hz for 30 min) at Baihui (GV 20), Hegu (LI 4) and Taichong (LR 3) acupoints, once daily, beginning 2 h after focal cerebral ischemia. Microglial activation and co-expression of CYLD and NF-κB were measured with immunofluorescence. Neuronal CX3CL1 expression was assayed to investigate the role of EA in the interaction between neurons and microglia via upregulation of CYLD. Then, CYLD, NF-κB p65 and p-IκBα protein expression was measured with Western blot. CYLD was mainly expressed in neurons of the peri-ischemic area after MCAO/R in rats and EA upregulated CYLD mRNA and protein from 24 to 72 h after focal cerebral ischemia/reperfusion. In addition, CYLD overexpression was positively correlated to neurobehavior and negatively connected with infarct volume and pro-inflammatory cytokines (TNF-α and IL-1β). Upregulation of CYLD by EA prevented NF-κB nuclear translocation and inhibition of neuronal CX3CL1 expression, which repressed activation of microglia. Finally, CYLD silencing significantly weakened suppression of the NF-κB signaling pathway by EA. In conclusion, upregulation of CYLD may underlie how EA could alleviate inflammatory injury after focal cerebral ischemia/reperfusion.
Performance of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis and rifampin resistance in a low-incidence, high-resource setting

Performance of the Xpert MTB/RIF assay, designed to simultaneously detect Mycobacterium tuberculosis complex (MTBC) and rifampin (RIF) resistance, has been well documented in low-resource settings with high TB-incidence. However, few studies have assessed its accuracy in low TB incidence settings. We evaluated the performance of Xpert MTB/RIF using clinical sputum specimens routinely collected from suspect pulmonary TB patients over a 4-year time period in San Diego County, California. Xpert MTB/RIF results were compared to acid-fast bacilli (AFB) smear microscopy, mycobacterial culture, and phenotypic drug susceptibility testing (DST). Of 751 sputum specimens, 134 (17.8%) were MTBC culture-positive and 2 (1.5%) were multidrug-resistant (MDR). For the detection of MTBC, Xpert MTB/RIF sensitivity was 89.6% (97.7% and 74.5% in smear-positive and -negative sputa, respectively) and specificity was 97.2%; while AFB smear sensitivity and specificity were 64.9% and 77.8%, respectively. Xpert MTB/RIF detected 35 of 47 smear-negative culture-positive specimens, and excluded 124 of 137 smear-positive culture-negative specimens. Xpert MTB/RIF also correctly excluded 99.2% (121/122) of nontuberculous mycobacteria (NTM) specimens, including all 33 NTM false-positives by smear microscopy. For the detection of RIF resistance, Xpert MTB/RIF sensitivity and specificity were 100% and 98.3%, respectively. Our findings demonstrate that Xpert MTB/RIF is able to accurately detect MTBC and RIF resistance in routinely collected respiratory specimens in a low TB-incidence setting, with comparable performance to that achieved in high-incidence settings; and suggest that under these conditions the assay has particular utility in detecting smear-negative TB cases, excluding smear-positive patients without MTBC disease, and differentiating MTBC from NTM.
Safe Driving in LA: Report from the Greatest Intervehicular Accident Detection Test Ever

The UN Economic Commission's Statistics of Road Traffic Accidents report of 2011 shows that every year, about 150 000 human beings lose their lives on the roads of the western world. Although it is a common belief that this figure could shrink with the use of new sensor and communication technologies, unfortunately, none such systems have hit the road to date. Ideally, if such technologies were put into place, vehicles could be part of a vehicular ad hoc network (VANET) capable of spreading relevant information about dangerous events (e.g., car accidents) to all approaching drivers. However, all this is mainly supported by simulation studies, as no practical results have been published to date, revealing the effective performances of such systems at work. In this paper, we fill this gap, presenting a detailed description of the greatest experiments (a few thousand throughout the streets of Los Angeles), to date, ever performed with an accident warning system specifically devised for highway scenarios. In particular, among all the possible candidate schemes, we ran a few thousand experiments with the accident warning system algorithm that was proven to be optimal in terms of bandwidth usage and covered distance in realistic scenarios. Our experiments confirm what has been observed before in theory and simulation, i.e., the use of such a system can reduce, by as much as 40%, the amount of vehicles involved in highway pileups.
Integration of Planning and Deformation Model Estimation for Robotic Cleaning of Elastically Deformable Objects

In this letter, an approach is presented to estimate the stiffness characteristics of elastically deformable objects, while being processed in a robotic cleaning system. Building on our previous work [J. D. Langsfeld, A. M. Kabir, K. N. Kaipa, and S. K. Gupta, “Robotic bimanual cleaning of deformable objects with online learning of part and tool models,” in Proc. IEEE Int. Conf. Autom. Sci. Eng., 2016, pp. 626–632. ], significant extensions are made in this letter by presenting new methods that lead to an overall improvement in the results. The robot system plans the actions of both the grasping and cleaning arms using its current model of the part deformation behavior, and attempts to minimize the overall cleaning time by finding plans that use a small number of grasping positions on the part. A finite-element method approach is used to model the part deformation and a general update algorithm is presented that can modify the stiffness parameters of the model to match observed deformation data collected during cleaning. This allows the system to very quickly discover the correct locations to grasp the part so as to minimize deformation. The methods described in this lettter are shown to achieve better results than the ones from our previous work: The results are much smoother, along with a twofold reduction in parameter-estimation error, and notable faster convergence.
Late Paleozoic geology of the Queensland Plateau (offshore northeastern Australia)

ABSTRACT The southwestern Pacific region consists of segmented and translated continental fragments of the Gondwanan margin. Tectonic reconstructions of this region are challenged by the fact that many fragmented continental blocks are submerged and/or concealed under younger sedimentary cover. The Queensland Plateau (offshore northeastern Australia) is one such submerged continental block. We present detrital zircon geochronological and morphological data, complemented by petrographic observations, from samples obtained from the only two drill cores that penetrated the Paleozoic metasedimentary strata of the Queensland Plateau (Ocean Drilling Program leg 133, sites 824 and 825). Results provide maximum age constraints of 319.4 ± 3.5 and 298.9 ± 2.5 Ma for the time of deposition, which in conjunction with evidence for deformation, indicate that the metasedimentary successions are most likely upper Carboniferous to lower Permian. A comparison of our results with a larger dataset of detrital zircon ages from the Tasmanides suggests that the Paleozoic successions of the Queensland Plateau formed in a backarc basin that was part of the northern continuation of the New England Orogen and/or the East Australian Rift System. However, unlike most of the New England Orogen, a distinctive component of the detrital zircon age spectra of the Mossman Orogen is also recognised, suggesting the existence of a late Paleozoic drainage system that crossed the northern Tasmanides en route from the North Australian Craton. A distinctive shift from abraded zircon grains to grains with well-preserved morphology at ca 305 Ma reflects a direct drainage of first-cycle sediments, most likely from an outboard arc and/or backarc magmatism.