Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic alterations in early‐stage pulmonary large cell neuroendocrine carcinoma

Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are high‐grade malignant neuroendocrine tumors. Histologic differentiation between SCLC and LCNEC is difficult in some cases and to the authors' knowledge, genetic alterations associated with LCNEC have not been identified. Therefore, the authors studied genetic alterations found in LCNEC and compared them with those of SCLC and classic large cell carcinoma (CLCC).
Aortic to brachial PWV ratio : le rôle hémodynamique des artères de conduction à prédominance musculaire par le gradient de rigidité artérielle

85 Introduction . 86 Methods . 86 Results . 88 Discussion . 97 Perspectives . 100 Acknowledgements . 100 Sources of Funding. 100 References . 101 Novelty and Significance . 104 Chapitre 7 Aortic-Brachial Pulse Wave Velocity Ratio : A Blood PressureIndependent Index of Vascular Aging . 105 Résumé . 106 Abstract . 107. 107 Introduction . 108 Methods . 109 Results . 110 Discussion . 114 Perspectives . 119
FutureMatch: Combining Human Value Judgments and Machine Learning to Match in Dynamic Environments

The preferred treatment for kidney failure is a transplant; however, demand for donor kidneys far outstrips supply. Kidney exchange, an innovation where willing but incompatible patient-donor pairs can exchange organs- — via barter cycles and altruist-initiated chains —provides a life-saving alternative.Typically, fielded exchanges act myopically, considering only the current pool of pairs when planning the cycles and chains. Yet kidney exchange is inherently dynamic, with participants arriving and departing. Also, many planned exchange transplants do not go to surgery due to various failures. So, it is important to consider the future when matching. Motivated by our experience running the computational side of a large nationwide kidney exchange, we present FutureMatch, a framework for learning to match in a general dynamic model. FutureMatch takes as input a high-level objective (e.g., "maximize graft survival of transplants over time'') decided on by experts, then automatically (i) learns based on data how to make this objective concrete and (ii) learns the ``means'' to accomplish this goal — a task, in our experience, that humans handle poorly. It uses data from all live kidney transplants in the US since 1987 to learn the quality of each possible match; it then learns the potentials of elements of the current input graph offline (e.g., potentials of pairs based on features such as donor and patient blood types), translates these to weights, and performs a computationally feasible batch matching that incorporates dynamic, failure-aware considerations through the weights. We validate FutureMatch on real fielded exchange data. It results in higher values of the objective. Furthermore, even under economically inefficient objectives that enforce equity, it yields better solutions for the efficient objective (which does not incorporate equity) than traditional myopic matching that uses the efficiency objective.
Ribosomal Protein S6 Kinase Is a Critical Downstream Effector of the Target of Rapamycin Complex 1 for Long-term Facilitation in Aplysia*

Long-term facilitation (LTF) in Aplysia is a leading cellular model for elucidating the biochemical mechanisms of synaptic plasticity underlying learning. In Aplysia, LTF requires translational control downstream of the target of rapamycin (TOR) complex 1 (TORC1). The major known downstream targets of TORC1 are 4E binding protein (4E-BP) and S6 kinase (S6K). By removing the site within these regulators required for their interaction with TORC1, we have generated dominant negative proteins that disrupt specific pathways downstream of TORC1. Expression of dominant negative S6K, but not dominant negative 4E-BP, in Aplysia sensory neurons (SNs) blocked 24-h LTF. TORC1 is directly activated by the small GTP-binding protein, Ras homologue enriched in brain (Rheb). To determine the effects of TORC1 activation on translation in Aplysia neurons, we have examined the effects of expressing a constitutively active form of the Aplysia orthologue of Rheb, ApRheb (ApRheb(Q63L)). Expression of ApRheb(Q63L) increased 4E-BP phosphorylation and the level of general, cap-dependent translation within the SN cell soma in a rapamycin-sensitive manner. This increase in cap-dependent translation was blocked neither by dominant negative 4E-BP nor dominant negative S6K. Thus, we demonstrate that S6K is an important downstream target of TORC1 in Aplysia and that it is necessary for 24-h LTF, but not for TORC1-mediated increases in somatic cap-dependent translation.
The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus

Abstract Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K+ channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15–20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN.
Integrated Stability and Activity Control of the Drosophila Rbf1 Retinoblastoma Protein*

Background: Rbf1 C terminus regulates protein turnover and potentiates its transcriptional activity. Results: Rbf1 protein levels and activity are differentially regulated by phosphorylation sites. Conclusion: Rbf1 turnover and activity processes are functionally separable, both influencing tissue development. Significance: This study highlights the importance of coupled control of Rbf1 turnover and activity, with implications for similar regulation of mammalian RB proteins in development and cancer. The retinoblastoma (RB) family transcriptional corepressors regulate diverse cellular events including cell cycle, senescence, and differentiation. The activity and stability of these proteins are mediated by post-translational modifications; however, we lack a general understanding of how distinct modifications coordinately impact both of these properties. Previously, we showed that protein turnover and activity are tightly linked through an evolutionarily conserved C-terminal instability element (IE) in the Drosophila RB-related protein Rbf1; surprisingly, mutant proteins with enhanced stability were less, not more active. To better understand how activity and turnover are controlled in this model RB protein, we assessed the impact of Cyclin-Cdk kinase regulation on Rbf1. An evolutionarily conserved N-terminal threonine residue is required for Cyclin-Cdk response and showed a dominant impact on turnover and activity; however, specific residues in the C-terminal IE differentially impacted Rbf1 activity and turnover, indicating an additional level of regulation. Strikingly, specific IE mutations that impaired turnover but not activity induced dramatic developmental phenotypes in the Drosophila eye. Mutation of the highly conserved Lys-774 residue induced hypermorphic phenotypes that mimicked the loss of phosphorylation control; mutation of the corresponding codon of the human RBL2 gene has been reported in lung tumors. Our data support a model in which closely intermingled residues within the conserved IE govern protein turnover, presumably through interactions with E3 ligases, and protein activity via contacts with E2F transcription partners. Such functional relationships are likely to similarly impact mammalian RB family proteins, with important implications for development and disease.
Cortisol-Induced Masculinization: Does Thermal Stress Affect Gonadal Fate in Pejerrey, a Teleost Fish with Temperature-Dependent Sex Determination?

Background Gonadal fate in many reptiles, fish, and amphibians is modulated by the temperature experienced during a critical period early in life (temperature-dependent sex determination; TSD). Several molecular processes involved in TSD have been described but how the animals “sense” environmental temperature remains unknown. We examined whether the stress-related hormone cortisol mediates between temperature and sex differentiation of pejerrey, a gonochoristic teleost fish with marked TSD, and the possibility that it involves glucocorticoid receptor- and/or steroid biosynthesis-modulation. Methodology/Principal Findings Larvae maintained during the period of gonadal sex differentiation at a masculinizing temperature (29°C; 100% males) consistently had higher cortisol, 11-ketotestoterone (11-KT), and testosterone (T) titres than those at a feminizing temperature (17°C; 100% females). Cortisol-treated animals had elevated 11-KT and T, and showed a typical molecular signature of masculinization including amh upregulation, cyp19a1a downregulation, and higher incidence of gonadal apoptosis during sex differentiation. Administration of cortisol and a non-metabolizable glucocorticoid receptor (GR) agonist (Dexamethasone) to larvae at a “sexually neutral” temperature (24°C) caused significant increases in the proportion of males. Conclusions/Significance Our results suggest a role of cortisol in the masculinization of pejerrey and provide a possible link between stress and testicular differentiation in this gonochoristic TSD species. Cortisol role or roles during TSD of pejerrey seem(s) to involve both androgen biosynthesis- and GR-mediated processes. These findings and recent reports of cortisol effects on sex determination of sequential hermaphroditic fishes, TSD reptiles, and birds provide support to the notion that stress responses might be involved in various forms of environmental sex determination.
Ideal and Real Systems: A study of notions

In the MIT LEGO Robot Design Competition, students build robots that interact with their environmentÑthe contest playing Þeld, the game objects, and the opponent robot or robotsÑin particular ways. The robots thus become part of a complex system of interactions that deÞne their existence. In this paper I explore the biases that students bring to the task of designing their robots. Of particular interest is studentsÕ recurring inclination to build robots that will perform properly only under ideal conditions. Students repeatedly build robots that are not well-equipped to deal with the exigencies of the real world, but rather with the speciÞcations of an idealized, abstracted worldÑa world that the robot designers would like to believe is a close representation of reality, but is not. This result points to limitations in the set of ideas about technological systems and methods that comprise the core of the engineering curriculum. What surprises many participants is that these ideas do not map well to the challenge of designing a robot to play in one of our contests. In Y. Kafai and M. Resnick (Eds.), Constructionism in Practice: Rethinking the Roles of Technology in Learning. Presented at the National Educational Computing Conference, Boston, MA, June 1994. MIT Media Laboratory, Cambridge, MA. CONSTRUCTIONISM IN PRACTICE ¥ NECC Õ94
The Amygdala, Panic Disorder, and Cardiovascular Responses

Abstract: The amygdala is implicated in a number of emotional responses including conditioned fear and anxiety, and it appears to regulate the behavioral and autonomic responses associated with such emotional responses. The basolateral nucleus of the amygdala (BLA) is under tonic GABAergic inhibition, and acutely blocking this inhibition results in increased anxiety‐like behavior, conditioned avoidance, and sympathetically mediated cardiovascular activation. By contrast, activation of the BLA with the stress‐related neuropeptide corticotropin‐releasing factor results in anxiety‐like behavior, but not cardiovascular activation. Furthermore, repeated activation of this region with subthreshold GABA blockade or corticotropin‐releasing factor‐mediated excitation (priming) results in a chronic anxiety‐like state, with susceptibility to panic‐like arousal following intravenous lactate infusions. The chronic anxiety state appears to result from a loss of basal inhibitory drive in the BLA as a result of NMDA‐dependent synaptic plasticity involving cyclic AMP and calcium calmodulin kinase II (CAM KII)‐mediated changes. The lactate‐induced panic‐like response appears to involve angiotensin‐II mediated activation of the BLA. These results suggest that the BLA has a significant role in regulating anxiety, autonomic responses, and the development of anxiety disorders.
PERFORMANCE ANALYSIS OF SPACE-TIME ADAPTIVE ANTENNA ELECTRONICS FOR TIME-OF-ARRIVAL ESTIMATION

Antenna arrays with adaptive signal processing are commonly utilized to allow the reception of signals in harsh interference environments. Modern interference suppression typically involves the use of space-time adaptive processing (STAP). The primary applications of STAP have been radar and communications systems, where interference suppression performance is commonly optimized for output signal-to-noise ratio (SINR); however, there is increasing demand for STAP in time-of-arrival estimation applications, such as geolocation. Since output SINR is an inadequate indication of TOA estimation performance, reconsideration of STAP for these applications is required. It is understood that TOA estimation variance is primarily dependent on post-correlation carrier-to-noise ratio (C/N). Consequently, the present work develops a novel STAP algorithm which maximizes C/N. The distinction between SINR and C/N will be established, and a performance analysis of the common STAP methods will be performed in the context of this new algorithm. Additionally, the analysis is extended to the TOA estimation variance. It will be demonstrated that optimal STAP systems for TOA estimation follow from the optimal C/N algorithm. In the end, this contributes not only useful performance bounds, but insight into the proper design of STAP systems specifically for TOA estimation applications.
Hemophagocytic Lymphohistiocytosis (HLH) is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer cell induced apoptosis

In 65 patients with hemophagocytic lymphohistiocytosis (HLH) we found an as yet undescribed heterogeneity of defects in cellular cytotoxicity when assay conditions were modified by the incubation time, the presence of mitogen or IL-2. The standard 4h natural killer (NK-) test against K562 targets was negative in all patients. In the so-called Type I (n=21), -II (n=5), and – IV (n=8) deficient patients, the negative NK function could be reconstituted by mitogen, by IL-2, or by prolongation of the incubation time (16h), respectively. The majority of patients (n=31) displayed the Type III defect, defined by a lack of any cellular cytotoxicity independently of assay variations. The characteristic hypercytokinemia also concerned counterregulatory cytokines such as pro-inflammatory IFN- (cid:1) being simultaneously elevated with suppressive IL-10 in 38% of Type I,II, IV deficient patients and in 71% of Type III deficient patients. Elevated IFN-(cid:1) alone correlated with high liver enzymes, but sCD95-Ligand and sCD25 did not, although these markers were expected to indicate the extent of histiocytic organ infiltration. Outcome analysis revealed more deaths in patients with Type III deficiency (p=0.017). Molecular defects were associated with homozygously mutated perforin only in 4 patients, but other Type III patients expressed normal transcripts of effector molecules for target cell apoptosis including perforin and granzyme family members, as demonstrated by RNAse protection analysis. Thus target cell recognition or differentiation defects are likely to explain this severe phenotype in HLH. Hyperactive phagocytes combined with NK defects may imply defects on the level of the antigen presenting cell. were attributed to patients of either Type I, II, III or IV NK deficiency. Spearman rank correlation coefficients (SCC) with corresponding scatter plots were calculated and scatter plots were drawn for all parameters in the patients with HLH and the subclassifications were defined by their distinct NK deficiency states. Contingency table analyses were applied to interpret differences amongst groups and Fisher’s exact test was used to compare death rates between groups. for the manifestation of HLH, and to clarify the physiological impact of defective cellular cytolysis and uncontrolled phagocytosis by an as yet ill defined cellular element of the antigen presenting cell repertoires.
Functional network integration of embryonic stem cell-derived astrocytes in hippocampal slice cultures

Embryonic stem (ES) cells provide attractive prospects for neural transplantation. So far, grafting strategies in the CNS have focused mainly on neuronal replacement. Employing a slice culture model, we found that ES cell-derived glial precursors (ESGPs) possess a remarkable capacity to integrate into the host glial network. Following deposition on the surface of hippocampal slices, ESGPs actively migrate into the recipient tissue and establish extensive cell-cell contacts with recipient glia. Gap junction-mediated coupling between donor and host astrocytes permits widespread delivery of dye from single donor cells. During maturation, engrafted donor cells display morphological, immunochemical and electrophysiological properties that are characteristic of differentiating native glia. Our findings provide the first evidence of functional integration of grafted astrocytes, and depict glial network integration as a potential route for widespread transcellular delivery of small molecules to the CNS.
Does Syndesmotic Injury Have a Negative Effect on Functional Outcome? A Multicenter Prospective Evaluation

Objective: To evaluate the effect of syndesmotic disruption on the functional outcomes of Weber B, SE4 ankle fractures treated operatively. Setting: Multicenter trauma hospitals. Patients: Data were prospectively gathered during a previous, multicenter randomized trial including 242 patients (136 women, 106 men) from 9 trauma centers with operatively treated Weber B SE4 ankle fractures. There were 81 patients (35%) with syndesmotic instability confirmed intraoperatively after fibula fixation. Intervention: Functional evaluations were performed postoperatively at 6, 12, 26, and 52 weeks. The presence of symptomatic hardware and peroneal tendon discomfort was evaluated with 9–12 months of follow-up. Main Outcome Measures: Functional outcomes evaluated included Short Musculoskeletal Function Assessment (SMFA), Bother index, and American Orthopaedic Foot and Ankle Society (AOFAS) scores. The recovery curve of the 2 groups was analyzed using a mixed linear regression analysis for repeated measures and included gender and race in the model. Symptomatic hardware and peroneal tendon discomfort were compared between the 2 groups with a &khgr;2 analysis. Results: The adjusted mean linear regression analyses demonstrated that patients without a syndesmotic injury had better functional outcomes for some outcome measures. SMFA scores at 12 weeks were statistically lower in patients without syndesmotic injury (P = 0.02), but not at other visits. AOFAS scores were significantly higher (P = 0.0006), and Bother index trended toward lower results (P = 0.07) in patients without syndesmotic injury at all time points. Isolated analyses (T-tests) at 1 year demonstrated a difference in the SMFA (P = 0.04) and Bother index (P = 0.05), but not the AOFAS (P = 0.21). Men consistently demonstrated better recovery than women for all outcomes, whereas race was not significant for any measure. Symptomatic hardware and peroneal tendon irritation was not statistically different between the groups. Conclusions: The recovery curves after ankle fractures were different based on syndesmotic injury. However, the difference was at the limit of clinical significance. Syndesmotic injury has a slightly detrimental effect on outcomes of operatively treated Weber B SE4 fractures. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
A Process Model for Recognizing Communicative Acts and Modeling Negotiation Subdialogues

Negotiation is an important part of task-oriented expert-consultation dialogues. This paper presents a plan-based model for understanding cooperative negotiation subdialogues. Our system infers both the communicative actions that people pursue when speaking and the beliefs underlying these actions. Beliefs, and the strength of these beliefs, are recognized from the surface from of utterances, from discourse acts, and from the explicit and implicit acceptance of previous utterances. Our algorithm for recognizing discourse actions combines linguistic, world, and contextual knowledge in a unified framework. By combining these different knowledge sources, we are able to recognize complex discourse acts such as expressing doubt, to identify the relationship of utterances to one another, and to model negotiation subdialogues. Since negotiation is an integral part of multiagent activity, our process model addresses an important aspect of cooperative interaction and thus is a step toward an intelligent and robust natural language consultation system.
Ascertainment issues in variance components models.

One of the main concerns in the family studies of complex diseases is the effect that ascertainment and correction for it may have on test procedures and estimators. Elston and Sobel [1979] and Hopper and Mathews [1982] proposed two ways to correct for ascertainment in the study of quantitative trait data. For single ascertainment, using a variance components approach, we present results of simulation studies comparing estimates from these two methods for different selection criteria. We also show results from simulations when ascertained families are analyzed either at random or by correcting for ascertainment. For discordant sibpairs, we compare a variance components model that incorporates ascertainment correction with the extreme discordant sib pairs (EDSP) design proposed by Risch and Zhang [1995]. Our results show that there is minimal difference between the two methods of ascertainment correction. In the presence of effects from a large genetic background and the segregation of a rare gene, both ascertainment affected the polygenic and environmental components of variance but had rather little impact on the estimate of the linked major gene component of variance. The results also show the EDSP is slightly more powerful the variance components procedures for common alleles, and the variance components procedure is much more powerful than using EDSP when there is a rare allele segregating in the population.