Miracle-dz/UniFAR-FTUs huggingface dataset:
Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

Mutations in genes encoding for GABAA receptor subunits is a well-established cause of genetic generalized epilepsy. GABA neurotransmission is implicated in several developmental processes including neurite outgrowth and synapse formation. Alteration in excitatory/inhibitory synaptic activities plays a critical role in epilepsy, thus here we investigated whether mutations in α1 subunit of GABAA receptor may affect dendritic spine and GABAergic bouton formation. In particular, we examined the effects of three mutations of the GABRA1 gene (D219N, A322D and K353delins18X) that were found in a cohort of French Canadian families with genetic generalized epilepsy. We used a novel single-cell genetic approach, by preparing cortical organotypic cultures from GABRA1flox/flox mice and simultaneously inactivating endogenous GABRA1 and transfecting mutant α1 subunits in single glutamatergic pyramidal cells and basket GABAergic interneurons by biolistic transfection. We found that GABRA1−/− GABAergic cells showed reduced innervation field, which was rescued by co-expressing α1-A322D and α1-WT but not α1-D219N. We further found that the expression of the most severe GABRA1 missense mutation (α1-A322D) induced a striking increase of spine density in pyramidal cells along with an increase in the number of mushroom-like spines. In addition, α1-A322D expression in GABAergic cells slightly increased perisomatic bouton density, whereas other mutations did not alter bouton formation. All together, these results suggest that the effects of different GABAAR mutations on GABAergic bouton and dendritic spine formation are specific to the mutation and cannot be always explained by a simple loss-of-function gene model. The use of single cell genetic manipulation in organotypic cultures may provide a better understanding of the specific and distinct neural circuit alterations caused by different GABAA receptor subunit mutations and will help define the pathophysiology of genetic generalized epilepsy syndromes.
Enhancement of Tyrosine Hydroxylase Phosphorylation and Activity by Glial Cell Line-derived Neurotrophic Factor*

Although glial cell-line derived neurotrophic factor (GDNF) acts as a potent survival factor for dopaminergic neurons, it is not known whether GDNF can directly alter dopamine synthesis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine biosynthesis, and its activity is regulated by phosphorylation on three seryl residues: Ser-19, Ser-31, and Ser-40. Using a TH-expressing human neuroblastoma cell line and rat primary mesencephalic neuron cultures, the present study examined whether GDNF alters the phosphorylation of TH and whether these changes are accompanied by increased enzymatic activity. Exposure to GDNF did not alter the TH protein level in either neuroblastoma cells or in primary neurons. However, significant increases in the phosphorylation of Ser-31 and Ser-40 were detected within minutes of GDNF application in both cell types. Enhanced Ser-31 and Ser-40 phosphorylation was associated with increased TH activity but not dopamine synthesis in neuroblastoma cells, possibly because of the absence of l-aromatic amino acid decarboxylase activity in these cells. In contrast, increased phosphorylation of Ser-31 and Ser-40 was found to enhance dopamine synthesis in primary neurons. Pharmacological experiments show that Erk and protein kinase A phosphorylate Ser-31 and Ser-40, respectively, and that their inhibition blocked both TH phosphorylation and activity. Our results indicate that, in addition to its role as a survival factor for dopaminergic neurons, GDNF can directly increase dopamine synthesis.
DISCUSSION PAPER SERIES COGNITIVE ABILITY , CHARACTER SKILLS , AND LEARNING TO PLAY EQUILIBRIUM : A LEVEL-K ANALYSIS

In this paper we investigate how cognitive ability and character skills influence behavior, success and the evolution of play towards Nash equilibrium in repeated strategic interactions. We study behavior in a p-beauty contest experiment and find striking differences according to cognitive ability: more cognitively able subjects choose numbers closer to equilibrium, converge more frequently to equilibrium play and earn more even as behavior approaches the equilibrium prediction. To understand better how subjects with different cognitive abilities learn differently, we estimate a structural model of learning based on level-k reasoning. We find a systematic positive relationship between cognitive ability and levels; furthermore, the average level of more cognitively able subjects responds positively to the cognitive ability of their opponents, while the average level of less cognitively able subjects does not respond. Finally, we compare the influence of cognitive ability to that of character skills, and find that both cognition and personality affect behavior and learning. More agreeable and emotionally stable subjects perform better and learn faster, although the effect of cognitive ability on behavior is stronger than that of character skills.
Radiosensitization of Primary Human Glioblastoma Stem-like Cells with Low-Dose AKT Inhibition

Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient–derived GBM cells. Therefore, low-dose–targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma. Mol Cancer Ther; 14(5); 1171–80. ©2015 AACR.
Cross‐diagnostic comparison of duration mismatch negativity and P3a in bipolar disorder and schizophrenia

Jahshan C, Wynn JK, Mathis KI, Altshuler LL, Glahn DC, Green MF. Cross‐diagnostic comparison of duration mismatch negativity and P3a in bipolar disorder and schizophrenia. Bipolar Disord 2012: 14: 239–248. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.
Sign-constrained least squares estimation for high-dimensional regression

Many regularization schemes for high-dimensional regression have been put forward. Most require the choice of a tuning parameter, using model selection criteria or cross-validation schemes. We show that a simple non-negative or sign-constrained least squares is a very simple and effective regularization technique for a certain class of high-dimensional regression problems. The sign constraint has to be derived via prior knowledge or an initial estimator but no further tuning or cross-validation is necessary. The success depends on conditions that are easy to check in practice. A sufficient condition for our results is that most variables with the same sign constraint are positively correlated. For a sparse optimal predictor, a non-asymptotic bound on the L1-error of the regression coefficients is then proven. Without using any further regularization, the regression vector can be estimated consistently as long as \log(p) s/n -> 0 for n -> \infty, where s is the sparsity of the optimal regression vector, p the number of variables and n sample size. Network tomography is shown to be an application where the necessary conditions for success of non-negative least squares are naturally fulfilled and empirical results confirm the effectiveness of the sign constraint for sparse recovery.
PET Imaging in Head and Neck Cancer Patients to Monitor Treatment Response: A Future Role for EGFR-Targeted Imaging

Approximately 50,000 new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed worldwide each year and subsequently treated with surgery, chemotherapy, radiotherapy, and/or targeted therapy. The heterogeneity of the patient population in terms of treatment response drives the search for tumor-specific biomarkers. Imaging of biomarkers can reveal patient-specific responses to therapies and, if assessed early after the start of treatment, may allow adaptation of treatment regimens. In this review, tracers that have been tested to monitor treatment efficacy in HNSCC by PET scanning prior to and early after the onset of treatment are discussed. An important imaging target for this application in HNSCC patients is the EGFR. It steers the pathways related to proliferation, hypoxia, DNA damage repair, and apoptosis, all treatment-resistance mechanisms. The anti-EGFR antibody cetuximab has been labeled with various radionuclides and has been tested as an imaging biomarker in several HNSCC models. These studies suggest that EGFR-targeting tracers can be used to monitor EGFR receptor expression in HNSCC and have the potential to noninvasively monitor cetuximab treatment and steer individualized treatment regimens. Multiple factors can influence the uptake of EGFR-targeting tracers. Here, we discuss the relevance of gene and protein overexpression, mutations, and amplifications related to EGFR signaling. In addition, monoclonal antibody properties and the effect on the host immune system are reviewed in light of the future role of EGFR-targeted imaging in HNSCC. Clin Cancer Res; 21(16); 3602–9. ©2015 AACR.
Does Reducing Inpatient Length of Stay Have Upstream Effects on the Emergency Room: Exploring the Impact of the General Internal Medicine Care Transformation Initiative.

OBJECTIVE The General Internal Medicine (GIM) Care Transformation Initiative implemented at one of four teaching hospitals in the same city resulted in improved efficiency of in-hospital care. Whether it had beneficial effects upstream in the emergency department (ED) is unclear. METHODS Controlled before-after study of ED length of stay (LOS) and crowding metrics for the intervention site (n = 108,951 visits) compared to the three other teaching hospitals (controls, n = 300,930 visits). Our primary outcome was ED LOS for GIM patients but secondary outcomes included ED LOS for all adults and ED crowding metrics. RESULTS The GIM Care Transformation was associated with an additional 2.8-hour reduction in median ED LOS (from 25.6 hours to 13.5 hours) over and above the 9.3-hour decline (from 30.6 hours to 21.3 hours) seen in the three control EDs for GIM patients who were hospitalized (p < 0.001). As less than one in 30 ED visits resulted in a GIM ward admission, the median ED LOS for all patients declined by 15 minutes (from 4.6 hours to 4.3 hours, p < 0.001) in the control hospitals and by 30 minutes (from 5.7 hours to 5.1 hours, p < 0.001) at the intervention hospital pre versus post (p = 0.04 for the 15-minute additional reduction, p < 0.001 for level change on interrupted time series). Other metrics of ED crowding improved by similar amounts at the intervention and control hospitals with no statistically significant differences. CONCLUSION Although the GIM Care Transformation Initiative was associated with substantial reductions in ED LOS for patients admitted to GIM wards at the intervention hospital, it resulted in only minor changes in overall ED LOS and no appreciable changes in ED crowding metrics.
Caenorhabditis elegans embryonic axial patterning requires two recently discovered posterior-group Hox genes.

Hox genes encode highly conserved transcription factors that control regional identities of cells and tissues along the developing anterior-posterior axis, probably in all bilaterian metazoans. However, in invertebrate embryos other than Drosophila, Hox gene functions remain largely unknown except by inference from sequence similarities and expression patterns. Recent genomic sequencing has shown that Caenorhabditis elegans has three Hox genes of the posterior paralog group [Ruvkun, G. & Hobert, O. (1998) Science 282, 2033-2041]. However, only one has been previously identified genetically, and it is not required for embryonic development [Chisholm, A. (1991) Development (Cambridge, U.K.) 111, 921-932]. Herein, we report identification of the remaining two posterior paralogs as the nob-1 gene and the neighboring php-3 gene. Elimination of nob-1 and php-3 functions causes gross embryonic defects in both posterior patterning and morphogenetic movements of the posterior hypodermis, as well as posterior-to-anterior cell fate transformations and lethality. The only other Hox gene essential for embryogenesis is the labial/Hox1 homolog ceh-13, required for more anterior patterning [Brunschwig, K. , Wittmann, C. , Schnabel, R. , Burglin, T. R. , Tobler, H. & Muller, F. (1999) Development (Cambridge, U.K.) 126, 1537-1546]. Therefore, essential embryonic patterning in C. elegans requires only Hox genes of the anterior and posterior paralog groups, raising interesting questions about evolution of the medial-group genes.
Feature Selection for Classification with Proteomic Data of Mixed Quality

In this paper we assess experimentally the performance of two state-of-the-art feature selection methods, called RFE and RELIEF, when used for classifying pattern proteomic samples of mixed quality. The data are generated by spiking human sera to artificially create differentiable sample groups, and by handling samples at different storage temperature. We consider two type of classifiers: support vector machines (SVM) and k-nearest neighbour (kNN). Results of leave-one-out cross validation (LOOCV) experiments indicate that RELIEF selects more stable feature subsets than RFE over the runs, where the selected features are mainly spiked ones. However, RFE outperforms RELIEF in terms of (average LOOCV) accuracy, both when combined with SVM and kNN. Perfect LOOCV accuracy is obtained by RFE combined with 1NN. Almost all the samples that are wrongly classified by the algorithms have high storage temperature. The results of experiments on this data indicate that when samples of mixed quality are analyzed computationally, feature selection of only relevant (spiked) features does not necessarily correspond to highest accuracy of classification.
Proactive Demand Response for Data Centers: A Win-Win Solution

In order to reduce the energy cost of data centers, recent studies suggest distributing computation workload among multiple geographically dispersed data centers by exploiting the electricity price difference. However, the impact of data center load redistribution on the power grid is not well understood yet. This paper takes the first step toward tackling this important issue by studying how the power grid can take advantage of the data centers' load distribution proactively for the purpose of power load balancing. We model the interactions between power grid and data centers as a two-stage problem where the utility company chooses proper pricing mechanisms to balance the electric power load in the first stage and the data centers seek to minimize their total energy cost by responding to the prices in the second stage. We show that the two-stage problem is a bilevel quadratic program, which is NP-hard and cannot be solved using standard convex optimization techniques. We introduce benchmark problems to derive upper and lower bounds for the solution of the two-stage problem. We further propose a branch and bound algorithm to attain the globally optimal solution, and propose a heuristic algorithm with low computational complexity to obtain an alternative close-to-optimal solution. We also study the impact of background load prediction error using the theoretical framework of robust optimization. The simulation results demonstrate that our proposed scheme can not only improve the power grid reliability, but also reduce the energy cost of data centers.
Parturient hypocalcemia in jersey cows fed alfalfa haylage-based diets with different cation to anion ratios.

Jersey cows were fed three alfalfa haylage-based diets with different cation-anion balances beginning 6 wk preceding third or later calving and ending 24 to 36 h postpartum. Sodium and Cl as percentages of dietary DM were . 08 and 1.66 in diet 1 (anionic, 5 cows), . 44 and . 91 in diet 2 (intermediate, 6 cows), and 1.60 and . 34 in diet 3 (cationic, 6 cows). Cation-anion balances were 22, 60, and 126 meq/100 g DM; Ca:P ratios averaged 4:1. Cows fed diet 1 in comparison with cows fed diets 2 or 3 over 6 wk had similar concentrations of Ca, P, and Na but higher concentrations of Mg and K in plasma and higher urinary excretions of Ca and Mg. Concentrations of 1,25-dihydroxyvitamin D 3 d before parturition were higher in cows fed diet 1 than in cows fed diets 2 or 3. Within 36 h after calving, mean concentrations of Ca in plasma (mg/dl, range) of cows fed diets 1 to 3, respectively, were 7 (8.7 to 6.2), 6.5 (7.8 to 3.9), and 6.3 (7.8 to 3.8). Number of cases of clinical milk fever by diet were 0 of 5, 2 of 6, and 1 of 6 cows. Alteration of dietary cation-anion balance by addition of Cl may effectively reduce incidence and severity of parturient hypocalcemia.
Similar Associations Between Personality Dimensions and Anxiety or Depressive Disorders in a Population Study of Turkish-Dutch, Moroccan-Dutch, and Native Dutch Subjects

Abstract It is well established that personality traits are associated with anxiety and depressive disorders in Western populations, but it is not known whether this is true also for people from non-Western cultures. In this study, we examined whether ethnicity moderates the association between personality dimensions and anxiety or depressive disorders or symptoms. In a random urban population sample, stratified by ethnicity, in Amsterdam, the Netherlands, we interviewed 309 native Dutch subjects, 203 Turkish-Dutch subjects, and 170 Moroccan-Dutch subjects. Dimensions of personality were measured using the NEO Five-Factor Inventory. Anxiety and depressive disorders and symptom levels were assessed with the Composite International Diagnostic Interview and the Symptom Checklist-90-Revised. The association between personality factors and disorders or symptoms of anxiety and depression was very similar in the three ethnic groups: all show the typical profile of high neuroticism and low extraversion, agreeableness, and conscientiousness.
High Levels of Donor CCL2/MCP‐1 Predict Graft‐Related Complications and Poor Graft Survival After Kidney‐Pancreas Transplantation

In this study we analyzed the role of CCL2, a member of the chemokine family, in early graft damage. Using simultaneous kidney‐pancreas transplantation (SPK) as a model, we showed that brain death significantly increases circulating CCL2 levels in humans. We found that in such situations, high donor CCL2 levels (measured before organ recovery and at the onset of cold preservation) correlate with increased postreperfusion release of CCL2 by both the graft and recipient throughout the week following transplantation (n = 28). In a retrospective study of 77 SPK recipients, we found a significant negative association between high donor levels of CCL2 and graft survival. Decreased survival in these patients is related to early posttransplant complications, including a higher incidence of pancreas thrombosis and delayed kidney function. Taken together our data indicate that high CCL2 levels in the donor serum predict both an increase in graft/recipient CCL2 production and poor graft survival. This suggests that the severity of the inflammatory response induced by brain death influences the posttransplant inflammatory response, independent of subsequent ischemia and reperfusion.
Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo

Rituximab (RTX), a chimeric anti‐CD20 antibody, is associated with direct induction of apoptosis and antibody‐dependent cell‐mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN‐enhanced RTX‐mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX‐induced apoptosis via upregulating phosphorylation of c‐Jun N‐terminal protein kinases (JNK), Bcl‐2, Bad; increasing release of cytochrome‐c; enhancing activation of caspase‐3, ‐8, ‐9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56lowCD16+ NK cells. Whole PBMCs but not NK cell‐depleted PBMCs treated with LEN augmented 30% of RTX‐dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10‐folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL‐bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX‐dependent NK cell‐mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.
Dietary intake and nutritional adequacy prior to conception and during pregnancy: a follow-up study in the north of Portugal

Abstract Objective To assess maternal diet and nutritional adequacy prior to conception and during pregnancy. Design Follow-up of a cohort of pregnant women with collection of questionnaire data throughout pregnancy and after delivery. Setting Antenatal clinics at two public hospitals in Porto, Portugal. Subjects Two hundred and forty-nine pregnant women who reported a gestational age below 13 weeks at the time they attended their first antenatal visit. Results Intakes of energy and macronutrients were within recommended levels for most women. Pregnancy was accompanied by increases in the dietary intake of vitamins A and E, riboflavin, folate, Ca and Mg, but declines in the intake of alcohol and caffeine. The micronutrients with higher inadequacy prevalences prior to pregnancy were vitamin E (83 %), folate (58 %) and Mg (19 %). These three micronutrients, together with Fe, were also those with the highest inadequacy prevalences during pregnancy (91 %, 88 %, 73 % and 21 %, respectively, for folate, Fe, vitamin E and Mg). Ninety-seven per cent of the women reported taking supplements of folic acid during the first trimester, but the median gestational age at initiation was 6·5 (interquartile range 5, 9) weeks. Self-reported prevalences of Fe and Mg supplementation were high, and increased throughout pregnancy. Conclusion The study identified low dietary intakes of vitamin E, folate and Mg both in the preconceptional period and during pregnancy, and low intake of Fe during pregnancy only. The low dietary intake of folate and the late initiation of supplementation indicate that current national guidelines are unlikely to be effective in preventing neural tube defects.