Miracle-dz/UniFAR-FTUs huggingface dataset:
Amyloid Associated Intermittent Network Disruptions in Cognitively Intact Older Subjects: Structural Connectivity Matters

Observations in animal models suggest that amyloid can cause network hypersynchrony in the early preclinical phase of Alzheimer's disease (AD). The aim of this study was (a) to obtain evidence of paroxysmal hypersynchrony in cognitively intact subjects (CN) with increased brain amyloid load from task-free fMRI exams using a dynamic analysis approach, (b) to investigate if and how hypersynchrony interferes with memory performance, and (c) to describe its relationship with gray and white matter connectivity. Florbetapir-F18 PET and task-free 3T functional and structural MRI were acquired in 47 CN (age = 70.6 ± 6.6), 17 were amyloid pos (florbetapir SUVR >1.11). A parcellation scheme encompassing 382 regions of interest was used to extract regional gray matter volumes, FA-weighted fiber tracts and regional BOLD signals. Graph analysis was used to characterize the gray matter atrophy profile and the white matter connectivity of each subject. The fMRI data was processed using a combination of sliding windows, graph and hierarchical cluster analysis. Each activity cluster was characterized by identifying strength dispersion (difference between pos and neg strength) their maximal and minimal pos and neg strength rois and by investigating their distribution and association with memory performance and gray and white matter connectivity using spearman rank correlations (FDR p < 0.05). The cluster analysis identified eight different activity clusters. Cluster 8 was characterized by the largest strength dispersion indicating hypersynchrony. Its duration/subject was positively correlated with amyloid load (r = 0.42, p = 0.03) and negatively with memory performance (CVLT delayed recall r = −0.39 p = 0.04). The assessment of the regional strength distribution indicated a functional disconnection between mesial temporal structures and the rest of the brain. White matter connectivity was increased in left lateral and mesial temporal lobe and was positively correlated with strength dispersion in the cross-modality analysis suggesting that it enables widespread hypersynchrony. In contrast, precuneus, gray matter connectivity was decreased in the right fusiform gyrus and negatively correlated with high degrees of strength dispersion suggesting that progressing gray matter atrophy could prevent the generation of paroxysmal hypersynchrony in later stages of the disease.
Deletion of the NR2A subunit prevents developmental changes of NMDA‐mEPSCs in cultured mouse cerebellar granule neurones

We investigated the role N‐methyl‐d‐aspartate (NMDA) receptor subunits play in shaping excitatory synaptic currents in cultures of cerebellar granule cells (CGCs) from NR2A knockout (NR2A−/−) and wild‐type (+/+) mice. Cultures were maintained in a condition that facilitates the occurrence of functional synapses, allowing us to record NMDA‐miniature excitatory postsynaptic currents (mEPSCs) in addition to NMDA receptor‐mediated whole‐cell currents at three ages in vitro. Whole‐cell NMDA current density decreased with development in both strains though currents from NR2A−/− neurones demonstrated greater sensitivity to CP101 606, an NR2B subunit specific blocker. Sensitivity to Mg2+ blockade decreased with age in vitro in +/+ but not in NR2A−/− CGCs. Immunocytochemistry revealed that dendrites and somas displayed distinct NR1 and NR2A subunit clusters which became increasingly colocalized in +/+ neurones. Qualitatively the overall NR2B subunit staining pattern was similar in +/+ and NR2A−/− neurones throughout development, suggesting that the NR2B subunit distribution is not mediated by the NR2A subunit. In addition, staining with markers for excitatory synapses showed that expression of NR2A subunit (but not NR2B) increases at both synaptic and extrasynaptic sites in +/+ neurones during development. In parallel, NMDA‐mEPSCs were faster in +/+ compared with NR2A−/− neurones at all time points studied, suggesting that the NR2A subunit begins to replace NR2B‐rich NMDA receptors even at early stages of development. Many NR2A−/− neurones were devoid of NMDA‐mEPSCs at the later time point, and transfection of the NR2A subunit in these neurones restored fast decay and the occurrence of NMDA‐mEPSCs. Taken together, our results indicate that the NR2A subunit is mainly responsible for the developmental changes observed in the maturation of excitatory synapses.
Response diversity determines the resilience of ecosystems to environmental change

A growing body of evidence highlights the importance of biodiversity for ecosystem stability and the maintenance of optimal ecosystem functionality. Conservation measures are thus essential to safeguard the ecosystem services that biodiversity provides and human society needs. Current anthropogenic threats may lead to detrimental (and perhaps irreversible) ecosystem degradation, providing strong motivation to evaluate the response of ecological communities to various anthropogenic pressures. In particular, ecosystem functions that sustain key ecosystem services should be identified and prioritized for conservation action. Traditional diversity measures (e.g. ‘species richness’) may not adequately capture the aspects of biodiversity most relevant to ecosystem stability and functionality, but several new concepts may be more appropriate. These include ‘response diversity’, describing the variation of responses to environmental change among species of a particular community. Response diversity may also be a key determinant of ecosystem resilience in the face of anthropogenic pressures and environmental uncertainty. However, current understanding of response diversity is poor, and we see an urgent need to disentangle the conceptual strands that pervade studies of the relationship between biodiversity and ecosystem functioning. Our review clarifies the links between response diversity and the maintenance of ecosystem functionality by focusing on the insurance hypothesis of biodiversity and the concept of functional redundancy. We provide a conceptual model to describe how loss of response diversity may cause ecosystem degradation through decreased ecosystem resilience. We explicitly explain how response diversity contributes to functional compensation and to spatio‐temporal complementarity among species, leading to long‐term maintenance of ecosystem multifunctionality. Recent quantitative studies suggest that traditional diversity measures may often be uncoupled from measures (such as response diversity) that may be more effective proxies for ecosystem stability and resilience. Certain conclusions and recommendations of earlier studies using these traditional measures as indicators of ecosystem resilience thus may be suspect. We believe that functional ecology perspectives incorporating the effects and responses of diversity are essential for development of management strategies to safeguard (and restore) optimal ecosystem functionality (especially multifunctionality). Our review highlights these issues and we envision our work generating debate around the relationship between biodiversity and ecosystem functionality, and leading to improved conservation priorities and biodiversity management practices that maximize ecosystem resilience in the face of uncertain environmental change.
An ecological study of cancer mortality rates including indices for dietary iron and zinc.

BACKGROUND Dietary iron and zinc affect the risk of cancer, with dietary iron generally correlated with increased risk and dietary zinc with reduced risk. However, zinc supplements have been found correlated with increased risk of cancer. PATIENTS AND METHODS An ecological study was conducted using state-averaged cancer mortality rate data for white Americans for 1970-94 with indices for alcohol consumption, smoking, Hispanic heritage, and urban residence plus dietary factors for four large U.S. regions. RESULTS The dietary zinc index was inversely correlated with 12 types of cancer, whereas the dietary iron index was directly correlated with 10 types of cancer which correlated with both iron directly and zinc inversely were bladder, breast, colon, esophageal, gastric, rectal cancer, and Hodgkin's lymphoma; those inversely with zinc only were laryngeal, nasopharyngeal, oral, skin and vulvar cancer. Solar UVB was inversely correlated with 10 of the 15 types of cancer for which the iron and/or zinc indices had significant correlations, the smoking and urban indices with nine, and the alcohol index with eight. CONCLUSION Although there are mechanisms that explain why zinc should reduce the risk of cancer, whereas iron should increase the risk, these indices may represent the dietary sources of these nutrients, e.g. whole grains for zinc and red meat for iron, and other components of these dietary factors.
Preliminary Results of Relationship between Preoperative Walking Ability and Magnetic Resonance Imaging Morphology in Patients with Lumbar Canal Stenosis: Comparison between Trefoil and Triangle Types of Spinal Stenosis

Study Design Cross-sectional. Purpose To examine the relationship between magnetic resonance imaging (MRI) morphology stenosis grades and preoperative walking ability in patients with lumbar canal stenosis (LCS). Overview of Literature No previous study has analyzed the correlation between MRI morphology stenosis grades and walking ability in patients with LCS. Methods This prospective study included 98 consecutive patients with LCS who were candidates for surgery. Using features identified in T2-weighted axial magnetic, stenosis type was determined at the maximal stenosis level, and only trefoil and triangle stenosis grade types were considered because of sufficient sample size. Intraobserver and interobserver reliability were assessed by calculating weighted kappa coefficients. Symptom severity was evaluated via the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ). Walking ability was assessed using the Self-Paced Walking Test (SPWT) and JOABPEQ subscales. Demographic characteristics, SPWT scores, and JOABPEQ scores were compared between patients with trefoil and triangle stenosis types. Results The mean patient age was 58.1 (standard deviation, 8.4) years. The kappa values of the MRI morphology stenosis grade types showed a perfect agreement between the stenosis grade types. The trefoil group (n=53) and triangle group (n=45) showed similar preoperative JOABPEQ subscale scores (e.g., low back pain, lumbar function, and mental health) and were not significantly different in age, BMI, duration of symptoms, or lumbar stenosis levels (all p>0.05); however, trefoil stenosis grade type was associated with a decreased walking ability according to the SPWT and JOABPEQ subscale scores. Conclusions These findings suggest preoperative walking ability is more profoundly affected in patients with trefoil type stenosis than in those with triangle type stenosis.
Muscle synergies as a predictive framework for the EMG patterns of new hand postures

Synchronous muscle synergies have been suggested as a framework for dimensionality reduction in muscle coordination. Many studies have shown that synergies form a descriptive framework for a wide variety of tasks. We examined if a muscle synergy framework could accurately predict the EMG patterns associated with untrained static hand postures, in essence, if they formed a predictive framework. Hand and forearm muscle activities were recorded while subjects statically mimed 33 postures of the American Sign Language alphabet. Synergies were extracted from a subset of training postures using non-negative matrix factorization and used to predict the EMG patterns of the remaining postures. Across the subject population, as few as 11 postures could form an eight-dimensional synergy framework that allowed for at least 90% prediction of the EMG patterns of all 33 postures, including trial-to-trial variations. Synergies were quite robust despite using different postures in the training set, and also despite using a varied number of postures. Estimated synergies were categorized into those which were subject-specific and those which were general to the population. Population synergies were sparser than the subject-specific synergies, typically being dominated by a single muscle. Subject-specific synergies were more balanced in the coactivation of multiple muscles. We suggest as a result that global muscle coordination may be a combination of higher order control of robust subject-specific muscle synergies and lower order control of individuated muscles, and that this control paradigm may be useful in the control of EMG-based technologies, such as artificial limbs and functional electrical stimulation systems.
The nuclear autoantigen CENP-B displays cytokine-like activities toward vascular smooth muscle cells.

OBJECTIVE A growing number of intracellular autoantigenic polypeptides have been found to play a second biologic role when they are present in the extracellular medium. We undertook this study to determine whether the CENP-B nuclear autoantigen could be added to this set of bifunctional molecules. METHODS Purified CENP-B or CENP-B released from apoptotic cells was tested for surface binding to a number of human cell types by cell-based enzyme-linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. The biologic effects of CENP-B on the migration, interleukin secretion, and signaling pathways of its specific target cells were evaluated. RESULTS CENP-B was found to bind specifically to the surface of human pulmonary artery smooth muscle cells (SMCs) and not to fibroblasts or endothelial cells (ECs). Furthermore, CENP-B bound preferentially to SMCs of the contractile type rather than to SMCs of the synthetic type. Binding of CENP-B to SMCs stimulated their migration during in vitro wound healing assays, as well as their secretion of interleukins 6 and 8. The mechanism by which CENP-B mediated these effects involved the focal adhesion kinase, Src, ERK-1/2, and p38 MAPK pathways. Finally, CENP-B released from apoptotic ECs was found to bind to SMCs, thus indicating a plausible in vivo source of extracellular CENP-B. CONCLUSION These novel biologic roles of the nuclear autoantigen CENP-B open up a new perspective for studying the pathogenic role of anti-CENP-B autoantibodies.
Factors associated with preterm delivery in mothers of children with Beckwith–Wiedemann syndrome: A case cohort study from the BWS registry

Pregnancy that results in a child with Beckwith–Wiedemann syndrome (BWS) is associated with preterm delivery. Based on previous case series, we hypothesized that preterm delivery of a child with BWS was due to known risk factors for preterm delivery such as polyhydramnios and gestational hypertension. A case cohort study using the BWS Registry at Washington University School of Medicine was undertaken. Cases were pregnancies that resulted in the birth of a child with BWS, controls were pregnancies resulting in the birth of siblings without BWS. Univariate analyses of maternal complications and logistic regression to predict preterm delivery were used. Children with BWS (n = 304) were delivered preterm at a significantly higher rate than their siblings (n = 269) odds ratio 19.1 (95% CI 9.1–40.2). Polyhydramnios, gestational hypertension, and vaginal bleeding also occurred at high rates in the BWS group with odds ratios of 31.6 (95% CI 12.6–79.1), 2.4 (95% CI 1.4–4.1), and 3.9 (95% CI 2.3–6.4), respectively. In a multivariate logistic regression model within the BWS group, polyhydramnios, vaginal bleeding, and gestational hypertension were significant predictors of preterm delivery, odds ratios of 2.9 (95% CI 1.6–5.4), 2.6 (95% CI 1.3–5.0), and 5.3 (2.3–12.0), respectively. However, a significant proportion, 6.5% (18 of 277), of patients in the BWS group delivered preterm without known risk factors. Preterm delivery of a child with BWS is associated with an increased frequency of polyhydramnios, gestational hypertension, and vaginal bleeding in the mother. However, preterm delivery also occurs in the absence of these risk factors. © 2005 Wiley‐Liss, Inc.
Renal Function and Renin Secretion after Administration of Ouabain and Ouabain Plus Furosemide in Conscious Sheep

The effects of ouabain or ouabain and furosemide on renal function and renin secretion were studied in conscious isovolemic sheep. The sheep received a continuous renal arterial infusion of papaverine, 7 mg/min, throughout the experiment. Ouabain alone (7 × 10−7 M in the renal plasma) produced significant decreases in glomerular filtration rate (GFR) and renal plasma flow (RPF) but not in renal perfusion pressure. Plasma [K+] rose after ouabain administration. Fractional (FENa) and absolute (UN.V) Na+ excretion were 2.9 ± 1.0% (mean ± SE) and 78 ± 54 μEq/min, respectively, during the papaverine infusion and rose to 19 ± 5.1% (P < 0.05) and 528 ± 116 μEq/min (P < 0.01) after ouabain administration. Despite the large changes in Na+ reabsorption, renin secretion was not stimulated. During the control period, renin secretion was 281 ± 131 ng/min and the average renin secretion after ouabain administration was 310 ± 78 ng/min (not significant). A smaller dose of ouabain (2 × 10−7 M) infused into the renal artery with 40 mg of furosemide, iv, did not decrease GFR but RPF was suppressed. FENa and UNBV averaged 4.4 ± 1.6% and 121 ± 44 μEq/min, respectively, while papaverine was infused into the renal artery and increased to 18 ± 4.8% (P < 0.05) and 636 ± 209 μEq/min (P < 0.05) after ouabain and furosemide were infused. Renin secretion was 118 ± 62 ng/min during the control period and averaged 240 ± 67 ng/min after ouabain plus furosemide. The difference was not statistically significant. Thus ouabain alone does not stimulate renin secretion in the conscious, isovolemic sheep despite a presumed increase in [NaCl] at the macula densa and inhibition of NaCl transport by the loop of Henle. Ouabain also blocks the normal stimulatory effects of furosemide on renin secretion.
Rapid quantification of adult and developing mouse spatial vision using a virtual optomotor system.

PURPOSE To develop a simple, rapid method of quantifying the spatial vision of mice. METHODS A rotating cylinder covered with a vertical sine wave grating was calculated and drawn in virtual three-dimensional (3-D) space on four computer monitors facing to form a square. C57BL/6 mice standing unrestrained on a platform in the center of the square tracked the grating with reflexive head and neck movements. The spatial frequency of the grating was clamped at the viewing position by repeatedly recentering the cylinder on the head. Acuity was quantified by increasing the spatial frequency of the grating until an optomotor response could not be elicited. Contrast sensitivity was measured at spatial frequencies between 0.03 and 0.35 cyc/deg. RESULTS Grating acuity was measurable on the day of eye opening (postnatal day [P]15: mean acuity, 0.031 cyc/deg) and reached a maximum (approximately 0.4 cyc/deg) by P24. A peak in the contrast sensitivity function emerged on P16 (4.7, or 21% contrast at 0.064 cyc/deg). The peak remained at 0.064 cyc/deg and climbed to a maximum sensitivity of 24.5, or 4% contrast, by P29. Acuity was obtained in each mouse in <10 minutes, and a detailed contrast sensitivity curve was generated in approximately 30 minutes. CONCLUSIONS The virtual optomotor system provides a simple and precise method for rapidly quantifying mouse vision. Behavioral measures of vision in mice are essential for interpreting the results of experiments designed to reveal the cellular and molecular mechanisms of vision and visual development and for evaluating potential treatments for visual diseases.
Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group.

PURPOSE MYCN amplification is rarely detected in patients with favorable-stage neuroblastoma (NB). To determine the clinical significance of MYCN amplification in children with favorable-stage NB, we performed a retrospective review of data from the Pediatric Oncology Group (POG) biology study 9047. PATIENTS AND METHODS MYCN status, tumor cell ploidy, treatment, and outcome of patients with stage A, B, or Ds NB, enrolled on POG 9047 between 1990 and 1999 were analyzed. Event-free survival (EFS) and overall (OS) survival rates were analyzed using the Kaplan-Meier method. RESULTS Of the 1,667 patients enrolled on POG 9047, 643 had favorable-stage disease. Of these, follow-up data were available on 568 (34%) with stage A, B, or Ds disease and normal MYCN copy number, and 32 (1.9%) patients with MYCN-amplified, stage A, B, or Ds tumors. Within the cohort lacking MYCN amplification, the 7-year EFS and OS rates (+/- SE) were 91% +/- 1% and 96% +/- 1%, respectively. Patients with MYCN amplification had significantly worse EFS and OS (50% +/- 9% and 59% +/- 9%, respectively, P < .0001). Within the cohort of children with MYCN amplification, the 7-year EFS and OS rates were 80% +/- 10% and 87% +/- 9%, respectively for patients with hyperdiploid tumors and 25% +/- 11% and 38% +/- 12% for patients with diploid/hypodiploid NBs (P = .0063 and P = .0074, respectively). CONCLUSION Tumor cell ploidy may be a clinically useful factor for prognostication and treatment stratification in children with MYCN-amplified, favorable-stage NB tumors.
Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase‐1 in rodents and in nonhuman primates

Clinical translation of dendritic cell (DC)‐based cell therapy requires preclinical studies in nonhuman primates (NHPs). The aim of this work was to establish the in vitro conditions for generation of NHP tolerogenic DCs (Tol‐DCs), as well as to analyze the molecular mechanisms by which these cells could control an immune response. Two populations of NHP bone marrow‐derived DCs (BMDCs) were obtained: adherent and nonadherent. Although both populations displayed a quite similar phenotype, they were very different functionally. We characterized the adherent BMDCs as Tol‐DCs that were poor stimulators of T cells and actively inhibited T‐cell proliferation, whereas the nonadherent population displayed immunogenic properties in vitro. Interestingly, the anti‐inflammatory and immunosuppressive enzyme heme oxygenase‐1 (HO‐1) was up‐regulated in Tol‐DCs, compared to the immunogenic BMDCs. We demonstrated that HO‐1 mediates the immunosuppressive properties of Tol‐DCs in vitro (in NHPs and rats) and that HO‐1 is involved in the in vivo tolerogenic effect of Tol‐DCs in a rat model of allotransplantation. In conclusion, here we characterized the in vitro generation of NHP Tol‐DCs. Furthermore, we showed for the first time that HO‐1 plays a role in the active inhibition of T‐cell responses by rat and NHP Tol‐DCs. —Moreau, A. , Hill, M. , Thebault, P., Deschamps, J. Y. , Chiffoleau, E. , Chauveau, C. , Moullier, P., Anegon, I. , Alliot‐Licht, B. , Cuturi M. C. Tolerogenic dendritic cells actively inhibit T cells through heme oxygenase‐1 in rodents and in nonhuman primates. FASEB J. 23, 3070–3077 (2009). www.fasebj. org