Miracle-dz/UniFAR-FTUs huggingface dataset:
Tracer transport in an isochronal ice-sheet model

The full history of ice sheet and climate interactions is recorded in the vertical profiles of geochemical tracers in polar ice sheets. Numerical simulations of these archives promise great advances both in the interpretation of these reconstructions and the validation of the models themselves. However, fundamental mathematical shortcomings of existing models subject tracers to spurious diffusion, thwarting straightforward solutions. Here, I propose a new vertical discretization for ice-sheet models that eliminates numerical diffusion entirely. Vertical motion through the model mesh is avoided by mimicking the real-world flow of ice as a thinning of underlying layers. A new layer is added to the surface at equidistant time intervals, isochronally, thus identifying each layer uniquely by its time of deposition and age. This new approach is implemented for a two-dimensional section through the summit of the Greenland ice sheet. The ability to directly compare simulations of vertical ice cores with reconstructed data is used to find optimal model parameters from a large ensemble of simulations. It is shown that because this tuning method uses information from all times included in the ice core, it constrains ice-sheet sensitivity more robustly than a realistic reproduction of the modern ice-sheet surface.
c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate.

myc−/− rat fibroblasts (KO cells) differ from myc+/+ (WT) cells and KO cells with enforced Myc re-expression (KO-Myc cells) with respect to mitochondrial structure and function, utilization of glucose and glutamine as energy-generating substrates, and ATP levels. Specifically, KO cells demonstrate low levels of glycolysis and oxidative phosphorylation, dysfunctional mitochondria and electron transport chain complexes, and depleted ATP stores. We examined here how these cells adapt to their energy-deficient state and how they differ in their uptake and utilization of long- and medium-chain fatty acids such as palmitate and octanoate, respectively. Metabolic tracing of these molecules showed that KO cells preferentially utilize them as β-oxidation substrates and that, rather than directing them into phospholipids, preferentially store them as neutral lipids. KO cell transcriptional profiling and functional assays revealed a generalized up-regulation of pathways involved in fatty acid transport and catabolism as well as evidence that these cells attempt to direct acetyl-CoA into the tricarboxylic acid (TCA) cycle for ATP production rather than utilizing it for anabolic purposes. Additional evidence to support this idea included the finding that AMP-dependent protein kinase was constitutively activated in KO cells. The complex control of pyruvate dehydrogenase, which links glycolysis to the TCA cycle, was also maximized to ensure the conversion of pyruvate to acetyl-CoA. Despite these efforts to maximize acetyl-CoA for energy-generating purposes, its levels remained chronically low in KO cells. This suggests that tumor cells with Myc deregulation might be susceptible to novel therapies that limit acetyl-CoA availability.
Prenatal Detection of Fetal Aneuploidy by Sonographic Ear Length

Objective. To determine the usefulness of a fetal ear length nomogram in the prenatal detection of fetal aneuploidy and to determine whether ear smallness in cases of aneuploidy is a primary or secondary event. Methods. Ear lengths of 447 singleton fetuses (October 1996 to October 1997) were prospectively evaluated between 14 and 41 weeks to establish a nomogram created by modeling the mean and SD separately. Records of aneuploid fetuses were retrospectively reviewed, and their ear lengths were plotted against the nomogram to determine detection rates, with ear length in or below the 10th and 50th percentiles for a given gestational age and biparietal diameter used as abnormal cutoffs. Results. The nomogram for fetal ear length measurements provided sufficient data to derive the 10th, 50th, and 90th percentiles on the basis of gestational age and biparietal diameter. The ear length of euploid fetuses was significantly correlated with gestational age (R2 = 0.96; P < .001) and biparietal diameter (R2 = 0.95; P < .001). From 96 aneuploid fetuses identified, 63 had ear lengths in or below the 10th percentile for gestational age (sensitivity, 66%). When using ear length against biparietal diameter, the sensitivities for all aneuploid fetuses for cutoffs at or below the 10th and 50th percentiles were 43% (40 of 93) and 83% (77 of 93), respectively. Conclusions. Most aneuploid fetuses have sonographically small ears (≤10th percentile for gestational age). This smallness is not entirely related to overall small fetal size, but in almost half the cases, the fetal ear length is disproportionately smaller than the biparietal diameter.
PKC-zeta-associated CK2 participates in the turnover of free IkappaBalpha.

The atypical PKC isoenzymes, zeta and iota, activate NF-kappaB, a mechanism thought to mediate the anti-apoptotic and proliferative features of these kinases. PKC-zeta has been shown to be associated with an IkappaBalpha kinase in resting cells. In this study, we have sought to identify the PKC-zeta associated kinase and understand how PKC-zeta mediates basal IkappaBalpha turnover in vivo. We demonstrate that the PKC-zeta-associated IkappaBalpha kinase is CK2. This kinase, previously shown to phosphorylate the PEST domain of IkappaB molecules, co-precipitates with PKC-zeta in resting cells. In vitro, PKC-zeta interacts with CK2-beta. The in vivo PKC-zeta-associated CK2 preferentially phosphorylates S293 of IkappaBalpha as compared to non-associated CK2. The functional relevance of this observation is supported by the fact that the turnover of free IkappaBalpha in resting cells is S293-dependent. Moreover, overexpressing PKC-zeta results in lower steady-state protein levels of free IkappaBalpha, which is dependent on S293. Lastly, it is shown that PKC-zeta wt but not kinase dead leads to the in vitro phosphorylation of both CK2-alpha and beta. These studies demonstrate that the association between CK2 and PKC-zeta may play a major role in the control of the basal turnover of free IkappaBalpha, in the absence of extracellular stimuli.
The Morphology, Integration, and Functional Efficacy of Striatal Grafts Differ between Cell Suspensions and Tissue Pieces

In order to develop a surgical protocol for use in clinical trials of striatal transplantation in Huntington's disease (HD), the issues involved in the preparation and implantation of the embryonic striatal tissue must be addressed. Rodent models of HD offer the best experimental paradigm with which to study various aspects of striatal transplantation. In this article we present the results of an investigation of the role of trypsin and the process of trituration in the preparation of cell suspensions compared to the use of solid pieces of tissue. The embryonic material was derived from the lateral ganglionic eminence (LGE) and implanted into the excitotoxically lesioned striatum of the host rats. Twelve weeks following implantation, retrograde tracing of projections from the graft to the globus pallidus was performed. Grafts derived from cell suspensions triturated in the presence of trypsin contained larger quantities of striatal tissue within the graft and more DARPP-32-positive medium spiny neurons than grafts implanted as fragments of tissue. Afferent and efferent connectivity was also better in the trypsinized suspension graft group. Modest recovery in paw reaching was observed contralateral to the grafted side in animals implanted with solid fragments of embryonic striatal tissue. No relationship was observed between functional effect and the graft anatomy. These results suggest that local graft–host interaction may also be involved in graft-mediated functional recovery.
Mesenchymal chondrosarcoma—observations on 30 new cases

Thirty new cases of mesenchymal chondrosarcoma are presented, bringing the total of well‐documented cases in the literature to only 51. Seventeen of these arose in soft tissues. The ribs and jaws were the most common sites of origin; only five tumors arose in major tubular bones. Females predominated slightly (57%), and more than half of the tumors were found during the second and third decades of life. The histology is characterized by sheets of highly undifferentiated small, oval, or round cells, and by islands of welldifferentiated cartilage. The small cells usually displayed a hemangiopericytoid or an alveolar pattern. Lobulation was common; calcification and metaplastic bone formation in the chondroid islands were frequent. The great variability in the clinical course is reemphasized, survival from the time of diagnosis to death in this series varying from 6 months to 13.5 years. Radical surgery appears to be the treatment of choice.
Predictive Biomarkers and Personalized Medicine Gender In fl uences the Class III and V b-Tubulin Ability to Predict Poor Outcome in Colorectal Cancer

Purpose: Colorectal cancer is one of the deadliest diseases in Western countries. To predict the outcome of therapy, we assessed the role of class III (TUBB3) and class V b-tubulin (TUBB6) as predictive biomarkers. Experimental Design: Using immunohistochemistry and nanofluidics, the expression of TUBB3 and TUBB6 was assessed in two cohorts of 180 and 134 patients, respectively. The CYP17A1 RS743572 was genotyped to identifyGGcarrierswith enhanced androgen levels. TUBB3 andTUBB6were investigated in 22 colorectal cancer cell lines in basal conditions and after serum starvation, the latter serving as activator of this prosurvival pathway. To ascertain the role of androgen receptor (AR) in such regulation, we silenced AR and checked TUBB3 and TUBB6 expression and sensitivity to chemotherapy. Results: There was a link between poor survival, the expression of TUBB3/TUBB6, and AR only in females. Conversely, only inmales carriers of the GG phenotype exhibited the worst outcome. Importantly, male cell lines were resistant to serum starvation and exhibited higher levels of TUBB6, thereby suggesting that the pathway is activatedby androgens. In female cells this phenomenonwas absent. Inboth genders, AR was the main driver of TUBB3/TUBB6 expression, as constitutive silencing of AR was associated with downregulation of TUBB3/TUBB6 expression and increased sensitivity to oxaliplatin and SN-38. Conclusions: The involvement of androgens in the TUBB3 pathway opens the way for clinical trials to assess the efficacy of antiandrogens for increasing the efficacy of chemotherapy in male colorectal cancer patients. Clin Cancer Res; 18(10); 2964–75. 2012 AACR.
The essential role of ERK in 4‐oxo‐2‐nonenal‐mediated cytotoxicity in SH‐SY5Y human neuroblastoma cells

Lipid peroxidation byproducts, such as 4‐hydroxynonenal (HNE) and 4‐oxo‐2‐nonenal (ONE), induce cell death in a wide variety of cell types, partly by modulating intracellular signaling pathways. However, the specific mechanisms involved, particularly for ONE, are unclear while c‐Jun N‐terminal kinase (JNK) has been shown to be essential in HNE‐mediated cytotoxicity. In this study, we examined the role of mitogen‐activated protein kinases signaling pathways in ONE‐induced cytotoxicity in SH‐SY5Y human neuroblastoma cells and found that ONE strongly induces the phosphorylation of extracellular signal‐regulated kinase (ERK) and JNK, but not p38 MAPK. Interestingly, a transient exposure of the cells to ONE resulted in cell death, which contrasts with HNE‐mediated toxicity. Importantly, blocking the ERK pathway, but not the JNK pathway, protected cells against ONE‐induced cytotoxicity indicating a striking difference between the ONE‐ and HNE‐mediated cytotoxicity mechanisms. Furthermore, inhibition of ERK reduced ONE‐induced phosphorylation of p53, a key modulator of the cellular stress response, and the proteolytic cleavage of poly (ADP‐ribose) polymerase (PARP), a hallmark of apoptosis. Overall, these data strongly suggest that ERK plays an essential role in ONE‐mediated cytotoxicity and that ERK is an upstream component of p53‐mediated apoptosis.
Do Global Rating Forms Enable Program Directors to Assess the ACGME Competencies?

Purpose. In 1999 the Accreditation Council for Graduate Medical Education (ACGME) mandated that GME programs require their residents to be proficient in six general competencies. The purpose of this study was to ascertain whether an existing global rating form could be modified to assess these competencies. Method. A rating form covering 23 skills described in the ACGME competencies was developed. The directors of 92 specialty and subspecialty programs at Thomas Jefferson University Hospital and the Albert Einstein Medical Center in Philadelphia were asked to rate residents at the end of the 2001–02 and 2002–03 academic years. Results. Ratings for 1,295 of 1,367 (95%) residents were available. Residents were awarded the highest mean ratings on items tied to professionalism, compassion, and empathy. The lowest mean ratings were assigned for items related to consideration of costs in care and management of resources. Factor analysis indicated that the program directors viewed overall competence in two dimensions of medical knowledge and interpersonal skills. This factor structure was stable for groups of specialties, and residents’ gender and training level. Mean ratings in each dimension were progressively higher for residents at advanced levels of training. Conclusion. Global rating forms, the tool that program directors use most frequently to document residents’ competence, may not be adequate to assess the six general competencies. The results are consistent with earlier published research indicating that physicians view competence in just two broad dimensions, which questions the premise of the six ACGME competencies. Further research is needed to validate and measure six distinct dimensions of clinical competence.
Neural Tube Defects in Embryos of Diabetic Mice: Role of the Pax-3 Gene and Apoptosis

Neural tube defects are among the most common of the malformations associated with diabetic embryopathy. To study the molecular mechanisms by which neural tube defects occur during diabetic pregnancy, we have developed a new experimental system using pregnant diabetic mice. In this system, the rate of neural tube defects is about three times higher in embryos of diabetic mice than in embryos of nondiabetic mice. Most of the defects affected presumptive midbrain and hindbrain structures and included open defects (i.e., exencephaly) and gross maldevelopment. By semiquantitative reverse transcription–polymerase chain reaction and in situ hybridization, we found that expression of Pax-3, a gene required for neural tube closure in the area of the midbrain and hindbrain, is significantly reduced in the embryos of diabetic mice. The same regions of the neural tube where Pax-3 had been underexpressed were found subsequently to contain high concentrations of cells undergoing apoptosis. Reduced expression of Pax-3 appears to be responsible for this apoptosis because apoptotic cells were also found at sites of neural tube defects in embryos carrying null mutation of the Pax-3 gene. Finally, mouse strains that carry null mutations in Pax-3 develop neural tube defects that resemble the malformations that occur in embryos of diabetic mice. These results suggest that Pax-3 is an important developmental control gene, expression of which is disturbed in embryos of diabetic mice, and that as a consequence, apoptosis of the neural tube occurs. This pathway may be responsible for many of the neural tube defects resulting from diabetic pregnancy.
Cytosolic NADPH Homeostasis in Glucose-starved Procyclic Trypanosoma brucei Relies on Malic Enzyme and the Pentose Phosphate Pathway Fed by Gluconeogenic Flux*

Background: NADPH production is critical for growth and oxidative stress management. Results: Redundancy of the pentose phosphate pathway and the cytosolic malic enzyme for NADPH synthesis is carbon source-independent in procyclic trypanosomes. Conclusion: The parasite has gluconeogenic capacity from proline. Significance: This work illustrates the flexible carbon source-dependent flux changes for essential NADPH supply. All living organisms depend on NADPH production to feed essential biosyntheses and for oxidative stress defense. Protozoan parasites such as the sleeping sickness pathogen Trypanosoma brucei adapt to different host environments, carbon sources, and oxidative stresses during their infectious life cycle. The procyclic stage develops in the midgut of the tsetse insect vector, where they rely on proline as carbon source, although they prefer glucose when grown in rich media. Here, we investigate the flexible and carbon source-dependent use of NADPH synthesis pathways in the cytosol of the procyclic stage. The T. brucei genome encodes two cytosolic NADPH-producing pathways, the pentose phosphate pathway (PPP) and the NADP-dependent malic enzyme (MEc). Reverse genetic blocking of those pathways and a specific inhibitor (dehydroepiandrosterone) of glucose-6-phosphate dehydrogenase together established redundancy with respect to H2O2 stress management and parasite growth. Blocking both pathways resulted in ∼10-fold increase of susceptibility to H2O2 stress and cell death. Unexpectedly, the same pathway redundancy was observed in glucose-rich and glucose-depleted conditions, suggesting that gluconeogenesis can feed the PPP to provide NADPH. This was confirmed by (i) a lethal phenotype of RNAi-mediated depletion of glucose-6-phosphate isomerase (PGI) in the glucose-depleted Δmec/Δmec null background, (ii) an ∼10-fold increase of susceptibility to H2O2 stress observed for the Δmec/Δmec/RNAiPGI double mutant when compared with the single mutants, and (iii) the 13C enrichment of glycolytic and PPP intermediates from cells incubated with [U-13C]proline, in the absence of glucose. Gluconeogenesis-supported NADPH supply may also be important for nucleotide and glycoconjugate syntheses in the insect host.
Kinetics for reaction of a circularized intervening sequence with CU, UCU, CUCU, and CUCUCU: mechanistic implications from the dependence on temperature and on oligomer and Mg2+ concentrations.

The self-splicing intervening sequence from the rRNA precursor in Tetrahymena thermophila produces a covalently closed, circularized form (C IVS). Reaction rates for reverse cyclization (linearization) of C IVS by the covalent addition of the oligoncleotides CU, UCU, CUCU, and CUCUCU have been measured. The dependence of the observed rates on oligomer and Mg2+ concentrations indicates the presence of intermediates that are generated by separate binding steps for both oligomer and Mg2+. Linearization of C IVS by OH- hydrolysis is suppressed in the presence of oligomer, suggesting oligomer binds near the active site. The binding constants derived for CU at 30 degrees C in 1 and 10 mM Mg2+ are 5 X 10(3) and 2.5 X 10(4) M-1, respectively. These are roughly 4 orders of magnitude larger than expected for simple Watson-Crick base pairing. The binding constants derived for UCU, CUCU, and CUCUCU at 30 degrees C in 10 mM Mg2+ are 1.2 X 10(5), 4 X 10(5), and greater than 10(7) M-1, respectively. The free energy increments for binding of UCU and CUCU relative to CU are similar to those expected from a nearest-neighbor model for addition of base pairs. This indicates the factors responsible for the unusually strong binding of CU to C IVS are restricted to two nucleotides. (ABSTRACT TRUNCATED AT 250 WORDS)
The antepartum glucose values that predict neonatal macrosomia differ from those that predict postpartum prediabetes or diabetes: implications for the diagnostic criteria for gestational diabetes.

BACKGROUND/OBJECTIVE The diagnosis of gestational diabetes mellitus on oral glucose tolerance test (OGTT) is used to identify risk of both neonatal large-for-gestational-age (LGA) and maternal postpartum prediabetes/diabetes. An assumption inherent in this practice, however, is that the glucose values that define gestational diabetes mellitus on the OGTT relate to both of these outcomes in the same way. Thus, to test this assumption, we sought to evaluate the predictive capacity of each glucose value on antepartum OGTT in relation to LGA and postpartum prediabetes/diabetes. DESIGN/SETTING/PARTICIPANTS A total of 412 women representing the full spectrum of antepartum glucose tolerance underwent 3-h OGTT in pregnancy, assessment of obstetrical outcome at delivery, and 2-h OGTT at 3 months postpartum. RESULTS Of the four glucose values (fasting, 1h, 2 h, 3 h) on antepartum OGTT, only the fasting measure was a significant predictor of LGA [odds ratio (OR) 2.00 per mmol/liter, 95% confidence interval (CI) 1.20-3.34] (P = 0.0076). In contrast, all three postload glucose values were significant predictors of postpartum prediabetes/diabetes (1 h glucose: OR 1.37, 95% CI 1.17-1.61, P < 0.0001; 2 h glucose: OR 1.55, 95% CI 1.32-1.83, P < 0.0001; 3 h glucose: OR 1.30, 95% CI 1.10-1.53, P = 0.002), whereas fasting glucose was not. Furthermore, whereas fasting glucose had the highest area under the receiver operating characteristic curve for predicting LGA (0.62), the 1- and 2-h glucose measures had the highest area under the receiver operating characteristic curve values for postpartum prediabetes/diabetes (0.68 and 0.72, respectively). CONCLUSIONS On antepartum OGTT, the fasting glucose value best predicts LGA risk, whereas postload glucose values predict postpartum prediabetes/diabetes. These relationships may have implications for the glycemic thresholds that define obstetrical and metabolic risk.
CELL‐VIRUS RELATIONSHIPS IN THE LUCKÉ RENAL ADENOCARCINOMA: AN ULTRASTRUCTURE STUDY *

Fawcett (1956) first reported the presence of “virus-like” particles in cells of kidney tumors from Vermont frogs. These particles, which were morphologically similar to herpes virus, were not seen in sections of normal f rog kidneys. Recently, ultrastructural studies by Lunger (1964n & 1964b) and by Darlington, Johnson, and Granoff (1964) have confirmed Fawcett’s original observation, and Lunger (1964b) by means of the negative stain technique, has established the morphological relationship of the virus seen in the Luck6 tumor to the herpes group. This report will communicate hitherto unpublished data concerning the incidence of renal tumors in Rana pipiens frogs obtained from the North Central states ( Wisconsin-Minnesota a rea) , and the association of intranuclear inclusions and viral particles with these tumors as compared to tumors of Vermont frogs. Emphasis will be placed on electron microscopic observations of virus-containing tumor cells, and from these observations a viral reproduction sequence will be proeosed.