Five Myofibrillar Lesion Types in Eccentrically Challenged, Unloaded Rat Adductor Longus Muscle—A Test Model

Sarcomere disruptions are observed in the adductor longus (AL) muscles following voluntary reloading of spaceflown and hindlimb suspension unloaded (HSU) rat, which resemble lesions in eccentrically challenged muscle. We devised and tested an eccentric contraction (ECCON) test system for the 14-day HSU rat AL. Six to 7 hours following ECCON, ALs were fixed to allow immunostaining and electron microscopy (EM). Toluidine blue-stained histology semithin sections were screened for lesion density (#/mm2). Serial semithin sections from the ECCON group were characterized for myosin immunointensity of lesions. Five myofibrillar lesion types were identified in histological semithin sections: focal contractions; wide A-bands; opaque areas; missing A-bands; and hyperstretched sarcomeres. Lesion density by type was greater for ECCON than NonECCON ALs (P ≤ 0.05; focal contractions and opaque regions). Lesion density (#-of-all-five-types/mm2) was significantly different (ECCON: 23.91 ± 10.58 vs. NonECCON: 5.48 ± 1.28, P ≤ 0.05; ECCON vs. SHAM: 0.00 ± 0.00; P ≤ 0.025). PostECCON optimal tension decreased (Poi-drop, 17.84 ± 4.22%) and was correlated to lesion density (R2 = 0.596), but prestretch tension demonstrated the highest correlation with lesion density (R2 = 0.994). In lesions, the darkly staining A-band lost the normally organized thick filament alignment to differing degrees across the different lesion types. Ranking the five lesion types by a measure of lesion length deformation (hypercontracted to hyperstretched) at the light microscopy level, related to the severity of thick filament registry loss across the lesion types at the electron microscopic level. This ranking suggested that the five lesion types seen in semithin sections at the light level represented a lesion progression sequence and paralleled myosin immunostaining loss as the distorted A-band filaments spread across the hyperlengthening lesion types. Lesion ultrastructure indicated damage involved calcium homeostasis loss (focal contraction lesions) and “thick-filamentcentering” failure of titin (wide A-band lesions) in the early stages of lesion development

Metabolic origins of spatial organization in the tumor microenvironment.

The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity

Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells

BACKGROUND: The TET family of dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), but their involvement in establishing normal 5mC patterns during mammalian development and their contributions to aberrant control of 5mC during cellular transformation remain largely unknown. We depleted TET1, TET2, and TET3 in a pluripotent embryonic carcinoma cell model and examined the impact on genome-wide 5mC, 5hmC, and transcriptional patterns. RESULTS: TET1 depletion yields widespread reduction of 5hmC, while depletion of TET2 and TET3 reduces 5hmC at a subset of TET1 targets suggesting functional co-dependence. TET2 or TET3 depletion also causes increased 5hmC, suggesting these proteins play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion results in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction. TET function is highly specific to chromatin environment: 5hmC maintenance by all TETs occurs at polycomb-marked chromatin and genes expressed at moderate levels; 5hmC removal by TET2 is associated with highly transcribed genes enriched for H3K4me3 and H3K36me3. Importantly, genes prone to hypermethylation in cancer become depleted of 5hmC with TET deficiency, suggesting that TETs normally promote 5hmC at these loci. Finally, all three TETs, but especially TET2, are required for 5hmC enrichment at enhancers, a condition necessary for expression of adjacent genes. CONCLUSIONS: These results provide novel insight into the division of labor among TET proteins and reveal important connections between TET activity, the chromatin landscape, and gene expression

Electronic Duality in Strongly Correlated Matter

Superconductivity develops from an attractive interaction between itinerant electrons that creates electron pairs which condense into a macroscopic quantum state--the superconducting state. On the other hand, magnetic order in a metal arises from electrons localized close to the ionic core and whose interaction is mediated by itinerant electrons. The dichotomy between local moment magnetic order and superconductivity raises the question of whether these two states can coexist and involve the same electrons. Here we show that the single 4f-electron of cerium in CeRhIn5 simultaneously produces magnetism, characteristic of localization, and superconductivity that requires itinerancy. The dual nature of the 4f-electron allows microscopic coexistence of antiferromagnetic order and superconductivity whose competition is tuned by small changes in pressure and magnetic field. Electronic duality contrasts with conventional interpretations of coexisting spin-density magnetism and superconductivity and offers a new avenue for understanding complex states in classes of materials.Comment: 14 pages, 4 figure

Effect of 17 Days of Bed Rest on Peak Isometric Force and Unloaded Shortening Velocity of Human Soleus Fibers

The purpose of this study was to examine the effect of prolonged bed rest (BR) on the peak isometric force (Po) and unloaded shortening velocity (Vo) of single Ca2+-activated muscle fibers. Soleus muscle biopsies were obtained from eight adult males before and after 17 days of 6° head-down BR. Chemically permeabilized single fiber segments were mounted between a force transducer and position motor, activated with saturating levels of Ca2+, and subjected to slack length steps. Vo was determined by plotting the time for force redevelopment vs. the slack step distance. Gel electrophoresis revealed that 96% of the pre- and 87% of the post-BR fibers studied expressed only the slow type I myosin heavy chain isoform. Fibers with diameter \u3e100 μm made up only 14% of this post-BR type I population compared with 33% of the pre-BR type I population. Consequently, the post-BR type I fibers (n = 147) were, on average, 5% smaller in diameter than the pre-BR type I fibers (n = 218) and produced 13% less absolute Po. BR had no overall effect on Po per fiber cross-sectional area (Po/CSA), even though half of the subjects displayed a decline of 9–12% in Po/CSA after BR. Type I fiber Vo increased by an average of 34% with BR. Although the ratio of myosin light chain 3 to myosin light chain 2 also rose with BR, there was no correlation between this ratio and Vo for either the pre- or post-BR fibers. In separate fibers obtained from the original biopsies, quantitative electron microscopy revealed a 20–24% decrease in thin filament density, with no change in thick filament density. These results raise the possibility that alterations in the geometric relationships between thin and thick filaments may be at least partially responsible for the elevated Vo of the post-BR type I fibers

Slow crossover in YbXCu4 intermediate valence compounds

We compare the results of measurements of the magnetic susceptibility Chi(T), the linear coefficient of specific heat Gamma(T)=C(T)/T and 4f occupation number nf(T) for the intermediate valence compounds YbXCu4 (X = Ag, Cd, In, Mg, Tl, Zn) to the predictions of the Anderson impurity model, calculated in the non-crossing approximation (NCA). The crossover from the low temperature Fermi liquid state to the high temperature local moment state is substantially slower in the compounds than predicted by the NCA; this corresponds to the ''protracted screening'' recently predicted for the Anderson Lattice. We present results for the dynamic susceptibility, measured through neutron scattering experiments, to show that the deviations between theory and experiment are not due to crystal field effects, and we present x-ray-absorption fine-structure (XAFS) results that show the local crystal structure around the X atoms is well ordered, so that the deviations probably do not arise from Kondo Disorder. The deviations may correlate with the background conduction electron density, as predicted for protracted screening.Comment: Submitted to Physical Review B on June 7, 2000, accepted for publication November 2, 2000. Changes to the original manuscript include: 1) a discussion of the relation of the slow crossover to the conduction electron density; 2) a discussion of the relation of the reported results to earlier photoemission results; and, 3) minor editorial change

Evidence of exactness of the mean field theory in the nonextensive regime of long-range spin models

The q-state Potts model with long-range interactions that decay as 1/r^alpha subjected to an uniform magnetic field on d-dimensional lattices is analized for different values of q in the nonextensive regime (alpha between 0 and d). We also consider the two dimensional antiferromagnetic Ising model with the same type of interactions. The mean field solution and Monte Carlo calculations for the equations of state for these models are compared. We show that, using a derived scaling which properly describes the nonextensive thermodynamic behaviour, both types of calculations show an excellent agreement in all the cases here considered, except for alpha=d. These results allow us to extend to nonextensive magnetic models a previous conjecture which states that the mean field theory is exact for the Ising one.Comment: 10 pages, 4 figure

Strongly Correlated F-Electron Systems: A PES Study

The term heavy fermions refers to materials (thus far only compounds with elements having an unfilled 4f or 5f shells) whose large specific heat {gamma}-values suggest that the conduction electrons at low temperatures have a very heavy effective mass. Magnetic susceptibility measurements, {chi}, generally yield a Curie-Weiss behavior at high temperatures with a well developed moment, which would be consistent with localized behavior of the f-electrons. Thus, the f-electrons appear to behave as non-interacting single impurities at elevated temperature. Below a characteristic Kondo temperature, T{sub K}, the susceptibility levels off or even decreases. This is interpreted as a compensation of the f-moment by the ligand conduction electrons that are believed to align anti-parallel to form a singlet state and has led to the widespread use of the Anderson Impurity Hamiltonian and the Single Impurity Model (SIM). Weak hybridization with these conduction electrons yields a narrow, highly temperature dependent, DOS at the Fermi energy, often referred to as the Kondo resonance (KR). At still lower temperatures it is generally agreed that in stoichiometric compounds a lattice of these singlet states finally results in extremely narrow bands at the Fermi energy, whose bandwidth is of the order k{sub B}T{sub K}. Clearly coherent bands cannot form above T{sub K} owing to the narrow width. A model for periodic Kondo systems will inevitably have to include the lattice. Preliminary PAM calculations indicate that this inclusion yields results differing qualitatively, rather than just quantitatively, from the SIM predictions. The photoemission data on single crystal heavy fermions are consistent with the following PAM predictions: (1) the temperature dependence of the KR is much slower than expected from the SIM; indeed, it is primarily7 due to broadening and Fermi function truncation; (2) the spectral weight of the KR relative to the localized 4f feature (not discussed here) is much larger than the SIM expectations (equivalently, n{sub f} values are far too small); (3) the KR and its sidebands does not lose spectral weight with T, but rather only broadens; (4) f-electrons in both Ce and U systems form narrow bands already far above T{sub K} (the jury is still out for Yb systems); (5) the width of these bands is much larger than k{sub B}T{sub K}; (6) f-character is obtained in only some regions of the Brillouin zone; i.e., momentum dependence of the KR above T{sub K}. While the PAM seems to predict the correct trends, they have no reason yet to rule out other models, such as those of Liu and Sheng and Cooper. Such discrimination may occur when the models develop sufficiently to allow real system calculations

Transformed non‐Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100290/1/bjh12570.pd

2003 AAPP Monograph Series

It is significant that the African American Professors Program (AAPP) at the University of South Carolina is producing the third edition of its annual monograph series at this time-the fifth anniversary of AAPP. The program graciously accepts the challenge of putting into place a requirement for the scholars to produce quality research papers worthy of publication. This provides widespread visibility for them and enhances their curriculum vitae concurrently. Scholars who have contributed manuscripts for this monograph are to be commended for adding this additional responsibility to their academic workload. Writing across disciplines adds to the intellectual diversity of these papers. From neophytes, relatively speaking, to an array of very experienced individuals, the chapters have been researched and comprehensively written. Founded in 1997 through the Department of Educational Leadership and Policies in the College of Education, AAPP was designed to address the underrepresentation of African American professors on college and university campuses. Its mission is to expand the pool of these professors in critical academic and research areas. Sponsored by the University of South Carolina, the W. K. Kellogg Foundation, and the South Carolina General Assembly, the program recruits students with bachelor\u27s, master\u27s, and doctoral degrees for disciplines in which African Americans currently are underrepresented. An important component of the program is the mentoring experience that is provided. Each student is assigned to a mentor/professor who guides the student through a selected academic program and provides various learning experiences. When possible, the mentor serves as chair of the student\u27s doctoral committee. The mentor also provides opportunities for the student to team teach, conduct research, and co-author publications. Students have the advantage of attending committee, faculty, and professional meetings, as well as engaging in a range of activities that characterize professional life in academia. Scholars enrolled in the program also are involved in programmatic and institutional workshops, independent research, and program development. The continuation of this monograph series is seen as responding to a window of opportunity to be sensitive to an academic expectation of graduates as they pursue career placement and, at the same time, one that allows for the dissemination of AAPP products to a broader community. The importance of this monograph series has been voiced by one of our 2002 AAPP graduates, Dr. Shundelle LaTjuan Dogan, a recent Harvard Administrative Fellow at Harvard University and now Program Officer for the Southern Education Foundation, Atlanta, Georgia. Dr. Dogan wrote: One thing in particular that I want to thank you for is having the African American Professors Program scholars publish articles for the monograph. I have to admit that writing the articles seemed like extra work at the time. However, in my recent interview process, organizations have asked me for samples of my writing. Including an article from a published monograph helped to make my portfolio much more impressive. You were right on target in having us do the monograph series. We hope that you will read this monograph of the African American Professors Program with enthusiasm or enlightenment. John McFadden, Ph.D. The Benjamin Elijah Mays Professor Director, African American Professors Program University of South Carolinahttps://scholarcommons.sc.edu/mcfadden_monographs/1006/thumbnail.jp