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The spatial organization of the genome is essential for its functions, including gene expression and chromosome segregation. Phase separation and loop extrusion have been proposed to underlie compartments and topologically associating domains, however, whether the fold of genomic DNA inside the nucleus is consistent with such mechanisms has been difficult to establish in situ. Here, we present a 3D DNA-tracing workflow that resolves genome architecture in single structurally well-preserved cells with nanometre resolution. Our findings reveal that genomic DNA generally behaves as a flexible random coil at the 100-kb scale. At CTCF sites however, we find Cohesin-dependent loops in a subset of cells, in variable conformations from the kilobase to megabase scale. The 3D-folds we measured in hundreds of single cells allowed us to formulate a computational model that explains how sparse and dynamic loops in single cells underlie the appearance of compact topological domains measured in cell populations. A nanoscale 3D DNA tracing workflow visualizes Cohesin-dependent loops in single, structurally well-preserved cells. Computer simulations based on the tracing data give further insight into how Cohesin folds compact domains in the genome.

Therapeutic regimens for chronic lymphocytic leukemia (CLL) have increasingly utilized monoclonal antibodies since the chimeric anti-CD20 antibody rituximab was introduced. Despite improved clinical outcomes, current CLL therapies are not curative. Therefore, antibodies with greater efficacy and novel targets are desirable. One promising target is CD37, a tetraspanin protein highly expressed on malignant B-cells in CLL and non-Hodgkin lymphoma. Although several novel CD37-directed therapeutics are emerging, detailed preclinical evaluation of these agents is limited by lack of appropriate animal models with spontaneous leukemia expressing the human CD37 (hCD37) target. To address this, we generated a murine CLL model that develops transplantable hCD37+ leukemia. Subsequently, we engrafted healthy mice with this leukemia to evaluate IMGN529, a novel hCD37-targeting antibody–drug conjugate. IMGN529 rapidly eliminated peripheral blood leukemia and improved overall survival. In contrast, the antibody component of IMGN529 could not alter disease course despite exhibiting substantial in vitro cytotoxicity. Furthermore, IMGN529 is directly cytotoxic to human CLL in vitro , depletes B-cells in patient whole blood and promotes killing by macrophages and natural killer cells. Our results demonstrate the utility of a novel mouse model for evaluating anti-human CD37 therapeutics and highlight the potential of IMGN529 for treatment of CLL and other CD37-positive B-cell malignancies.

Cross-sectional studies reported that chronic resistance training is associated with arterial stiffening in men. These findings are in marked contrast to those found with aerobic exercise and may have important clinical relevance with regard to cardiovascular disease risk. However, the effect of resistance training on arterial stiffness has not been confirmed by interventional studies nor has this relation been investigated in women. To determine whether a strength training program increases regional and central arterial stiffness in women, 23 healthy young women (29 ± 1 years; mean ± SD) participated in a high-intensity strength and power training program for 11 weeks. Ten other women (27 ± 2 years) served as time controls. In the intervention group, one repetition maximal strength increased 12% to 17% (P < .0001), and leg fat-free mass (via DEXA) increased significantly. Brachial blood pressure (BP) and fasting plasma lipid and lipoprotein concentrations did not change across the 11 weeks. Carotid augmentation index, a measure of arterial wave reflection and arterial stiffness, increased from −8% ± 13% to 1% ± 18% (P < .05), and carotid-femoral pulse wave velocity increased (791 ± 88 v 833 ± 96 cm/sec; P < .05). There were no changes in femoral-ankle pulse wave velocity, a segmental measure of peripheral arterial stiffness. We concluded that a high-intensity resistance training program increases arterial stiffness and wave reflection in young healthy women. Our present interventional results are consistent with the previous cross-sectional studies in men in which high-intensity strength training is associated with arterial stiffening.

Increasing numbers of doctors in training are taking career breaks, with burnout cited as a potential cause. This study analysed General Medical Council (GMC) national training survey data (renal medicine) to understand the impacts of changing workforce demographics on trainee outcomes and wellbeing. Increasing proportions of female, Black, Asian and minority ethnic (BAME), and international medical graduates are entering the workforce. Specialty exam pass rates have fallen and are lower for BAME and international medical graduates in renal medicine. Time to complete higher specialty training has increased for female trainees. Self-reported burnout rates for renal trainees were higher than other medical specialties and highest for male BAME trainees. Burnout was only partially mitigated by less-than-full-time working, but had no impact on progression, sick-leave or time out of training. It is important to recognise changes to the workforce and proactively plan to effectively support a more diverse group of trainees, to enable them to succeed and reduce differential attainment.

Damaged articular cartilage has a limited ability to repair. Operative removal of damaged cartilage and penetration into the subchondral bone to allow population of the defect with progenitor cells can result in filling of the defect with repair tissue. However, this repair tissue often degenerates over time because of its inability to withstand the mechanical forces to which it is subjected. We previously reported that recombinant human bone morphogenetic protein-2 (rhBMP-2) improves the repair of full-thickness defects of cartilage as long as six months postoperatively. We have now extended that study to examine the quality of the repair tissue at one year. Full-thickness defects of cartilage were created in the trochlear groove of twenty-five adult New Zealand White rabbits. Eight defects were left empty, eight were filled with a collagen sponge, and nine were filled with a collagen sponge impregnated with five micrograms of rhBMP-2. The animals were killed at fifty-two weeks postoperatively, and the gross appearance of the healed defect was assessed. The repair tissue was examined histologically and was evaluated, according to a grading scale, by four individuals who were blinded with respect to the treatment. The tissue sections were immunostained with antibodies against type-I collagen, type-II collagen, aggrecan, and link protein. The residence time of the rhBMP-2 in the cartilage defect was evaluated in vivo with use of scintigraphic imaging of radiolabeled protein. One year after a single implantation of a collagen sponge containing five micrograms of rhBMP-2, the defects had a significantly better histological appearance than the untreated defects (those left empty or filled with a collagen sponge). The histological features that showed improvement were integration at the margin, cellular morphology, architecture within the defect, and reformation of the tidemark. The total scores were also better for the defects treated with rhBMP-2 than for the untreated defects, but in no instance was the repair tissue identical to normal articular cartilage. The thickness of the cartilage in the defects treated with rhBMP-2 was 70 percent that of the normal cartilage, an observation that was identical to that at twenty-four weeks postoperatively. Immunostaining demonstrated significantly less type-I collagen in the defects treated with rhBMP-2 than in the untreated defects. Immunostaining for other matrix components showed no difference among the treatment groups. The mean residence time of rhBMP-2 in the cartilage defects was eight days with an elimination half-life of 5.6 days. Detectable amounts of rhBMP-2 were present as long as fourteen days after implantation. The problems associated with operative repair of cartilage include the formation of fibrocartilage rather than normal articular cartilage and the degeneration of that repair tissue over time. Our results demonstrate that the addition of rhBMP-2 to the operative site after creation of a full-thickness defect results in an improvement in the histological appearance and composition of the extracellular matrix at one year postoperatively. If these experimental results translate directly to the clinical situation, it is possible that the addition of rhBMP-2 to existing operative treatments for the repair of cartilage may improve the repair process and may help to maintain the integrity of the repair tissue.

Glutamine synthetase [L-glutamate:ammonia ligase (ADP-forming); EC 6.3.1.2] specific activity, cellular content, mRNA abundance, and gene transcription rate increase by >100-fold during adipocyte differentiation of 3T3-L1 cells. In 3T3-L1 adipocytes dexamethasone increases, whereas insulin as well as N6,O2′-dibutyryladenosine 3′,5′-cyclic monophosphate decrease, glutamine synthetase gene expression. We analyzed the nucleotide sequence of a 1.9-kilobase Sal I--EcoRI restriction fragment from a 3T3-L1 glutamine synthetase genomic clone. This genomic fragment is composed of 1851 base pairs (bp) and includes the first exon and 1029 bp of the 5′ flanking sequence. The 600 bp at the 3′ end of the 1.9-kb Sal I--EcoRI restriction fragment constitute an open reading frame. We identified the transcription start site at a location 222 bp upstream of the glutamine synthetase coding sequence. The 5′ flanking region of the gene encompasses several potential regulatory elements including TATA and CAAT sequences and a 40-bp poly(dT-dG)· poly(dC-dA) putative enhancer element. Potential hormone and fat-specific regulatory elements are also located upstream of the transcription start site; they include glucocorticoid and cAMP response elements and fatspecific elements. These potential regulatory elements could account for the differentiation-associated changes and hormone-mediated changes seen in glutamine synthetase gene transcription and mRNA abundance.

Although “the ties between women's rights movements and nonviolence have been deep and enduring,” women's movements are not the only movements to rely upon nonviolent collective action. The Indian nationalist movement with Gandhi innovated with passive resistance; the U.S. black civil rights movement employed nonviolent civil disobedience as its major collective action; and peace and environmental movements in the 1980s and 1990s have employed nonviolent tactics. The ties between women's movements and nonviolence, however, are notable insofar as nonviolent tactics predominate in the collective action repertoires of women's movements (Rucht forthcoming). Because nonviolent tactics prevail, they are more visibly connected to those movements.

This article investigates the intersections and tensions between two collective identities, those of class and gender, for working-class women involved in supporting the 1989-1990 strike against Pittston Coal Group in southwestern Virginia. In the case of this year-long (and ultimately successful) strike, women were organized by United Mine Workers of America (UMWA) staff in strike support activities, but they also sought to organize themselves as women. The tensions between their identity as members of the working class and their identity as women are revealed by examining their forms of activism, their relationship with the UMWA, the divisions between groups of activist women, and the articulation of women's involvement in the strike. The experiences of these women are briefly compared with women's activism in the 1984-1985 British Coal strike. The article concludes by arguing that collective identity is best understood as it emerges in response to specific contexts.

The 1992 proposal to close 31 coal pits in GB provoked two weekends of demonstrations & an incredible public outcry because of the large number of lost jobs. Women's groups began to mobilize, or remobilize after earlier strikes, in support of the miners. The particular case of Lancashire Women against Pit Closures (WAPC), which remobilized to defend the Parkside Colliery, is described. Women pitched a pit-camp & articulated their position as primary participants in the men's movement & major constructors of the context in which the anti-pit-closure campaign was fought. Their efforts are discussed in terms of the themes of women's location in the social movement & the articulation of movement standing as a resource for political action. WAPC's relationally & autonomy-based claims were in potential conflict; their standing affected the group's capacity for action & success. 1 Photograph, 1 Appendix, 59 References. M. Pflum