Chromosome Segregation Is Biased by Kinetochore Size

Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore—the critical chromosomal interface with spindle microtubules—impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor-independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity

Association Of G-Quadruplex Forming Sequences With Human MtDNA Deletion Breakpoints

Background: Mitochondrial DNA (mtDNA) deletions cause disease and accumulate during aging, yet our understanding of the molecular mechanisms underlying their formation remains rudimentary. Guanine-quadruplex (GQ) DNA structures are associated with nuclear DNA instability in cancer; recent evidence indicates they can also form in mitochondrial nucleic acids, suggesting that these non-B DNA structures could be associated with mtDNA deletions. Currently, the multiple types of GQ sequences and their association with human mtDNA stability are unknown. Results: Here, we show an association between human mtDNA deletion breakpoint locations (sites where DNA ends rejoin after deletion of a section) and sequences with G-quadruplex forming potential (QFP), and establish the ability of selected sequences to form GQ in vitro. QFP contain four runs of either two or three consecutive guanines (2G and 3G, respectively), and we identified four types of QFP for subsequent analysis: intrastrand 2G, intrastrand 3G, duplex derived interstrand (ddi) 2G, and ddi 3G QFP sequences. We analyzed the position of each motif set relative to either 5\u27 or 3\u27 unique mtDNA deletion breakpoints, and found that intrastrand QFP sequences, but not ddi QFP sequences, showed significant association with mtDNA deletion breakpoint locations. Moreover, a large proportion of these QFP sequences occur at smaller distances to breakpoints relative to distribution-matched controls. The positive association of 2G QFP sequences persisted when breakpoints were divided into clinical subgroups. We tested in vitro GQ formation of representative mtDNA sequences containing these 2G QFP sequences and detected robust GQ structures by UV–VIS and CD spectroscopy. Notably, the most frequent deletion breakpoints, including those of the common deletion , are bounded by 2G QFP sequence motifs. Conclusions: The potential for GQ to influence mitochondrial genome stability supports a high-priority investigation of these structures and their regulation in normal and pathological mitochondrial biology. These findings emphasize the potential importance of helicases that subsequently resolve GQ to maintain the stability of the mitochondrial genome

Relationship Between Non-Hodgkin's Lymphoma and Blood Levels of Epstein-Barr Virus in Children in North-Western Tanzania: A Case Control Study.

Non-Hodgkin's Lymphomas (NHL) are common in African children, with endemic Burkitt's lymphoma (BL) being the most common subtype. While the role of Epstein-Barr Virus (EBV) in endemic BL is known, no data are available about clinical presentations of NHL subtypes and their relationship to Human Immunodeficiency Virus (HIV) infection and Epstein Barr Virus (EBV) load in peripheral blood of children in north-western, Tanzania. A matched case control study of NHL subtypes was performed in children under 15 years of age and their respective controls admitted to Bugando Medical Centre, Sengerema and Shirati district designated hospitals in north-western, Tanzania, between September 2010 and April 2011. Peripheral blood samples were collected on Whatman 903 filter papers and EBV DNA levels were estimated by multiplex real-time PCR. Clinical and laboratory data were collected using a structured data collection tool and analysed using chi-square, Fisher and Wilcoxon rank sum tests where appropriate. The association between NHL and detection of EBV in peripheral blood was assessed using conditional logistic regression model and presented as odds ratios (OR) and 95% confidence intervals (CI). A total of 35 NHL cases and 70 controls matched for age and sex were enrolled. Of NHLs, 32 had BL with equal distribution between jaw and abdominal tumour, 2 had large B cell lymphoma (DLBCL) and 1 had NHL-not otherwise specified (NHL-NOS). Central nervous system (CNS) presentation occurred only in 1 BL patient; 19 NHLs had stage I and II of disease. Only 1 NHL was found to be HIV-seropositive. Twenty-one of 35 (60%) NHL and 21 of 70 (30%) controls had detectable EBV in peripheral blood (OR = 4.77, 95% CI 1.71 - 13.33, p = 0.003). In addition, levels of EBV in blood were significantly higher in NHL cases than in controls (p = 0.024). BL is the most common childhood NHL subtype in north-western Tanzania. NHLs are not associated with HIV infection, but are strongly associated with EBV load in peripheral blood. The findings suggest that high levels of EBV in blood might have diagnostic and prognostic relevance in African children

Municipal water quantities and health in Nunavut households: an exploratory case study in Coral Harbour, Nunavut, Canada

Background: Access to adequate quantities of water has a protective effect on human health and well-being. Despite this, public health research and interventions are frequently focused solely on water quality, and international standards for domestic water supply minimums are often overlooked or unspecified. This trend is evident in Inuit and other Arctic communities even though numerous transmissible diseases and bacterium infections associated with inadequate domestic water quantities are prevalent. Objectives: Our objective was to explore the pathways by which the trucked water distribution systems being used in remote northern communities are impacting health at the household level, with consideration given to the underlying social and environmental determinants shaping health in the region. Methods: Using a qualitative case study design, we conducted 37 interviews (28 residents, 9 key informants) and a review of government water documents to investigate water usage practices and perspectives. These data were thematically analysed to understand potential health risks in Arctic communities and households. Results: Each resident receives an average of 110 litres of municipal water per day. Fifteen of 28 households reported experiencing water shortages at least once per month. Of those 15, most were larger households (5 people or more) with standard sized water storage tanks. Water shortages and service interruptions limit the ability of some households to adhere to public health advice. The households most resilient, or able to cope with domestic water supply shortages, were those capable of retrieving their own drinking water directly from lake and river sources. Residents with extended family and neighbours, whom they can rely on during shortages, were also less vulnerable to municipal water delays. Conclusions: The relatively low in-home water quantities observed in Coral Harbour, Nunavut, appear adequate for some families. Those living in overcrowded households, however, are accessing water in quantities more typically seen in water insecure developing countries. We recommend several practical interventions and revisions to municipal water supply systems

CHANG-ES XI: Circular Polarization in the Cores of Nearby Galaxies

We detect 5 galaxies in the CHANG-ES (Continuum Halos in Nearby Galaxies -- an EVLA Survey) sample that show circular polarization (CP) at L-band in our high resolution data sets. Two of the galaxies (NGC~4388 and NGC~4845) show strong Stokes $V/I\,\equiv\,m_C\,\sim\,2$\%, two (NGC~660 and NGC~3628) have values of $m_C\sim \,0.3$\%, and NGC~3079 is a marginal detection at $m_C\sim \,0.2$\%. The two strongest $m_C$ galaxies also have the most luminous X-ray cores and the strongest internal absorption in X-rays. We have expanded on our previous Faraday conversion interpretation and analysis and provide analytical expressions for the expected $V$ signal for a general case in which the cosmic ray electron energy spectral index can take on any value. We provide examples as to how such expressions could be used to estimate magnetic field strengths and the lower energy cutoff for CR electrons. Four out of our detections are {\it resolved}, showing unique structures, including a {\it jet} in NGC~4388 and a CP `conversion disk' in NGC~4845. The conversion disk is inclined to the galactic disk but is perpendicular to a possible outflow direction. Such CP structures have never before been seen in any galaxy to our knowledge. None of the galaxy cores show linear polarization at L-band. Thus CP may provide a unique probe of physical conditions deep into radio AGNs.Comment: 30 pages, 4 figures, accepted to MNRA

Towards a relevant set of state variables to describe static granular packings

We analyze, experimentally and numerically, the steady states, obtained by tapping, of a two-dimensional granular layer. Contrary to the usual assumption, we show that the reversible (steady state branch) of the density-acceleration curve is nonmonotonous. Accordingly, steady states with the same mean volume can be reached by tapping the system with very different intensities. Simulations of dissipative frictional disks show that equal volume steady states have different values of the force moment tensor. Additionally, we find that steady states of equal stress can be obtained by changing the duration of the taps; however, these states present distinct mean volumes. These results confirm previous speculations that the volume and the force moment tensor are both needed to describe univocally equilibrium states in static granular assemblies

Type-based allocation analysis for co-recursion in lazy functional languages

This paper presents a novel type-and-effect analysis for pre-dicting upper-bounds on memory allocation costs for co-recursive def-initions in a simple lazily-evaluated functional language. We show thesoundness of this system against an instrumented variant of Launch-bury’s semantics for lazy evaluation which serves as a formal cost model.Our soundness proof requires an intermediate semantics employing indi-rections. Our proof of correspondence between these semantics that weprovide is thus a crucial part of this work.The analysis has been implemented as an automatic inference system.We demonstrate its effectiveness using several example programs thatpreviously could not be automatically analysed.Postprin