Molecular bases underlying chromosome fragility at Replication Slow Zones in Saccharomyces cerevisiae

Chromosome rearrangements such as translocations and deletions are frequently associated with human cancers. Such rearrangement of the chromosome can be initiated by a DNA break (DSB) that, when inappropriately repaired, may alter chromosome structure. Mammalian common fragile sites are the best-characterised, naturally occurring breakage-prone regions and are deleted or rearranged in many tumour cells. Analogous chromosomal regions also exist in the budding yeast, S. cerevisiae. One example of a yeast fragile site is the replication slow zone (RSZ), so called because the rate of replication fork progression through these regions is slow compared to other regions within the same chromosome. Inactivation of the essential checkpoint kinase, Mec1, in mec1-ts mutants results in replication fork stalling followed by chromosome breakage at RSZs. Interestingly, inhibition of ATR, the mammalian homologue of Mec1, also leads to chromosome instability at common fragile sites, suggesting that the mechanism by which endogenous DSBs are generated is conserved between yeast and mammals. This study aims to enhance our current understanding of common fragile sites using yeast RSZs as a model. First, RSZs were characterised in terms of chromosomal features and determinants in order to identify similarities between RSZs and mammalian common fragile sites and to assess whether yeast RSZs as a suitable system for studying common fragile sites in more complex organisms. Next, the mechanism underlying chromosome fragility at RSZs was investigated by examining the contribution of various chromosomal processes to break formation at these sites. These include: (i) replication fork restart processes (ii) spindle force, (iii) chromosome condensation and decatenation, (iv) chromosome segregation, and (v) cytokinesis. The analyses suggest that chromosome breakage within RSZs requires the actions of the evolutionarily conserved type II topoisomerase and condensin complex. Finally, factors involved in maintaining the stability of RSZs were also explored. The Rrm3 helicase and Psy2 phosphatase complex were found to suppress chromosome breakage at RSZs in a manner dependent on Tel1, another checkpoint kinase. These findings suggest that Tel1 is somehow implicated in chromosome stability at RSZs. The findings presented in this study further our understanding of RSZs and the molecular bases governing their fragility, providing some insight into the mechanism of fragile site instability in mammals

Jumps in Besov spaces and fine properties of Besov and fractional Sobolev functions

In this paper we analyse functions in Besov spaces $B^{1/q}_{q,\infty}(\mathbb{R}^N,\mathbb{R}^d),q\in (1,\infty)$, and functions in fractional Sobolev spaces $W^{r,q}(\mathbb{R}^N,\mathbb{R}^d),r\in (0,1),q\in [1,\infty)$. We prove for Besov functions $u\in B^{1/q}_{q,\infty}(\mathbb{R}^N,\mathbb{R}^d)$ the summability of the difference between one-sided approximate limits in power $q$, $|u^+-u^-|^q$, along the jump set $\mathcal{J}_u$ of $u$ with respect to Hausdorff measure $\mathcal{H}^{N-1}$, and establish the best bound from above on the integral $\int_{\mathcal{J}_u}|u^+-u^-|^qd\mathcal{H}^{N-1}$ in terms of Besov constants. We show for functions $u\in B^{1/q}_{q,\infty}(\mathbb{R}^N,\mathbb{R}^d),q\in (1,\infty)$ that \begin{equation} \liminf\limits_{\varepsilon \to 0^+}\fint_{B_{\varepsilon}(x)} |u(z)-u_{B_{\varepsilon}(x)}|^qdz=0 \end{equation} for every $x$ outside of a $\mathcal{H}^{N-1}$-sigma finite set. For fractional Sobolev functions $u\in W^{r,q}(\mathbb{R}^N,\mathbb{R}^d)$ we prove that \begin{equation} \lim_{\rho\to 0^+}\fint_{B_{\rho}(x)}\fint_{B_{\rho}(x)} |u\big(z\big)-u(y)|^qdzdy=0 \end{equation} for $\mathcal{H}^{N-rq}$ a.e. $x$, where $q\in[1,\infty)$, $r\in(0,1)$ and $rq\leq N$. We prove for $u\in W^{1,q}(\mathbb{R}^N),1<q\leq N$, that \begin{equation} \lim\limits_{\varepsilon\to 0^+}\fint_{B_{\varepsilon}(x)} |u(z)-u_{B_{\varepsilon}(x)}|^qdz=0 \end{equation} for $\mathcal{H}^{N-q}$ a.e. $x\in \mathbb{R}^N$

Learning of Soil Behavior from Measured Response of a Full Scale Test Wall in Sandy Soil

In urban deep excavations, instruments are placed to monitor deformations and to control construction and reduce the risk of excessive and potentially damaging deformations. The second author has introduced a new inverse analysis approach that utilizes measured excavation performance to extract the underlying soil behavior. The extracted soil behavior can be used in predicting the behavior of similar excavations. This paper provides a first implementation of this inverse analysis approach to a well instrumented full scale test wall in a sand deposit. A wall consisting of soldier beams with wood lagging was instrumented to study anchored (one and two level tie backs) wall behavior in sandy soil deposits at Texas A&M. Strain gauges, load cells, inclinometers, and settlement points were placed in two sections of the excavation to monitor the excavation behavior. The measured excavation response for the section with two-level tie-backs is used to extract the constitutive model through the inverse analyses approach. The extracted constitutive model is used in predicting the underlying soil behavior for the section with one tie-back level. The predicted behavior of the excavation and its agreement with measurements at the site are discussed in detail

On fine differentiability properties of Sobolev functions

We study fine differentiability properties of functions in Sobolev spaces. We prove that the difference quotient of $f\in W^{1}_{p}(\mathbb R^n)$ converges to the formal differential of this function in the W^{1}_{p,\loc}-topology \cp_p-a.~e. under an additional assumption of existence of a refined weak gradient. This result is extended to convergence of remainders in the corresponding Taylor formula for functions in $W^{k}_{p}$ spaces. In addition we prove $L_p-$approximately differentiability \cp_p-a.e for functions $f\in W^1_p(\mathbb{R}^n)$ with a refined weak gradient.Comment: 24 page

Non-Linear Site Response Analysis for Deep Deposits in the New Madrid Seismic Zone

The New Madrid Seismic Zone, the most seismically active zone in the Eastern US, is overlain by deep unconsolidated deposits of the Mississippi Embayment. The deposits range in thickness from about 20 m in the St. Louis area to about 1 km in the Memphis Area and consist of silts, clays and sands. The influence of these deposits on the propagation of seismic waves to the ground surface remains a major source of uncertainty. A new non-linear one-dimensional site response analysis model is introduced for the vertical propagation of horizontal shear waves in deep soil deposits. The model accounts for the effect of large confining pressures on the strain dependent modulus degradation and damping of the soil. The capability of the new model is illustrated using soil columns at three typical locations within the Mississippi Embayment including a 1000 m column representative of conditions in Memphis. The analyses show that high frequency components usually filtered using conventional wave propagation methods, are preserved. The analyses show that spectral amplification factors for the deep deposits in the period range of 0.6-5sec range between 2 and 6, and at longer long periods (up to 10 set) can be as high as 8

Effects of maternal hyperthermia on neurodevelopment: a literature review

Maternal hyperthermia, defined as a body temperature above 38°C (100.4°F) is due to various etiologies during pregnancy, and has been a subject of growing research interest. This phenomenon is considered a potential environmental teratogen contributing to the development of neural tube defects (NTDs) and other neurodevelopmental disorders. NTDs such as anencephaly and spina bifida, are known to be multifactorial in origin, resulting from a complex interplay between genetic and environmental factors. In this review, we aim to comprehensively analyze the effect of maternal hyperthermia on neurodevelopmental disorders and associated congenital anomalies. In addition, we will highlight both the infectious and noninfectious causes of maternal hyperthermia, as well as any risks and potential preventive measures. The literature search identified studies reporting associations between maternal hyperthermia and adverse fetal outcomes. We have evaluated the link between maternal fever due to infections during pregnancy and the increased likelihood of NTDs, particularly anencephaly and spina bifida, as well as Neurodevelopmental disorders. ​​In addition, the effects of non-infectious causes of maternal hyperthermia, including exercise and exposure to heat sources like saunas and hot tubs, on neurodevelopment have also been studied with varying degrees of evidence. Maternal hyperthermia elevates the risk of NTDs and neurodevelopmental disorders in infants, with folic acid offering partial protection, while other factors elevate this risk. However, further research is needed to define the precious association of these factors

Steric and Polar Factors Affecting Heteroring Opening of 2-[2-carboxy-3,4,5,6-tetrachloro]phenyl-4H-3,1-Benzoxazin-4-one by Nitrogen and Carbon Nucleophiles

The behavior of 2-[2-carboxy-3,4,5,6-tetrachloro]phenyl-4H-3,1-Benzoxazin-4-  one towards Nitrogen nucleophiles and Carbon nucleophiles under Friedel–Crafts' reaction conditions has been investigated and steric versus polar factors affecting ring opening has been studied