Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone

During mouse sex determination, transient expression of the Y-linked gene Sry up-regulates its direct target gene Sox9, via a 3.2 kb testis specific enhancer of Sox9 (TES), which includes a core 1.4 kb element, TESCO. SOX9 activity leads to differentiation of Sertoli cells, rather than granulosa cells from the bipotential supporting cell precursor lineage. Here, we present functional analysis of TES/TESCO, using CRISPR/Cas9 genome editing in mice. Deletion of TESCO or TES reduced Sox9 expression levels in XY fetal gonads to 60 or 45% respectively relative to wild type gonads, and reduced expression of the SOX9 target Amh. Although human patients heterozygous for null mutations in SOX9, which are assumed to have 50% of normal expression, often show XY female sex reversal, mice deleted for one copy of Sox9 do not. Consistent with this, we did not observe sex reversal in either TESCO-/- or TES-/- XY embryos or adult mice. However, embryos carrying both a conditional Sox9 null allele and the TES deletion developed ovotestes. Quantitative analysis of these revealed levels of 23% expression of Sox9 compared to wild type, and a significant increase in the expression of the granulosa cell marker Foxl2. This indicates that the threshold in mice where sex reversal begins to be seen is about half that of the ~50% levels predicted in humans. Our results demonstrate that TES/TESCO is a crucial enhancer regulating Sox9 expression in the gonad, but point to the existence of additional enhancers that act redundantly

The New Deal for Communities experience: a final assessment - The New Deal for Communities evaluation: Final report – Volume 7

We show that for all integers $t\geq 8$ and arbitrarily small $\epsilon>0$, there exists a graph property $\Pi$ (which depends on $\epsilon$) such that $\epsilon$-testing $\Pi$ has non-adaptive query complexity $Q=\~{\Theta}(q^{2-2/t})$, where $q=\~{\Theta}(\epsilon^{-1})$ is the adaptive query complexity. This resolves the question of how beneficial adaptivity is, in the context of proximity-dependent properties (\cite{benefits-of-adaptivity}). This also gives evidence that the canonical transformation of Goldreich and Trevisan (\cite{canonical-testers}) is essentially optimal when converting an adaptive property tester to a non-adaptive property tester. To do so, we provide optimal adaptive and non-adaptive testers for the combined property of having maximum degree $O(\epsilon N)$ and being a \emph{blow-up collection} of an arbitrary base graph $H$.Comment: Keywords: Sublinear-Time Algorithms, Property Testing, Dense-Graph Model, Adaptive vs Nonadaptive Queries, Hierarchy Theore

Cooperation of the Dam1 and Ndc80 kinetochore complexes enhances microtubule coupling and is regulated by aurora B

The Dam1 complex, regulated by aurora B phosphorylation, confers a more stable microtubule association for the Ndc80 complex at kinetochores (see also related paper by Lampert et al. in this issue)

A Fast Counting Method for 6-motifs with Low Connectivity

A $k$-motif (or graphlet) is a subgraph on $k$ nodes in a graph or network. Counting of motifs in complex networks has been a well-studied problem in network analysis of various real-word graphs arising from the study of social networks and bioinformatics. In particular, the triangle counting problem has received much attention due to its significance in understanding the behavior of social networks. Similarly, subgraphs with more than 3 nodes have received much attention recently. While there have been successful methods developed on this problem, most of the existing algorithms are not scalable to large networks with millions of nodes and edges. The main contribution of this paper is a preliminary study that genaralizes the exact counting algorithm provided by Pinar, Seshadhri and Vishal to a collection of 6-motifs. This method uses the counts of motifs with smaller size to obtain the counts of 6-motifs with low connecivity, that is, containing a cut-vertex or a cut-edge. Therefore, it circumvents the combinatorial explosion that naturally arises when counting subgraphs in large networks

MiRNA-Mediated Control of HLA-G Expression and Function

HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3′UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3′UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G

The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome

<p>Abstract</p> <p>Background</p> <p>To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles.</p> <p>Methods</p> <p>A retrospective cohort study including all patients who had IVF-ET from January 2003–December 2005 conducted at a tertiary center.</p> <p>Results</p> <p>A total of 2464 cycles were analysed. Pregnancy rate (PR) was 35.8%. PR increased linearly (r = 0.864) from 29.4% among patients with a lining of less than or equal to 6 mm, to 44.4% among patients with a lining of greater than or equal to 17 mm. ROC showed that endometrial thickness is not a good predictor of PR, so a definite cut-off value could not be established (AUC = 0.55).</p> <p>Conclusion</p> <p>There is a positive linear relationship between the endometrial thickness measured on the day of hCG injection and PR, and is independent of other variables. Hence aiming for a thicker endometrium should be considered.</p

HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation.

The internal ribosome entry site (IRES) of the hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. Functional studies of the HCV IRES have focused on 80S ribosome formation but have not explored its role after the 80S ribosome is poised at the start codon. Here, we report that mutations of an IRES domain that docks in the 40S subunit's decoding groove cause only a local perturbation in IRES structure and result in conformational changes in the IRES-rabbit 40S subunit complex. Functionally, the mutations decrease IRES activity by inhibiting the first ribosomal translocation event, and modeling results suggest that this effect occurs through an interaction with a single ribosomal protein. The ability of the HCV IRES to manipulate the ribosome provides insight into how the ribosome's structure and function can be altered by bound RNAs, including those derived from cellular invaders