Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

The human KDM7 subfamily histone H3 Nϵ-methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X-linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues. The calculations reveal key roles of a flexible protein environment in productive formation of enzyme-substrate complexes and suggest targeting the flexible KDM7 linker region is of interest from a medicinal chemistry perspective.     

Divergent 2-Chloroquinazolin-4(3H)-one Rearrangement: Twisted-Cyclic Guanidine Formation or Ring-Fused N-Acylguanidines via a Domino Process

A highly efficient 2-chloroquinazolin-4(3H)-one rearrangement was developed that predictably generates either twisted-cyclic or ring-fused guanidines in a single operation, depending on the presence of a primary versus secondary amine in the accompanying diamine reagent. Exclusive formation of twisted-cyclic guanidines results from pairing 2-chloroquinazolinones with secondary diamines. Use of primary amine-containing diamines permits a domino quinazolinone rearrangement/intramolecular cyclization, gated through (E)-twisted-cyclic guanidines, to afford ring-fused N-acylguanidines. This scalable, structurally tolerant transformation generated 55 guanidines and delivered twisted-cyclic guanidines with robust plasma stability and an abbreviated total synthesis of an antitumor ring-fused guanidine (4 steps, 55 % yield).     

Multifunctional Cationic PeptoStars as siRNA Carrier: Influence of Architecture and Histidine Modification on Knockdown Potential

RNA interference provides enormous potential for the treatment of several diseases, including cancer. Nevertheless, successful therapies based on siRNA require overcoming various challenges, such as poor pharmacokinetic characteristics of the small RNA molecule and inefficient cytosolic accumulation. In this respect, the development of functional siRNA carrier systems is a major task in biomedical research. To provide such a desired system, the synthesis of 3‐arm and 6‐arm PeptoStars is aimed for. The different branched polypept(o)idic architectures share a stealth‐like polysarcosine corona for efficient shielding and a multifunctional polylysine core, which can be independently varied in size and functionality for siRNA complexation‐, transport and intra cellular release. The special feature of star‐like polypept(o)ides is in their uniform small size (<20 nm) and a core–shell structure, which implies a high stability and stealth‐like properties and thus, they may combine long circulation times and a deep penetration of cancerous tissue. Initial toxicity and complement studies demonstrate well tolerated cationic PeptoStars with high complexation capability toward siRNA (N/P ratio up to 3:1), which can lead to potent RNAi for optimized systems. Here, the synthetic development of 3‐arm and 6‐arm polypept(o)idic star polymers, their modification with endosomolytic moieties, and first in vitro insights on RNA interference are reported on.     

Monte Carlo approximation through Gibbs output in generalized linear mixed models

Geyer (J. Roy. Statist. Soc. 56 (1994) 291) proposed Monte Carlo method to approximate the whole likelihood function. His method is limited to choosing a proper reference point. We attempt to improve the method by assigning some prior information to the parameters and using the Gibbs output to evaluate the marginal likelihood and its derivatives through a Monte Carlo approximation. Vague priors are assigned to the parameters as well as the random effects within the Bayesian framework to represent a non-informative setting. Then the maximum likelihood estimates are obtained through the Newton Raphson method. Thus, out method serves as a bridge between Bayesian and classical approaches. The method is illustrated by analyzing the famous salamander mating data by generalized linear mixed models.     

Tame combing and almost convexity conditions

We give the first examples of groups which admit a tame combing with linear radial tameness function with respect to any choice of finite presentation, but which are not minimally almost convex on a standard generating set. Namely, we explicitly construct such combings for Thompson??s group F and the Baumslag?CSolitar groups BS(1, p) with p ??? 3. In order to make this construction for Thompson??s group F, we significantly expand the understanding of the Cayley complex of this group with respect to the standard finite presentation. In particular we describe a quasigeodesic set of normal forms and combinatorially classify the arrangements of 2-cells adjacent to edges that do not lie on normal form paths.     

The structure and maximum number of maximum independent sets in trees

A subset of vertices is a maximum independent set if no two of the vertices are joined by an edge and the subset has maximum cardinality. in this paper we answer a question posed by Herb Wilf. We show that the greatest number of maximum independent sets for a tree of n vertices is We give the families of trees on which these maxima are achieved. Proving which trees are extremal depends upon the structure of maximum independent sets in trees. This structure is described in terms of adjacency rules between three types of vertices, those which are in all, no, or some maximum independent sets. We show that vertices that are in some but not all maximum independent sets of the tree are joined in pairs by the α-critical edges (edges whose removal increases the size of a maximum independent set). The number of maximum independent sets is shown to depend on the structure within the tree of the α-critical edges.     

Optimal risk retention under partial insurance

This paper examines the situation where a risk-averse insured determines the optimal amount of deductible (or stop-loss) insurance. The insurer uses two different premium principles, the expected value principle and the exponential principle. The insured has an exponential utility function. Specific numerical results are obtained for the optimal stop-loss limit in the case of a group life insurance plan. The exact results are contrasted with those obtained by using the normal approximation instead of the exact distribution of aggregate claims.     

Teaching Multiple Modes of Representation in Middle‐School Science Classrooms: Impact on Student Learning and Multimodal Use

This quasi‐experimental study investigated how explicit instruction about multiple modes of representation (MMR) impacted grades 7 (n = 61) and 8 (n = 141) students’ learning and multimodal use on end‐of‐unit assessments. Half of each teacher's (n = 3) students received an intervention consisting of explicit instruction on MMR in science discourse, in addition to regular science instruction enhanced by a focus on MMR; comparison groups of students received regular science instruction. Three ordinary least squares regression models used student demographic variables and whether or not students received the intervention to predict students’ (a) gain scores on end‐of‐unit tests, (b) voluntary use of embedded MMR on unit tests, and (c) retention of science knowledge as measured by a state end‐of‐level criterion‐referenced assessment. Analyses showed that explicit instruction on MMR did not make a significant impact on student gain scores, the amount of embeddedness on unit tests, or end‐of‐level scores. However, Models 2 and 3 showed Hispanics and females used MMR more on end‐of‐unit tests than Whites or males, respectively, whether or not they received the intervention. Hispanics and females scored lower than Whites or males, respectively, on end‐of‐level, multiple‐choice assessments. Implications for classroom teachers and educational researchers in relation to these underserved populations are discussed.     

A Carbene‐Extended ATRA Reaction

Atom‐transfer radical addition (ATRA) reactions have gained a strong foothold in organic synthesis by virtue of their operational simplicity, synthetic versatility, and perfect atom economy. A rich chemical space can be accessed through clever combinations of the simple starting materials. Many variations of this general motif have been reported. However, the vast majority involve the addition of an organic halide across a C=C double bond, resulting in the formation of 1,2‐bifunctional products. This report introduces a significant expansion of this general reactivity concept to give 1,3‐bifunctional adducts through the combination of 1,1‐ATRA to a carbenoid and 1,2‐ATRA to an alkyne. Both processes operate under mild conditions (RT, 5 h) with the same commercial catalyst (CoBr₂, dppbz).