The conserved XPF:ERCC1-like Zip2:Spo16 complex controls meiotic crossover formation through structure-specific DNA binding.

In eukaryotic meiosis, generation of haploid gametes depends on the formation of inter-homolog crossovers, which enable the pairing, physical linkage, and eventual segregation of homologs in the meiosis I division. A class of conserved meiosis-specific proteins, collectively termed ZMMs, are required for formation and spatial control of crossovers throughout eukaryotes. Here, we show that three Saccharomyces cerevisiae ZMM proteins-Zip2, Zip4 and Spo16-interact with one another and form a DNA-binding complex critical for crossover formation and control. We determined the crystal structure of a Zip2:Spo16 subcomplex, revealing a heterodimer structurally related to the XPF:ERCC1 endonuclease complex. Zip2:Spo16 lacks an endonuclease active site, but binds specific DNA structures found in early meiotic recombination intermediates. Mutations in multiple DNA-binding surfaces on Zip2:Spo16 severely compromise DNA binding, supporting a model in which the complex's central and HhH domains cooperate to bind DNA. Overall, our data support a model in which the Zip2:Zip4:Spo16 complex binds and stabilizes early meiotic recombination intermediates, then coordinates additional factors to promote crossover formation and license downstream events including synaptonemal complex assembly

Robotic Resistance Treadmill Training Improves Locomotor Function in Children With Cerebral Palsy: A Randomized Controlled Pilot Study

Objective To determine whether applying controlled resistance forces to the legs during the swing phase of gait may improve the efficacy of treadmill training as compared with applying controlled assistance forces in children with cerebral palsy (CP). Design Randomized controlled study. Setting Research unit of a rehabilitation hospital. Participants Children with spastic CP (N=23; mean age, 10.6y; range, 6–14y; Gross Motor Function Classification System levels, I–IV). Interventions Participants were randomly assigned to receive controlled assistance (n=11) or resistance (n=12) loads applied to the legs at the ankle. Participants underwent robotic treadmill training 3 times a week for 6 weeks (18 sessions). A controlled swing assistance/resistance load was applied to both legs starting from the toe-off to mid-swing phase of gait during training. Main Outcome Measures Outcome measures consisted of overground walking speed, 6-minute walk distance, and Gross Motor Function Measure scores and were assessed pre and post 6 weeks of training and 8 weeks after the end of training. Results After 6 weeks of treadmill training in participants from the resistance training group, fast walking speed and 6-minute walk distance significantly improved (18% and 30% increases, respectively), and 6-minute walk distance was still significantly greater than that at baseline (35% increase) 8 weeks after the end of training. In contrast, overground gait speed and 6-minute walk distance had no significant changes after robotic assistance training. Conclusions The results of the present study indicated that robotic resistance treadmill training is more effective than assistance training in improving locomotor function in children with CP

Sparse Coding and Autoencoders

In "Dictionary Learning" one tries to recover incoherent matrices $A^* \in \mathbb{R}^{n \times h}$ (typically overcomplete and whose columns are assumed to be normalized) and sparse vectors $x^* \in \mathbb{R}^h$ with a small support of size $h^p$ for some $0 <p < 1$ while having access to observations $y \in \mathbb{R}^n$ where $y = A^*x^*$. In this work we undertake a rigorous analysis of whether gradient descent on the squared loss of an autoencoder can solve the dictionary learning problem. The "Autoencoder" architecture we consider is a $\mathbb{R}^n \rightarrow \mathbb{R}^n$ mapping with a single ReLU activation layer of size $h$. Under very mild distributional assumptions on $x^*$, we prove that the norm of the expected gradient of the standard squared loss function is asymptotically (in sparse code dimension) negligible for all points in a small neighborhood of $A^*$. This is supported with experimental evidence using synthetic data. We also conduct experiments to suggest that $A^*$ is a local minimum. Along the way we prove that a layer of ReLU gates can be set up to automatically recover the support of the sparse codes. This property holds independent of the loss function. We believe that it could be of independent interest.Comment: In this new version of the paper with a small change in the distributional assumptions we are actually able to prove the asymptotic criticality of a neighbourhood of the ground truth dictionary for even just the standard squared loss of the ReLU autoencoder (unlike the regularized loss in the older version

Multipolar Black Body Radiation Shifts for the Single Ion Clocks

Appraising the projected $10^{-18}$ fractional uncertainty in the optical frequency standards using singly ionized ions, we estimate the black-body radiation (BBR) shifts due to the magnetic dipole (M1) and electric quadrupole (E2) multipoles of the magnetic and electric fields, respectively. Multipolar scalar polarizabilities are determined for the singly ionized calcium (Ca$^+$) and strontium (Sr$^+$) ions using the relativistic coupled-cluster method; though the theory can be exercised for any single ion clock proposal. The expected energy shifts for the respective clock transitions are estimated to be $4.38(3) \times 10^{-4}$ Hz for Ca$^+$ and $9.50(7) \times 10^{-5}$ Hz for Sr$^+$. These shifts are large enough and may be prerequisite for the frequency standards to achieve the foreseen $10^{-18}$ precision goal.Comment: 1 figure, 4 table

Stable Frank-Kasper phases of self-assembled, soft matter spheres

Single molecular species can self-assemble into Frank Kasper (FK) phases, finite approximants of dodecagonal quasicrystals, defying intuitive notions that thermodynamic ground states are maximally symmetric. FK phases are speculated to emerge as the minimal-distortional packings of space-filling spherical domains, but a precise quantitation of this distortion and how it affects assembly thermodynamics remains ambiguous. We use two complementary approaches to demonstrate that the principles driving FK lattice formation in diblock copolymers emerge directly from the strong-stretching theory of spherical domains, in which minimal inter-block area competes with minimal stretching of space-filling chains. The relative stability of FK lattices is studied first using a diblock foam model with unconstrained particle volumes and shapes, which correctly predicts not only the equilibrium {\sigma} lattice, but also the unequal volumes of the equilibrium domains. We then provide a molecular interpretation for these results via self-consistent field theory, illuminating how molecular stiffness regulates the coupling between intra-domain chain configurations and the asymmetry of local packing. These findings shed new light on the role of volume exchange on the formation of distinct FK phases in copolymers, and suggest a paradigm for formation of FK phases in soft matter systems in which unequal domain volumes are selected by the thermodynamic competition between distinct measures of shape asymmetry.Comment: 40 pages, 22 figure

Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20–25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer.</jats:p