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Precision predictions of soft and hard diffraction, elastic, and total proton proton cross sections, based on a Regge-theory inspired tensor-Pomeron implementation of the RENORM model, are compared to TOTEM, ATLAS, and CMS results at the LHC.

ObjectiveWe aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A-rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls. MethodsA total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near-transfer WM tests (Digit-Span, Spatial-Span), self-reported executive functioning, and functional magnetic resonance images during 1-back and 2-back tasks were performed at baseline and each follow-up visit, and LMX1A-rs4657412 was genotyped in all participants. ResultsAlthough HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p<0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p0.001), but not after nonadaptive WMT (training by training type corrected, p=0.01 to p=0.05) 1 month later. HIV participants (especially LMX1A-G carriers) also had poorer self-reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p=0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p<0.0001), with normalization of brain activation in HIV participants, especially the LMX1A-AA carriers (LMX1A genotype by HIV status, cluster-corrected-p<0.0001). InterpretationAdaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV-LMX1A-AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17-34

This paper proposes a new iterative solution method for nonlinear stochastic optimal control problems based on path integral analysis. First, we provide an iteration law for solving a stochastic Hamilton-Jacobi-Bellman (SHJB) equation associated to this problem, which is a nonlinear partial differential equation (PDE) of second order. Each iteration procedure of the proposed method is represented by a Cauchy problem for a linear parabolic PDE, and its explicit solution is given by the Feynman-Kac formula. Second, we derive a suboptimal feedback controller at each iteration by using the path integral analysis. Third, the convergence property of the proposed method is investigated. Here, some conditions are provided so that the sequence of solutions for the proposed iteration converges, and the SHJB equation is satisfied. Finally, numerical simulations demonstrate the effectiveness of the proposed method.

Background: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis, which has significant negative impact on quality of life. The cellular and molecular inflammatory pathways involved in PPPP have not been well studied. Objective: Study the expression of cytokines and chemokines involved in the IL-17/IL-23 axis in palmoplantar pustular psoriasis and other difficult to treat psoriasis areas (palms, scalp, elbows and lower legs). Methods: Skin biopsies were performed on a total of 80 patients with PPPP, non-pustular palmoplantar psoriasis (NPPPP), or psoriasis located on elbows, knees and scalp as well as 10 healthy subjects. RT-PCR, immunohistochemistry and flow cytometry on cells extracted from skin biopsies were used to compare PPPP to other forms of psoriasis. Results: There was a significant (p < 0.05) increase in the expression of IL-113, IL-6, LL-37, IL-19, IL-17A, CXCL1 and CXCL2 in PPPP as compared to NPPPP. However, there was no significant difference in expression of IL-23 in PPPP as compared to NPPPP and other forms of psoriasis. The proportion of IL-22(+) but not IL-17A(+) mast cells was higher in PPPP as compared to NPPPP (p <0.05). Conclusion: These results suggest that the IL-17A pathway may play a more important role in PPPP than in NPPPP. (C) 2016 Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology.

The core architecture of the eukaryotic cell was established well over one billion years ago, and is largely retained in all extant lineages. However, eukaryotic cells also possess lineage-specific features, frequently keyed to specific functional requirements. One quintessential core eukaryotic structure is the nuclear pore complex (NPC), responsible for regulating exchange of macromolecules between the nucleus and cytoplasm as well as acting as a nuclear organizational hub. NPC architecture has been best documented in one eukaryotic supergroup, the Opisthokonts (e.g. Saccharomyces cerevisiae and Homo sapiens), which although compositionally similar, have significant variations in certain NPC subcomplex structures. The variation of NPC structure across other taxa in the eukaryotic kingdom however, remains poorly understood. We explored trypanosomes, highly divergent organisms, and mapped and assigned their NPC proteins to specific substructures to reveal their NPC architecture. We showed that the NPC central structural scaffold is conserved, likely across all eukaryotes, but more peripheral elements can exhibit very significant lineage-specific losses, duplications or other alterations in their components. Amazingly, trypanosomes lack the major components of the mRNA export platform that are asymmetrically localized within yeast and vertebrate NPCs. Concomitant with this, the trypanosome NPC is ALMOST completely symmetric with the nuclear basket being the only major source of asymmetry. We suggest these features point toward a stepwise evolution of the NPC in which a coating scaffold first stabilized the pore after which selective gating emerged and expanded, leading to the addition of peripheral remodeling machineries on the nucleoplasmic and cytoplasmic sides of the pore.

The stable structural conformations that occur along the complete reaction coordinate for ion channel opening have never been observed. In this study, we describe the equilibrium ensemble of structures of Slo2.2, a neuronal Na+-activated K+ channel, as a function of the Na+ concentration. We find that Slo2.2 exists in multiple closed conformations whose relative occupancies are independent of Na+ concentration. An open conformation emerges from an ensemble of closed conformations in a highly Na+-dependent manner, without evidence of Na+-dependent intermediates. In other words, channel opening is a highly concerted, switch-like process. The midpoint of the structural titration matches that of the functional titration. A maximum open conformation probability approaching 1.0 and maximum functional open probability approaching 0.7 imply that, within the class of open channels, there is a subclass that is not permeable to ions.

mRNA is cotranscrptionally processed and packaged into messenger ribonucleoprotein particles (mRNPs) in the nucleus. Prior to export through the nuclear pore, mRNPs undergo several obligatory remodeling reactions. In yeast, one of these reactions involves loading of the mRNA-binding protein Yra1 by the DEAD-box ATPase Sub2 as assisted by the hetero-pentameric THO complex. To obtain molecular insights into reaction mechanisms, we determined crystal structures of two relevant complexes: a THO hetero-pentamer bound to Sub2 at 6.0 angstrom resolution; and Sub2 associated with an ATP analogue, RNA, and a C-terminal fragment of Yra1 (Yra1-C) at 2.6 angstrom resolution. We found that the 25 nm long THO clamps Sub2 in a half-open configuration; in contrast, when bound to the ATP analogue, RNA and Yra1-C, Sub2 assumes a closed conformation. Both THO and Yra1-C stimulated Sub2's intrinsic ATPase activity. We propose that THO surveys common landmarks in each nuclear mRNP to localize Sub2 for targeted loading of Yra1.

Ageing is driven by a loss of transcriptional and protein homeostasis(1-3) and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses(4,5). However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.

Precision predictions of soft and hard diffraction, elastic scattering, and total proton-proton cross sections, based on a tensor-Pomeron implementation of the RENORM model, are compared to the latest experimental results at the LHC and cosmic-ray experiments, and extended to the planned SuperCollider energies.