There and Back Again

We present a programming pattern where a recursive function defined over a data structure traverses another data structure at return time. The idea is that the recursive calls get us `there' by traversing the first data structure and the returns get us `back again' while traversing the second data structure. We name this programming pattern of traversing a data structure at call time and another data structure at return time ``There And Back Again'' (TABA). The TABA pattern directly applies to computing symbolic convolutions and to multiplying polynomials. It also blends well with other programming patterns such as dynamic programming and traversing a list at double speed. We illustrate TABA and dynamic programming with Catalan numbers. We illustrate TABA and traversing a list at double speed with palindromes and we obtain a novel solution to this traditional exercise. Finally, through a variety of tree traversals, we show how to apply TABA to other data structures than lists. A TABA-based function written in direct style makes full use of an ALGOL-like control stack and needs no heap allocation. Conversely, in a TABA-based function written in continuation-passing style and recursively defined over a data structure (traversed at call time), the continuation acts as an iterator over a second data structure (traversed at return time). In general, the TABA pattern saves one from accumulating intermediate data structures at call time

Partial Evaluation of the Euclidian Algorithm (Extended Version)

Some programs are easily amenable to partial evaluation becausetheir control flow clearly depends on one of their parameters. Specializingsuch programs with respect to this parameter eliminates theassociated interpretive overhead. Some other programs, however, donot exhibit this interpreter-like behavior. Each of them presents a challengefor partial evaluation. The Euclidian algorithm is one of them,and in this article, we make it amenable to partial evaluation.We observe that the number of iterations in the Euclidian algorithmis bounded by a number that can be computed given either of the twoarguments. We thus rephrase this algorithm using bounded recursion.The resulting program is better suited for automatic unfolding andthus for partial evaluation. Its specialization is efficient.Keywords: partial evaluation, scientific computation

There and Back Again

We illustrate a variety of programming problems that seemingly require two separate list traversals, but that can be efficiently solved in one recursive descent, without any other auxiliary storage but what can be expected from a control stack. The idea is to perform the second traversal when returning from the first. This programming technique yields new solutions to traditional problems. For example, given a list of length 2n or 2n+1, where n is unknown, we can detect whether this list is a palindrome in n+1 recursive calls and no heap allocation

A Sporozoite Asparagine-Rich Protein Controls Initiation of Plasmodium Liver Stage Development

Plasmodium sporozoites invade host hepatocytes and develop as liver stages (LS) before the onset of erythrocytic infection and malaria symptoms. LS are clinically silent, and constitute ideal targets for causal prophylactic drugs and vaccines. The molecular and cellular mechanisms underlying LS development remain poorly characterized. Here we describe a conserved Plasmodium asparagine-rich protein that is specifically expressed in sporozoites and liver stages. Gene disruption in Plasmodium berghei results in complete loss of sporozoite infectivity to rodents, due to early developmental arrest after invasion of hepatocytes. Mutant sporozoites productively invade host cells by forming a parasitophorous vacuole (PV), but subsequent remodelling of the membrane of the PV (PVM) is impaired as a consequence of dramatic down-regulation of genes encoding PVM-resident proteins. These early arrested mutants confer only limited protective immunity in immunized animals. Our results demonstrate the role of an asparagine-rich protein as a key regulator of Plasmodium sporozoite gene expression and LS development, and suggest a requirement of partial LS maturation to induce optimal protective immune responses against malaria pre-erythrocytic stages. These findings have important implications for the development of genetically attenuated parasites as a vaccine approach

There and Back Again

We present a programming pattern where a recursive function traverses a data structure--typically a list--at return time. The idea is that the recursive calls get us there (typically to a base case) and the returns get us back again while traversing the data structure. We name this programming pattern of traversing a data structure at return time ``There And Back Again'' (TABA). The TABA pattern directly applies to computing a symbolic convolution. It also synergizes well with other programming patterns, e.g., dynamic programming and traversing a list at double speed. We illustrate TABA and dynamic programming with Catalan numbers. We illustrate TABA and traversing a list at double speed with palindromes and we obtain a novel solution to this traditional exercise. A TABA-based function written in direct style makes full use of an Algol-like control stack and needs no heap allocation. Conversely, in a TABA-based function written in continuation-passing style, the continuation acts as a list iterator. In general, the TABA pattern saves one from constructing intermediate lists in reverse order.See also BRICS-RS-05-3

Establishing two principal dimensions of cognitive variation in Logopenic Progressive Aphasia

Logopenic Progressive Aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits, even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is independent of language function and disease severity.This work was supported in part by funding to Forefront, a collaborative research group specialized to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council (NHMRC) of Australia program grant (APP1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE110001021). Siddharth Ramanan is supported by a Faculty of Science Ph.D. Research Scholarship from The University of Sydney. Olivier Piguet is supported by an NHMRC Senior Research Fellowship (APP1103258). Muireann Irish is supported by an ARC Future Fellowship (FT160100096) and an ARC Discovery Project (DP180101548). Matthew A. Lambon Ralph is supported by a UKRI-MRC Programme Grant (MR/R023883/1) and an ERC Advanced grant (GAP: 670428 - BRAIN2MIND_NEUROCOMP)

Gender Differences in the Labor Market Effects of the Dollar

Although the dollar has been shown to influence the expected wages of workers, the analysis to date has focused on the male workforce. We show that exchange rate fluctuations also have important implications for women's wages. The dominant wage effects for women—like those for men—arise at times of job transition. Changes in the value of the dollar can cause the wage gap between women who change jobs and women who stay on in their jobs to expand or contract sharply, with the most pronounced effects occurring among the least educated women and women in highly competitive manufacturing industries. In addition, it appears that women who stay on in their jobs show greater wage sensitivity to currency movements than do their male counterparts

Revisiting an IgG Fc Loss-of-Function Experiment: The Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity

The role of the complement system in HIV-1 immunity and pathogenesis is multifaceted, and an improved understanding of complement activities mediated by HIV-1-specific antibodies has the potential to inform and advance clinical development efforts. A seminal nonhuman primate challenge experiment suggested that complement was dispensable for the protective effect of the early broadly neutralizing antibody (bnAb) b12, but recent experiments have raised questions about the breadth of circumstances under which this conclusion may hold. Here, we reassess the original observation using Fc variants of IgG1 b12 that enhance complement activity and report that complement fixation on recombinant antigen, virions, and cells and complement-dependent viral and cellular lysis in vitro vary among bnAbs. Specifically, while the clinically significant V3 glycan-specific bnAb 10-1074 demonstrates activity, we found that b12 does not meaningfully activate the classical complement cascade. Consistent with avid engagement by C1q and its complex system of regulatory factors, these results suggest that complement-mediated antibody activities demonstrate a high degree of context dependence and motivate revisiting the role of complement in antibody-mediated prevention of HIV-1 infection by next-generation bnAbs in new translational studies in animal models. IMPORTANCE Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies

Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during Experimental Autoimmune Encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.</p> <p>Methods</p> <p>WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG)_35-55peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays.</p> <p>Results</p> <p>Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals.</p> <p>Conclusions</p> <p>These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.</p

Methamphetamine Self-Administration Is Associated with Persistent Biochemical Alterations in Striatal and Cortical Dopaminergic Terminals in the Rat

Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers