Grey and white matter correlates of recent and remote autobiographical memory retrieval:Insights from the dementias

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events

Testing Nelder-Mead based repulsion algorithms for multiple roots of nonlinear systems via a two-level factorial design of experiments

This paper addresses the challenging task of computing multiple roots of a system of nonlinear equations. A repulsion algorithm that invokes the Nelder-Mead (N-M) local search method and uses a penalty-type merit function based on the error function, known as 'erf', is presented. In the N-M algorithm context, different strategies are proposed to enhance the quality of the solutions and improve the overall efficiency. The main goal of this paper is to use a two-level factorial design of experiments to analyze the statistical significance of the observed differences in selected performance criteria produced when testing different strategies in the N-M based repulsion algorithm. The main goal of this paper is to use a two-level factorial design of experiments to analyze the statistical significance of the observed differences in selected performance criteria produced when testing different strategies in the N-M based repulsion algorithm.Fundação para a Ciência e Tecnologia (FCT

Sympatric Speciation: When Is It Possible in Bacteria?

This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping.Ellison Medical FoundationSwiss National Science Foundation (PA00P1_131448/1

The Ku-binding motif is a conserved module for recruitment and stimulation of non-homologous end-joining proteins

The Ku-binding motif (KBM) is a short peptide module first identified in APLF that we now show is also present in Werner syndrome protein (WRN) and in Modulator of retrovirus infection homologue (MRI). We also identify a related but functionally distinct motif in XLF, WRN, MRI and PAXX, which we denote the XLF-like motif. We show that WRN possesses two KBMs; one at the N terminus next to the exonuclease domain and one at the C terminus next to an XLF-like motif. We reveal that the WRN C-terminal KBM and XLF-like motif function cooperatively to bind Ku complexes and that the N-terminal KBM mediates Ku-dependent stimulation of WRN exonuclease activity. We also show that WRN accelerates DSB repair by a mechanism requiring both KBMs, demonstrating the importance of WRN interaction with Ku. These data define a conserved family of KBMs that function as molecular tethers to recruit and/or stimulate enzymes during NHEJ

PESSTO: survey description and products from the first data release by the Public ESO Spectroscopic Survey of Transient Objects

Context. The Public European Southern Observatory Spectroscopic Survey of Transient Objects (PESSTO) began as a public spectroscopic survey in April 2012. PESSTO classifies transients from publicly available sources and wide-field surveys, and selects science targets for detailed spectroscopic and photometric follow-up. PESSTO runs for nine months of the year, January – April and August – December inclusive, and typically has allocations of 10 nights per month. Aims. We describe the data reduction strategy and data products that are publicly available through the ESO archive as the Spectroscopic Survey data release 1 (SSDR1). Methods. PESSTO uses the New Technology Telescope with the instruments EFOSC2 and SOFI to provide optical and NIR spectroscopy and imaging. We target supernovae and optical transients brighter than 20.5m for classification. Science targets are selected for follow-up based on the PESSTO science goal of extending knowledge of the extremes of the supernova population. We use standard EFOSC2 set-ups providing spectra with resolutions of 13–18 Å between 3345−9995 Å. A subset of the brighter science targets are selected for SOFI spectroscopy with the blue and red grisms (0.935−2.53 μm and resolutions 23−33 Å) and imaging with broadband JHKs filters. Results. This first data release (SSDR1) contains flux calibrated spectra from the first year (April 2012–2013). A total of 221 confirmed supernovae were classified, and we released calibrated optical spectra and classifications publicly within 24 h of the data being taken (via WISeREP). The data in SSDR1 replace those released spectra. They have more reliable and quantifiable flux calibrations, correction for telluric absorption, and are made available in standard ESO Phase 3 formats. We estimate the absolute accuracy of the flux calibrations for EFOSC2 across the whole survey in SSDR1 to be typically ~15%, although a number of spectra will have less reliable absolute flux calibration because of weather and slit losses. Acquisition images for each spectrum are available which, in principle, can allow the user to refine the absolute flux calibration. The standard NIR reduction process does not produce high accuracy absolute spectrophotometry but synthetic photometry with accompanying JHKs imaging can improve this. Whenever possible, reduced SOFI images are provided to allow this. Conclusions. Future data releases will focus on improving the automated flux calibration of the data products. The rapid turnaround between discovery and classification and access to reliable pipeline processed data products has allowed early science papers in the first few months of the survey

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.This research was supported by USPHS grant NS073976 (TKH) and P30 ES 06676 that support the NIEHS Center Cell Biology Core and Molecular Genomics Core of UTMB’s NIEHS Center for DNA sequencing. TKP is supported by CA129537 and CA154320. This work was also supported by Fundação para a Ciência e Tecnologia through the project [PTDC/SAU-GMG/101572/2008] and through fellowships [SFRH/BPD/91562/2012 to ASF, SFRH/BD/51059/2010 to ANC]. IB is supported by NIEHS R01 ES018948 and NIAID/AI06288

The Edinburgh Social Cognition Test (ESCoT):Examining the effects of age on a new measure of theory of mind and social norm understanding

<div><p>Current measures of social cognition have shown inconsistent findings regarding the effects of healthy aging. Moreover, no tests are currently available that allow clinicians and researchers to examine cognitive and affective theory of mind (ToM) and understanding of social norms within the same test. To address these limitations, we present the Edinburgh Social Cognition Test (ESCoT) which assesses cognitive and affective ToM and inter- and intrapersonal understanding of social norms. We examined the effects of age, measures of intelligence and the Broader Autism Phenotype (BAP) on the ESCoT and established tests of social cognition. Additionally, we investigated the convergent validity of the ESCoT based on traditional social cognition measures. The ESCoT was administered alongside Reading the Mind in Films (RMF), Reading the Mind in Eyes (RME), Judgement of Preference and Social Norm Questionnaire to 91 participants (30 aged 18–35 years, 30 aged 45–60 years and 31 aged 65–85 years). Poorer performance on the cognitive and affective ToM ESCoT subtests were predicted by increasing age. The affective ToM ESCoT subtest and RMF were predicted by gender, where being female predicted better performance. Unlike the ESCoT, better performance on the RMF was predicted by higher verbal comprehension and perceptual reasoning abilities, while better performance on the RME was predicted by higher verbal comprehension scores. Lower scores on inter-and intrapersonal understanding of social norms were both predicted by the presence of more autism-like traits while poorer interpersonal understanding of social norms performance was predicted by increasing age. These findings show that the ESCoT is a useful measure of social cognition and, unlike established tests of social cognition, performance is not predicted by measures of verbal comprehension and perceptual reasoning. This is particularly valuable to obtain an accurate assessment of the influence of age on our social cognitive abilities.</p></div

Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1

Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic β-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag−/− mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.National Institutes of Health (U.S.) (NIH grant R01-CA075576)National Institutes of Health (U.S.) (NIH grant R01-CA055042)National Institutes of Health (U.S.) (NIH grant R01-CA149261)National Institutes of Health (U.S.) (NIH grant P30-ES00002)National Institutes of Health (U.S.) (NIH grant P30-ES02109)National Center for Research Resources (U.S.) (grant number M01RR-01066)National Center for Research Resources (U.S.) (grant number UL1 RR025758, Harvard Clinical and Translational Science Center

Male Choice in the Stream-Anadromous Stickleback Complex

Studies of mating preferences and pre-mating reproductive isolation have often focused on females, but the potential importance of male preferences is increasingly appreciated. We investigated male behavior in the context of reproductive isolation between divergent anadromous and stream-resident populations of threespine stickleback, Gasterosteus aculeatus, using size-manipulated females of both ecotypes. Specifically, we asked if male courtship preferences are present, and if they are based on relative body size, non-size aspects of ecotype, or other traits. Because male behaviors were correlated with each other, we conducted a principal components analysis on the correlations and ran subsequent analyses on the principal components. The two male ecotypes differed in overall behavioral frequencies, with stream-resident males exhibiting consistently more vigorous and positive courtship than anadromous males, and an otherwise aggressive behavior playing a more positive role in anadromous than stream-resident courtship. We observed more vigorous courtship toward smaller females by (relatively small) stream-resident males and the reverse pattern for (relatively large) anadromous males. Thus size-assortative male courtship preferences may contribute to reproductive isolation in this system, although preferences are far from absolute. We found little indication of males responding preferentially to females of their own ecotype independent of body size