Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Do adults with high functioning autism or Asperger Syndrome differ in empathy and emotion recognition?

The present study examined whether adults with high functioning autism (HFA) showed greater difficulties in (i) their self-reported ability to empathise with others and/or (ii) their ability to read mental states in others’ eyes than adults with Asperger syndrome (AS). The Empathy Quotient (EQ) and ‘Reading the Mind in the Eyes’ Test (Eyes Test) were compared in 43 adults with AS and 43 adults with HFA. No significant difference was observed on EQ score between groups, while adults with AS performed significantly better on the Eyes Test than those with HFA. This suggests that adults with HFA may need more support, particularly in mentalizing and complex emotion recognition, and raises questions about the existence of subgroups within autism spectrum conditions

From Fan Parks to Live Sites: Mega events and the territorialisation of urban space

This article draws on the work of Gilles Deleuze and Felix Guattari to consider the phenomenon of Live Sites and Fan Parks which are now enshrined within the viewing experience of mega sports events. Empirically, the article draws upon primary research on Live Sites generated during the London 2012 Olympic Games. Live Sites are represented as new spaces within which to critically locate and conceptually explore the shifting dynamics of urban space, subjectivity and its performative politic. The authors argue that the first, or primary, spaces of mega sporting events (the official venues) and their secondary counterparts (Live Sites) simply extend brandscaping tendencies but that corporate striation is always incomplete, opening up possibilities for disruption and dislocation

Nonsense-mediated mRNA decay efficiency varies in choroideremia providing a target to boost small molecule therapeutics

Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC). Nonsense mediated decay (NMD) is the cell's natural surveillance mechanism, that detects and destroys PTC containing transcripts, with UPF1 being the central NMD modulator. NMD efficiency can be variable amongst individuals with some transcripts escaping destruction, leading to the production of a truncated non-functional or partially functional protein. Nonsense suppression drugs, such as ataluren, target these transcripts and read-through the PTC, leading to the production of a full length functional protein. Patients with higher transcript levels are considered to respond better to these drugs, as more substrate is available for read-through. Using RT-qPCR, we show that CHM mRNA expression in blood from nonsense mutation CHM patients is 2.8-fold lower than controls, and varies widely amongst patients, with 40% variation between those carrying the same UGA mutation (c.715 C > T; p.[R239*]). These results indicate that although NMD machinery is at work, efficiency is highly variable and not wholly dependent on mutation position. No significant difference in CHM mRNA levels was seen between two patients' fibroblasts and their iPSC-derived RPE. There was no correlation between CHM mRNA expression and genotype, phenotype or UPF1 transcript levels. NMD inhibition with caffeine was shown to restore CHM mRNA transcripts to near wildtype levels. Baseline mRNA levels may provide a prognostic indicator for response to nonsense suppression therapy, and caffeine may be a useful adjunct to enhance treatment efficacy where indicated

Action Experience and Action Discovery in Medicated Individuals with Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that markedly affects voluntary action. While regular dopamine treatment can help restore motor function, dopamine also influences cognitive portions of the action system. Previous studies have demonstrated that dopamine medication boosts action-effect associations, which are crucial for the discovery of new voluntary actions. In the present study, we investigated whether neural processes involved in the discovery of new actions are altered in PD participants on regular dopamine treatment, compared to healthy age-matched controls. We recorded brain electroencephalography (EEG) activity while PD patients and age-matched controls performed action discovery (AD) and action control tasks. We found that the novelty P3, a component normally present when there is uncertainty about the occurrence of the sensory effect, was enhanced in PD patients. However, AD was maintained in PD patients, and the novelty P3 demonstrated normal learning-related reductions. Crucially, we found that in PD patients the causal association between an action and its resulting sensory outcome did not modulate the amplitude of the feedback correct-related positivity (fCRP), an EEG component sensitive to the association between an action and its resulting effect. Collectively, these preliminary results suggest that the formation of long-term action-outcome representations may be maintained in PD patients on regular dopamine treatment, but the initial experience of action-effect association may be affected

Atypical processing of gaze cues and faces explains comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD)

This study investigated the neurobiological basis of comorbidity between autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). We compared children with ASD, ADHD or ADHD+ASD and typically developing controls (CTRL) on behavioural and electrophysiological correlates of gaze cue and face processing. We measured effects of ASD, ADHD and their interaction on the EDAN, an ERP marker of orienting visual attention towards a spatially cued location and the N170, a right-hemisphere lateralised ERP linked to face processing. We identified atypical gaze cue and face processing in children with ASD and ADHD+ASD compared with the ADHD and CTRL groups. The findings indicate a neurobiological basis for the presence of comorbid ASD symptoms in ADHD. Further research using larger samples is needed

Estimated generic prices for novel treatments for drug resistant tuberculosis

Background: Estimated annual incidence of MDR-TB is 480,000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or re-purposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course. Objectives: To estimate generic prices for novel TB drugs that would be possible given large-scale competitive manufacture. Methods: Prices for linezolid, moxifloxacin, and clofazimine were estimated based on per-kilogram prices of active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The costs of projection for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarit y. Generic prices for bedaquiline, delamanid, and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis, and per-step yields. Costing algorithms reflected variable regulatory requirements, efficiency of scale based on demand, and were validated by testing predictive ability against widely-available TB medicines. Results: Estimated generic prices were USD $8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$3 /month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine, and $4-$8/month for moxifloxacin. Estimated generic prices were 87%-94% lower than current lowest available prices for bedaquiline, 95%-98% for delamanid, 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current cost s $734-$1,799), $53-$276 for pretomanid-based three-drug regimens, and $238-$507 for a delamanid-based four-drug regimen. Conclusions: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets

Reconsidering the New Normal: Trauma, Vulnerability & Resilience in Post-Katrina New Orleans

Traumatic anthropogenic or natural disasters can redefine the ecological and social diversity of cities, with "new normal" conditions often emerging in post-trauma urban landscapes. The objective of our ULTRA project is to examine how the pace and trajectory of recovery in post-Katrina New Orleans reflect ecological and social diversity. Specifically, we are examining potential parallels and interactions between ecological and social diversity within and among neighborhoods, and across the New Orleans metropolitan area. We are doing so by (1) organizing and coordinating a network of scholars and practitioners to exchange experience and knowledge and thereby advance understanding of connections between diversity and recovery in post-trauma urban ecosystems; (2) assembling a central data archive on the structure and diversity of ecological communities of New Orleans, which involves conducting an inventory of the post-Katrina urban forest; (4) and conducting a GIS-based spatial analysis of pre- and post-trauma landscape and social metrics derived from satellite imagery and the 2000 and 2010 federal census, analyzed for diversification and compared to stabilization metrics. This citywide study is being supplemented with three fine-grained studies in the neighborhoods of the Lower Ninth Ward, Hollygrove, and Pontchartrain Park. Qualitative data collected in these neighborhoods provides insight into the relationships between trauma and ecological and social diversity, and identify variation in the timing, pace, and trajectory of neighborhood recovery. In the future, we will expand our efforts to consider how diversity reflects the availability and valuation of ecosystem services in post-trauma urban landscapes. Our intent is to develop New Orleans as a natural laboratory for the study of ecological and community resiliency

The relationship between early neural responses to emotional faces at age 3 and later autism and anxiety symptoms in adolescents with autism

Both autism spectrum (ASD) and anxiety disorders are associated with atypical neural and attentional responses to emotional faces, differing in affective face processing from typically developing peers. Within a longitudinal study of children with ASD (23 male, 3 female), we hypothesized that early ERPs to emotional faces would predict concurrent and later ASD and anxiety symptoms. Greater response amplitude to fearful faces corresponded to greater social communication difficulties at age 3, and less improvement by age 14. Faster ERPs to neutral faces predicted greater ASD symptom improvement over time, lower ASD severity in adolescence, and lower anxiety in adolescence. Early individual differences in processing of emotional stimuli likely reflect a unique predictive contribution from social brain circuitry early in life

A conserved loop-wedge motif moderates reaction site search and recognition by FEN1

DNA replication and repair frequently involve intermediate two-way junction structures with overhangs, or flaps, that must be promptly removed; a task performed by the essential enzyme flap endonuclease 1 (FEN1). We demonstrate a functional relationship between two intrinsically disordered regions of the FEN1 protein, which recognise opposing sides of the junction and order in response to the requisite substrate. Our results inform a model in which short-range translocation of FEN1 on DNA facilitates search for the annealed 3′‑terminus of a primer strand, which is recognised by breaking the terminal base pair to generate a substrate with a single nucleotide 3′‑flap. This recognition event allosterically signals hydrolytic removal of the 5′-flap through reaction in the opposing junction duplex, by controlling access of the scissile phosphate diester to the active site. The recognition process relies on a highly-conserved ‘wedge’ residue located on a mobile loop that orders to bind the newly-unpaired base. The unanticipated ‘loop–wedge’ mechanism exerts control over substrate selection, rate of reaction and reaction site precision, and shares features with other enzymes that recognise irregular DNA structures. These new findings reveal how FEN1 precisely couples 3′-flap verification to function