Visuospatial memory in apraxia: Exploring quantitative drawing metrics to assess the representation of local and global information.

Neuropsychological evidence suggests that visuospatial memory is subserved by two separable processing systems, with dorsal underpinnings for global form and ventral underpinnings for the integration of part elements. Previous drawing studies have explored the effects of Gestalt organisation upon memory for hierarchical stimuli, and we here present an exploratory study of an apraxic dorsal stream patient's (MH) performance. We presented MH with a stimulus set (previously reported by Riddoch et al., Cognitive Neuropsychology, 20(7), 641-671, 2003) and devised a novel quantitative scoring system to obtain a finer grain of insight into performance. Stimuli possessed either good or poor Gestalt qualities and were reproduced in a copy condition and two visual memory conditions (with unlimited viewing before the model was removed, or with 3 s viewing). MH's copying performance was impaired in comparison to younger adult and age-matched older adult controls, with a variety of errors at the local level but relatively few at the global level. However, his performance in the visual memory conditions revealed impairments at the global level. For all participants, drawing errors were modulated by the Gestalt qualities of the stimuli, with accuracy at the global and local levels being lesser for poor global stimuli in all conditions. These data extend previous observations of this patient, and support theories that posit interaction between dorsal and ventral streams in the representation of hierarchical stimuli. We discuss the implications of these findings for our understanding of visuospatial memory in neurological patients, and also evaluate the application of quantitative metrics to the interpretation of drawings.

YY1 Binding to Regulatory Elements That Lack Enhancer Activity Promotes Locus Folding and Gene Activation.

Enhancers activate their cognate promoters over huge distances but how enhancer/promoter interactions become established is not completely understood. There is strong evidence that cohesin-mediated loop extrusion is involved but this does not appear to be a universal mechanism. Here, we identify an element within the mouse immunoglobulin lambda (Igλ) light chain locus, HSCλ1, that has characteristics of active regulatory elements but lacks intrinsic enhancer or promoter activity. Remarkably, knock-out of the YY1 binding site from HSCλ1 reduces Igλ transcription significantly and disrupts enhancer/promoter interactions, even though these elements are >10 kb from HSCλ1. Genome-wide analyses of mouse embryonic stem cells identified 2671 similar YY1-bound, putative genome organizing elements that lie within CTCF/cohesin loop boundaries but that lack intrinsic enhancer activity. We suggest that such elements play a fundamental role in locus folding and in facilitating enhancer/promoter interactions.

A human genome editing-based MLL::AF4 ALL model recapitulates key cellular and molecular leukemogenic features.

Cellular ontogeny and MLL breakpoint site influence the capacity of MLL-edited CD34+ hematopoietic cells to initiate and recapitulate infant patients' features in pro-B-cell acute lymphoblastic leukemia (B-ALL). We provide key insights into the leukemogenic determinants of MLL-AF4+ infant B-ALL.

Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia.

In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties.

Potential for natural attenuation of crude oil hydrocarbons in benthic microbiomes near coastal communities in Kivalliq, Nunavut, Canada.

Oil spilled in marine environments can settle to the seafloor through aggregation and sedimentation processes. This has been predicted to be especially relevant in the Arctic due to plankton blooms initiated by melting sea ice. These conditions exist in the Kivalliq region in Nunavut, Canada, where elevated shipping traffic has increased the risk of accidental spills. Experimental microcosms combining surface sediment and crude oil were incubated at 4 °C over 21 weeks to evaluate the biodegradation potential of seabed microbiomes. Sediments sampled near the communities of Arviat and Chesterfield Inlet were assessed for biodegradation capabilities by combining hydrocarbon geochemistry with 16S rRNA gene and metagenomic sequencing, revealing decreased microbial diversity but enrichment of oil-degrading taxa. Alkane and aromatic hydrocarbon losses corresponded to detection of genes and genomes that encode enzymes for aerobic biodegradation of these compounds, pointing to the utility of marine microbiome surveys for predicting the fate of oil released into Arctic marine environments.

Temporal analyses reveal a pivotal role for sense and antisense enhancer RNAs in coordinate immunoglobulin lambda locus activation.

Transcription enhancers are essential activators of V(D)J recombination that orchestrate non-coding transcription through complementary, unrearranged gene segments. How transcription is coordinately increased at spatially distinct promoters, however, remains poorly understood. Using the murine immunoglobulin lambda (Igλ) locus as model, we find that three enhancer-like elements in the 3' Igλ domain, Eλ3-1, HSCλ1 and HSE-1, show strikingly similar transcription factor binding dynamics and close spatial proximity, suggesting that they form an active enhancer hub. Temporal analyses show coordinate recruitment of complementary V and J gene segments to this hub, with comparable transcription factor binding dynamics to that at enhancers. We find further that E2A, p300, Mediator and Integrator bind to enhancers as early events, whereas YY1 recruitment and eRNA synthesis occur later, corresponding to transcription activation. Remarkably, the interplay between sense and antisense enhancer RNA is central to both active enhancer hub formation and coordinate Igλ transcription: Antisense Eλ3-1 eRNA represses Igλ activation whereas temporal analyses demonstrate that accumulating levels of sense eRNA boost YY1 recruitment to stabilise enhancer hub/promoter interactions and lead to coordinate transcription activation. These studies therefore demonstrate for the first time a critical role for threshold levels of sense versus antisense eRNA in locus activation.

MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia.

Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.

Hydrocephalus: A neuropsychological and theoretical primer.

Hydrocephalus is a common neurological condition, the hallmark feature of which is an excess in production, or accumulation, of cerebrospinal fluid in the ventricles. Although it is associated with diffuse damage to paraventricular brain areas, patients are broadly typified by a particular pattern of cognitive impairments that include deficits in working memory, attention, and spatial abilities. There have, however, been relatively few neuropsychological accounts of the condition. Moreover, theories of the relationship between aetiology and impairment appear to have emerged in isolation of each other, and proffer fundamentally different accounts. In this primer, we aim to provide a comprehensive and contemporary overview of hydrocephalus for the neuropsychologist, covering cognitive sequelae and theoretical interpretations of their origins. We review clinical and neuropsychological assays of cognitive profiles, along with the few studies that have addressed more integrative behaviours. In particular, we explore the distinction between congenital or early-onset hydrocephalus with a normal-pressure variant that can be acquired later in life. The relationship between these two populations is a singularly interesting one in neuropsychology since it can allow for the examination of typical and atypical developmental trajectories, and their interaction with chronic and acute impairment, within the same broad neurological condition. We reflect on the ramifications of this for our subject and suggest avenues for future research.

The developmental trajectories of children's reorientation to global and local properties of environmental geometry.

The way in which organisms represent the shape of their environments during navigation has been debated in cognitive, comparative, and developmental psychology. While there is evidence that adult humans encode the entire boundary shape of an environment (a global-shape representation), there are also data demonstrating that organisms reorient using only segments of the boundary that signal a goal location (a local-shape representation). Developmental studies offer unique insights into this debate; however, most studies have used designs that cannot dissociate the type of boundary-shape representation that children use to guide reorientation. Thus, we examined the developmental trajectories of children's reorientation according to local and global boundary shape. Participants aged 6-12 years were trained to find a goal hidden in one corner of a virtual arena, after which they were required to reorient in a novel test arena. From 10.5 years, children performed above chance when the test arena permitted reorientation based only on local-shape (Experiment 2), or only global-shape (Experiment 3) information. Moreover, when these responses were placed into conflict, older children reoriented with respect to global-shape information (Experiment 4). These age-related findings were not due to older children being better able to reorient in virtual environments per se: when trained and tested within the same environment (Experiment 1), children performed above chance from 6 years. Together, our results suggest (a) the ability to reorient on the basis of global- and local-shape representations develops in parallel, and (b) shape-based information is weighted to determine which representation informs reorientation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Redefinition of Fatty Liver Disease from NAFLD to MAFLD through the Lens of Drug Development and Regulatory Science.

Metabolic (dysfunction)-associated fatty liver disease (MAFLD) affects a third of the population and is a leading cause of liver-related death. Since no effective treatments exist, novel approaches to drug development are required. Unfortunately, outdated terminology and definitions of the disease are hampering efforts to develop new drugs and treatments. An international consensus panel has put forth an influential proposal for the disease to be renamed from nonalcoholic fatty liver disease (NAFLD) to MAFLD, including a proposal for how the disease should be diagnosed. As allies with the many stakeholders in MAFLD care-including patients, patients' advocates, clinicians, researchers, nurse and allied health groups, regional societies, and others-we are aware of the negative consequences of the NAFLD term and definition. We share the sense of urgency for change and will act in new ways to achieve our goals. Although there is much work to be done to overcome clinical inertia and reverse worrisome recent trends, the MAFLD initiative provides a firm foundation to build on. It provides a roadmap for moving forward toward more efficient care and affordable, sustainable drug and device innovation in MAFLD care. We hope it will bring promising new opportunities for a brighter future for MAFLD care and improve care and outcomes for patients of one of the globe's largest and costliest public health burdens. From this viewpoint, we have revisited this initiative through the perspectives of drug development and regulatory science.

Capture-C: a modular and flexible approach for high-resolution chromosome conformation capture.

Chromosome conformation capture (3C) methods measure the spatial proximity between DNA elements in the cell nucleus. Many methods have been developed to sample 3C material, including the Capture-C family of protocols. Capture-C methods use oligonucleotides to enrich for interactions of interest from sequencing-ready 3C libraries. This approach is modular and has been adapted and optimized to work for sampling of disperse DNA elements (NuTi Capture-C), including from low cell inputs (LI Capture-C), as well as to generate Hi-C like maps for specific regions of interest (Tiled-C) and to interrogate multiway interactions (Tri-C). We present the design, experimental protocol and analysis pipeline for NuTi Capture-C in addition to the variations for generation of LI Capture-C, Tiled-C and Tri-C data. The entire procedure can be performed in 3 weeks and requires standard molecular biology skills and equipment, access to a next-generation sequencing platform, and basic bioinformatic skills. Implemented with other sequencing technologies, these methods can be used to identify regulatory interactions and to compare the structural organization of the genome in different cell types and genetic models.

Searching for individual determinants of probabilistic cueing in large-scale immersive virtual environments.

Large-scale search behaviour is an everyday occurrence, yet its underlying mechanisms are not commonly examined within experimental psychology. Key to efficient search behaviour is the sensitivity to environmental cues that might guide exploration, such as a target appearing with greater regularity in one region than another. Spatial cueing by probability has been examined in visual search paradigms, but the few studies that have addressed its contribution to large-scale search and foraging present contrasting accounts of the conditions under which a cueing effect can be reliably observed. In the present study, participants physically searched a virtual arena by inspecting identical locations until they found the target. The target was always present, although its location was probabilistically defined so that it appeared in the cued hemispace on 80% of trials. In Experiment 1, when participants' starting positions were stable, a probabilistic cueing effect was observed, with a strong bias towards searching the cued side. In Experiment 2, the starting position changed across the experiment, such that the cued region was defined in allocentric co-ordinates only. In this case, a probabilistic cueing effect was not observed across the sample. Analysis of individual differences in Experiment 2 suggests, however, that some participants may have learned the contingency underpinning the target's location, although these differences were unrelated to other tests of visuospatial ability. These results suggest that the ability to learn the likelihood of an item's fixed location when starting from different perspectives is driven by individual differences in other cognitive or perceptual factors.

Sources of variation in search and foraging: A theoretical perspective.

Search-the problem of exploring a space of alternatives to identify target goals-is a fundamental behaviour for many species. Although its foundation lies in foraging, most studies of human search behaviour have been directed towards understanding the attentional mechanisms that underlie the efficient visual exploration of two-dimensional (2D) scenes. With this review, we aim to characterise how search behaviour can be explained across a wide range of contexts, environments, spatial scales, and populations, both typical and atypical. We first consider the generality of search processes across psychological domains. We then review studies of interspecies differences in search. Finally, we explore in detail the individual and contextual variables that affect visual search and related behaviours in established experimental psychology paradigms. Despite the heterogeneity of the findings discussed, we identify that variations in control processes, along with the ability to regulate behaviour as a function of the structure of search space and the sampling processes adopted, to be central to explanations of variations in search behaviour. We propose a tentative theoretical model aimed at integrating these notions and close by exploring questions that remain unaddressed.

Room to breathe: Using adaptive architecture to examine the relationship between alexithymia and interoception.

OBJECTIVE: Individuals with alexithymia experience difficulties interpreting emotional states in self and others, which has been associated with interoceptive impairment. Current theories are primarily based on subjective and conscious measures of interoceptive sensitivity, such as heartrate detection, but it is unclear whether similar observations would be found for objective or implicit psychophysiological measures. The present exploratory study assesses the potential of a novel assay through the use of adaptive immersive architecture [ExoBuilding]. METHODS: N = 88 participants were screened for alexithymic traits and N = 27 individuals, representing the range of scores, were sampled to participate in the behavioural task. In a repeated-measures design, participants were placed within ExoBuilding and asked to match their respiration to its movement. Performance was compared to a two-dimensional pacer condition. Behavioural (accuracy) and psychophysiological (Respiratory Sinus Arrhythmia [RSA] and heartrate) measures were compared across conditions, and also related to individual alexithymic traits. RESULTS: Participants with higher levels of alexithymia performed less accurately than participants with lower levels, in both conditions. High-alexithymia participants showed a smaller reduction in heartrate over the course of the ExoBuilding condition than low-alexithymia participants, although there were no differences in RSA between conditions or participants. CONCLUSION: Alexithymia extends beyond conscious interoceptive activities and is also observed in immersive contexts that usually exert psychophysiological effects on typical occupants. These initial findings highlight the importance of considering both conscious and implicit measures of interoception, and we suggest ways in which theories of alexithymia might benefit from capturing this distinction.

Paediatric playground and tree-related injuries: Hospital admissions in the Midland region of New Zealand.

AIM: To examine the incidence and outcomes of paediatric playground and tree-related injuries in the Midland region of New Zealand. METHODS: A retrospective review of Midland Trauma Registry hospitalisation data between January 2012 and December 2018 was undertaken. Cases included children aged 0-14 years hospitalised for playground and tree-related injuries. Demographic and event information, injury severity and hospital-related outcomes were examined. RESULTS: Playground and tree-related hospitalisations (n = 1941) occurred with an age-standardised rate of 144.3/100 000 (confidence interval (CI) 127.3-161.3) and increased 1.4% (CI 1.3-4.2%) annually. The highest incidence was observed in 5-9-year olds (248.8/100 000) with 0-4 and 10-14-year olds at 86.0 and 89.2/100 000, respectively. Injuries most commonly occurred at home, school or pre-school (77.1%), 93.7% were due to falls and, the upper extremity was the most frequently injured body region (69.9%), particularly due to forearm (55.6%) and upper arm (34.7%) fractures. Tree-related incidents comprised 11.6% of all injuries and explained 57.1% of injuries classified as major severity. Fifty-eight percent of children were hospitalised for 1 day and 97.0% for less than 5 days. Estimated hospital costs were NZ$1.2 million annually with a median of NZ$3898 per incident. Injuries classified as minor severity accounted for 86.5% of the total estimated cost. CONCLUSION: Children aged 5-9 years' experience high rates of costly hospitalisation for playground and tree-related injuries. Targeted injury prevention initiatives, particularly in the home and school environments, are imperative to reduce the incidence and burden of playground and tree-related injuries to affected children, their families and hospital resources.

Blood alcohol screening and outcomes in trauma team activation patients at a level 1 trauma centre in New Zealand.

OBJECTIVE: A causal relationship between alcohol consumption and injury exists and the prevalence of harmful alcohol intakes in New Zealand adults is high. The present study investigates compliance to blood alcohol (BA) screening policy and the epidemiological profile and hospital-related outcomes of trauma team activation (TTA) patients with positive BA at a New Zealand level 1 trauma centre. METHODS: A retrospective review of Midland Trauma Registry hospitalisation data between January 2012 and December 2019 was conducted. Eligible patients (n = 2168) were ≥15 years who received TTA at Waikato Hospital. BA screening rates, demographic and event information, injury severity and hospital-related outcomes were examined. RESULTS: The average BA screening rate was 94.0% (95% confidence interval 92.9-95.0%) and 17.9% of screened patients were BA+ . BA+ patients were younger than BA- (34.7 and 40.5 years, P < 0.0001). More males than females (20.6 and 12.4%, P < 0.0001), Maori (30.8%) compared to non-Maori (<16.0%) and unemployed/beneficiaries (33.4%) compared to employed patients (15.5%) were BA+ . Road transport crashes accounted for the highest proportion (45.2%) but, in comparison there were higher odds of BA+ from interpersonal violence (odds ratio 4.48, P < 0.0001). No difference between BA+ and BA- was observed in survival rate, injury severity scores, length of intensive care and total hospital stay. CONCLUSION: Between 2012 and 2019, Waikato Hospital demonstrated high compliance to BA screening policy for TTA patients. Appropriate alcohol awareness initiatives that focus on road safety and interpersonal violence are required to reduce the preventable prevalence and burden of alcohol-related trauma in the Waikato region.

Photooxidation and biodegradation potential of a light crude oil in first-year sea ice.

Disappearing sea ice in the Arctic region results in a pressing need to develop oil spill mitigation techniques suitable for ice-covered waters. The uncertainty around the nature of an oil spill in the Arctic arises from the ice-covered waters and sub-zero temperatures, and how they may influence natural attenuation efficiency. The Sea-ice Environmental Research Facility was used to create a simulated Arctic marine setting. This paper focuses on the potential for biodegradation of the bulk crude oil content (encapsulated in the upper regions of the ice), to provide insight regarding the possible fate of crude oil in an Arctic marine setting. Cheaper and faster methods of chemical composition analysis were applied to the samples to assess for weathering and transformation effects. Results suggest that brine volume in ice may not be sufficient at low temperatures to encompass biodegradation and that seawater is more suitable for biodegradation.

A novel class of sulfur-containing aminolipids widespread in marine roseobacters.

Marine roseobacter group bacteria are numerically abundant and ecologically important players in ocean ecosystems. These bacteria are capable of modifying their membrane lipid composition in response to environmental change. Remarkably, a variety of lipids are produced in these bacteria, including phosphorus-containing glycerophospholipids and several amino acid-containing aminolipids such as ornithine lipids and glutamine lipids. Here, we present the identification and characterization of a novel sulfur-containing aminolipid (SAL) in roseobacters. Using high resolution accurate mass spectrometry, a SAL was found in the lipid extract of Ruegeria pomeroyi DSS-3 and Phaeobacter inhibens DSM 17395. Using comparative genomics, transposon mutagenesis and targeted gene knockout, we identified a gene encoding a putative lyso-lipid acyltransferase, designated salA, which is essential for the biosynthesis of this SAL. Multiple sequence analysis and structural modeling suggest that SalA is a novel member of the lysophosphatidic acid acyltransferase (LPAAT) family, the prototype of which is the PlsC acyltransferase responsible for the biosynthesis of the phospholipid phosphatidic acid. SAL appears to play a key role in biofilm formation in roseobacters. salA is widely distributed in Tara Oceans metagenomes and actively expressed in Tara Oceans metatranscriptomes. Our results raise the importance of sulfur-containing membrane aminolipids in marine bacteria.