UNG2 and RPA Activity on ssDNA-dsDNA Junctions

Uracil DNA glycosylase, or UNG2, is an enzyme that is involved in DNA repair. Its primary job is to eliminate harmful uracil bases from DNA strands. To do this, the enzyme is assisted by replication protein A (RPA). RPA helps UNG2 in the identification of uracil bases by targeting UNG2 activity near ssDNA-dsDNA junctions (1-3). The results from assays presented here agree with published findings that showed UNG2 is heavily targeted by RPA to uracil bases that are close to ssDNA-dsDNA junctions (for example, uracil located 9 bps from the junction as opposed to 33 bps) (1,2). However, these previous experiments were performed in the absence of a macromolecular crowding agent. Inert compounds such as PEG8K can be used experimentally to better represent the physiologic environment inside a cell, which is very crowded with proteins and other small molecules and differs from dilute conditions often used in enzyme assays. In the presence of a crowding agent (PEG8K), we found that RPA balances UNG2’s selectivity for uracil sites near ssDNA-dsDNA junctions that contain a 5’ ssDNA section. In other words, UNG2 becomes less targeted to uracils that are very close to the junction (i.e., U9). Interestingly, this effect was not seen when we examined RPA effects on UNG2 activity using ssDNA-dsDNA junctions substrates that contain a 3’ ssDNA section

Brain structural correlates of functional capacity in first-episode psychosis

Impaired functional capacity is a core feature of schizophrenia and presents even in first-episode psychosis (FEP) patients. Impairments in daily functioning tend to persist despite antipsychotic therapy but their neural basis is less clear. Previous studies suggest that volume loss in frontal cortex might be an important contributor, but findings are inconsistent. We aimed to comprehensively investigate the brain structural correlates of functional capacity in FEP using MRI and a reliable objective measure of functioning [University of California, San Diego Performance-Based Skills Assessment (UPSA)]. In a sample of FEP (n = 39) and a well-matched control group (n = 21), we measured cortical thickness, gray matter volume, and white matter tract integrity (fractional anisotropy, FA) within brain regions implicated by previous work. The FEP group had thinner cortex in various frontal regions and fusiform, and reduced FA in inferior longitudinal fasciculus (ILF). In FEP, poorer functional capacity correlated with reduced superior frontal volume and lower FA in left ILF. Importantly, frontal brain volumes and integrity of the ILF were identified as the structural correlates of functional capacity in FEP, controlling for other relevant factors. These findings enhance mechanistic understanding of functional capacity deficits in schizophrenia by specifying the underlying neural correlates. In future, this could help inform intervention strategies

Perceptual biases and metacognition and their association with anomalous self experiences in first episode psychosis

Anomalous self-experiences have been described as a prerequisite for anomalous perceptual experiences. Later, these anomalous perceptual experiences may then be metacognitively appraised as distressing, maintaining these experiences and later leading to anomalous (delusional) beliefs. This model of anomalous events may potentially be driven by perceptual biases and metacognitive deficits. This cross-sectional study explored the association between perceptual biases, metacognition and anomalous self- and perceptual experiences and delusional beliefs in First Episode Psychosis (FEP) and a matched healthy control sample. Fifty-eight individuals with FEP and seventy-two healthy controls were included in the main analysis. Increased auditory perceptual biases were significantly associated with increased state and trait anomalous self-experiences, in particular alienation from surroundings and emotional numbing. No significant associations were found between metacognitive efficiency and anomalous experiences. These findings may be consistent with the minimal self-disturbance model of schizophrenia spectrum vulnerability, particularly with the hyperreflexivity concept

Bridging the digital divide in psychological therapies: observational study of engagement with the SlowMo mobile app for paranoia in psychosis

Background: Marginalized groups are more likely to experience problems with technology-related access, motivation, and skills. This is known as the “digital divide.” Technology-related exclusion is a potential barrier to the equitable implementation of digital health. SlowMo therapy was developed with an inclusive, human-centered design to optimize accessibility and bridge the “digital divide.” SlowMo is an effective, blended digital psychological therapy for paranoia in psychosis. Objective: This study explores the “digital divide” and mobile app engagement in the SlowMo randomized controlled trial. Methods: Digital literacy was assessed at baseline, and a multidimensional assessment of engagement (ie, adherence [via system analytics and self-report] and self-reported user experience) was conducted at 12 weeks after therapy. Engagement was investigated in relation to demographics (ie, gender, age, ethnicity, and paranoia severity). Results: Digital literacy data demonstrated that technology use and confidence were lower in Black people and older people (n=168). The engagement findings indicated that 80.7% (96/119) of therapy completers met the a priori analytics adherence criteria. However, analytics adherence did not differ by demographics. High rates of user experience were reported overall (overall score: mean 75%, SD 17.1%; n=82). No differences in user experience were found for ethnicity, age, or paranoia severity, although self-reported app use, enjoyment, and usefulness were higher in women than in men. Conclusions: This study identified technology-related inequalities related to age and ethnicity, which did not influence engagement with SlowMo, suggesting that the therapy design bridged the “digital divide.” Intervention design may moderate the influence of individual differences on engagement. We recommend the adoption of inclusive, human-centered design to reduce the impact of the “digital divide” on therapy outcomes

The Lantern Vol. 55, No. 2, Spring 1989

• Sitting On a Summer Bench • A Perfect Daughter I Could Never Be • Roots And Wings • Sensai • The Last Three Weeks of August • Grown Up • What Size? • Hidden Colors • Victims • I Listen for Your Voice • Thoughts • In Remembrance of Grandpa • Jesus Christ, Terry • Penance • The Guys Are Driving High • You and Me and Big Ginko • The Good Ole Days of Seventh Grade • Cycles • Leather Upholstery • Chicago Kris in Cairo • Lemonade and Medicine • My Last 7:15 Communionhttps://digitalcommons.ursinus.edu/lantern/1134/thumbnail.jp

Highlights of children with Cancer UK’s workshop on drug delivery in paediatric brain tumours

The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood–brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Regulation of type 1 diabetes development and B-cell activation in nonobese diabetic mice by early life exposure to a diabetogenic environment

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D

A community-based geological reconstruction of Antarctic Ice Sheet deglaciation since the Last Glacial Maximum

A robust understanding of Antarctic Ice Sheet deglacial history since the Last Glacial Maximum is important in order to constrain ice sheet and glacial-isostatic adjustment models, and to explore the forcing mechanisms responsible for ice sheet retreat. Such understanding can be derived from a broad range of geological and glaciological datasets and recent decades have seen an upsurge in such data gathering around the continent and Sub-Antarctic islands. Here, we report a new synthesis of those datasets, based on an accompanying series of reviews of the geological data, organised by sector. We present a series of timeslice maps for 20ka, 15ka, 10ka and 5ka, including grounding line position and ice sheet thickness changes, along with a clear assessment of levels of confidence. The reconstruction shows that the Antarctic Ice sheet did not everywhere reach the continental shelf edge at its maximum, that initial retreat was asynchronous, and that the spatial pattern of deglaciation was highly variable, particularly on the inner shelf. The deglacial reconstruction is consistent with a moderate overall excess ice volume and with a relatively small Antarctic contribution to meltwater pulse 1a. We discuss key areas of uncertainty both around the continent and by time interval, and we highlight potential priorit. © 2014 The Authors