Constraint Treatment for Chronic Aphasia: Do Treatment Gains Generalize to Story Retelling?

The current investigation included 8 participants with aphasia of greater than 3 years duration in Constraint-Induced Language Therapy (CILT). We sought to determine if CILT treatment gains generalized to Narrative Story Card (Helm-Estabrooks & Nicholas, 2003) retelling. We examined two outcome measures, number words produced and content information units, to determine whether quantity of language, quality of language, or both increased with CILT. Although CILT was beneficial to people with chronic aphasia, gains made in treatment generalized only modestly to Narrative Story Card retelling for most participants. Performance across individuals was quite variable and was not well-characterized by group performance

A purely kinetic description of the evaporation of water droplets

The process of water evaporation, although deeply studied, does not enjoy a kinetic description that captures known physics and can be integrated with other detailed processes such as drying of catalytic membranes embedded in vapor-fed devices and chemical reactions in aerosol whose volumes are changing dynamically. In this work, we present a simple, three-step kinetic model for water evaporation that is based on theory and validated by using well-established thermodynamic models of droplet size as a function of time, temperature, and relative humidity as well as data from time-resolved measurements of evaporating droplet size. The kinetic mechanism for evaporation is a combination of two limiting processes occurring in the highly dynamic liquid-vapor interfacial region: direct first order desorption of a single water molecule and desorption resulting from a local fluctuation, described using third order kinetics. The model reproduces data over a range of relative humidities and temperatures only if the interface that separates bulk water from gas phase water has a finite width, consistent with previous experimental and theoretical studies. The influence of droplet cooling during rapid evaporation on the kinetics is discussed; discrepancies between the various models point to the need for additional experimental data to identify their origin

Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification

AbstractWomen heterozygous for mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2 have a highly elevated risk of developing breast cancer [1]. BRCA1 and BRCA2 encode large proteins with no sequence similarity to one another. Although involvement in DNA repair and transcription has been suggested, it is still not understood how loss of function of these genes leads to breast cancer [2]. Embryonic fibroblasts (MEFs) derived from mice homozygous for a hypomorphic mutation (Brca2Tr2014) within the 3′ region of exon 11 in Brca2[3], or a similar mutation (Brca2Tr) [4], proliferate poorly in culture and overexpress the tumour suppressor p53 and the cyclin-dependent kinase inhibitor p21Waf1/Cip1. These MEFs have intact p53-dependent DNA damage G1–S [3,4] and G2–M checkpoints [4], but are impaired in DNA double-strand break repair [3] and develop chromosome aberrations [4]. Here, we report that Brca2Tr2014/Tr2014 MEFs frequently develop micronuclei. These abnormal DNA-containing bodies were formed through both loss of acentric chromosome fragments and by chromosome missegregation, which resulted in aneuploidy. Absence of Brca2 also led to centrosome amplification, which we found associated with the formation of micronuclei. These data suggest a potential mechanism whereby loss of BRCA2 may, within subclones, drive the loss of cell-cycle regulation genes, enabling proliferation and tumourigenesis

Engaging Healthcare Users through Gamification in Knowledge Sharing of Continuous Improvement in Healthcare

Knowledge management systems are key for capturing, retaining, and communicating results from projects and presenting information to staff. The purpose of a knowledge management system is to tap into the vast wisdom from projects and experts across an organization. This research focuses on the knowledge management system within the Veterans Health Administration that was developed as a repository of information on continuous improvement tools such as flowcharts, value stream mapping, 5S, and the application of these in healthcare projects. The use of social network analysis and gamification improves website organization, user participation, and dissemination of shared knowledge related to continuous improvement of operations. The purpose of gamification is to engage, teach, entertain, measure, and improve the ease of use of information systems. The goal of this research is to utilize gamification theory within the knowledge management system to drive behaviors in a targeted audience and engage users in aspects such as writing, contributing, getting the feedback, which will create a more robust, cohesive system. A thorough review of the current knowledge management system was conducted, and a gap analysis was performed comparing the goals and objectives for the system to the current results. Next, gamification techniques with the potential to improve performance were identified and strategies to implement these were developed

Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.We thank the CRUK—CI Genomics, BRU, and Bioinformatics Cores for technical assistance and the EMBL-EBI systems team for management of computational resources. This research was supported by the European Molecular Biology Laboratory (E.S.W., D.T., J.C.M., P.F.), Cancer Research UK (B.M.S., T.F.R., F.C., C.F., A.R., D.T.O.), the BOLD ITN (B.M.S.), Darwin Fellowship (A.K.), the Wellcome Trust (WT202878/B/16/Z, WT108749/Z/15/Z) (P.F.), (WT202878/A/16/Z) (D.T.O), (WT095606) (A.C.F.-S) and (WT098051) (P.F., D.T.O.), EMBO Long-term (ALTF1518-2012) and Advanced Fellowships (aALTF1672-2014) (E.S.W.), and by the European Research Council (award 615584) and EMBO Young Investigator Programme (D.T.O.)

Preparing the Perfect Cuttlefish Meal: Complex Prey Handling by Dolphins

Dolphins are well known for their complex social and foraging behaviours. Direct underwater observations of wild dolphin feeding behaviour however are rare. At mass spawning aggregations of giant cuttlefish (Sepia apama) in the Upper Spencer Gulf in South Australia, a wild female Indo-Pacific bottlenose dolphin (Tursiops aduncus) was observed and recorded repeatedly catching, killing and preparing cuttlefish for consumption using a specific and ordered sequence of behaviours. Cuttlefish were herded to a sand substrate, pinned to the seafloor, killed by downward thrust, raised mid-water and beaten by the dolphin with its snout until the ink was released and drained. The deceased cuttlefish was then returned to the seafloor, inverted and forced along the sand substrate in order to strip the thin dorsal layer of skin off the mantle, thus releasing the buoyant calcareous cuttlebone. This stepped behavioural sequence significantly improves prey quality through 1) removal of the ink (with constituent melanin and tyrosine), and 2) the calcareous cuttlebone. Observations of foraging dolphin pods from above-water at this site (including the surfacing of intact clean cuttlebones) suggest that some or all of this prey handling sequence may be used widely by dolphins in the region. Aspects of the unique mass spawning aggregations of giant cuttlefish in this region of South Australia may have contributed to the evolution of this behaviour through both high abundances of spawning and weakened post-spawning cuttlefish in a small area (>10,000 animals on several kilometres of narrow rocky reef), as well as potential long-term and regular visitation by dolphin pods to this site

Assessment of function and clinical utility of alcohol and other drug web sites: An observational, qualitative study

Background The increasing popularity and use of the internet makes it an attractive option for providing health information and treatment, including alcohol/other drug use. There is limited research examining how people identify and access information about alcohol or other drug (AOD) use online, or how they assess the usefulness of the information presented. This study examined the strategies that individuals used to identify and navigate a range of AOD websites, along with the attitudes concerning presentation and content. Methods Members of the general community in Brisbane and Roma (Queensland, Australia) were invited to participate in a 30-minute search of the internet for sites related to AOD use, followed by a focus group discussion. Fifty one subjects participated in the study across nine focus groups. Results Participants spent a maximum of 6.5 minutes on any one website, and less if the user was under 25 years of age. Time spent was as little as 2 minutes if the website was not the first accessed. Participants recommended that AOD-related websites should have an engaging home or index page, which quickly and accurately portrayed the site’s objectives, and provided clear site navigation options. Website content should clearly match the title and description of the site that is used by internet search engines. Participants supported the development of a portal for AOD websites, suggesting that it would greatly facilitate access and navigation. Treatment programs delivered online were initially viewed with caution. This appeared to be due to limited understanding of what constituted online treatment, including its potential efficacy. Conclusions A range of recommendations arise from this study regarding the design and development of websites, particularly those related to AOD use. These include prudent use of text and information on any one webpage, the use of graphics and colours, and clear, uncluttered navigation options. Implications for future website development are discussed

Measurement of Myofilament-Localised Calcium Dynamics in Adult Cardiomyocytes and the Effect of Hypertrophic Cardiomyopathy Mutations

Rationale: Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation, or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here we develop and characterise genetically encoded Ca2+ indicators restricted to the myofilament to directly visualise Ca2 changes in the sarcomere. Objective: To produce and validate myofilament restricted Ca2+ imaging probes in an adenoviral transduction adult cardiomyocyte model using drugs that alter myofilament function (MYK-461, omecamtiv mecarbil and levosimendan) or following co-transduction of two established hypertrophic cardiomyopathy (HCM) disease causing mutants (cTnT R92Q and cTnI R145G) that alter myofilament Ca2+ handling. Methods and Results: When expressed in adult ventricular cardiomyocytes RGECO-TnT/TnI sensors localise correctly to the sarcomere without contractile impairment. Both sensors report cyclical changes in fluorescence in paced cardiomyocytes with reduced Ca2+ on and increased Ca2+ off rates compared with unconjugated RGECO. RGECO-TnT/TnI revealed changes to localised Ca2+ handling conferred by MYK-461 and levosimendan, including an increase in Ca2+ binding rates with both levosimendan and MYK-461 not detected by an unrestricted protein sensor. Co-adenoviral transduction of RGECO-TnT/TnI with HCM causing thin filament mutants showed that the mutations increase myofilament [Ca2+] in systole, lengthen time to peak systolic [Ca2+], and delay [Ca2+] release. This contrasts with the effect of the same mutations on cytoplasmic Ca2+, when measured using unrestricted RGECO where changes to peak systolic Ca2+ are inconsistent between the two mutations. These data contrast with previous findings using chemical dyes that show no alteration of [Ca2+] transient amplitude or time to peak Ca2+. Conclusions: RGECO-TnT/TnI are functionally equivalent. They visualise Ca2+ within the myofilament and reveal unrecognised aspects of small molecule and disease associated mutations in living cells

Universal cures for idiosyncratic illnesses: a genealogy of therapeutic reasoning in the mental health field

Over the past decades, there has been a significant increase in prescriptions of psychotropic drugs for mental disorders. So far, most of the explanations of the phenomenon have focused on the process of medicalization, but little attention has been cast towards physicians' day-to-day clinical reasoning, and the way it affects therapeutic decision-making. This article addresses the complex relationship between aetiology, diagnosis and drug treatment by examining the style of reasoning underlying prescribing practices through an historical lens. A genealogy of contemporary prescribing practices is proposed, that draws significant comparisons between 19th-century medicine and modern psychiatry. Tensions between specific, standardized cures and specific, idiosyncratic patients have been historically at play in clinical reasoning - and still are today. This inquiry into the epistemological foundations of contemporary drug prescription reveals an underlying search for scientific legitimacy

Pervasive lesion segregation shapes cancer genome evolution

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, quantification of oncogenic selection, and fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.This work was supported by: Cancer Research UK (20412, 22398), the European Research Council (615584, 682398), the Wellcome Trust (WT108749/Z/15/Z, WT106563/Z/14/A, WT202878/B/16/Z), the European Molecular Biology Laboratory, the MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16), and the ERDF/Spanish Ministry of Science, Innovation and Universities-Spanish State Research Agency/DamReMap Project (RTI2018-094095-B-I00)