A common mechanism for recruiting the Rrm3 and RTEL1 accessory helicases to the eukaryotic replisome

The eukaryotic replisome is assembled around the CMG (CDC45-MCM-GINS) replicative helicase, which encircles the leading-strand DNA template at replication forks. When CMG stalls during DNA replication termination, or at barriers such as DNA-protein crosslinks on the leading strand template, a second helicase is deployed on the lagging strand template to support replisome progression. How these ‘accessory’ helicases are targeted to the replisome to mediate barrier bypass and replication termination remains unknown. Here, by combining AlphaFold structural modelling with experimental validation, we show that the budding yeast Rrm3 accessory helicase contains two Short Linear Interaction Motifs (SLIMs) in its disordered N-terminus, which interact with CMG and the leading-strand DNA polymerase Polε on one side of the replisome. This flexible tether positions Rrm3 adjacent to the lagging strand template on which it translocates, and is critical for replication termination in vitro and Rrm3 function in vivo. The primary accessory helicase in metazoa, RTEL1, is evolutionarily unrelated to Rrm3, but binds to CMG and Polε in an analogous manner, revealing a conserved docking mechanism for accessory helicases in the eukaryotic replisome

Att knyta samman konst, kulturhistoria och natur

Denna studie undersöker hur gestaltningsprinciper kan möjliggöra ett samspel mellan konst, kulturhistoria och befintlig natur med syfte att stärka platsens identitet och enhetlighet. Studien har gjorts på Konstens väg i Övertorneå kommun och metoden består av litteraturläsning, platsbesök och analyser. För att bättre förstå platsens identitet har en förstudie gjorts med fokus på platsens olika naturvärden och kulturhistoriska skikt. Gestaltningsprinciper har formulerats baserat på utvalda nyckelvärden. Studien visar hur man kan utvärdera och prioritera olika värden och hur man lyfter fram dem. Idén bakom projektet Konstens väg var att skapa ett konststråk. Men utöver de tre konstverk som redan har köpts in, varav ett inte placerats ut än, finns det ingen konkret plan. Platsen saknar struktur och tydlighet. Arbetet har resulterat i följande tre gestaltningsprinciper; Friluftsliv i panorama, Identitet och tydlighet och Hållbarhet och framtid. Tanken är att låta hela platsens utformning genomsyras av dessa principer. Som ett komplement till gestaltningsprinciperna har 15 platser av intresse längs vägen valts ut. Varje plats beskrivs kort och innehåller idéer om eventuell utformning. Studien är ett försök att skapa ett ramverk som kan bidra med enlighet och identitet. Principerna är avsedda att fungera som riktlinjer för fortsatt planering och design.This study examines how design principles can allow an interaction between art, cultural history and site-specific nature with purpose to strengthen a place's identity and uniformity. The study includes Konstens väg in Övertorneå municipality and has been carried out through reading literature, site visits and analyzes. In order to bring out the identity of Konstens väg, the pilot study examines different values of the local nature and cultural-historical layers. Design principles were formulated based on selected key values. The study has provided many insights into how one may evaluate and prioritize different values and how to highlight those. The idea behind the project Konstens väg was to create a walk involving public art. But apart from three art pieces that already have been bought, where of two have been placed, there is no concrete plan. The site lacks structure and distinctiveness. The work has resulted in three design principles, which are; Outdoor life in panorama, Identity and clarity and Sustainability and future. The idea is to let the entire site be permeated by these principles. As a complement to the designprinciples, 15 places of interest have been selected. Each place comes with a short description and some ideas how they could be designed. This study is an attempt to establish a framework that can provide a sense of uniformity and identity. The principles are intended to serve as guidelines for continued planning and design

Augmentation of Urinary Lactoferrin Enhances Host Innate Immune Clearance of Uropathogenic Escherichia coli.

Urinary tract infection (UTI) is a prominent global health care burden. Although UTI is readily treated with antibiotics in healthy adults, complicated cases in immune-compromised individuals and the emerging antibiotic resistance of several uropathogens have accelerated the need for new treatment strategies. Here, we surveyed the composition of urinary exosomes in a mouse model of uropathgenic Escherichia coli (UPEC) UTI to identify specific urinary tract defense constituents for therapeutic development. We found an enrichment of the iron-binding glycoprotein lactoferrin in the urinary exosomes of infected mice. In subsequent in vitro studies, we identified human bladder epithelial cells as a source of lactoferrin during UPEC infection. We further established that exogenous treatment with human lactoferrin (hLf) reduces UPEC epithelial adherence and enhances neutrophil antimicrobial functions including bacterial killing and extracellular trap production. Notably, a single intravesicular dose of hLf drastically reduced bladder bacterial burden and neutrophil infiltration in our murine UTI model. We propose that lactoferrin is an important modulator of innate immune responses in the urinary tract and has potential application in novel therapeutic design for UTI

A Response to New Investment and Development: STRATEGIES FOR PRODUCING EQUITABLE OUTCOMES IN THE HARRISON NEIGHBORHOOD

Professional paper for the fulfillment of the Master of Public Policy degree.Why Equitable Development Strategies are Necessary for Harrison As Harrison experiences new investment in public infrastructure as well as an influx of affluent residents, it is crucial that structural changes be made to address its’ history of inequality, discrimination, and disinvestment that the residents of Harrison have been experiencing for generations. Any new development that occurs in the Harrison neighborhood must be equitable and increase the quality of life outcomes such as affordable housing, quality education, living wage employment, healthy environments, and transportation options. Public and private investments, programs, and policies directly or indirectly affecting Harrison must meet the needs of existing residents, taking into account past history and current conditions. Equitable development should be used as a tool to advance racial equity and increase the capacity of people of color and low-income people to strengthen their communities and determine their own future and what they anticipate the future of their neighborhood to become. Equitable development will be successful when long-standing residents, residents who have faced substantial barriers to opportunity, experience beneficial outcomes from the growth at the same rate or more than the new “gentry”

LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy

A global transcriptional network connecting noncoding mutations to changes in tumor gene expression.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer

Do cladistic and morphometric data capture common patterns of morphological disparity?

The distinctly non-random diversity of organismal form manifests itself in discrete clusters of taxa that share a common body plan. As a result, analyses of disparity require a scalable comparative framework. The difficulties of applying geometric morphometrics to disparity analyses of groups with vastly divergent body plans are overcome partly by the use of cladistic characters. Character-based disparity analyses have become increasingly popular, but it is not clear how they are affected by character coding strategies or revisions of primary homology statements. Indeed, whether cladistic and morphometric data capture similar patterns of morphological variation remains a moot point. To address this issue, we employ both cladistic and geometric morphometric data in an exploratory study of disparity focussing on caecilian amphibians. Our results show no impact on relative intertaxon distances when different coding strategies for cladistic characters were used or when revised concepts of homology were considered. In all instances, we found no statistically significant difference between pairwise Euclidean and Procrustes distances, although the strength of the correlation among distance matrices varied. This suggests that cladistic and geometric morphometric data appear to summarize morphological variation in comparable ways. Our results support the use of cladistic data for characterizing organismal disparity

Widening access to medicine: A realist review

The under-participation of students from disadvantaged population groups in medical education reflects broader complex structural and societal issues, highlighting that widening access (WA) selection pathways into medicine are highly context dependent. While much literature on WA pathways exists, to date this is limited to small, mostly descriptive, single-site studies; hence there is a need for more robust and theory-driven approaches to yield transferable findings. This realist review sought to develop explanatory theory on designing and implementing selection pathways that successfully widen access to medicine and increase cohort diversity.A realist approach to evidence synthesis identified the mechanisms (M) of action underpinning WA interventions for selection into medical school. We examined how these mechanisms triggered outcomes (O) related to increasing cohort diversity within different contexts (C). Our research design was informed by Pawson’s five iterative strategies for realist review: (1) locate existing theories, (2) search for evidence, (3) select articles, (4) extract and organise data and (5) synthesise the evidence and draw conclusions.Of the 6300 studies identified and screened in the main search, 32 met the inclusion criteria. Five types of WA interventions were reported across the 32 papers:(1) Minimising Bias(2) Modifying selection criteria(3) Collaborating with community(4) Preparing applicants for selection and studying medicine(5) Combining College with Medical SchoolOur realist analysis developed and refined 19 context-intervention-mechanism-outcome (CIMO) configurations. Mechanisms were categorised as addressing institutional, situational, or dispositional barriers to selection into medicine. While situational factors were often the impetus for implementing a WA intervention, the interventions themselves were developed with either an institutional or dispositional focus.There are several known situational barriers that influence the decision of individuals from under-represented minority groups just to apply to medical school. The reviewed studies reported on interventions that demonstrated positive gains in increasing applicants, offers and matriculants in several under-represented populations. More research is needed around mitigating barriers earlier in the journey to medical school (pre-application) through to supportive interventions provided once accepted (post-admission, retention, and graduation) to fully diversify the health workforce.This review highlights how institutions all use demographic characteristics to identify under-represented students, but these demographics are usually blunt one-dimensional measures of disadvantage and therefore limited. This review highlights how sociocultural conditions and policy, either external or within an institution, will drive the commitment and resources made available for a WA intervention. Based on the findings of the review reported here, the review team were left wondering if the interventions being applied are genuinely widening access for disadvantaged applicants to medical education