Maintenance of genome integrity via activities of the cohesin network

Correct segregation of sister chromatids is an important mechanism for keeping the genome intact. The cohesin complex holds the sister chromatids together from the time of their formation during replication, until separation at anaphase and is thereby mediating cohesion between the sister chromatids, essential for correct chromatid segregation. Members of the cohesin network in addition play essential roles in the repair of double strand breaks (DSBs), and have been shown to be involved in regulation of transcription. Thus, cohesin is a master regulator of a majority of the cellular processes required for transfer of the correct genetic information from one cell generation to the next. The aim with this thesis was to further elucidate the function(s) of the cohesin network in genome integrity. In doing so, either budding yeast or human cell cultures were used. In budding yeast, cohesin is recruited to the vicinity of an induced DSB and cohesion is established genome wide. This phenomenon of re-­?establishment of cohesion is called Damage induced (DI-­?) cohesion. By investigating the function of Polymerase ? in DI-­?cohesion, we found that it is differentially regulated at the break site and genome-­?wide. We also suggested that the function of break proximal DI-­?cohesion is to support DSB repair, while the genome wide DI-­? cohesion is important for correct chromosomal segregation and for survival following repeated break induction. A gene regulatory role of cohesin and its loading complex Scc2/4 has been described in several organisms, but not investigated thoroughly in yeast. Thus, we investigated the gene transcription profiles in Scc2-­?deficient cells in the absence and presence of DNA damage. We conclude that Scc2 is indeed instrumental for gene regulation also in budding yeast, both globally in an undamaged situation, and in response to DSB induction. Our data also indicate that the difference in gene response between WT and Scc2-­? deficient cells is not based on overt changes in cohesin binding. Mutations in NIPBL (human ortholog of SCC2), are frequent in Cornelia de Lange syndrome (CdLS) patients. By studying the DSB repair in B-­?cells originated from CdLS patient, we found a shift towards the alternative, microhomology-­?based, end joining pathway during class switch recombination, implicating that NIPBL is important for classical NonHomologous End Joining (NHEJ). Our results suggest that NIPBL plays an important and conserved role for NHEJ, in addition to its previously known function in homologous recombination. Altogether I have with this thesis highlighted the importance of the cohesin network in DI-­?cohesion and DNA DSB repair, as well as in the transcriptional regulation, all important components of the systems used for maintenance of genome integrity

A comparative study of the calf breeding on KRAV affiliated and conventional dairy farms

In order to investigate if the KRAV-regulations have any effects on the health and welfare of calves, KRAV-affiliated farms were compared to conventional farms with respect to calf management and outcome. The dairy calf has had a low economical impact during history. Even today the value of the calf is low and a lot of calves have a poor health status. The calf breeding is built on tradition and on the fact, that cheap antibiotics have made it possible to ignore, the recommendations about good hygiene in the calf's environment. KRAV which started 1985 is the Swedish organisation that stipulates rules for organic farming. The investigation was carried out as a questionnaire and it was given to 40 different farms, 20 KRAV affiliated and 20 conventional. Those farms are participating in an animal health project about metabolic diseases at the department of Clinical Sciences, SLU. The questionnaire was divided into four different parts and the questions were about calf rearing in general and also about the relationship between cow and calf. Thirty-one farmers answered the questionnaire, 17 KRAV affiliated farmers and 14 conventional farmers. The results from the study showed that the KRAV affiliated farms weaned the calves later then the conventional farms. The KRAV affiliated farms also gave the calves milk in a nipple bucket or let them suckle a nurse cow while most of the conventional farms gave the calves milk in an open bucket. Eleven of 14 conventional farms and all the KRAV affiliated farms kept the cow and calf together after calving, but the conventional farms separated the cow and calf earlier then the KRAV affiliated farms. The health status of the calves showed no differences between the farms. The farmers also summoned a veterinarian equally often. The study showed differences between the KRAV affiliated and the conventional farms but those differences didn't affect the health of the calves.En enkätstudie genomfördes med syfte att undersöka om KRAV:s regler påverkade kalvars hälsa jämfört med konventionell kalvuppfödning. Mjölkkokalven har historiskt sett haft liten ekonomisk betydelse. Även idag är kalvens värde lågt och kalvhälsan är ofta eftersatt. Dagens kalvhållning bygger på tradition och på att tillgången till billig antibiotika har gjort att god hygien har kunnat försummas. Kontrollföreningen för alternativ odling (KRAV) bildades 1985 och har sedan dess formulerat regler om djurhållning utöver djurskyddslagen. Enkäten var uppdelad i fyra delar och tog upp frågor generellt om kalvuppfödning samt om relationen ko och kalv. Den delades ut till 40 gårdar, hälften KRAV- och hälften konventionella, vilka deltar i ett djurhälsoprojekt om metaboliska sjukdomar. Projektet genomförs på Institutionen för kliniska vetenskaper, SLU. Trettioen av 40 djurägare besvarade enkäten (17 KRAV och 14 konventionella). Resultaten från enkätundersökningen visade att KRAV-gårdarna avvande kalvarna senare än konventionella gårdar och att de gav mjölk i spenhink eller med amko medan de flesta konventionella gårdar gav mjölk i öppen hink. Elva av 14 konventionella gårdar och alla KRAV-gårdar lät ko och kalv gå tillsammans efter kalvning, men de konventionella gårdarna skilde kalven från kon tidigare än KRAV-gårdarna. Det var lika många sjuka kalvar på KRAV- och konventionella gårdar och gårdarna tillkallade veterinär lika ofta. I studien kunde skillnader i kalvuppfödningen på KRAV- och konventionella gårdar visas, men dessa skillnader påverkade inte kalvarnas hälsa

Exploring the competition between variable renewable electricity and a carbon-neutral baseload technology

In this paper we explore the competition between variable renewable energy sources (VRE) and a carbon-neutral baseload technology in the transition to a low-carbon power system. We study a stylized system subject to a gradually increasing carbon tax using an agent-based model where agents are power companies investing in new capacity. The agents make predictions of the profitability of different investment options. Five electricity generating technologies are available in the model: coal, gas, wind, solar PV and a more expensive carbon-neutral baseload technology. We compare the output from our model with a corresponding optimization model. We present two main findings: (1)\ua0installed capacity of VRE initially increases with a carbon tax. However, once the carbon tax has reached a certain level the installed capacity of VRE starts to decline due to competition with the stylized carbon-neutral baseload technology. (2)\ua0With limited foresight we find that the model underinvests (first 25 years) in wind and then overinvests in wind compared to the optimal solution. The reasons for these dynamic phenomena are explained and an extensive sensitivity analysis is carried out

Differences in Dementia Care Between Swedish-Born and Foreign-Born from Countries with Different Country Level Socioeconomic Position : A Nationwide Register-Based Study

BACKGROUND: With a growing elderly population worldwide, the prevalence of dementia is rapidly increasing. Studies from high income countries have shown that belonging to a minority ethnic group increases the risk of health disadvantages.OBJECTIVE: The aim of the present registry-based study was to identify potential differences in diagnostics, treatment, and care of individuals with dementia focusing on foreign-born in Sweden and the impact of country level socioeconomic position (SEP).METHODS: The study was based on a large dataset from the Swedish Dementia Registry (SveDem) and the Swedish Tax Agency's population registry. Data on demographic variables, cognitive tests, clinical assessments, medication, diagnosis, and interventions initiated at diagnosis were collected. Country level SEP was determined by country of birth as classified by World Bank Country and Lending groups.RESULTS: Of 57,982 patients with dementia registered in SveDem, 7,171 (12.4%) were foreign-born. The foreign-born were significantly younger at diagnosis (p < 0.001), had a lower MMSE score (p < 0.001), lower odds of receiving a specific dementia diagnosis (p < 0.001), lower use of acetylcholinesterase inhibitors (p < 0.001), and overall a higher use of neuroleptics compared with the Swedish-born group. The lower SEP, the greater differences to Swedish-born were seen in many of the examined variables.CONCLUSION: There were significant differences in dementia diagnostics, treatment, and care between foreign-born and Swedish-born, a lower SEP indicating greater differences. Further research should focus on various socioeconomic aspects and health care outcomes for a more profound analysis of equity in dementia care

Skenande statskollaps; Fred bortom räckhåll? - En fallstudie av FN:s insatser i Kongo-Kinshasa

I över 50 år har Kongo-Kinshasa varit utsatt for krig, och landet präglas idag av en skenande statskollaps. Vi har utkristalliserat tre fundamentala orsaker till konflikten som anses relevanta i samband med vår frågestallning, vilken behandlar FN-styrkan MONUC: s insatser i landet. Maktspel över Kongos enorma naturtillgångar, politisk problematik och etniska skiljelinjer är grunden till såväl konflikten som landets politiska instabilitet. FN-styrkan, som är en av de största i sitt slag och har befunnit sig i landet sedan år 2000, arbetar mot fredsbevarande och fredsfrämjande mål vilka ofta fokuserat på att mildra den humanitära katastrof som råder. Granskning har genomförts av MONUC: s arbete i att vara behjälpliga till att motverka de viktigaste källorna till konflikten. Genom organisationsteorin A "Garbage Can Model" får problematik inom FN högt förklaringsvärde till att MONUC: s insatser blivit så kritiserade. Att stoppa källorna till konflikten är av yttersta vikt för en långsiktigt hållbar lösning och ett efterlängtat slut på detta blodiga krig

A missense mutation in PMEL17 is associated with the Silver coat color in the horse

BACKGROUND: The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype. RESULTS: Segregation data on the Silver locus (Z) were obtained within one half-sib family that consisted of a heterozygous Silver colored stallion with 34 offspring and their 29 non-Silver dams. We typed 41 genetic markers well spread over the horse genome, including one single microsatellite marker (TKY284) close to the candidate gene PMEL17 on horse chromosome 6 (ECA6q23). Significant linkage was found between the Silver phenotype and TKY284 (θ = 0, z = 9.0). DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys). This mutation showed complete association with the Silver phenotype across multiple horse breeds, and was not found among non-Silver horses with one clear exception; a chestnut colored individual that had several Silver offspring when mated to different non-Silver stallions also carried the exon 11 mutation. In total, 64 Silver horses from six breeds and 85 non-Silver horses from 14 breeds were tested for the exon 11 mutation. One additional mutation located in intron 9, only 759 bases from the missense mutation, also showed complete association with the Silver phenotype. However, as one could expect to find several non-causative mutations completely associated with the Silver mutation, we argue that the missense mutation is more likely to be causative. CONCLUSION: The present study shows that PMEL17 causes the Silver coat color in the horse and enable genetic testing for this trait

Allt annat än 21 grader och vindstilla - En studie i att utveckla ett gemensamt varumärke för Helsingborgs cityhandel

Cityhandelns framtid, med externa köpcentrum som en stark konkurrent, har diskuterats under en längre period. I diskussionerna finns både de som hävdar att köpcentrum skapar en attraktiv region som gynnar cityhandeln samt de som menar att cityhandeln urholkas. Det byggs idag åtskilliga nya köpcentrum och utbyggnader sker i rask takt. Detta torde för cityhandelns aktörer kunna ses som en sporre att tillsammans skapa ett mer attraktivt och spännande alternativ. Uppsatsen har haft syftet att analysera hur Helsingborgs cityhandel via varumärkesutveckling och storytelling skulle kunna stärka sin konkurrenskraft. Studien visar på att potential finns till att skapa ett gemensamt varumärke. Den största utmaningen visar sig vara att få nätverket att fungera och begreppet storytelling kan ses som en outnyttjad möjlighet för cityhandeln

Anti-infectious and anti-inflammatory effects of peptide fragments sequentially derived from the antimicrobial peptide centrocin 1 isolated from the green sea urchin, Strongylocentrotus droebachiensis

Bacterial resistance against antibiotic treatment has become a major threat to public health. Antimicrobial peptides (AMPs) have emerged as promising alternative agents for treatment of infectious diseases. This study characterizes novel synthetic peptides sequentially derived from the AMP centrocin 1, isolated from the green sea urchin, for their applicability as anti-infective agents.The microbicidal effect of centrocin 1 heavy chain (CEN1 HC-Br), its debrominated analogue (CEN1 HC), the C-terminal truncated variants of both peptides, i.e. CEN1 HC-Br (1--20) and CEN1 HC (1--20), as well as the cysteine to serine substituted equivalent CEN1 HC (Ser) was evaluated using minimal microbicidal concentration assay. The anti-inflammatory properties were assessed by measuring the inhibition of secretion of pro-inflammatory cytokines. All the peptides tested exhibited marked microbicidal and anti-inflammatory properties. No difference in efficacy was seen comparing CEN1 HC-Br and CEN1 HC, while the brominated variant had higher cytotoxicity. C-terminal truncation of both peptides reduced salt-tolerability of the microbicidal effect as well as anti-inflammatory actions. Also, serine substitution of cysteine residue decreased the microbicidal effect. Thus, from the peptide variants tested, CEN1 HC showed the best efficacy and safety profile. Further, CEN1 HC significantly reduced bacterial counts in two different animal models of infected wounds, while Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance against this peptide under continued selection pressure. In summary, CEN1 HC appears a promising new antimicrobial agent, and clinical studies are warranted to evaluate the applicability of this AMP for local treatment of infections in man

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

Parkinson's disease (PD) patients often suffer from visuospatial deficits, which have been considered a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar deficits can be assessed. It has been demonstrated that specific parameters in this task is disrupted after unilateral injections of 6-hydroxydopamine (6-OHDA), which have been associated with the dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) systems. However, the impact of these systems on parameters in the CRT task had not yet been investigated. To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with depletion of the NA or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements compared to sham-lesion controls on the side contralateral to the lesion. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period compared to the other two groups with a 6-OHDA lesion. There was however no difference between the three different lesion groups in the other parameters assessed in the task. These data confirm previous findings demonstrating that the majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, this study has also shown that the NAergic system may play an important role in contributing to the attentive performance influencing the capacity to react to the presented lateralised stimuli

Impaired cognitive and motor function are coincident with l -DOPA-induced dyskinesia in a model of Parkinson’s disease

Dopamine transmission has been implicated in motor and cognitive function. In Parkinson’s disease (PD), dopamine replacement using the precursor drug l-DOPA is the predominant treatment approach, but long-term exposure leads to the onset of dyskinesias (LIDs). Chronic l-DOPA exposure has been associated with changes in gene expression and altered cortico-striatal plasticity. The aim of this research was to assess the functional consequence of long-term l-DOPA exposure on cognitive and motor function using a rodent model of PD. Across two independent experiments, we assessed the impact of chronic l-DOPA exposure, or a control D2R agonist, on motor and cognitive function in intact and in hemi parkinsonian rats, in the absence of drug. Abnormal involuntary movements associated with LID were measured and brain tissues were subsequently harvested for immunohistochemical analysis. Exposure to chronic l-DOPA, but not the D2R agonist, impaired motor and cognitive function, when animals were tested in the absence of drug. A meta-analysis of the two experiments allowed further dissociation of l-DOPA -treated rats into those that developed LIDs (dyskinetic) and those that did not develop LIDs (non-dyskinetic). This analysis revealed impaired cognitive and motor performance were evident only in dyskinetic, but not in non-dyskinetic, rats. These data reveal a functional consequence of the altered plasticity associated with LID onset and have implications for understanding symptom progression in the clinic