Light curves and colours of the ejecta from Dimorphos after the DART impact.

On 26 September 2022, the Double Asteroid Redirection Test (DART) spacecraft struck Dimorphos, a satellite of the asteroid 65803 Didymos1. Because it is a binary system, it is possible to determine how much the orbit of the satellite changed, as part of a test of what is necessary to deflect an asteroid that might threaten Earth with an impact. In nominal cases, pre-impact predictions of the orbital period reduction ranged from roughly 8.8 to 17 min (refs. 2,3). Here we report optical observations of Dimorphos before, during and after the impact, from a network of citizen scientists' telescopes across the world. We find a maximum brightening of 2.29 ± 0.14 mag on impact. Didymos fades back to its pre-impact brightness over the course of 23.7 ± 0.7 days. We estimate lower limits on the mass contained in the ejecta, which was 0.3-0.5% Dimorphos's mass depending on the dust size. We also observe a reddening of the ejecta on impact.

Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity.

BACKGROUND: Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8+ NKG2D+ T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood. OBJECTIVES: To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression. METHODS: We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort. RESULTS: Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression. CONCLUSIONS: Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D+ CD8+ T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8+ T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.

The impact of emergency department patient-controlled analgesia (PCA) on the incidence of chronic pain following trauma and non-traumatic abdominal pain.

The effect of patient-controlled analgesia during the emergency phase of care on the prevalence of persistent pain is unkown. We studied individuals with traumatic injuries or abdominal pain 6 months after hospital admission via the emergency department using an opportunistic observational study design. This was conducted using postal questionnaires that were sent to participants recruited to the multi-centre pain solutions in the emergency setting study. Patients with prior chronic pain states or opioid use were not studied. Questionnaires included the EQ5D, the Brief Pain Inventory and the Hospital Anxiety and Depression scale. Overall, 141 out of 286 (49% 95%CI 44-56%) patients were included in this follow-up study. Participants presenting with trauma were more likely to develop persistent pain than those presenting with abdominal pain, 45 out of 64 (70%) vs. 24 out of 77 (31%); 95%CI 24-54%, p < 0.001. There were no statistically significant associations between persistent pain and analgesic modality during hospital admission, age or sex. Across both abdominal pain and traumatic injury groups, participants with persistent pain had lower EQ5D mobility scores, worse overall health and higher anxiety and depression scores (p < 0.05). In the abdominal pain group, 13 out of 50 (26%) patients using patient-controlled analgesia developed persistent pain vs. 11 out of 27 (41%) of those with usual treatment; 95%CI for difference (control - patient-controlled analgesia) -8 to 39%, p = 0.183. Acute pain scores at the time of hospital admission were higher in participants who developed persistent pain; 95%CI 0.7-23.6, p = 0.039. For traumatic pain, 25 out of 35 (71%) patients given patient-controlled analgesia developed persistent pain vs. 20 out of 29 (69%) patients with usual treatment; 95%CI -30 to 24%, p = 0.830. Persistent pain is common 6 months after hospital admission, particularly following trauma. The study findings suggest that it may be possible to reduce persistent pain (at least in patients with abdominal pain) by delivering better acute pain management. Further research is needed to confirm this hypothesis.

Genetics of immune-mediated inflammatory diseases.

Immune-mediated inflammatory diseases (IMIDs) are characterized by dysregulation of the normal immune response, which leads to inflammation. Together, they account for a high disease burden in the population, given that they are usually chronic conditions with associated co-morbidities. Examples include systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease and type 1 diabetes. Since the advent of genome-wide association studies, evidence of considerable genetic overlap in the loci predisposing to a wide range of IMIDs has emerged. Understanding the genetic risk and extent of genetic overlap between IMIDs may help to determine which genes control which aspects of the different diseases; it may identify potential novel therapeutic targets for a number of these conditions, and/or it may facilitate repurposing existing therapies developed originally for different conditions. The findings show that autoantibody-mediated autoimmune diseases cluster more closely with each other than autoantibody-negative diseases such as psoriasis, psoriatic arthritis, Crohn's disease and ankylosing spondylitis which, instead, form a seronegative genetic cluster. The genetic clustering largely mirrors the known response to existing biological therapies, but apparent anomalies in treatment response are discussed.

Estimating snow mass in North America through assimilation of AMSR-E brightness temperature observations using the Catchment land surface model and support vector machines.

To estimate snow mass across North America, brightness temperature observations collected by the Advanced Microwave Scanning Radiometer from 2002 to 2011 were assimilated into the Catchment model using a support vector machine (SVM) as the observation operator and a one-dimensional ensemble Kalman filter. The performance of the assimilation system is evaluated through comparisons against ground-based measurements and reference snow products. In general, there are no statistically significant skill differences between the domain-averaged, model-only ("open loop", or OL) snow estimates and assimilation estimates. The assessment of improvements (or degradations) in snow estimates is difficult because of limitations in the measurements (or products) used for evaluation. It is found that assimilation estimates agree slightly better in terms of root-mean-square error (RMSE) and Nash-Sutcliffe model efficiency with ground-based snow depth measurements than OL estimates in 82% (56 out of 62) of pixels that are colocated with at least two ground-based stations. Assimilation estimates tend to agree slightly better in terms of mean difference with reference snow products over tun-dra snow, alpine snow, maritime snow, and sparsely-vegetated, snow covered pixels. Changes in snow mass via assimilation translate into improvements (e.g.,by 22% on average in terms of RMSE, relative to OL) in cumulative runoff estimates when compared against discharge measurements in 11 out of 13 snow-dominated basins in Alaska. These results suggest that a SVM can potentially serve as an effective observation operator for snow mass estimation within a radiance assimilation system, but a better observational baseline is required to document a statistically significant improvement.

Investigation of the genetic overlap between rheumatoid arthritis and psoriatic arthritis in a Greek population.

OBJECTIVES: Several rheumatoid arthritis (RA) susceptibility loci have also been found to be associated with psoriatic arthritis (PsA), demonstrating that there is a degree of genetic overlap between various autoimmune diseases. We sought to investigate whether single nucleotide polymorphisms (SNPs) mapping to previously reported RA and/or PsA susceptibility loci, including PLCL2, CCL21, REL, STAT4, CD226, PTPN22, and TYK2, are associated with risk for the two diseases in a genetically homogeneous Greek population. METHOD: This study included 392 RA patients, 126 PsA patients, and 521 healthy age- and sex-matched controls from Greece. Genotyping of the SNPs was performed with Taqman primer/probe sets. Bioinformatic analysis was performed using BlastP, PyMOL, and Maestro and Desmond. RESULTS: A significant association was detected between the GC genotype of rs34536443 (TYK2) in both the PsA and RA cohorts. The C allele of this SNP was associated with PsA only. Evidence for association with PsA was also found for the GG genotype and G allele of the rs10181656 SNP of STAT4. The TC genotype of the rs763361 SNP of CD226 was associated with PsA only. CONCLUSIONS: Genetic overlap between PsA and RA was detected for the rs34536443 SNP of the TYK2 gene within a Greek population. An association of STAT4 (rs10181656) with PsA was confirmed whereas CD226 (rs763361) was associated with PsA but not with RA, in contrast to previous reports. The different findings of this study compared to previous ones highlights the importance of comparative studies that include various ethnic or racial populations.

The cost-effectiveness of patient-controlled analgesia vs. standard care in patients presenting to the Emergency Department in pain, who are subsequently admitted to hospital.

The clinical effectiveness of patient-controlled analgesia has been demonstrated in a variety of settings. However, patient-controlled analgesia is rarely utilised in the Emergency Department. The aim of this study was to compare the cost-effectiveness of patient-controlled analgesia vs. standard care in participants admitted to hospital from the Emergency Department with pain due to traumatic injury or non-traumatic abdominal pain. Pain scores were measured hourly for 12 h using a visual analogue scale. Cost-effectiveness was measured as the additional cost per hour in moderate to severe pain avoided by using patient-controlled analgesia rather than standard care (the incremental cost-effectiveness ratio). Sampling variation was estimated using bootstrap methods and the effects of parameter uncertainty explored in a sensitivity analysis. The cost per hour in moderate or severe pain averted was estimated as £24.77 (€29.05, US$30.80) (bootstrap estimated 95%CI £8.72 to £89.17) for participants suffering pain from traumatic injuries and £15.17 (€17.79, US$18.86) (bootstrap estimate 95%CI £9.03 to £46.00) for participants with non-traumatic abdominal pain. Overall costs were higher with patient-controlled analgesia than standard care in both groups: pain from traumatic injuries incurred an additional £18.58 (€21.79 US$23.10) (95%CI £15.81 to £21.35) per 12 h; and non-traumatic abdominal pain an additional £20.18 (€23.67 US$25.09) (95%CI £19.45 to £20.84) per 12 h.

Standing up in multiple sclerosis (SUMS): protocol for a multi-centre randomised controlled trial evaluating the clinical and cost effectiveness of a home-based self-management standing frame programme in people with progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an incurable, unpredictable but typically progressive neurological condition. It is the most common cause of neurological disability in young adults. Within 15 years of diagnosis, approximately 50 % of affected people are unable to walk unaided, and over time an estimated 25 % depend on a wheelchair. Typically, people with such limited mobility are excluded from clinical trials. Severely impaired people with MS spend much of their day sitting, often with limited ability to change position. In response, secondary complications can occur including: muscle wasting, pain, reduced skin integrity, spasms, limb stiffness, constipation, and associated psychosocial problems such as depression and lowered self-esteem. Effective self-management strategies, which can be implemented relatively easily and cheaply within people's homes, are needed to improve or maintain mobility and reduce sedentary behaviour. However this is challenging, particularly in the latter stages of disease. Regular supported standing using standing frames is one potential option. METHODS/DESIGN: SUMS is a pragmatic multi-centre randomised controlled trial evaluating use of Oswestry standing frames with blinded outcome assessment and full economic evaluation. Participants will be randomly allocated (1:1) to either a home-based, self-management standing programme (with advice and support) along with their usual care or to usual care alone. Those in the intervention group will be asked to stand for a minimum of 30 min three times weekly over 20 weeks. Each participant will be followed-up at 20 and 36 weeks post baseline. The primary clinical outcome is motor function, assessed using the Amended Motor Club Assessment. The primary economic endpoint is quality-adjusted life years. The secondary outcomes include measures of explanatory physical impairments, key clinical outcomes, and health-related quality of life. An embedded qualitative component will explore participant's and carer's experiences of the standing programme. DISCUSSION: This is the first large scale multi-centre trial to assess the clinical and cost effectiveness of a home based standing frame programme for people who are severely impaired by MS. If demonstrated to be effective and cost-effective, we will use this evidence to develop recommendations for a health service delivery model which could be implemented across the United Kingdom. TRIAL REGISTRATION: ISRCTN69614598 DATE OF REGISTRATION: 3.2.16 (retrospectively registered).

Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions.

BACKGROUND: Chronic plaque psoriasis can be subdivided into two groups according to the age of onset: type 1 (early onset, before 40 years) and type 2 (late onset, at or beyond 40 years). So far, 36 genetic loci have been associated with early-onset psoriasis in genome-wide association studies of white populations, while few studies have investigated genetic susceptibility to late-onset psoriasis. OBJECTIVES: To characterize the genetics underpinning late-onset psoriasis. METHODS: We genotyped 543 cases of late-onset psoriasis and 4373 healthy controls using the Immunochip array, a dense genotyping chip containing single-nucleotide polymorphisms previously associated with autoimmune diseases. Imputation using SNP2HLA and stepwise logistic regression analysis was performed for markers spanning the human leucocyte antigen gene region. RESULTS: Two loci (HLA-C and IL12B) previously associated with early-onset psoriasis showed significant association at a genome-wide threshold in the current study (P < 5 × 10(-8)). Six more loci (TRAF3IP2, IL23R, RNF114, IFIH1, IL23A and HLA-A) showed study-wide significant association (P < 2·3 × 10(-5); calculated using Genetic type 1 error calculator). Additionally, we identified an association at IL1R1 on chromosome 2q13, which is not associated with early-onset disease. CONCLUSIONS: This is the largest study to date of genetic loci in late-onset psoriasis, and demonstrates the overlap that exists with early-onset psoriasis. It also suggests that some loci are associated exclusively with late-onset psoriasis.

Retinogenesis: stochasticity and the competency model.

The vertebrate retina is made up of seven principal cell types. These seven retinal cell types arise from multipotent retinal progenitor cells (RPCs). The competency model was proposed suggesting that RPCs undergo a series of irreversible transitions between competency states, in each of which the RPCs are competent to generate a different subset of cell types, but not retinal cells generated at previous moments. In this work, we generalize the stochastic model of neurogenesis of Barton et al. (2014), assuming that the same factor that regulates the differentiation, regulates the competency. The model reproduces the timing of production of different retinal cell types in rats such as it was experimentally measured. The results show that the evolution of the competency during retinogenesis could be explained by a single factor. Its evolution during the cell cycle and the stochastic inheritance in cell divisions determine the sequence and the overlap of production of different retinal cell types during development.

A HPLC-SRM-MS based method for the detection and quantification of methotrexate in urine at doses used in clinical practice for patients with rheumatological disease: a potential measure of adherence.

Rheumatoid arthritis (RA) is a common autoimmune disease that causes significant disability and reduced life expectancy. The folate antagonist methotrexate (MTX) is first-line therapy for RA when used weekly at low doses (5-25 mg). However, the true rate of adherence to MTX is uncertain. This is in part due to the different methods of measurement of adherence employed with no biochemical test currently available to determine adherence to low dose MTX. Common methods of MTX measurement include immunoassays in patients with high dose therapy, but these assays cross-react with MTX metabolites and lack the sensitivity required to measure adherence to low dose MTX. HPLC-SRM-MS (selected reaction monitoring-mass spectrometry) has several theoretical advantages over immunoassays with improved specificity, minimal cross-reaction and higher sensitivity. The aim of this study was to develop an assay to measure MTX and its major metabolite 7-OH-MTX in urine as a tool to monitor adherence to low dose MTX in clinic. As a proof of concept, urine samples from 4 participants with RA were measured after directly observed therapy. The assay showed improved sensitivity compared to that reported by immunoassays, with low carryover and high within-run precision. In participant samples, MTX was measurable in the urine for up to 105 hours after administration and 7-OH-MTX was detectable up to 98 hours after administration, suggesting that this assay is suitable for the measurement of adherence to therapy. The assay requires minimal sample preparation and can be adopted by other laboratories with minimal study set up.

Association of a complement receptor 1 gene variant with baseline erythrocyte sedimentation rate levels in patients starting anti-TNF therapy in a UK rheumatoid arthritis cohort: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort.

Eligibility for anti-tumour necrosis factor (TNF) therapy in most European countries is restricted to severe, active rheumatoid arthritis (RA). The DAS28 score is a marker of disease severity and incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein. We aimed to determine the relation between genetic variants known to affect ESR and levels of ESR in patients with active RA. DNA samples were genotyped for four single-nucleotide polymorphisms (SNPs) rs7527798 (CR1L), rs6691117 (CR1), rs10903129 (TMEM57) and rs1043879 (C1orf63). The association between SNPs and baseline ESR, baseline DAS28-ESR, and change in DAS28-ESR was evaluated. Baseline ESR was significantly associated with CR1 rs6691117 genotype (P=0.01). No correlation was identified between baseline DAS28-ESR or change in DAS28-ESR. In conclusion, genetic variation in the gene encoding CR1 may alter ESR levels but not DAS28-ESR, indicating no adjustment for CR1 genotype is required in the assessment of patients with severe active RA.

A stochastic model of neurogenesis controlled by a single factor.

The researches on cortical neurogenesis reveal that asymmetric division plays a key role in controlling the balance between the self-renewal of stem cells and the beginning of the neural differentiation. In such a process a neural stem cell divides by mitosis, originating a postmitotic neuron and other pluripotent stem cell available for subsequent differentiation events. In addition, studies of cell lineage trees of cultured neural progenitors reveal tree shapes and subtrees recurrent, consistent with a stochastic model of division symmetrical/asymmetrical. These considerations have led us to develop a stochastic model of neurogenesis in order to explore the possibility that this is controlled primarily by a single factor (i.e. the concentration of mNumb in the cell). We contrast the predictions of our model with experimental data and compare it with other models of neurogenesis.

Enrichment of vitamin D response elements in RA-associated loci supports a role for vitamin D in the pathogenesis of RA.

The aim of this study was to explore the role of vitamin D in rheumatoid arthritis (RA) pathogenesis by investigating the enrichment of vitamin D response elements (VDREs) in confirmed RA susceptibility loci and testing variants associated with vitamin D levels for association with RA. Bioinformatically, VDRE genomic positions were overlaid with non-HLA (human leukocyte antigen)-confirmed RA susceptibility regions. The number of VDREs at RA loci was compared to a randomly selected set of genomic loci to calculate an average relative risk (RR). Single-nucleotide polymorphisms (SNPs) in the DHCR7/NADSYN1 (nicotinamide adenine dinucleotide synthase 1) and CYP2R1 loci, previously associated with circulating vitamin D levels, were tested in UK RA cases (n=3870) and controls (n=8430). Significant enrichment of VDREs was seen at RA loci (P=9.23 × 10(-8)) when regions were defined either by gene (RR 5.50) or position (RR 5.86). SNPs in the DHCR7/NADSYN1 locus showed evidence of positive association with RA, rs4944076 (P=0.008, odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.24). The significant enrichment of VDREs at RA-associated loci and the modest association of variants in loci-controlling levels of circulating vitamin D supports the hypothesis that vitamin D has a role in the development of RA.

Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients.

We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P-trend 0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83-1.32) and OR=0.81 (95% CI 0.53-1.24), respectively; toxicity: OR=1.38 (95% CI 0.90-2.12) and OR=1.19 (95% CI 0.80-1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

An investigation of rheumatoid arthritis loci in patients with early-onset psoriasis validates association of the REL gene.

BACKGROUND: Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. OBJECTIVES: By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis. METHODS: We investigated 18 SNPs, previously confirmed as being associated with RA, in a U.K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects. RESULTS: Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P=0·0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA. CONCLUSION: Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.

Sustained vs. oscillating expressions of Ngn2, Dll1 and Hes1: a model of neural differentiation of embryonic telencephalon.

Neural progenitor cells show oscillatory expression of the Notch ligand Delta-like1 (Dll1), the Notch target Hes1 and the proneural gene Neurogenin 2 (Ngn2) during embryonic development of the mammalian telencephalon. On the other hand, expression of these genes is sustained in postmitotic neurons (upregulated for Ngn2 and Dll1, down regulated for Hes1). These facts suggest that a switch from oscillatory to sustained expression of proneural and other genes is critical in neural fate decisions. Moreover, despite controversies over the role of Numb in determining the neural fate in mammals, there is evidence that inheritance of Numb during neurogenic cell division is involved in neural differentiation. It is also known that mNumb activates Notch1 receptor degradation. The arrest of oscillations in a given cell may be due to increasing degradation of Notch1 brought about by mNumb during neurogenic division. We introduce a modification in a previous model of the gene network for two cells coupled by the Delta-Notch pathway (Wang et al., 2011). We analyze the consequences of an asymmetry between two neighbor cells in the rate of degradation of Notch (mimicking the effect of asymmetric inheritance of mNumb during the neurogenic division). The results show that a slight difference in Notch degradation between the two cells keeps oscillation going in one of them while oscillation stops in the other. Moreover, when Delta-Notch coupling is canceled, both cells show sustained expression (upregulated levels for Ngn2 and Dll1, downregulated for Hes1). We show that the model is stable against parameter variations. Moreover, to take into account the possible influence of the environment on both cells, neighboring cells are included in a mean field approximation. Both, parameter fluctuations and effects of the environment lead to asynchronous oscillations of Hes1/Ngn2 in different progenitor cells.

A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register.

Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.

Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy.

The era of genome-wide association studies has revolutionized the search for genetic susceptibility loci in complex genetic conditions such as psoriasis. There are currently 16 loci with confirmed evidence for association with psoriasis susceptibility but there is the potential for more to be discovered as the genetic heritability of the disease has not yet been fully explained. Many of the associated loci overlap with those for psoriatic arthritis. In contrast to psoriasis susceptibility, few studies have been performed to identify predictors of drug response in psoriasis. As large-scale collaborations and registries for psoriasis and psoriatic arthritis are established, it is likely that a genome-wide approach may be used as a more effective method of searching for genetic predictors of treatment response. However, candidate gene studies will still have a role; for example, it is likely that some disease susceptibility genes will also be markers of treatment response, based on evidence from other diseases. This review summarizes recent advances in investigating the role genetics plays in psoriasis susceptibility and contrasts these to advances made in psoriatic arthritis. Further, it describes the genetics of treatment response in the two diseases and indicates how susceptibility loci could be used to identify drug response in the future.