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Abstract Peptidoglycan polymerases, enterobacterial common antigen polymerases, O-antigen ligases, and other bacterial polysaccharide polymerases (BP-Pols) are glycosyltransferases (GTs) that build bacterial surface polysaccharides. These integral membrane enzymes share the particularity of using diphospholipid-activated sugars and were previously missing in the carbohydrate-active enzymes database (CAZy; www.cazy.org ). While the first three classes formed well-defined families of similar proteins, the sequences of BP-Pols were so diverse that a single family could not be built. To address this, we developed a new clustering method using a combination of a sequence similarity network and hidden Markov model comparisons. Overall, we have defined 17 new GT families including 14 of BP-Pols. We find that the reaction stereochemistry appears to be conserved in each of the defined BP-Pol families, and that the BP-Pols within the families transfer similar sugars even across Gram-negative and Gram-positive bacteria. Comparison of the new GT families reveals three clans of distantly related families, which also conserve the reaction stereochemistry.

Objective: To investigate whether structural hand OA or its progression is associated with structural knee OA progression after two years in a population with symptomatic knee OA. Methods: We used baseline and two-year follow-up data from the IMI-APPROACH cohort. Symptomatic hand and knee OA were defined using ACR criteria. Radiographs of hands and knees were scored semi-quantitatively for osteophytes and joint space narrowing (JSN) following the OARSI atlas, and Kellgren-Lawrence (KL) scale. Knee images were also scored quantitatively with the Knee Image Digital Analysis (KIDA). Progression was defined as change above the minimal detectable change on patient level, except for KIDA (most affected knee compartment level). With logistic regression analyses the severity or progression of hand OA was associated with knee OA progression. Results: In 221 participants (mean age 66, 77% women, mean BMI 27.7, 19% hand OA), OA progression occurred in 18%–28%, and 9%–38% in hands and knees respectively, depending on features. Baseline structural hand OA features were not significantly associated with knee OA progression, except for hand osteophytes with KIDA osteophytes progression (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01–1.06). Progression of structural hand OA features was not significantly associated with knee OA progression, except for hand osteophyte or JSN progression, which was significantly associated with knee osteophyte progression (OR 0.44, 95%CI 0.22–0.84 and OR 0.43, 95%CI 0.18–0.94, respectively), and hand osteophyte progression for knee JSN (OR 2.51, 95%CI 1.15–5.48). Conclusions: In patients with symptomatic knee OA, no consistent associations between baseline structural hand OA or hand OA progression and knee OA progression were shown.

Importance: Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) have been linked to shorter telomere length (TL). While understanding this association has critical clinical implications for respiratory diseases, previous studies exploring these associations were conducted in European populations. The present study aims to investigate this relationship in an Asian population. Objective: To examine the causal relationship between leukocyte TL and COPD and ILD in an Asian population. Design: Setting, and Participants: We used a genome-wide association study summary statistics-based two-sample Mendelian randomization (MR) design to investigate the association between leukocyte TL, genetically predicted by nine single-nucleotide polymorphisms and the risk of COPD and ILD. Participants were Japanese individuals enrolled in the Biobank Japan Project, including 3315 COPD patients and 806 ILD patients. Exposure: Leukocyte TL was genetically predicted by nine single-nucleotide polymorphisms. Results: The inverse-variance weighted estimates showed a significant inverse association between leukocyte TL and COPD (odds ratio [OR] = 0.78; 95 % confidence interval [CI]: 0.64, 0.95; P = 0.01) and ILD (OR = 0.29; 95 % CI: 0.14, 0.61; P = 0.001), respectively. All sensitivity analyses yielded consistent results. The MR-Egger regression intercept test showed no evidence of horizontal pleiotropy (Pintercept: COPD, 0.56; ILD: 0.70). Conclusion: and Relevance: Our findings suggest that leukocyte telomere shortening may causally increase the risk of COPD and ILD. These results highlight the potential importance of TL for these respiratory diseases.

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.

Differences in gene-wide DNA methylation of the Alzheimer’s disease (AD)-associated genes BIN1, HLA-DRB5, SORL1, SLC24A4, and ABCA7 are reported to be associated with AD in post-mortem brain samples. We investigated whether the same associations could be found in leukocytes collected pre-mortem. Using cohort data of 544 Swedish twins (204 dementia diagnoses), we replicated the findings in HLA-DRB5 and SLC24A4 at P

ABSTRACTIn agricultural production, intercropping is a widely used system with many benefits. Lupin (Lupinus angustifolius L.) is a legume that contains a large variety of plant secondary metabolites, which have multiple functions in the plant, e.g. signalling, nodulation and stress response. An untargeted metabolomics approach was applied to investigate how the metabolome of lupin was affected by intercropped barley (Hordeum vulgare L.). The only primary metabolite of lupin affected by intercropping was tryptophan. Several secondary metabolites were affected by intercropping in lupin, and five flavonoids were annotated hereof. The flavonoid levels were increased, and tryptophan levels decreased in lupin when intercropped. Two flavonoids are prenylated, and prenylated flavonoids are believed to play a role in the plant’s stress response. Furthermore, flavonoids are involved in plant defence and the nodulation process. Thus the present flavonoids may affect regulation of lupin N2-fixation activity.Highlights Intercropping caused a change in the secondary metabolites of Lupinus angustifolius L.Prenylated flavonoids were generated in Lupinus angustifolius L. as a response to intercroppingTryptophan was the only identified primary metabolite affected by intercropping

Objectives: To efficiently assess the disease-modifying potential of new osteoarthritis treatments, clinical trials need progression-enriched patient populations. To assess whether the application of machine learning results in patient selection enrichment, we developed a machine learning recruitment strategy targeting progressive patients and validated it in the IMI-APPROACH knee osteoarthritis prospective study. Design: We designed a two-stage recruitment process supported by machine learning models trained to rank candidates by the likelihood of progression. First stage models used data from pre-existing cohorts to select patients for a screening visit. The second stage model used screening data to inform the final inclusion. The effectiveness of this process was evaluated using the actual 24-month progression. Results: From 3500 candidate patients, 433 with knee osteoarthritis were screened, 297 were enrolled, and 247 completed the 2-year follow-up visit. We observed progression related to pain (P, 30%), structure (S, 13%), and combined pain and structure (P ​+ ​S, 5%), and a proportion of non-progressors (N, 52%) ∼15% lower vs an unenriched population. Our model predicted these outcomes with AUC of 0.86 [95% CI, 0.81–0.90] for pain-related progression and AUC of 0.61 [95% CI, 0.52–0.70] for structure-related progression. Progressors were ranked higher than non-progressors for P ​+ ​S (median rank 65 vs 143, AUC = 0.75), P (median rank 77 vs 143, AUC = 0.71), and S patients (median rank 107 vs 143, AUC = 0.57). Conclusions: The machine learning-supported recruitment resulted in enriched selection of progressive patients. Further research is needed to improve structural progression prediction and assess this strategy in an interventional trial.

Abstract Background To investigate the effects of two different exercise interventions during pregnancy on gestational weight gain (GWG) and obstetric and neonatal outcomes compared to standard care. Additionally, we aimed to improve standardization of GWG measurements by developing a model to estimate GWG for a standardized pregnancy period of 40 weeks and 0 days accounting for individual differences in gestational age (GA) at delivery. Methods In a randomized controlled trial we compared the effects of structured supervised exercise training (EXE) three times per week throughout pregnancy versus motivational counselling on physical activity (MOT) seven times during pregnancy with standard care (CON) on GWG and obstetric and neonatal outcomes. Uniquely, to estimate GWG for a standardized pregnancy period, we developed a novel model to predict GWG based on longitudinally observed body weights during pregnancy and at admission for delivery. Observed weights were fitted to a mixed effects model that was used to predict maternal body weight and estimate GWG at different gestational ages. Obstetric and neonatal outcomes, among them gestational diabetes mellitus (GDM) and birth weight, were obtained after delivery. GWG and the investigated obstetric and neonatal outcomes are secondary outcomes of the randomized controlled trial, which might be underpowered to detect intervention effects on these outcomes. Results From 2018–2020, 219 healthy, inactive pregnant women with median pre-pregnancy BMI of 24.1 (21.8–28.7) kg/m2 were included at median GA 12.9 (9.4–13.9) weeks and randomized to EXE (n = 87), MOT (n = 87) or CON (n = 45). In total 178 (81%) completed the study. GWG at GA 40 weeks and 0 days did not differ between groups (CON: 14.9 kg [95% CI, 13.6;16.1]; EXE: 15.7 kg [14.7;16.7]; MOT: 15.0 kg [13.6;16.4], p = 0.538), neither did obstetric nor neonatal outcomes. For example, there were no differences between groups in the proportions of participants developing GDM (CON: 6%, EXE: 7%, MOT: 7%, p = 1.000) or in birth weight (CON: 3630 (3024–3899), EXE: 3768 (3410–4069), MOT: 3665 (3266–3880), p = 0.083). Conclusions Neither structured supervised exercise training nor motivational counselling on physical activity during pregnancy affected GWG or obstetric and neonatal outcomes compared to standard care. Trial registration ClinicalTrials.gov; NCT03679130; 20/09/2018.

Background. While nerve and tendon transfer surgery can restore upper extremity function and independence after midcervical spinal cord injury, few individuals (∼14%) undergo surgery. There is limited information regarding these complex and time-sensitive treatment options. Patient decision aids (PtDAs) convey complex health information and help individuals make informed, preference-consistent choices. The purpose of this study is to evaluate a newly created PtDA for people with spinal cord injury who are considering options to optimize upper extremity function. Methods. The PtDA was developed by our multidisciplinary group based on clinical evidence and the Ottawa Decision Support Framework. A prospective pilot study enrolled adults with midcervical spinal cord injury to evaluate the PtDA. Participants completed surveys about knowledge and decisional conflict before and after viewing the PtDA. Acceptability measures and suggestions for further improvement were also solicited. Results. Forty-two individuals were enrolled and completed study procedures. Participants had a 20% increase in knowledge after using the PtDA ( P

Objective: To determine whether the comorbidity burden and co-existing comorbidities are cross-sectionally and/or longitudinally associated with pain and pain sensitization in a cohort study of people with hand OA. Design: We examined whether comorbidity burden and individual comorbidities based on the self-administered Comorbidity Index (range: 0–42) at baseline were associated with pain outcomes at baseline and 3 years follow-up. Pain outcomes included hand and overall bodily pain (range: 0–10) as well as pressure pain thresholds at the tibialis anterior muscle (kg/cm2) and temporal summation (distal radioulnar joint) as measures of central pain sensitization. We performed linear regression analyses adjusted for age, sex, body mass index, physical exercise and education. Results: We included 300 and 196 participants in cross-sectional and longitudinal analyses, respectively. Using baseline data, the burden of comorbidities was associated with greater pain in hands (beta ​= ​0.61, 95% CI 0.37, 0.85) and overall body (beta ​= ​0.60, 95% CI 0.37, 0.87). Similar strength of associations was found between comorbidity burden (baseline) and follow-up pain. Among the individual comorbidities, back pain and depression were associated with nearly one unit higher pain score in hands and overall body at both baseline and follow-up. Only back pain was related to lower pressure pain thresholds at follow up (beta ​= ​−0.24, 95% CI −0.50, −0.001). Conclusion: People with hand OA and greater comorbidity burden, co-existing back pain or depression reported greater pain severity than their counterparts, also 3 years later. These results acknowledge the relevance of accounting for comorbidities in the pain experience in people with hand OA.