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The Tibetan Plateau has a significant role with regard to atmospheric circulation and the monsoon in particular. Changes between a closed plant cover and open bare soil are one of the striking effects of land use degradation observed with unsustainable range management or climate change, but experiments investigating changes of surface properties and processes together with atmospheric feedbacks are rare and have not been undertaken in the world's two largest alpine ecosystems, the alpine steppe and the Kobresia pygmaea pastures of the Tibetan Plateau. We connected measurements of micro-lysimeter, chamber, 13C labelling, and eddy covariance and combined the observations with land surface and atmospheric models, adapted to the highland conditions. This allowed us to analyse how three degradation stages affect the water and carbon cycle of pastures on the landscape scale within the core region of the Kobresia pygmaea ecosystem. The study revealed that increasing degradation of the Kobresia turf affects carbon allocation and strongly reduces the carbon uptake, compromising the function of Kobresia pastures as a carbon sink. Pasture degradation leads to a shift from transpiration to evaporation while a change in the sum of evapotranspiration over a longer period cannot be confirmed. The results show an earlier onset of convection and cloud generation, likely triggered by a shift in evapotranspiration timing when dominated by evaporation. Consequently, precipitation starts earlier and clouds decrease the incoming solar radiation. In summary, the changes in surface properties by pasture degradation found on the highland have a significant influence on larger scales.

BackgroundEarly stages of rheumatic diseases are still difficult to diagnose and treatment is delayed often due to the lack of practicing rheumatologists. Therefore, novel ways of diagnostic strategies are urgently needed.ObjectivesEvaluation of a structured screening system for selecting and treating patients (pts) with rheumatoid arthritis (RA) or rheumatic and musculoskeletal diseases (RMD) with health professional assistants (HPA, trained specialist nurses).Methods177 pts visited a screening appointment for early arthritis (EA) between February 2015 and July 2016 in a specialised EA clinic. Inclusion criterion was arthritis in ≥one joint for less than one year. Pts had three options for accessing the screening: phone call with qualified HPAs, online questionnaire or attending a walk in clinic (figure 1). Upon screening, all pts filled in a digital questionnaire about their symptoms and comorbidities. In group 1 an HPA performed the joint count and analysed the questionnaire for 116 pts before giving a suspected diagnosis. Subsequently, a rheumatologist saw these pts and also made a suspected diagnosis. 61 pts in group 2 were examined directly by a rheumatologist. In case of a suspected RMD or abnormal laboratory parameters, pts received a new appointment for completing diagnostics, or in acute cases, treatment was started immediately. All pts had the opportunity of a new appointment in case of persistency or worsening of the symptoms.ResultsPts had a mean age of 50.9±15.2 years and 135 (76.3%) pts were female. 160 (90.4%) pts had access to the screening by phone call. 10 (5.7%) pts used the online questionnaire, and 7 (3.9%) pts used the walk-in consultation. Pts waited 3.1±1.8 weeks for a screening appointment. According to the digital questionnaire pts had symptoms for 58.1±90.5 weeks at the screening appointment. 34 (56.7%) pts with RMD visited the screening clinic within six months after symptom onset. 2 (1.7%) pts had an RMD that had not been suspected by the HPA upon screening in group 1 and subsequently received conventional disease modifying antirheumatic drugs (cDMARDs) and glucocorticoids (GC). In group 2, 3 (4.9%) pts received cDMARDs although in the screening an RMD had not been initially suspected by the rheumatologist. In total 69 (39.0%) pts finally had an RMD, whereof 43 (24.3%) pts had an RA. 44 (24.9%) pts received therapy with a cDMARDs and 6 (3.4%) had the recommendation for a therapy with cDMARDs but refused treatment. Therapy with cDMARDs started 44.8±41.9 days after screening. 21 (11.9%) pts could already start with GC at the screening appointment. 27 (15.2%) pts without a diagnosed RMD visited the rheumatologist at least twice.Abstract THU0148 – Figure 1HPA, Health professional assistant; RMD, rheumatic and musculoskeletal disease.ConclusionsHPAs can select pts with RMDs efficiently in a structured screening system which leads to treating RMDs at an early stage in times of limited resources.AcknowledgementsAbbvie supported the project within the T2T Initiative Germany.Disclosure of InterestNone declared

BackgroundEarly stages of rheumatic diseases (0–12 weeks) including rheumatoid arthritis (RA) are still difficult to diagnose. For this reason, incorrect referrals to a rheumatologist result in a high use of resources in outpatient clinics.ObjectivesImplementation of a structured screening system for selecting and treating patients (pts) with RA or other rheumatic and musculoskeletal diseases (RMD).Methods98 pts visited a screening appointment for early arthritis (EA) between February 2015 and September 2015 in special EA departments. Inclusion criterion was arthritis ≥ one joint for less than one year recorded by phone. Qualified health professional assistants (HPA) conducted the phone call. Upon screening, all pts filled in a tablet based questionnaire to be developed for future online use about their symptoms. Subsequently, 53 pts (group 1) were seen first by an HPA who analysed the questionnaire and performed the joint count. Based on these findings, the HPA made a suspected diagnosis. Afterwards, also a rheumatologist saw these pts and made a suspected diagnosis. In comparison, the rheumatologist directly examined 45 pts without an HPA (group 2). In both groups, typical clinical findings led to a new appointment, or in acute cases, treatment was started immediately. If an RMD was suspected or laboratory parameters were abnormal, pts received a second appointment as well. The documentation of the real-life data was carried out by the Medpath© system based on medical and flexible adaptable paths.ResultsMean duration between phone call and screening was 19.6±12.8 days. Pts had an age of 18–80 years (mean 51.1±15.5 years), and 73 pts (74.5%) were female. Although all pts had reported symptoms of less than one year over the phone, only 70 pts (71.4%) fulfilled this criterion when asked in the questionnaire. In group 1, according to the HPA 22 of 53 (41.5%) pts had an RMD upon screening. The suspected diagnoses of HPA and rheumatologist corresponded in 43 of 53 (81.1%) pts in the screening. In group 2, the rheumatologist suspected 14 of 45 (31.1%) pts having an RMD in the first visit.59 (60.2%) pts had no RMD. 23 (23.5%) pts had RA that was seropositive in 14 (14.3%) pts. All RA pts were recommended a therapy with conventional disease modifying antirheumatic drugs (cDMARDs) and glucocorticoids (GC), which 21 (21.4%) pts started 17.2±27.6 days after screening. 3 (3%) pts initially had a preclinical seropositive RA, which changed into definite RA in need for treatment with cDMARDs after 191 days in one patient. 3 (3%) pts received inpatient treatment and systemic lupus erythematosus was diagnosed in one case.ConclusionsThe structured screening system efficiently selects pts with RMDs and leads to treating RMD at an early stage in times of limited resources.AcknowledgementAbbvie supports the project within the T2T Initiative Germany.Disclosure of InterestNone declared

Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention. Epigenetic aging—an accurate measure of biological aging in humans—can run in reverse. A thymus regeneration protocol has enabled estimated biological age to decrease in healthy 51‐ to 65‐year‐old men by 1.5 years after 1 year of treatment (or by 2.5 years compared to chronological age). This significantly exceeds the heretofore theoretical concept of “longevity escape velocity,” wherein biological age is reduced by 1 year for every 1 year of chronological age.

Combining single-cell cytometry datasets increases the analytical flexibility and the statistical power of data analyses. However, in many cases the full potential of co-analyses is not reached due to technical variance between data from different experimental batches. Here, we present cyCombine, a method to robustly integrate cytometry data from different batches, experiments, or even different experimental techniques, such as CITE-seq, flow cytometry, and mass cytometry. We demonstrate that cyCombine maintains the biological variance and the structure of the data, while minimizing the technical variance between datasets. cyCombine does not require technical replicates across datasets, and computation time scales linearly with the number of cells, allowing for integration of massive datasets. Robust, accurate, and scalable integration of cytometry data enables integration of multiple datasets for primary data analyses and the validation of results using public datasets. Combining single-cell cytometry datasets increases the analytical flexibility and the statistical power of data analyses. Here, the authors present a method to robustly integrate cytometry data from different batches, experiments, or even different experimental techniques.

Understanding the dynamics of stability and change is key to accelerate sustainability transitions. This paper aims to advance and inspire sustainability transition research on this matter by collecting insights from interpretative environmental discourse literature. We develop a heuristic that identifies and describes core discursive elements and dynamics in a socio-technical system. In doing so, we show how the interplay of meta-, institutionalized, and alternative discourses, dominant, marginal, and radical narratives, as well as weak and strong discursive agency influence the socio-technical configuration. The heuristic suggests three discursive lock-ins reinforcing the stabilization of socio-technical systems: unchallenged values and assumptions, incumbents’ discursive agency, and narrative co-optation. Furthermore, it explores three pathways of discursive change: disruptive, dynamic and cross-sectoral. Overall, this paper puts forward a discursive perspective on sustainability transitions. It offers additional analytical approaches and concepts for discursive transition studies, elaborated insights on the dynamics within and between the analytical dimensions of a socio-technical system, as well as a theoretical baseline for analyzing discursive lock-in mechanisms and pathways of discursive change.

The design and development of therapeutic monoclonal antibodies (mAbs) through optimizing their pharmacokinetic (PK) and pharmacodynamic (PD) properties is crucial to improve efficacy while minimizing adverse events. Many of these properties are interdependent, which highlights the inherent challenges in therapeutic antibody design, where improving one antibody property can sometimes lead to changes in others. Here, we discuss optimization approaches for PK/PD properties of therapeutic mAbs.

Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae ( Asp RedAm, Uniprot code Q2TW47) that can catalyse the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalysing imine formation as well as reduction. Crystal structures of Asp RedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient ( R )-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover numbers of up to 32,000 and space time yields up to 3.73 g l −1  d −1 . An enzyme ( Asp RedAm) capable of coupling carbonyls with a variety of amines in a reductive amination has now been discovered. Kinetic studies revealed that the enzyme catalysed both the imine formation step, as well as the reduction step. Structure and mutagenesis studies have highlighted essential catalytic residues and preparative scale examples have demonstrated total turnover numbers of up to 32,000.

Previous studies have reported the effects of absolute pitch (AP) and musical proficiency on the functioning of specific brain regions or distinct subnetworks, but they provided an incomplete account of the effects of AP and musical proficiency on whole-brain networks. In this study, we used EEG to estimate source-space whole-brain functional connectivity in a large sample comprising AP musicians (n ​= ​46), relative pitch (RP) musicians (n ​= ​45), and Non-musicians (n ​= ​34) during resting state, naturalistic music listening, and audiobook listening. First, we assessed the global network density of the participants’ functional networks in these conditions. As revealed by cluster-based permutation testing, AP musicians showed a decreased mean degree compared to Non-musicians whereas RP musicians showed an intermediate mean degree not statistically different from Non-musicians or AP-musicians. This effect was present during naturalistic music and audiobook listening, but, crucially, not during resting state. Second, we identified the subnetworks that drove group differences in global network density using the network-based statistic approach. We found that AP musicians showed decreased functional connectivity between major hubs of the default mode network during both music and audiobook listening compared to Non-musicians. Third, we assessed group differences in global network topology while controlling for network density. We did not find evidence for group differences in the clustering coefficient and characteristic path length. Taken together, we found first evidence of diminished whole-brain functional networks in AP musicians during the perception of naturalistic auditory stimuli. These differences might reflect a complex interplay between AP ability, musical proficiency, music processing, and auditory processing per se. •Absolute pitch (AP) musicians show decreased whole-brain functional connectivity.•Effect present during acoustic stimulation, but not during resting state.•No evidence for an effect of AP or musical proficiency on network topology.