Exploiting jet binning to identify the initial state of high-mass resonances

If a new high-mass resonance is discovered at the Large Hadron Collider, model-independent techniques to identify the production mechanism will be crucial to understand its nature and effective couplings to Standard Model particles. We present a powerful and model-independent method to infer the initial state in the production of any high-mass color-singlet system by using a tight veto on accompanying hadronic jets to divide the data into two mutually exclusive event samples (jet bins). For a resonance of several hundred GeV, the jet binning cut needed to discriminate quark and gluon initial states is in the experimentally accessible range of several tens of GeV. It also yields comparable cross sections for both bins, making this method viable already with the small event samples available shortly after a discovery. Theoretically, the method is made feasible by utilizing an effective field theory setup to compute the jet cut dependence precisely and model independently and to systematically control all sources of theoretical uncertainties in the jet binning, as well as their correlations. We use a 750 GeV scalar resonance as an example to demonstrate the viability of our method.Comment: 6 pages, 2 figures, v2: journal versio

Cyclic triterpenoid production with tailored Saccharomyces cerevisiae

Triterpenoids are secondary plant metabolites derived from squalene and consist of six isoprene units (C30). Many of them or their synthetic derivatives are currently being investigated as medicinal products for various diseases. The cyclic triterpenoid betulinic acid is of special interest for the pharmaceutical and nutritional industry as it has antiretroviral, antimalarial, and anti-inflammatory properties and has potential as an anticancer agent (Muffler et al. 2011, Mullauer et al. 2010). Despite their obvious industrial potential, the application is often hindered by their low abundance in natural plant sources. This poses challenges in a biosustainable production of such compounds due to wasteful and costly product purification. Here, we present a novel biotechnological process for the production of betulinic acid using tailored Saccharomyces cerevisiae strains. The multi-scale optimization of this microbial process included: - pathway engineering by determination of optimal gene combination and dosage, - compartment engineering to increase the reaction space of the betulinic acid pathway, and - strain engineering by implementation of different push, pull and block strategies. In parallel we developed the fermentation process and were able to boost the performance of the engineered yeast by optimization of medium composition, cultivation conditions, carbon source and mode of fermentation operation in lab scale bioreactors. Product purification was achieved by a one-step extraction with acetone. The final process was evaluated in terms of economic and ecological efficiency and rated to be competitive with existing plant extraction procedures with potential for further performance improvement. Please click Additional Files below to see the full abstract

Asteroid 2008 TC3, not a polymict ureilitic but a polymict C1 chondrite parent body? Survey of 249 Almahata Sitta fragments

On October 7, 2008, the asteroid 2008 TC3 exploded as it entered the Earth’s atmosphere, producing significant dust (in the atmosphere) and delivering thousands of stones in a strewn field in Sudan, collectively known as the Almahata Sitta (AhS) stones. About 600 fragments were officially recovered in 2008 and 2009. Further rocks were collected since the fall event by local people. From these stones, 249 were classified at the Institut für Planetologie in Münster (MS) known as MS‐xxx or MS‐MU‐xxx AhS subsamples. Most of these rocks are ureilitic in origin (168; 67%): 87 coarse‐grained ureilites, 60 fine‐grained ureilites, 15 ureilites with variable texture/mineralogy, four trachyandesites, and two polymict breccias. We identified 81 non‐ureilitic fragments, corresponding to 33% of the recovered samples studied in Münster. These included chondrites, namely 65 enstatite chondrites (43 EL; 22 EH), 11 ordinary chondrites (OC), one carbonaceous chondrite, and one unique R‐like chondrite. Furthermore, three samples represent a unique type of enstatite achondrite. Since all AhS stones must be regarded as individual specimens independent from each other, the number of fresh ureilite and enstatite chondrite falls in our meteorite collections has been increased by several hundred percent. Overall, the samples weigh between <1 and 250 g and have a mean mass of ~15 g. If we consider—almost 15 years after the fall—the mass calculations, observations during and after the asteroid entered the atmosphere, the mineralogy of the C1 stones AhS 91A and AhS 671, and the experimental work on fitting the asteroid spectrum (e.g., Goodrich et al., 2019; Jenniskens et al., 2010; Shaddad et al., 2010), the main portion of the meteoroid was likely made of the fine‐grained (carbonaceous) dust and was mostly lost in the atmosphere. In particular, the fact that C1 materials were found has important implications for interpreting asteroid 2008 TC3's early spectroscopic results. Goodrich et al. (2019) correctly suggested that if scientists had not recovered the “water‐free” samples (e.g., ureilites, enstatites, and OC) from the AhS strewn field, 2008 TC3 would have been assumed to be a carbonaceous chondrite meteoroid. Considering that the dominating mass of the exploding meteoroid consisted of carbonaceous materials, asteroid 2008 TC3 cannot be classified as a polymict ureilite; consequently, we state that the asteroid was a polymict carbonaceous chondrite breccia, specifically a polymict C1 object that may have formed by late accretion at least 50–100 Ma after calcium–aluminum‐rich inclusions

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

Background/Aims: Complement activation is important in post-transplantation renal injury, but data on its role as predictor of transplant outcome/complications when assessed in donor kidneys are lacking. Methods: In human renal transplant biopsies with delayed graft function (DGF, n=12), antibody mediated rejection (ABMR, n=8), T-cell mediated rejection (TCMR, n=11), 1 year protocol biopsies (control, n=10) and corresponding zero-biopsies we performed immunohistochemical analyses of 6 complement factors using FFPE sections and correlated the findings with kidney function, as assessed by serum creatinine, and morphological changes including interstitial fibrosis and tubular atrophy (IF/TA). Results: In DGF, TCMR and ABMR significant complement deposition was observed, which was less pronounced in corresponding zero-biopsies. Zero-biopsies with subsequent ABMR showed glomerular complement factor D and C3c expression. Moreover, glomerular C3c and C9 and tubular MASP-2 and Collectin-11 expression in zero-biopsies significantly correlated with serum creatinine at diagnosis of DGF, TCMR or ABMR. Glomerular C1q was significantly increased in ABMR, but not in DGF and TCMR. In contrast, peritubular C1q was significantly enhanced in DGF and TCMR compared to zero-biopsies. Using C3d as a surrogate marker for complement activity we could confirm that stained complement factors are frequently associated with complement activity. Conclusion: Complement deposition strongly correlated with histopathological changes observed in renal transplants. All 3 complement pathways were operational in biopsies with DGF, TCMR and ABMR albeit with differential abundance and localization. Since complement deposition in zero-biopsies correlated with graft function and morphological changes, early specific complement inhibition in renal transplantation may be a new therapeutic option to prevent graft loss

Grip strength values and cut-off points based on over 200,000 adults of the German National Cohort - a comparison to the EWGSOP2 cut-off points

BACKGROUND: The European Working Group on Sarcopenia in Older People (EWGSOP) updated in 2018 the cut-off points for low grip strength to assess sarcopenia based on pooled data from 12 British studies. OBJECTIVE: Comparison of the EWGSOP2 cut-off points for low grip strength to those derived from a large German sample. METHODS: We assessed the grip strength distribution across age and derived low grip strength cut-off points for men and women (peak mean -2.5 × SD) based on 200,389 German National Cohort (NAKO) participants aged 19–75 years. In 1,012 Cooperative Health Research in the Region of Augsburg (KORA)-Age participants aged 65–93 years, we calculated the age-standardised prevalence of low grip strength and time-dependent sensitivity and specificity for all-cause mortality. RESULTS: Grip strength increased in the third and fourth decade of life and declined afterwards. Calculated cut-off points for low grip strength were 29 kg for men and 18 kg for women. In KORA-Age, the age-standardised prevalence of low grip strength was 1.5× higher for NAKO-derived (17.7%) compared to EWGSOP2 (11.7%) cut-off points. NAKO-derived cut-off points yielded a higher sensitivity and lower specificity for all-cause mortality. CONCLUSIONS: Cut-off points for low grip strength from German population-based data were 2 kg higher than the EWGSOP2 cut-off points. Higher cut-off points increase the sensitivity, thereby suggesting an intervention for more patients at risk, while other individuals might receive additional diagnostics/treatment without the urgent need. Research on the effectiveness of intervention in patients with low grip strength defined by different cut-off points is needed

miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells

SummaryTo investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance

The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA.1 phenotype.

Variant of concern (VOC) Omicron-BA.1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and animal models are urgently needed. Here, we characterize Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in hamsters, ferrets and hACE2-expressing mice, and immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In hamsters, Delta shows dominance over Omicron-BA.1, and in ferrets Omicron-BA.1 infection is abortive. In hACE2-knock-in mice, Delta and a Delta spike clone also show dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observe Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of replication and pathogenicity. Finally, the Omicron-BA.1 spike clone is less well-controlled by mRNA-vaccination in K18-hACE2-mice and becomes more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance

The spike gene is a major determinant for the SARS-CoV-2 Omicron-BA. 1 phenotype

Variant of concern (VOC) Omicron-BA.1 has achieved global predominance in early 2022. Therefore, surveillance and comprehensive characterization of Omicron-BA.1 in advanced primary cell culture systems and animal models are urgently needed. Here, we characterize Omicron-BA.1 and recombinant Omicron-BA.1 spike gene mutants in comparison with VOC Delta in well-differentiated primary human nasal and bronchial epithelial cells in vitro, followed by in vivo fitness characterization in hamsters, ferrets and hACE2-expressing mice, and immunized hACE2-mice. We demonstrate a spike-mediated enhancement of early replication of Omicron-BA.1 in nasal epithelial cultures, but limited replication in bronchial epithelial cultures. In hamsters, Delta shows dominance over Omicron-BA.1, and in ferrets Omicron-BA.1 infection is abortive. In hACE2-knock-in mice, Delta and a Delta spike clone also show dominance over Omicron-BA.1 and an Omicron-BA.1 spike clone, respectively. Interestingly, in naïve K18-hACE2 mice, we observe Delta spike-mediated increased replication and pathogenicity and Omicron-BA.1 spike-mediated reduced replication and pathogenicity, suggesting that the spike gene is a major determinant of replication and pathogenicity. Finally, the Omicron-BA.1 spike clone is less well-controlled by mRNA-vaccination in K18-hACE2-mice and becomes more competitive compared to the progenitor and Delta spike clones, suggesting that spike gene-mediated immune evasion is another important factor that led to Omicron-BA.1 dominance

The Stubenberg meteorite—An LL6 chondrite fragmental breccia recovered soon after precise prediction of the strewn field

On March 6, 2016 at 21:36:51 UT, extended areas of Upper Austria, Bavaria (Germany) and the southwestern part of the Czech Republic were illuminated by a very bright bolide. This bolide was recorded by instruments in the Czech part of the European Fireball Network and it enabled complex and precise description of this event including prediction of the impact area. So far six meteorites totaling 1473 g have been found in the predicted area. The first pieces were recovered on March 12, 2016 on a field close to the village of Stubenberg (Bavaria). Stubenberg is a weakly shocked (S3) fragmental breccia consisting of abundant highly recrystallized rock fragments embedded in a clastic matrix. The texture, the large grain size of plagioclase, and the homogeneous compositions of olivine (Fa31.4) and pyroxene (Fs25.4) clearly indicate that Stubenberg is an LL6 chondrite breccia. This is consistent with the data on O, Ti, and Cr isotopes. Stubenberg does not contain solar wind-implanted noble gases. Data on the bulk chemistry, IR spectroscopy, cosmogenic nuclides, and organic components also indicate similarities to other metamorphosed LL chondrites. Noble gas studies reveal that the meteorite has a cosmic ray exposure (CRE) age of 36 ± 3 Ma and that most of the cosmogenic gases were produced in a meteoroid with a radius of at least 35 cm. This is larger than the size of the meteoroid which entered the Earth's atmosphere, which is constrained to <20 cm from short-lived radionuclide data. In combination, this might suggest a complex exposure history for Stubenberg.PostprintPeer reviewe

Framework and baseline examination of the German National Cohort (NAKO)

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19–74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2–3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4–5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10654-022-00890-5