Discovering the sluggishness of triathlon running - using the attractor method to quantify the impact of the bike-run transition

Running in a triathlon, a so-called brick run, is uniquely influenced by accumulated load from its preceding disciplines. Crucially, however, and irrespective of race type, the demands of a triathlon always exceed the sum of its parts. Triathletes of all levels commonly report subjectively perceived incoordination within the initial stages of the cycle run transition (T2). Although minimizing it, and its influence on running kinematics, can positively impact running and overall triathlon performance, the mechanisms behind the T2 effect remain unclear. In the present study, we assessed the influence of the pre-load exercise mode focusing on the biomechanical perspective. To analyze inertial sensor-based raw data from both legs, the so-called Attractor Method was applied. The latter represents a sensitive approach, allowing to quantify subtle changes of cyclic motions to uncover the transient effect, a potentially detrimental transient phase at the beginning of a run. The purpose was to analyze the impact of a pre-load on the biomechanics of a brick run during a simulated Olympic Distance triathlon (without the swimming section). Therefore, we assessed the influence of pre-load exercise mode on running pattern (δM) and precision (δD), and on the length of the transient effect (tT) within a 10 km field-based run in 22 well-trained triathletes. We found that δD, but not δM, differed significantly between an isolated run (IRun) and when it was preceded by a 40 km cycle (TRun) or an energetically matched run (RRun). The average distance ran until overcoming the transient phase (tT) was 679 m for TRun, 450 m for RRun, and 29 4 m for IRun. The results demonstrated that especially the first kilometer of a triathlon run is prone to an uncoordinated running sensation, which is also commonly reported by athletes. That is, i) the T2 effect appeared more linked to variability in running style than to running style per se ii) run tT distance was influenced by preceding exercise load mode, being greater for a TRun than for the RRun condition, and iii) the Attractor Method seemed to be a potentially promising method of sensitively monitoring T2 adaptation under ecologically valid conditions

Inherited liver shunts in dogs elucidate pathways regulating embryonic development and clinical disorders of the portal vein

Congenital disorders of the hepatic portal vasculature are rare in man but occur frequently in certain dog breeds. In dogs, there are two main subtypes: intrahepatic portosystemic shunts, which are considered to stem from defective closure of the embryonic ductus venosus, and extrahepatic shunts, which connect the splanchnic vascular system with the vena cava or vena azygos. Both subtypes result in nearly complete bypass of the liver by the portal blood flow. In both subtypes the development of the smaller branches of the portal vein tree in the liver is impaired and terminal branches delivering portal blood to the liver lobules are often lacking. The clinical signs are due to poor liver growth, development, and function. Patency of the ductus venosus seems to be a digenic trait in Irish wolfhounds, whereas Cairn terriers with extrahepatic portosystemic shunts display a more complex inheritance. The genes involved in these disorders cannot be identified with the sporadic human cases, but in dogs, the genome-wide study of the extrahepatic form is at an advanced stage. The canine disease may lead to the identification of novel genes and pathways cooperating in growth and development of the hepatic portal vein tree. The same pathways likely regulate the development of the vascular system of regenerating livers during liver diseases such as hepatitis and cirrhosis. Therefore, the identification of these molecular pathways may provide a basis for future proregenerative intervention

Experimental Performance of a Trickle-Bed Reactor for Biological Methanation

Federal Ministry for Economic Affairs and Energy123127

Evolutionary transformations of myoseptal tendons in gnathostomes.

Axial undulations in fishes are powered by a series of three-dimensionally folded myomeres separated by sheets of connective tissue, the myosepta. Myosepta have been hypothesized to function as transmitters of muscular forces to axial structures during swimming, but the difficulty of studying these delicate complex structures has precluded a more complete understanding of myoseptal mechanics. We have developed a new combination of techniques for visualizing the three-dimensional morphology of myosepta, and here we present their collagen-fibre architecture based on examination of 62 species representing all of the major clades of notochordates. In all gnathostome fishes, each myoseptum bears a set of six specifically arranged tendons. Because these tendons are not present outside the gnathostomes (i.e. they are absent from lampreys, hagfishes and lancelets), they represent evolutionary novelties of the gnathostome ancestor. This arrangement has remained unchanged throughout 400 Myr of gnathostome evolution, changing only on the transition to land. The high uniformity of myoseptal architecture in gnathostome fishes indicates functional significance and may be a key to understanding general principles of fish swimming mechanics. In the design of future experiments or biomechanical models, myosepta have to be regarded as tendons that can distribute forces in specific directions

WNT11/ROR2 signaling is associated with tumor invasion and poor survival in breast cancer

Background!#!Breast cancer has been associated with activation of the WNT signaling pathway, although no driver mutations in WNT genes have been found yet. Instead, a high expression of the alternative WNT receptor ROR2 was observed, in particular in breast cancer brain metastases. However, its respective ligand and downstream signaling in this context remained unknown.!##!Methods!#!We modulated the expression of ROR2 in human breast cancer cells and characterized their gene and protein expression by RNA-Seq, qRT-PCR, immunoblots and reverse phase protein array (RPPA) combined with network analyses to understand the molecular basis of ROR2 signaling in breast cancer. Using co-immunoprecipitations, we verified the interaction of ROR2 with the identified ligand, WNT11. The functional consequences of WNT11/ROR2 signaling for tumor cell aggressiveness were assessed by microscopy, impedance sensing as well as viability and invasion assays. To evaluate the translational significance of our findings, we performed gene set enrichment, expression and survival analyses on human breast cancer brain metastases.!##!Results!#!We found ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. ROR2 overexpression induced a BRCAness-like phenotype in a cell-context specific manner and rendered cells resistant to PARP inhibition. High levels of ROR2 were furthermore associated with defects in cell morphology and cell-cell-contacts leading to increased tumor invasiveness. On a molecular level, ROR2 overexpression upregulated several non-canonical WNT ligands, in particular WNT11. Co-immunoprecipitation confirmed that WNT11 indeed interacts with the cysteine-rich domain of ROR2 and triggers its invasion-promoting signaling via RHO/ROCK. Knockdown of WNT11 reversed the pro-invasive phenotype and the cellular changes in ROR2-overexpressing cells.!##!Conclusions!#!Taken together, our study revealed a novel auto-stimulatory loop in which ROR2 triggers the expression of its own ligand, WNT11, resulting in enhanced tumor invasion associated with breast cancer metastasis

Rates of bacterial co-infections and antimicrobial use in COVID-19 patients: a retrospective cohort study in light of antibiotic stewardship

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. Bacterial co-infections are associated with unfavourable outcomes in respiratory viral infections; however, microbiological and antibiotic data related to COVID-19 are sparse. Adequate use of antibiotics in line with antibiotic stewardship (ABS) principles is warranted during the pandemic. We performed a retrospective study of clinical and microbiological characteristics of 140 COVID-19 patients admitted between February and April 2020 to a German University hospital, with a focus on bacterial co-infections and antimicrobial therapy. The final date of follow-up was 6 May 2020. Clinical data of 140 COVID-19 patients were recorded: The median age was 63.5 (range 17-99) years; 64% were males. According to the implemented local ABS guidelines, the most commonly used antibiotic regimen was ampicillin/sulbactam (41.5%) with a median duration of 6 (range 1-13) days. Urinary antigen tests for Legionella pneumophila and Streptococcus peumoniae were negative in all cases. In critically ill patients admitted to intensive care units (n = 50), co-infections with Enterobacterales (34.0%) and Aspergillus fumigatus (18.0%) were detected. Blood cultures collected at admission showed a diagnostic yield of 4.2%. Bacterial and fungal co-infections are rare in COVID-19 patients and are mainly prevalent in critically ill patients. Further studies are needed to assess the impact of antimicrobial therapy on therapeutic outcome in COVID-19 patients to prevent antimicrobial overuse. ABS guidelines could help in optimising the management of COVID-19. Investigation of microbial patterns of infectious complications in critically ill COVID-19 patients is also required

Intensive Care Risk Estimation in COVID-19 Pneumonia Based on Clinical and Imaging Parameters: Experiences from the Munich Cohort

The evolving dynamics of coronavirus disease 2019 (COVID-19) and the increasing infection numbers require diagnostic tools to identify patients at high risk for a severe disease course. Here we evaluate clinical and imaging parameters for estimating the need of intensive care unit (ICU) treatment. We collected clinical, laboratory and imaging data from 65 patients with confirmed COVID-19 infection based on polymerase chain reaction (PCR) testing. Two radiologists evaluated the severity of findings in computed tomography (CT) images on a scale from 1 (no characteristic signs of COVID-19) to 5 (confluent ground glass opacities in over 50% of the lung parenchyma). The volume of affected lung was quantified using commercially available software. Machine learning modelling was performed to estimate the risk for ICU treatment. Patients with a severe course of COVID-19 had significantly increased interleukin (IL)-6, C-reactive protein (CRP), and leukocyte counts and significantly decreased lymphocyte counts. The radiological severity grading was significantly increased in ICU patients. Multivariate random forest modelling showed a mean ± standard deviation sensitivity, specificity and accuracy of 0.72 ± 0.1, 0.86 ± 0.16 and 0.80 ± 0.1 and a receiver operating characteristic-area under curve (ROC-AUC) of 0.79 ± 0.1. The need for ICU treatment is independently associated with affected lung volume, radiological severity score, CRP, and IL-6

SARS-CoV-2 serology increases diagnostic accuracy in CT-suspected, PCR-negative COVID-19 patients during pandemic

Background!#!In the absence of PCR detection of SARS-CoV-2 RNA, accurate diagnosis of COVID-19 is challenging. Low-dose computed tomography (CT) detects pulmonary infiltrates with high sensitivity, but findings may be non-specific. This study assesses the diagnostic value of SARS-CoV-2 serology for patients with distinct CT features but negative PCR.!##!Methods!#!IgM/IgG chemiluminescent immunoassay was performed for 107 patients with confirmed (group A: PCR + ; CT ±) and 46 patients with suspected (group B: repetitive PCR-; CT +) COVID-19, admitted to a German university hospital during the pandemic's first wave. A standardized, in-house CT classification of radiological signs of a viral pneumonia was used to assess the probability of COVID-19.!##!Results!#!Seroconversion rates (SR) determined on day 5, 10, 15, 20 and 25 after symptom onset (SO) were 8%, 25%, 65%, 76% and 91% for group A, and 0%, 10%, 19%, 37% and 46% for group B, respectively; (p < 0.01). Compared to hospitalized patients with a non-complicated course (non-ICU patients), seroconversion tended to occur at lower frequency and delayed in patients on intensive care units. SR of patients with CT findings classified as high certainty for COVID-19 were 8%, 22%, 68%, 79% and 93% in group A, compared with 0%, 15%, 28%, 50% and 50% in group B (p < 0.01). SARS-CoV-2 serology established a definite diagnosis in 12/46 group B patients. In 88% (8/9) of patients with negative serology > 14 days after symptom onset (group B), clinico-radiological consensus reassessment revealed probable diagnoses other than COVID-19. Sensitivity of SARS-CoV-2 serology was superior to PCR > 17d after symptom onset.!##!Conclusions!#!Approximately one-third of patients with distinct COVID-19 CT findings are tested negative for SARS-CoV-2 RNA by PCR rendering correct diagnosis difficult. Implementation of SARS-CoV-2 serology testing alongside current CT/PCR-based diagnostic algorithms improves discrimination between COVID-19-related and non-related pulmonary infiltrates in PCR negative patients. However, sensitivity of SARS-CoV-2 serology strongly depends on the time of testing and becomes superior to PCR after the

Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors

To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-) Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-) Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.Funding Agencies|Swedish Cancer Society; Swedish Research Council; Linkoping University; Swedish Childhood cancer foundation; Knut and Alice Wallenbers Stiftelse; Hematolinne</p