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"Scholl, Daniel"
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The material properties of a bacterial-derived biomolecular condensate tune biological function in natural and synthetic systems
Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. It remains incompletely resolved how biological function is encoded in these assemblies and whether this depends on their material state. The conserved intrinsically disordered protein PopZ forms condensates at the poles of the bacterium
Caulobacter crescentus
, which in turn orchestrate cell-cycle regulating signaling cascades. Here we show that the material properties of these condensates are determined by a balance between attractive and repulsive forces mediated by a helical oligomerization domain and an expanded disordered region, respectively. A series of PopZ mutants disrupting this balance results in condensates that span the material properties spectrum, from liquid to solid. A narrow range of condensate material properties supports proper cell division, linking emergent properties to organismal fitness. We use these insights to repurpose PopZ as a modular platform for generating tunable synthetic condensates in human cells.
“Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. Here the authors show that PopZ condensate dynamics support cell division and using PopZ modular architecture, the tunable PopTag platform was developed to enable designer condensates.”
Journal Article
A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes
Bifunctional Rel stringent factors, the most abundant class of RelA/SpoT homologs, are ribosome-associated enzymes that transfer a pyrophosphate from ATP onto the 3′ of guanosine tri-/diphosphate (GTP/GDP) to synthesize the bacterial alarmone (p)ppGpp, and also catalyze the 3′ pyrophosphate hydrolysis to degrade it. The regulation of the opposing activities of Rel enzymes is a complex allosteric mechanism that remains an active research topic despite decades of research. We show that a guanine-nucleotide-switch mechanism controls catalysis by
Thermus thermophilus
Rel (Rel
Tt
). The binding of GDP/ATP opens the N-terminal catalytic domains (NTD) of Rel
Tt
(Rel
Tt
NTD
) by stretching apart the two catalytic domains. This activates the synthetase domain and allosterically blocks hydrolysis. Conversely, binding of ppGpp to the hydrolase domain closes the NTD, burying the synthetase active site and precluding the binding of synthesis precursors. This allosteric mechanism is an activity switch that safeguards against futile cycles of alarmone synthesis and degradation.
Structural and smFRET analysis reveals the mechanism of opposing catalytic activities of bifunctional Rel enzymes; that is, activation of one of the catalytic domains leads to allosteric inactivation of the other.
Journal Article
Tibial shaft anatomy differs between Caucasians and East Asian individuals
Purpose
The orientation and distance from the shaft of the femur and tibia to the articular surface centre is important for performing total knee arthroplasty (TKA) with cementless stems. It is important to understand anatomic differences between races to match the tibial and femoral shaft axis to the knee articular surface. Thus, the purpose of this study was to compare knee morphology between Caucasian and East Asian individuals to determine the optimal placement of tibial and femoral stems.
Methods
A retrospective study was conducted on a matched cohort of 50 East Asians (21F, 29M) and 50 Caucasians (21F, 29M) by age and gender. CT scans were obtained in healthy volunteers using < 2-mm slices. The distance from the proximal tibial diaphysis axis to the tibial plateau centre and the distance from the distal femoral diaphysis axis to the centre of distal femoral articular surface were measured separately. Tibial measurements were taken using Akagi’s anteroposterior (AP) axis and the widest mediolateral (ML) diameter, and femoral measurements were based on Whiteside’s line and the surgical epicondylar axis.
Results
The ML distance between the tibial shaft centre and Akagi’s line was significantly higher for Asians (9.9 ± 2.7 mm, Caucasians 7.7 ± 3.1 mm,
p
< 0.001). The distance between the femoral shaft centre and Whiteside’s line was lower, although not significantly different (Asians 1.9 ± 1.0 mm, Caucasians 2.2 ± 1.1 mm, n.s.). However, there were no differences in the AP dimension for the femur or tibia comparing Asians to Caucasians in both tibial side (Asians 10.6 ± 3.3 mm vs. Caucasians 10.9 ± 4.0 mm) and femoral side (Asians 18.1 ± 1.7 mm vs. Caucasians 17.5 ± 1.6 mm).
Conclusion
East Asian individuals have more offset in the ML dimension for the tibia. This finding is clinical relevant, as this dimensional difference should be taken into consideration when designing primary and revision TKA stemmed tibial implants for East Asian individuals.
Level of evidence
Case–control study, Level III.
Journal Article
Domain-interface dynamics of CFTR revealed by stabilizing nanobodies
The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins.
The leading cause of cystic fibrosis is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). Here authors we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein.
Journal Article
Thoughts Are Free—Differences Between Unstructured and Structured Reflections of Teachers with Different Levels of Expertise
In teacher education research, the primary source of data used to measure teachers’ reflective skills are written reflection products, which are often collected in the context of field experiences following specific structural guidelines (e.g., portfolio texts). However, it is unclear how appropriate written products are for this purpose, considering teachers’ everyday professional lives, in which reflection is a mostly verbal, highly self-directed process depending on the teachers’ level of expertise. Therefore, in our study, we analyzed how teachers’ free, unstructured reflections differ from reflections structured by model-based reflection prompts. In an exploratory qualitative research design with theoretical sampling, a total of 22 prospective teachers at four different levels of expertise were asked to reflect on two standardized fictitious vignettes using a think-aloud approach. For the first vignette, participants reflected in an unstructured way. For the second vignette, the reflection was structured using simple model-based reflection prompts. On average, the participants showed a significantly better reflective performance in the structured condition, but no significant differences in relation to the level of expertise were observed. The results contribute to a better understanding of the validity of typical reflections used in teacher education as an indicator of reflective practice in the professional field.
Journal Article
A topological switch in CFTR modulates channel activity and sensitivity to unfolding
The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the
cftr
gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the β-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions.
The cystic fibrosis transmembrane conductance regulator anion channel can adopt an alternate conformation of its nucleotide-binding domain, which affects channel activity and, under certain conditions, leads to unfolding and protein degradation.
Journal Article
Analytical Competence of Teachers
This article focuses on the analytical competence of teachers, which can be defined as the ability to properly perceive and assess lessons in terms of the effectiveness of pupils' learning. However, learning opportunities for fostering this competence in teacher education can only be justified if the components of this construct are theoretically defined and empirically proven. This was the purpose of two studies on which we report here. The studies were combined to a mixed methods design in which the analytical competence of teachers has been investigated. The data were collected using a quantitative method (standardized test; N = 800) as well as a qualitative method (content analysis of interviews; N = 18). The construct of teachers' analytical competence was defined as having two dimensions: a content and a formal dimension. The content dimension is made up of two factors: pedagogical knowledge and content knowledge. The formal dimension of the construct is defined using different levels as factors of complexity with which teachers can process information relevant for teaching. Both studies provided empirical evidence for the validity of the underlying construct. Based on these results, recommendations for teacher education are given.
Journal Article
Analytical Competence of Teachers
This article focuses on the analytical competence of teachers, which can be defined as the ability to properly perceive and assess lessons in terms of the effectiveness of pupils’ learning. However, learning opportunities for fostering this competence in teacher education can only be justified if the components of this construct are theoretically defined and empirically proven. This was the purpose of two studies on which we report here. The studies were combined to a mixed methods design in which the analytical competence of teachers has been investigated. The data were collected using a quantitative method (standardized test; N = 800) as well as a qualitative method (content analysis of interviews; N = 18). The construct of teachers’ analytical competence was defined as having two dimensions: a content and a formal dimension. The content dimension is made up of two factors: pedagogical knowledge and content knowledge. The formal dimension of the construct is defined using different levels as factors of complexity with which teachers can process information relevant for teaching. Both studies provided empirical evidence for the validity of the underlying construct. Based on these results, recommendations for teacher education are given.
Journal Article
Screening for Syphilis in Arrestees: Usefulness for Community-wide Syphilis Surveillance and Control
Background: Syphilis screening of jail arrestees has been promoted as an effective method for both disease control and surveillance. Goals: To evaluate the yield of the East Baton Rouge Parish Jail screening program in detecting previously undiagnosed syphilis, to evaluate the program as a means for monitoring community syphilis rates, and to characterize arrestees at greatest risk for syphilis infection. Study Design: From July 1994 to December 1998, arrestees brought to the East Baton Rouge Parish Jail were screened for syphilis. Annual early syphilis prevalence in screened arrestees was calculated and compared with the annual period prevalence of early syphilis in the general population of East Baton Rouge Parish, as reported by laboratories and health providers. A case-control study of cases detected at the jail from 1995 to 1997 and contemporary controls was conducted. Results: A total of 50,941 arrestees were booked into the East Baton Rouge Parish Jail, of whom 38,573 (76%) were screened for syphilis. Of the 38,573 arrestees screened, 494 (1.3%) were diagnosed with untreated syphilis. Of these, 299 (61%) were treated for syphilis before release. The estimated prevalence of early syphilis in arrestees decreased by 68% during the study period, from 0.79% in 1994 to 0.25% in 1998. During this time, the East Baton Rouge Parish community rates decreased by 79%, from 150 cases per 100,000 to 31 cases per 100,000. In female arrestees, a booking charge of prostitution was associated with syphilis (odds ratio [OR] 7.0; 95% CI, 1.5, 39.3). In male arrestees, a booking charge of felony theft was associated with syphilis (OR 4.8; 95% CI, 1.8,13.8). However, only 15 (12%) of the early syphilis cases would have been detected if screening had been based on the booking charges found to be associated with syphilis in this study. Conclusions: Routine syphilis screening and treatment in jail settings is feasible and identifies many persons with syphilis. Monitoring of syphilis prevalence among arrestees is a useful method for monitoring community prevalence of syphilis. Analysis of booking charges may be useful for determining factors associated with syphilis infection, but not for developing screening criteria.
Journal Article