Evolutionarily assembled cis-regulatory module at a human ciliopathy locus

Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.     

Cartwheel architecture of Trichonympha basal body

Centrioles and basal bodies are essential for the formation of cilia, flagella, and centrosomes. They exhibit a characteristic ninefold symmetry imparted by a cartwheel thought to contain rings of SAS-6 proteins. We used cryoelectron tomography to investigate the architecture of the exceptionally long cartwheel of the flagellate Trichonympha. We found that the cartwheel is a stack of central rings that exhibit a vertical periodicity of 8.5 nanometers and is able to accommodate nine SAS-6 homodimers. The spokes that emanate from two such rings associate into a layer, with a vertical periodicity of 17 nanometers on the cartwheel margin. Thus, by using the power of biodiversity, we unveiled the architecture of the cartwheel at the root of the ninefold symmetry of centrioles and basal bodies.     

Formation and subdivision of deformation structures during plastic deformation

During plastic deformation of metals and alloys, dislocations arrange in ordered patterns. How and when these self-organization processes take place have remained elusive, because in situ observations have not been feasible. We present an x-ray diffraction method that provided data on the dynamics of individual, deeply embedded dislocation structures. During tensile deformation of pure copper, dislocation-free regions were identified. They showed an unexpected intermittent dynamics, for example, appearing and disappearing with proceeding deformation and even displaying transient splitting behavior. Insight into these processes is relevant for an understanding of the strength and work-hardening of deformed materials.     

The role of agro-ecological factors and transboundary transhumance in shaping the genetic diversity in four indigenous cattle populations of Benin

The indigenous cattle population of Benin is a diverse mix of taurine and hybrid breeds shaped by diverse ecological and climatic conditions with eight agro-ecological zones (AEZ). Presumably, the taurine breeds face current endangerment due to ongoing indicine introgression following climate change and transboundary transhumance. The aim of the study was to investigate the genetic diversity and population structure of the indigenous breeds Lagune, Somba, Pabli and Borgou considering spatial agro-ecological and socio-economic factors (transhumance) based on 50k SNP and microsatellite data. Among the four sampled breeds, six genetic clusters were identified using model-free (discriminant analysis of principal components) and model-based (TESS and ADMIXTURE) methods separating taurine from hybrid breeds. Results based on an extension with publicly available historic SNP data sets from taurine and indicine West African cattle and additional outgroups provided additional insight into changes of genetic structure in the sampled breeds over time. Both taurine breeds, Somba and Lagune, showed a stable foundation but also spatially limited partial indicine introgression associated with transhumance leading to high genetic diversity. In addition, we found evidence for spatial diversity and changes in genetic structure over time in the Borgou breed in comparison of our samples with the historic samples which could be explained by potential continuous indicine introgression into the Borgou breed in two sample regions. Results for the Pabli breed do not conclusively point to full absorbance by the Borgou in comparison with all available Borgou samples. Further research is needed in this regard.     

The impact of vatinoxan on medetomidine–ketamine–midazolam immobilization in Patagonian maras (Dolichotis patagonum)

ObjectiveTo compare cardiovascular and ventilatory effects, immobilization quality and effects on tissue perfusion of a medetomidine–ketamine–midazolam combination with or without vatinoxan (MK-467), a peripherally acting α₂-adrenoceptor antagonist.Study designRandomized, blinded, crossover study.AnimalsA group of nine healthy Patagonian maras (Dolichotis patagonum).MethodsMaras were immobilized twice with: 1) medetomidine hydrochloride (0.1 mg kg^–1) + ketamine (5 mg kg^–1) + midazolam (0.1 mg kg^–1) (MKM) + saline or 2) MKM + vatinoxan hydrochloride (0.8 mg kg^–1), administered intramuscularly. Drugs were mixed in the same syringe. At 20, 30 and 40 minutes after injection, invasive blood pressure, heart rate, respiration rate, end-tidal CO₂, haemoglobin oxygen saturation, and muscle oxygenation were measured, arteriovenous oxygen content difference was calculated. Muscle tone, jaw tone, spontaneous blinking and palpebral reflex were evaluated. Times to initial effect, recumbency, initial arousal and control of the head were recorded. Paired t test, Wilcoxon matched-pairs signed rank test and analysis of variance were used to compare protocols; (p < 0.05).ResultsVatinoxan significantly reduced systolic (p = 0.0002), mean (MAP; p < 0.0001) and diastolic (p < 0.0001) arterial blood pressures between 20 and 40 minutes. MAPs at 30 minutes (mean ± standard deviation) with MKM and MKM + vatinoxan were 105 ± 12 and 71 ± 14 mmHg, respectively. Without vatinoxan, four animals were hypertensive (MAP > 120 mmHg), whereas with vatinoxan, four animals were hypotensive (MAP < 60 mmHg). Muscle and jaw tone were significantly more frequently present with MKM (both p = 0.039). Other measurements did not significantly differ between protocols.Conclusions and clinical relevanceIn Patagonian maras, vatinoxan attenuated the increase in blood pressure induced by medetomidine. Muscle and jaw tone were more frequently present with MKM, indicating that quality of immobilization with vatinoxan was more profound.     

Rheology and microscopic topology of entangled polymeric liquids

The viscoelastic properties of high molecular weight polymeric liquids are dominated by topological constraints on a molecular scale. In a manner similar to that of entangled ropes, polymer chains can slide past but not through each other. Tube models of polymer dynamics and rheology are based on the idea that entanglements confine a chain to small fluctuations around a primitive path that follows the coarse-grained chain contour. Here we provide a microscopic foundation for these highly successful phenomenological models. We analyze the topological state of polymeric liquids in terms of primitive paths and obtain parameter-free, quantitative predictions for the plateau modulus, which agree with experiment for all major classes of synthetic polymers.     

Tumor regression in cancer patients by very low doses of a T cell-engaging antibody

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non-Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell-engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.     

Rapid stakeholder and conflict assessment for natural resource management using cognitive mapping: The case of Damdoi Forest Enterprise,Vietnam

Understanding stakeholders perceptions and motivations is of significant importance in relation to conservation and protected area projects. The importance of stakeholder analysis is widely recognized as a necessary means for gaining insight into the complex systemic interactions between natural processes, management policies, and local people depending on the resource. Today, community and group-based participatory inquiry approaches are widely used for this purpose. Recently, participatory approaches have been critiqued for not considering power relations and conflict internal to the community. In this article, we suggest that the five-step Rapid Stakeholder and Conflict Assessment (RSCA) methodology addresses this critique. The objective of the methodology is to provide a facilitator with a comprehensive foundation on which to plan and conduct subsequent participatory project development. The RSCA integrates elements of soft systems and critical systems thinking. Qualitative research interviews and cognitive mapping of stakeholders mental models are used for collection of empirical material and analysis. The RSCA methodology is demonstrated in a case study concerning buffer zone management in the coastal wetlands of southern Vietnam. The case study shows that the RSCA methodology can provide an efficient way of obtaining a holistic and critical understanding of a complex resource management situation, thus potentially enhancing project performance in an instrumental as well as an ethical sense.