A new burnetiamorph (Therapsida: Biarmosuchia) from the Lower Beaufort Group of South Africa

The basal clade Burnetiamorpha is known from only two specimens representing two genera, Proburnetia from the Severodvinskian horizon of the Vyatka River Basin in the Kotelnich district of Russia, and Burnetia from the Dicynodon Assemblage Zone of the Beaufort Group of South Africa. Both genera are of Late Tatarian (Late Permian) age. This paper describes the cranial morphology of a new genus of burnetiamorph, Bullacephalus , from the Late Permian Tapinocephalus Assemblage Zone of the Beaufort Group of South Africa. It is known from a relatively complete skull and lower jaw and is the best preserved burnetiamorph yet discovered. Apart from being the oldest member of the clade, Bullacephalus is also morphologically the least derived and provides new evidence on the phylogeny of this poorly understood group of basal therapsids.     

Long bone scaling in Captorhinidae: do limb bones scale according to elastic similarity in sprawling basal amniotes?

Captorhinids are a speciose clade of sauropsids that are crucial to understand several aspects of basal amniote general biology. Members of the Captorhinidae explored different diets and, amongst basal amniotes, were one of the first groups to demonstrate high‐fibre herbivory. Several papers have been published on the cranial anatomy of captorhinids, but there are relatively few studies which focus on the post‐cranium, especially on the appendicular skeleton and long bones. This contribution presents the first quantitative long bone scaling in Captorhinidae performed through morphometric analyses. From classical biomechanical research, it is well‐established that to accommodate an increase in size, gravity will result in elastic deformation of long bones. This outcome is especially significant in terrestrial tetrapods with a sprawling limb posture such as captorhinids, where great torsional stresses are applied to long bones, both during locomotion and in the resting phase. In this paper, we test whether the consistent evolutionary size increase in captorhinids led to major re‐patterning in long bone structure as theoretically expected, based on the theory of elastic similarity. Morphometric analysis shows that, apart from a small positive allometry in the humerus, captorhinid long bones scale geometrically as body size increases. Thus, the predicted elastic similarity to maintain similar levels in peak stress with an increase in dimensions does not seem not to apply to long bone evolution in captorhinids. We propose that, as already observed experimentally in larger‐bodied varanid lizards, large captorhinids could also mitigate size‐related increases in stress by reducing femur rotation and increasing the percentage of the stride cycle during which the right hindfoot was on the ground (i.e. the duty factor). In this way, large captorhinids could avoid reaching peak stress thresholds by sacrificing speed during locomotion and without a substantial long bone re‐patterning or postural change.     

<Emphasis Type="Italic">TRAF1/C5</Emphasis>polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies

Introduction  

Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients.     

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.     

When and how did the terrestrial mid-Permian mass extinction occur? Evidence from the tetrapod record of the Karoo Basin,South Africa

A mid-Permian (Guadalupian epoch) extinction event at approximately 260 Ma has been mooted for two decades. This is based primarily on invertebrate biostratigraphy of Guadalupian–Lopingian marine carbonate platforms in southern China, which are temporally constrained by correlation to the associated Emeishan Large Igneous Province (LIP). Despite attempts to identify a similar biodiversity crisis in the terrestrial realm, the low resolution of mid-Permian tetrapod biostratigraphy and a lack of robust geochronological constraints have until now hampered both the correlation and quantification of terrestrial extinctions. Here we present an extensive compilation of tetrapod-stratigraphic data analysed by the constrained optimization (CONOP) algorithm that reveals a significant extinction event among tetrapods within the lower Beaufort Group of the Karoo Basin, South Africa, in the latest Capitanian. Our fossil dataset reveals a 74–80% loss of generic richness between the upper Tapinocephalus Assemblage Zone (AZ) and the mid-Pristerognathus AZ that is temporally constrained by a U–Pb zircon date (CA-TIMS method) of 260.259 ± 0.081 Ma from a tuff near the top of the Tapinocephalus AZ. This strengthens the biochronology of the Permian Beaufort Group and supports the existence of a mid-Permian mass extinction event on land near the end of the Guadalupian. Our results permit a temporal association between the extinction of dinocephalian therapsids and the LIP volcanism at Emeishan, as well as the marine end-Guadalupian extinctions.     

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Background

Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC₅₀ values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC₅₀) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.

Results

The PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC₅₀ = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC₅₀ = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆G_solv) were also considered.

Conclusions

A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC₅₀ data.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.     

Loss of CDK5RAP2 affects neural but not non-neural mESC differentiation into cardiomyocytes

Biallelic mutations in the gene encoding centrosomal CDK5RAP2 lead to autosomal recessive primary microcephaly (MCPH), a disorder characterized by pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. The current model for the microcephaly phenotype in MCPH invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool. The isolated neural phenotype, despite the ubiquitous expression of CDK5RAP2, and reports of progressive microcephaly in individual MCPH cases prompted us to investigate neural and non-neural differentiation of Cdk5rap2-depleted and control murine embryonic stem cells (mESC). We demonstrate an accumulating proliferation defect of neurally differentiating Cdk5rap2-depleted mESC and cell death of proliferative and early postmitotic cells. A similar effect does not occur in non-neural differentiation into beating cardiomyocytes, which is in line with the lack of non-central nervous system features in MCPH patients. Our data suggest that MCPH is not only caused by premature differentiation of progenitors, but also by reduced propagation and survival of neural progenitors.     

RETRACTED ARTICLE: Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium

Introduction  

Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease. Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator. Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well. We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients.     

A Relict Rhinesuchid (Amphibia: Temnospondyli) From The Lower Triassic Of South Africa

' Lydekkerina ' putterilli Broom from the Lystrosaurus Assemblage Zone (Middle Beaufort Group, South Africa) is shown to be a paedomorphic rhinesuchid ( Broomistega putterilli gen. nov.) rather than a lydekkerinid or juvenile stage of the rhinesuchid Uranocentrodon , as previously presumed. The most conspicuous characters, not related to its paedomorphic condition, include the shape of the parietals and the structure of the parasphenoid body and exoccipitals. The pattern of cranial growth changes in Broomistega has been investigated by comparison of the holotype with two hitherto undescribed immature specimens. For several characters referring to the size and position of the orbits, and re-modelling of the jugal proportions, retarded timing of growth transformations, compared to ontogenetic patterns in Permian rhinesuchids (typified by Muchocephalus ) is demonstrated. Some features of the evolution of the basicranial region of the skull, in the transition from rhinesuchids to more advanced capitosauroids, are re-evaluated. key words : temnospondyls, rhinesuchids, relict, paedomorphosis, growth changes.