A partial hominoid humerus from the middle miocene of Castell de Barberà (Vallès-Penedès Basin, Catalonia, Spain)

The hominoid right partial humerus IPS4334, from the middle Miocene (MN 8) of Castell de Barberà (Vallès-Penedès Basin, Catalonia, Spain), is described. It preserves the mid-distal portion of the shaft until the proximal margins of the radial and coronoid fossae, as well as the proximal portion of the olecranon fossa; the capitulum, the trochlea and the two epicondyles are missing. Although morphological comparisons are restricted, available evidence indicates that IPS4334 is more derived towards the modern hominoid condition than the Klein Hadersdorf specimen attributed to Griphopithecus (ca. 13-14 Ma), thus being most similar (except for its larger size and greater robusticity) to the presumably juvenile specimen of Dryopithecus fontani from Saint Gaudens in France (ca. 11-12 Ma). On the basis of shaft measurements and allometric regressions derived for extant hominoids, a body mass estimate around 50 kg is derived for IPS4334. Morphological similarities with the Saint Gaudens specimen, together with the large body mass estimate, suggest a tentative attribution of IPS4334 to cf. D. fontani, which is the largest hominoid taxon so far recorded from the Vallès-Penedès Basin. The larger size and higher robusticity of IPS4334 as compared to the Saint Gaudens specimen might be explained by the juvenile status of the latter and/or sexual dimorphism. When both specimens are considered together with a partial femur from Abocador de Can Mata, D. fontani emerges as a less suspensory ape than the late Miocene Hispanopithecus, the locomotor repertoire of the former emphasizing climbing, but still displaying a significant quadrupedal component.     

Metabolic and molecular action of <Emphasis Type="Italic">Trigonella foenum-graecum</Emphasis> (fenugreek) and trace metals in experimental diabetic tissues

Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion, resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of diabetes mellitus; their use, however, is restricted by their limited action, pharmaco-kinetic properties, secondary failure rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and anti-hyperlipedemic properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin mimetic effects of Trigonella, manganese and vanadium.     

First partial face and upper dentition of the Middle Miocene hominoid Dryopithecus fontani from Abocador de Can Mata (Vallès‐Penedès Basin,Catalonia, NE Spain): Taxonomic and phylogenetic implications

A well‐preserved 11.8‐million‐years‐old lower face attributed to the seminal taxon Dryopithecus fontani (Primates, Hominidae) from the Catalan site ACM/C3‐Ae of the Hostalets de Pierola area (Vallès‐Penedès Basin, Catalonia, NE Spain) is described. The new data indicate that D. fontani is distinct at the genus level from Late Miocene European taxa previously attributed to Dryopithecus, which are here reassigned to Hispanopithecus. The new facial specimen also suggests that D. fontani and the Middle Miocene Pierolapithecus catalaunicus are not synonymous. Anatomical and morphometric analyses further indicate that the new specimen shows a combination of lower facial features—hitherto unknown in Miocene hominoids—that resembles the facial pattern of Gorilla, thus providing the first nondental evidence of gorilla‐like lower facial morphology in the fossil record. Considering the current evidence, the gorilla‐like facial pattern of D. fontani is inferred to be derived relative to previously known stem hominids, and might indicate that this taxon is either an early member of the Homininae or, alternatively, a stem hominid convergent with the lower facial pattern of Gorilla. The biogeographic implications of both alternatives are discussed. This new finding in the Hostalets de Pierola section reinforces the importance of this area for understanding the elusive question of the Middle Miocene origin and early radiation of great apes. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc.     

A partial skeleton of the fossil great ape Hispanopithecus laietanus from Can Feu and the mosaic evolution of crown-hominoid positional behaviors

The extinct dryopithecine Hispanopithecus (Primates: Hominidae), from the Late Miocene of Europe, is the oldest fossil great ape displaying an orthograde body plan coupled with unambiguous suspensory adaptations. On the basis of hand morphology, Hispanopithecus laietanus has been considered to primitively retain adaptations to above-branch quadrupedalism-thus displaying a locomotor repertoire unknown among extant or fossil hominoids, which has been considered unlikely by some researchers. Here we describe a partial skeleton of H. laietanus from the Vallesian (MN9) locality of Can Feu 1 (Vallès-Penedès Basin, NE Iberian Peninsula), with an estimated age of 10.0-9.7 Ma. It includes dentognathic and postcranial remains of a single, female adult individual, with an estimated body mass of 22-25 kg. The postcranial remains of the rib cage, shoulder girdle and forelimb show a mixture of monkey-like and modern-hominoid-like features. In turn, the proximal morphology of the ulna-most completely preserved in the Can Feu skeleton than among previously-available remains-indicates the possession of an elbow complex suitable for preserving stability along the full range of flexion/extension and enabling a broad range of pronation/supination. Such features, suitable for suspensory behaviors, are however combined with an olecranon morphology that is functionally related to quadrupedalism. Overall, when all the available postcranial evidence for H. laietanus is considered, it emerges that this taxon displayed a locomotor repertoire currently unknown among other apes (extant or extinct alike), uniquely combining suspensory-related features with primitively-retained adaptations to above-branch palmigrady. Despite phylogenetic uncertainties, Hispanopithecus is invariably considered an extinct member of the great-ape-and-human clade. Therefore, the combination of quadrupedal and suspensory adaptations in this Miocene crown hominoid clearly evidences the mosaic nature of locomotor evolution in the Hominoidea, as well as the impossibility to reconstruct the ancestral locomotor repertoires for crown hominoid subclades on the basis of extant taxa alone.     

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.     

New dental remains of Hispanopithecus laietanus (Primates: Hominidae) from Can Llobateres 1 and the taxonomy of Late Miocene hominoids from the Vallès-Penedès Basin (NE Iberian Peninsula)

Here we report 12 teeth of the fossil great ape Hispanopithecus (Hominidae: Dryopithecinae: Hispanopithecini), recovered in 2011 from the locality of Can Llobateres 1 (MN9, early Vallesian, Late Miocene, ca. 9.7 Ma [millions of years ago]) in the Vallès-Penedès Basin (Catalonia, Spain). Besides an isolated dP³ from layer CLL1.1b in the eastern (classical) sector of the site, all of the remaining teeth come from facies CLL1.0 (roughly equivalent to CLL1.2 and CLL1.1b), located in the newly excavated western sector, and representing at least two different individuals. Based on facet congruence and degree of wear, all of the upper cheek teeth, a central incisor and a lateral incisor most likely correspond to a single young adult individual of unknown sex, whereas a very worn I² and a female C¹ represent one or two additional individual(s). Morphological and metrical comparisons allow us to attribute these remains to Hispanopithecus laietanus, which is the single hominoid species recognized at CLL1. The newly described teeth represent a significant addition to the hypodigm of this taxon, enabling us to more completely assess the degree of variation displayed by several teeth. In light of the new specimens, the previous tooth position assignment of several upper molars from Can Llobateres and Can Poncic is revised, and the criteria employed to distinguish Hispanopithecus crusafonti from H. laietanus are critically evaluated. On the basis of the available upper cheek teeth from these localities, a distinction at the species level between both samples is tentatively favored, mainly on the basis of P³, M¹ and M² proportions as well as I¹ lingual morphology and proportions. The results of the 2011 field season unambiguously confirm that hominoid-bearing fossiliferous layers from CLL1 are not exhausted. Additional excavations at this site are promising for the discovery of additional remains of H. laietanus in the near future.     

Early human dispersals into the Iberian Peninsula: a comment on Martínez et al.(2010) and Garcia et al. (2011)

Garcia et al. (2011) recently discussed early human dispersals into the Iberian Peninsula, describing several putative lithic artifacts (Martínez et al., 2010) recovered from layer 7 of the Vallpara díssection (Madurell-Malapeira et al., 2010) in Terrassa (Vallès-Penedès Basin, Catalonia, Spain). According to the authors' opinion, such evidence (1) fills a gap in the chronology of early human occupation in Iberia, (2) indicates that these populations had primary and early access to carcasses, and (3) confirms that early human populations were equipped with advanced cultural traits enabling them to survive in unfavourable climatic conditions. We argue below that the record of human activity at Vallparadís (Martínez et al., 2010;Garcia et al., 2011) is doubtful and even that if confirmed, a chronological gap would remain (contra Garcia et al., 2011). Additional remarks on assertions by these authors on the Vallparadís geology, taphonomy and paleonvironment are also provided.     

Murine Borrelia arthritis is highly dependent on ASC and caspase-1, but independent of NLRP3

Introduction

The protein platform called the NOD-like-receptor -family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1β, resulting in bioactive IL-1β. IL-1β is a potent proinflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B. burgdorferi recognition leads to inflammasome activation and processing of IL-1β in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis.

Methods

Lyme arthritis was elicited by live B. burgdorferi, injected intra-articularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences.

Results

We demonstrate that ASC/caspase-1-driven IL-1β is crucial for induction of B. burgdorferi-induced murine Lyme arthritis. In addition, we show that B. burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial.

Conclusions

Murine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC- and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis.