The endocast from Dana Aoule North (DAN5/P1): A 1.5 million year-old human braincase from Gona, Afar, Ethiopia.

The nearly complete cranium DAN5/P1 was found at Gona (Afar, Ethiopia), dated to 1.5-1.6 Ma, and assigned to the species Homo erectus.

Increased core body temperature exacerbates defective protein prenylation in mouse models of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.

Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages.

Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo.

Canine sexual dimorphism in was nearly human-like.

Body and canine size dimorphism in fossils inform sociobehavioral hypotheses on human evolution and have been of interest since Darwin's famous reflections on the subject. Here, we assemble a large dataset of fossil canines of the human clade, including all available fossils recovered from the Middle Awash and Gona research areas in Ethiopia, and systematically examine canine dimorphism through evolutionary time. In particular, we apply a Bayesian probabilistic method that reduces bias when estimating weak and moderate levels of dimorphism.

Estimating sexual size dimorphism in fossil species from posterior probability densities.

Accurate characterization of sexual dimorphism is crucial in evolutionary biology because of its significance in understanding present and past adaptations involving reproductive and resource use strategies of species. However, inferring dimorphism in fossil assemblages is difficult, particularly with relatively low dimorphism. Commonly used methods of estimating dimorphism levels in fossils include the mean method, the binomial dimorphism index, and the coefficient of variation method.

Synthesis and Characterization of Bone Binding Antibiotic-1 (BBA-1), a Novel Antimicrobial for Orthopedic Applications.

Osteomyelitis and orthopedic infections are major clinical problems, limited by a lack of antibiotics specialized for such applications. In this paper, we describe the design and synthesis of a novel bone-binding antibiotic (BBA-1) and its subsequent structural and functional characterization. The synthesis of BBA-1 was the result of a two-step chemical conjugation of cationic selective antimicrobial-90 (CSA-90) and the bisphosphonate alendronate (ALN) via a heterobifunctional linker.

Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation.

Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton.

Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues.

Fossil Cercopithecidae from the Early Pliocene Sagantole Formation at Gona, Ethiopia.

The Early Pliocene Sagantole Fm. in the Gona Project area, Afar State, Ethiopia, is noted for discoveries of the early hominin Ardipithecus ramidus. A large series of fossil cercopithecid primates dated to between 4.

Oxysterols: From physiological tuners to pharmacological opportunities.

Oxysterols are oxygenated forms of cholesterol generated via autooxidation by free radicals and ROS, or formed enzymically by a variety of enzymes such as those involved in the synthesis of bile acids. Although found at very low concentrations in vivo, these metabolites play key roles in health and disease, particularly in development and regulating immune cell responses, by binding to effector proteins such as LXRα, RORγ and Insig and directly or indirectly regulating transcriptional programmes that affect cell metabolism and function. In this review, we summarise the routes by which oxysterols can be generated and subsequently modified to other oxysterol metabolites and highlight their diverse and profound biological functions and opportunities to alter their levels using pharmacological approaches.

Co-occurrence of Acheulian and Oldowan artifacts with cranial fossils from Gona, Afar, Ethiopia.

Although stone tools generally co-occur with early members of the genus , they are rarely found in direct association with hominins. We report that both Acheulian and Oldowan artifacts and crania were found in close association at 1.26 million years (Ma) ago at Busidima North (BSN12), and ca.

Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency.

The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the gene encoding mevalonate kinase. Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases.

Ardipithecus ramidus postcrania from the Gona Project area, Afar Regional State, Ethiopia.

Functional analyses of the 4.4 Ma hominin Ardipithecus ramidus postcrania revealed a previously unknown and unpredicted locomotor pattern combining arboreal clambering and a form of terrestrial bipedality. To date, all of the fossil evidence of Ar.

From vesicle to cytosol.

Drugs called bisphosphonates are used to treat a range of bone diseases, but how do they reach the enzymes that are their target?

Melphalan modifies the bone microenvironment by enhancing osteoclast formation.

Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.

Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases.

Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate-cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1β (IL-1β). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions.

Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche.

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation.

A highly sensitive prenylation assay reveals in vivo effects of bisphosphonate drug on the Rab prenylome of macrophages outside the skeleton.

Bisphosphonate drugs such as zoledronic acid (ZOL), used for the treatment of common bone disorders, target the skeleton and inhibit bone resorption by preventing the prenylation of small GTPases in bone-destroying osteoclasts. Increasing evidence indicates that bisphosphonates also have pleiotropic effects outside the skeleton, most likely via cells of the monocyte/macrophage lineage exposed to nanomolar circulating drug concentrations. However, no effects of such low concentrations of ZOL have been reported using existing approaches.

Late Miocene hominin teeth from the Gona Paleoanthropological Research Project area, Afar, Ethiopia.

Since 2000, significant collections of Latest Miocene hominin fossils have been recovered from Chad, Kenya, and Ethiopia. These fossils have provided a better understanding of earliest hominin biology and context. Here, we describe five hominin teeth from two periods (ca.

Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer.

Unlabelled: Recent clinical trials have shown that bisphosphonate drugs improve breast cancer patient survival independent of their antiresorptive effects on the skeleton. However, because bisphosphonates bind rapidly to bone mineral, the exact mechanisms of their antitumor action, particularly on cells outside of bone, remain unknown. Here, we used real-time intravital two-photon microscopy to show extensive leakage of fluorescent bisphosphonate from the vasculature in 4T1 mouse mammary tumors, where it initially binds to areas of small, granular microcalcifications that are engulfed by tumor-associated macrophages (TAM), but not tumor cells.

Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells.

Nitrogen-containing bisphosphonates (N-BPs) such as zoledronic acid (ZOL) are the gold standard treatment for diseases of excessive bone resorption. N-BPs inactivate osteoclasts via inhibition of farnesyl diphosphate synthase (FPPS), thereby preventing the prenylation of essential small GTPases. Not all patients respond to N-BP therapy to the same extent, and some patients, for example with tumour-associated bone disease or Paget's disease, appear to develop resistance to N-BPs.