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OBJECTIVE: The purpose of this review is to elucidate the metabolic processes involved in the pathogenesis of adolescent idiopathic scoliosis (AIS) in light of research by the present authors as well as current literature. METHODS: Pathogenetic mechanisms

The emergence and diversification of the genus Homo has been linked to various environmental and climatic events. Foremost among these is the increase in aridity and expansion of savanna grasslands in the Late Pliocene of Africa. According to a widely cited hypothesis, the hominid genera Homo and Paranthropus diverged from a more primitive hominid species, probably a species of Australopithecus, between 2.5 and 3.0 Ma as a consequence of global climatic cooling and concomitant environmental change. Nevertheless, interpretations of environmental change in the African Plio-Pleistocene remain controversial, and testable hypotheses linking early hominids to particular environmental processes are compromised by the lack of controls on taphonomic and collection biases that affect most hominid localities as well as poor stratigraphic and chronological resolution. In this study we present evidence of relationships between faunal and environmental change in the context of the well-dated and abundant fossil record of the lower Omo Valley, Ethiopia, using controls for taphonomic and collection biases. Faunal evidence indicates that major environmental changes occurred in the Late Pliocene of East Africa as closed and wooded habitats gave way to more open habitats. However, the pace of change itself varied significantly during this interval. A period of relatively gradual faunal change between 2.9 and 2.5 Ma was followed by a variable pattern of accelerated change beginning 2.5- 2.4 Ma. The appearance of Homo and the first occurrence of stone artifacts in the Omo correlate in time with this shift in faunal variability, suggesting that ecosystem instability provided opportunities and selection pressures important to the dispersal, and possibly also the origination, of the genus Homo.

The lower Omo valley in southwestern Ethiopia provides crucial evidence on the evolutionary paleoecology of PlioPleistocene mammals, including hominids. The Omo sample is made up of nearly 50,000 vertebrate fossils collected by two teams of researchers--the French and American contigents of the International Omo Research Expedition. The French and American collections constitute two independently derived samples that can be compared for taphonomic and collection biases in relation to patterns of faunal change and hominid paleoecology. Comparison of the two samples reveals interesting differences and similarities. In both collections, taxa indicative of open environments vary in concert and become more common through time. The earlier part of the sequence is characterized by a high abundance of suids whereas bovids dominate the latter part of the sequence, beginning at about 2.3 Ma. In general the same taxa are encountered from the bottom to the top of the sequence in both collections. The two collections do differ in the geographic distribution of some taxa, especially during the best-documented intervals (lower Member G units G4 to G13). Grazing bovids and Kobus sigmoidalis are more common in the northern exposures (collected primarily by the American team), while Menelikia and Kobus ancystrocera are more common in the southern areas (collected primarily by the French team). The higher abundance of Menelikia in the southern areas implies that a wetter, more closed environment existed in the lower parts of the Omo drainage just as an expanding lake was beginning to dominate the paleo-landscape at about 2 Ma.

The relationship between climatic and faunal change provides key evidence for hypotheses concerning cause and effect in evolution. In this context, an appropriate scale of faunal analysis is the sedimentary basin, which presents an intermediate level of resolution between large-scale patterns of climatic change and local patterns observed in paleontological localities. Here we integrate and compare data from two of the most fossiliferous sedimentary basins that preserve East African Plio-Pleistocene mammals, the Turkana Basin and the Hadar Region (Kenya and Ethiopia). The data derive from the Hadar Faunal catalog and the Turkana Basin Paleoecology Database. Our results show that the fauna from different areas of the Turkana Basin (Omo, West Turkana, Koobi Fora) did not always vary synchronously. Thus, the proportion of alcelaphine and antilopine bovids in the Omo is very low (less than 5% of the fauna) in the early part of the sequence, but increases after 2.5 Ma and shows pronounced peaks after 2 Ma. In contrast, at East and West Turkana, these bovids have higher abundances than in the Omo and do not show pronounced trends through time. At Hadar, a marked increase in alcelaphine bovids occurs several hundred thousand years earlier than in the Omo. These results show that although climate may have driven some faunal changes in Africa, local and regional environmental differences linked to tectonic and volcanic processes also played a role in shaping the habitats and adaptive pressures affecting early hominid evolution.

Vertebrate faunas provide important evidence for hominid paleoecology over a wide range of scales, from site-specific analysis of taxa directly associated with hominid fossils and archeological materials to assessments of faunal indicators for ecological change through time that affected human evolution. At each level of resolution, the quality and credibility of the paleoecological data depend on the successful integration of three areas of study: taxonomy, taphonomy, and geology (stratigraphy/sedimentology/geochronology). The foundation for paleoecology rests on accurate taxonomic identification of specimens and correct placement of these taxa in a time/space continuum. There are two aspects to the time/space continuum problem: (1) primary data-the locality, stratigraphic position, and geological context of each taxonomic occurrence in the rock record, (2) inferred data--the original ecological habitat of a taxon and its temporal and spatial relationship to other taxa, including hominids. Taphonomy, sedimentology and ecomorphological inference provide the means to take primary data from the occurrence of a fossil taxon and use this to infer past ecology. The validity of inferences relating faunal evidence to the ecology of a hominid species depends on the level of resolution of this evidence, i.e., how it relates spatially and temporally to the hominid remains. Contributions to this symposium provide an overview of primary data from many East African Pliocene sites and present different methods for inferring paleoenvironmental contexts, paleoecological relationships, and evolutionary patterns that work together to increase understanding of the ecological context of human evolution.

Objective: The purpose of this review is to elucidate the metabolic processes involved in the pathogenesis of adolescent idiopathic scoliosis (AIS) in light of research by the present authors as well as current literature.Methods: Pathogenetic mechanisms involved in AIS were modeled as (a) a form of neuromuscular scoliosis (in conjunction with an adverse mechanical environment such as bipedality), in which hormonal and other chemical factors act as regulators of skeletal muscle tone and function; (b) as a consequence of an abnormality in growth of the spinal column (in conjunction with an adverse mechanical environment such as bipedality), in which hormones and other chemical factors act as regulators of growth; and (c) as a mechanical failure of one side of the vertebral column due to a defect in trabecular formation or mineralization (in conjunction with an adverse mechanical environment such as bipedality); in which hormonal and other chemical factors act as regulators of bone formation, mineralization and/or resorption.Results and Conclusion: Current evidence supporting these models individually or in combination is discussed. [ABSTRACT FROM AUTHOR]

Ca 2+ signaling plays a key role in normal and abnormal platelet functions. Understanding platelet Ca 2+ signaling requires the knowledge of proteins involved in this process. Among these proteins are Ca 2+ ATPases or Ca 2+ pumps that deplete the cytosol of Ca 2+ ions. Here, we will particularly focus on two Ca 2+ pump families: the plasma membrane Ca 2+ ATPases (PMCAs) that extrude cytosolic Ca 2+ towards the extracellular medium and the sarco/endoplasmic reticulum Ca 2+ ATPases (SERCAs) that pump Ca 2+ into the endoplasmic reticulum (ER). In the present review, we will summarize data on platelet Ca 2+ ATPases including their identification and biogenesis. First of all, we will present the Ca 2+ ATPase genes and their isoforms expressed in platelets. We will especially focus on a member of the SERCA family, SERCA3, recently found to give rise to a number of species-specific isoforms. Next, we will describe the differences in Ca 2+ ATPase patterns observed in human and rat platelets. Last, we will analyze how the expression of Ca 2+ ATPase isoforms changes during megakaryocytic maturation and show that megakaryocytopoiesis is associated with a profound reorganization of the expression and/or activity of Ca 2+ ATPases. Taken together, these data provide new aspects of investigations to better understand normal and abnormal platelet Ca 2+ signaling. [ABSTRACT FROM AUTHOR]

The sarco(endo) plasmic reticulum Ca2+ ATPases (SERCA) system is a key regulator of calcium cycling and signaling in cardiac and vascular myocytes and is composed of several isoforms. We aimed to characterize 1) the expression of the different SERCA isoforms in normal mouse cardiovascular tissues and 2) the modulation of the SERCA isoform system during cardiovascular pathologies (heart failure and/or atherosclerosis).Five SERCA isoforms - 2a, 2b, 3a, 3b and 3c were detected by RT-PCR and immunoblot in normal mouse heart and thoracic aorta. Absolute mRNA quantification (Table) confirmed that SERCA2a was the predominant isoform in the heart (∼99% of total SERCA mRNA) whereas the ubiquitous isoform SERCA2b represents less than ∼0.1%. Within cardiomyocytes (CM), SERCA2a and 2b were co-localized in the longitudinal SR, whereas SERCA3b was located at the junctional reticulum. In the aorta, SERCA2a accounted for ∼86.0% and SERCA2b for ∼7%. Among SERCA3 isoforms (3a, 3b and 3c), SERCA3b was the most expressed (∼6.5%) and was predominantly found in endothelial and vascular smooth muscle cells (VSMC), together with SERCA2a and 2b.In failing CM the SERCA2a expression was 2-fold down-regulated (from 9.65 to 5.01 pg/10 ng of total mRNA). Furthermore, both SERCA2a and SERCA2b were re-localized from longitudinal to junctional SR. A strong down-regulation of SERCA2a was also observed in atherosclerotic vessels (from 0.27 to 0.13 pg/10 ng of total mRNA) containing mainly synthetic VSMC; the proportion of both SERCA2b and SERCA3b increased to reach 8% and 7% respectively.In summary, we established that 1) the overall expression of SERCA mRNA is ∼ 50 fold higher in the heart compared to vascular tissues; 2) although several SERCA isoforms are expressed in cardiovascular tissues, SERCA2a is the major isoform in both cardiac and vascular myocytes; 3) nearly half the amount of SERCA2a mRNA is measured in both failing cardiomyocytes and synthetic VSMCs compared to healthy tissues. Together with the evidence of SERCA2a delocalization from longitudinal reticulum in hypertrophied cardiomyocytes, our study prove that SERCA2a is the principal regulator of excitation-contraction coupling in both CMs and contractile VSMCs and also supports a dynamic and integrated regulation of the SERCA isoform system, which deserves further studies. [ABSTRACT FROM AUTHOR]

High-dose irradiation can trigger numerous endothelial dysfunctions, including apoptosis, the overexpression of adhesion molecules, and alteration of adherens junctions. Altogether, these endothelial dysfunctions contribute to the development of tissue inflammation and organ damage. The development of endothelial dysfunctions may depend on protein phosphorylation by various protein kinases, but the possible role of protein kinase A (PKA) has not been investigated so far, and efficient compounds able to protect the endothelium from irradiation effects are needed. Here we report the beneficial effects of the PKA inhibitor KT5720 on a panel of irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). High-dose X-irradiation (15 Gy) triggered the late apoptosis of HPMECs independent of the ceramide/P38 MAP kinase pathway or p53. In contrast, the treatment of HPMECs with KT5720 completely prevented irradiation-induced apoptosis, whether applied before or after cell irradiation. Immunostainings of irradiated monolayers revealed that KT5720 treatment preserved the overall integrity of endothelial monolayers and adherens junctions linking endothelial cells. Real-time impedance measurements performed in HPMEC monolayers confirmed the overall protective role of KT5720 against irradiation. Treatment with KT5720 before or after irradiation also reduced irradiation-induced ICAM-1 overexpression. Finally, the possible role for PKA in the development of endothelial dysfunctions is discussed, but the potency of KT5720 to inhibit the development of a panel of irradiation-induced endothelial dysfunctions, whether applied before or after irradiation, suggests that this compound could be of great interest for both the prevention and treatment of vascular damages in the event of exposure to a high dose of radiation.

Ca 2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation "two-pore channel" (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2 -/- ) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment. In cardiomyocytes isolated from Tpcn1/2 -/- mice, we observed a reduction in the contractile function with a decrease in the sarcoplasmic reticulum Ca 2+ content and a reduced expression of various key proteins regulating Ca 2+ stores, such as calsequestrin. We also found that two main regulators of the energy metabolism, AMP-activated protein kinase and mTOR, were down regulated. We found an increase in the expression of TPC1 and TPC2 in a model of transverse aortic constriction (TAC) mice and in chronically isoproterenol infused WT mice. In this last model, adaptive cardiac hypertrophy was reduced by Tpcn1/2 deletion. Here, we propose a central role for TPCs and lysosomes that could act as a hub integrating information from the excitation-contraction coupling mechanisms, cellular energy metabolism and hypertrophy signaling., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Ltd.)

The Miocene was a key time in the evolution of African ecosystems witnessing the origin of the African apes and the isolation of eastern coastal forests through an expanding arid corridor. Until recently, however, Miocene sites from the southeastern regions of the continent were unknown. Here, we report the first Miocene fossil teeth from the shoulders of the Urema Rift in Gorongosa National Park, Mozambique. We provide the first 1) radiometric ages of the Mazamba Formation, 2) reconstructions of paleovegetation in the region based on pedogenic carbonates and fossil wood, and 3) descriptions of fossil teeth. Gorongosa is unique in the East African Rift in combining marine invertebrates, marine vertebrates, reptiles, terrestrial mammals, and fossil woods in coastal paleoenvironments. The Gorongosa fossil sites offer the first evidence of woodlands and forests on the coastal margins of southeastern Africa during the Miocene, and an exceptional assemblage of fossils including new species., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Pathophysiologic platelet activation leads to thrombo-occlusive diseases such as myocardial infarction or ischemic stroke. Niemann-Pick C1 protein (NPC1) is involved in the regulation of lysosomal lipid trafficking and calcium ion (Ca 2+ ) signaling, and its genetic mutation causes a lysosomal storage disorder. Lipids and Ca 2+ are key players in the complex orchestration of platelet activation., Objectives: The present study aimed to determine the impact of NPC1 on Ca 2+ mobilization during platelet activation in thrombo-occlusive diseases., Methods: Using MK/platelet-specific knockout mice of Npc1 (Npc1 Pf4∆/Pf4∆ ), ex vivo and in vitro approaches as well as in vivo models of thrombosis, we investigated the effect of Npc1 on platelet function and thrombus formation., Results: We showed that Npc1 Pf4∆/Pf4∆  platelets display increased sphingosine levels and a locally impaired membrane-associated and SERCA3-dependent Ca 2+  mobilisation compared to platelets from wildtype littermates (Npc1 lox/lox ). Further, we observed decreased platelet., Conclusion: Our findings highlight that NPC1 regulates membrane-associated and SERCA3-dependent Ca 2+ mobilization during platelet activation and that MK/platelet-specific ablation of Npc1 protects against experimental models of arterial thrombosis and myocardial or cerebral ischemia/reperfusion injury., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

During the middle Pliocene (∼3.8-3.2 Ma), both Australopithecus afarensis and Kenyanthropus platyops are known from the Turkana Basin, but between 3.60 and 3.44 Ma, most hominin fossils are found on the west side of Lake Turkana. Here, we describe a new hominin locality (ET03-166/168, Area 129) from the east side of the lake, in the Lokochot Member of the Koobi Fora Formation (3.60-3.44 Ma). To reconstruct the paleoecology of the locality and its surroundings, we combine information from sedimentology, the relative abundance of associated mammalian fauna, phytoliths, and stable isotopes from plant wax biomarkers, pedogenic carbonates, and fossil tooth enamel. The combined evidence provides a detailed view of the local paleoenvironment occupied by these Pliocene hominins, where a biodiverse community of primates, including hominins, and other mammals inhabited humid, grassy woodlands in a fluvial floodplain setting. Between <3.596 and 3.44 Ma, increases in woody vegetation were, at times, associated with increases in arid-adapted grasses. This suggests that Pliocene vegetation included woody species that were resilient to periods of prolonged aridity, resembling vegetation structure in the Turkana Basin today, where arid-adapted woody plants are a significant component of the ecosystem. Pedogenic carbonates indicate more woody vegetation than other vegetation proxies, possibly due to differences in temporospatial scale and ecological biases in preservation that should be accounted for in future studies. These new hominin fossils and associated multiproxy paleoenvironmental indicators from a single locale through time suggest that early hominin species occupied a wide range of habitats, possibly including wetlands within semiarid landscapes. Local-scale paleoecological evidence from East Turkana supports regional evidence that middle Pliocene eastern Africa may have experienced large-scale, climate-driven periods of aridity. This information extends our understanding of hominin environments beyond the limits of simple wooded, grassy, or mosaic environmental descriptions., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Blood platelet Ca 2+ stores are regulated by 2 Ca 2+ -ATPases (SERCA2b and SERCA3). On thrombin stimulation, nicotinic acid adenosine dinucleotide phosphate mobilizes SERCA3-dependent stores, inducing early adenosine 5'-diphosphate (ADP) secretion, potentiating later SERCA2b-dependent secretion., Objectives: The aim of this study was to identify which ADP P2 purinergic receptor (P2Y1 and/or P2Y12) is(are) involved in the amplification of platelet secretion dependent on the SERCA3-dependent Ca 2+ mobilization pathway (SERCA3 stores mobilization) as triggered by low concentration of thrombin., Methods: The study used the pharmacologic antagonists MRS2719 and AR-C69931MX, of the P2Y1 and P2Y12, respectively, as well as Serca3 -/- mice and mice exhibiting platelet lineage-specific inactivation of the P2Y1 or P2Y12 genes., Results: We found that in mouse platelets, pharmacological blockade or gene inactivation of P2Y12 but not of P2Y1 led to a marked inhibition of ADP secretion after platelet stimulation with low concentration of thrombin. Likewise, in human platelets, pharmacological inhibition of P2Y12 but not of P2Y1 alters amplification of thrombin-elicited secretion through SERCA2b stores mobilization. Finally, we show that early SERCA3 stores secretion of ADP is a dense granule secretion, based on parallel adenosine triphosphate and serotonin early secretion. Furthermore, early secretion involves a single granule, based on the amount of adenosine triphosphate released., Conclusion: Altogether, these results show that at low concentrations of thrombin, SERCA3- and SERCA2b-dependent Ca 2+ mobilization pathways cross-talk via ADP and activation of the P2Y12, and not the P2Y1 ADP receptor. The relevance in hemostasis of the coupling of the SERCA3 and the SERCA2b pathways is reviewed., (© 2022 The Author(s).)

The immunosuppressant drug Cyclosporin A (CsA) has been widely used to prevent the development of Graft-versus-Host Disease (GvHD) that can occur after transplantation, including allogeneic graft after accidental high-dose irradiation in humans. Here, we show that CsA alone stimulates ICAM-1 overexpression in human pulmonary microvascular endothelial cells (HPMECs) through Toll-Like Receptor 4 (TLR4) and NF-κB activation. In HPMECs, CsA treatment significantly worsened the overexpression of ICAM-1 induced by high-dose irradiation (15 Gy). This additive effect of CsA was also observed when ICAM-1 overexpression was induced by another pathway (Ca 2+ entry) in macrovascular endothelial cells. In addition, CsA triggered apoptosis as well as rearrangement of the actin cytoskeleton and adherens junctions (VE-Cadherin) in microvascular endothelial monolayers. High-dose irradiation triggered similar deleterious effects in endothelial monolayers and, again, CsA treatment strongly aggravated the effects of irradiation. Altogether, these results suggest that post-transplant CsA treatment may exacerbate the deleterious effects of irradiation on the endothelium., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Gorongosa National Park in Mozambique hosts a large population of baboons, numbering over 200 troops. Gorongosa baboons have been tentatively identified as part of Papio ursinus on the basis of previous limited morphological analysis and a handful of mitochondrial DNA sequences. However, a recent morphological and morphometric analysis of Gorongosa baboons pinpointed the occurrence of several traits intermediate between P. ursinus and P. cynocephalus, leaving open the possibility of past and/or ongoing gene flow in the baboon population of Gorongosa National Park. In order to investigate the evolutionary history of baboons in Gorongosa, we generated high and low coverage whole genome sequence data of Gorongosa baboons and compared it to available Papio genomes., Results: We confirmed that P. ursinus is the species closest to Gorongosa baboons. However, the Gorongosa baboon genomes share more derived alleles with P. cynocephalus than P. ursinus does, but no recent gene flow between P. ursinus and P. cynocephalus was detected when available Papio genomes were analyzed. Our results, based on the analysis of autosomal, mitochondrial and Y chromosome data, suggest complex, possibly male-biased, gene flow between Gorongosa baboons and P. cynocephalus, hinting to direct or indirect contributions from baboons belonging to the "northern" Papio clade, and signal the presence of population structure within P. ursinus., Conclusions: The analysis of genome data generated from baboon samples collected in central Mozambique highlighted a complex set of evolutionary relationships with other baboons. Our results provided new insights in the population dynamics that have shaped baboon diversity., (© 2022. The Author(s).)