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Mugharet el'Aliya: Affinities of an enigmatic north African Aterian maxillary fragment

Roding, Carolin; Stringer, Chris; Lacruz, Rodrigo S.; Harvati, Katerina
Objectives: This study uses a virtual framework to examine the left maxillary fragment of the juvenile fossil from Mugharet el'Aliya, Morocco, found in association with an Aterian lithic industry. Previously, this fossil had been ascribed to modern humans or the Neanderthal lineage based on its "archaic"/"Neanderthal-like" features and apparent large size. Here, we conducted a novel 3D shape comparative analysis of the maxillary fragment to clarify its taxonomic affinities with regard to its size and ontogeny. Materials and Methods: Eighty Computed Tomography and surface scans representing ontogenetic samples of Homo sapiens and Homo neanderthalensis were used to capture species-specific differences. The toolkit of geometric morphometrics in combination with surface registration and an elastic iterative closest point algorithm were used to create a dataset of meshes with an identical number of corresponding vertices for the maxillae. Multivariate statistics were applied to Procrustes superimposed coordinates derived from the vertices of this dataset. Results: Our analysis showed affinities of the Mugharet el'Aliya individual with our H. sapiens sample, especially with a subadult individual from Qafzeh. No size-independent affinities with Neanderthals of comparable dental age could be identified. Discussion: Our results add to the evidence connecting fossils from western Asia, especially Qafzeh and Skhul, and the North African Aterian. Furthermore, Mugharet el'Aliya adds to our knowledge of the ontogenetic development of adult morphology that is frequently used to characterize hominin groups, for example, Neanderthals and modern humans.
ISSN: 2692-7691
CID: 5408622

PMCA Ca2+ clearance in dental enamel cells depends on the magnitude of cytosolic Ca2

Bomfim, Guilherme Henrique Souza; Giacomello, Marta; Lacruz, Rodrigo S
Enamel formation (amelogenesis) is a two-step process whereby crystals partially grow during the secretory stage followed by a significant growth expansion during the maturation stage concurrent with an increase in vectorial Ca2+ transport. This requires tight regulation of cytosolic Ca2+ (c Ca2+ ) concentration in the enamel forming ameloblasts by controlling Ca2+ influx (entry) and Ca2+ extrusion (clearance). Gene and protein expression studies suggest that the plasma membrane Ca2+ -ATPases (PMCA1-4) are likely involved in c Ca2+ extrusion in ameloblasts, yet no functional analysis of these pumps has been reported nor whether their activity changes across amelogenesis. PMCAs have high Ca2+ affinity and low Ca2+ clearance which may be a limiting factor in their contribution to enamel formation as maturation stage ameloblasts handle high Ca2+ loads. We analyzed PMCA function in rat secretory and maturation ameloblasts by blocking or potentiating these pumps. Low/moderate elevations in c Ca2+ measured using the Ca2+ probe Fura-2-AM show that secretory ameloblasts clear Ca2+ faster than maturation stage cells through PMCAs. This process was completely inhibited by an external alkaline (pH 9.0) solution or was significantly delayed by the PMCA blockers vanadate and caloxin 1b1. Eliciting higher c Ca2+ transients via the activation of the ORAI1 Ca2+ channel showed that the PMCAs of maturation ameloblasts were more efficient. Inhibiting PMCAs decreased the rate of Ca2+ influx via ORAI1 but potentiation with forskolin had no effect. Our findings suggest that PMCAs are functional Ca2+ pumps during amelogenesis regulating c Ca2+ upon low and/or moderate Ca2+ stimulus in secretory stage, thus participating in amelogenesis.
PMID: 36515675
ISSN: 1530-6860
CID: 5394442

Overexpression of RCAN1, a Gene on Human Chromosome 21, Alters Cell Redox and Mitochondrial Function in Enamel Cells

Li, Yi; Costiniti, Veronica; Souza Bomfim, Guilherme H; Neginskaya, Maria; Son, Ga-Yeon; Rothermel, Beverly; Pavlov, Evgeny; Lacruz, Rodrigo S
The regulator of calcineurin (RCAN1) has been implicated in the pathogenesis of Down syndrome (DS). Individuals with DS show dental abnormalities for unknown reasons, and RCAN1 levels have been found to be elevated in several tissues of DS patients. A previous microarray analysis comparing cells of the two main formative stages of dental enamel, secretory and maturation, showed a significant increase in RCAN1 expression in the latter. Because the function of RCAN1 during enamel formation is unknown, there is no mechanistic evidence linking RCAN1 with the dental anomalies in individuals with DS. We investigated the role of RCAN1 in enamel by overexpressing RCAN1 in the ameloblast cell line LS8 (LS8+RCAN1). We first confirmed that RCAN1 is highly expressed in maturation stage ameloblasts by qRT-PCR and used immunofluorescence to show its localization in enamel-forming ameloblasts. We then analyzed cell redox and mitochondrial bioenergetics in LS8+RCAN1 cells because RCAN1 is known to impact these processes. We show that LS8+RCAN1 cells have increased reactive oxygen species (ROS) and decreased mitochondrial bioenergetics without changes in the expression of the complexes of the electron transport chain, or in NADH levels. However, LS8+RCAN1 cells showed elevated mitochondrial Ca2+ uptake and decreased expression of several enamel genes essential for enamel formation. These results provide insight into the role of RCAN1 in enamel and suggest that increased RCAN1 levels in the ameloblasts of individuals with DS may impact enamel formation by altering both the redox environment and mitochondrial function, as well as decreasing the expression of enamel-specific genes.
PMID: 36429004
ISSN: 2073-4409
CID: 5374552

Ca2+-activated chloride channel ANO1: A new regulator of osteoclast function

Partridge, Nicola C; Lacruz, Rodrigo S
A paper by Sun et al. identified the Ca2+-activated Cl- channel anoctamin 1 or ANO1 (TMEM16A) as an important regulator of osteoclast function by interacting with RANKL activating signaling pathways involved in bone resorption. Although Cl- transporters (e.g. ClC7, CLIC5) have been known to be involved in the active process of bone resorption, ANO1 appears to control osteoclast differentiation and function to levels beyond those of other Cl-transporters. Regulating ANO1 function might be a useful target for therapeutics in osteoporosis.
PMID: 35908317
ISSN: 1532-1991
CID: 5289812

On the Connections between TRPM Channels and SOCE

Souza Bomfim, Guilherme H; Niemeyer, Barbara A; Lacruz, Rodrigo S; Lis, Annette
Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca2+-ATPases and Ca2+ exchangers ensure that cytosolic Ca2+ levels ([Ca2+]cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca2+-release-activated Ca2+ (CRAC) channels and voltage-dependent Ca2+ channels (CACNAs), are highly Ca2+-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca2+ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca2+ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg2+, Ca2+, Zn2+ and Na+ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca2+ handling and highlight the available evidence for this interaction.
PMID: 35406753
ISSN: 2073-4409
CID: 5201822

Mitochondria modulate ameloblast Ca2+ signaling

Costiniti, Veronica; Bomfim, Guilherme H S; Neginskaya, Maria; Son, Ga-Yeon; Mitaishvili, Erna; Giacomello, Marta; Pavlov, Evgeny; Lacruz, Rodrigo S
The role of mitochondria in enamel, the most mineralized tissue in the body, is poorly defined. Enamel is formed by ameloblast cells in two main sequential stages known as secretory and maturation. Defining the physiological features of each stage is essential to understand mineralization. Here, we analyzed functional features of mitochondria in rat primary secretory and maturation-stage ameloblasts focusing on their role in Ca2+ signaling. Quantification of the Ca2+ stored in the mitochondria by trifluoromethoxy carbonylcyanide phenylhydrazone stimulation was comparable in both stages. The release of endoplasmic reticulum Ca2+ pools by adenosine triphosphate in rhod2AM-loaded cells showed similar mitochondrial Ca2+ (m Ca2+ ) uptake. However, m Ca2+ extrusion via Na+ -Li+ -Ca2+ exchanger was more prominent in maturation. To address if m Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) played a role in cytosolic Ca2+ (c Ca2+ ) buffering, we stimulated Ca2+ influx via the store-operated Ca2+ entry (SOCE) and blocked MCU with the inhibitor Ru265. This inhibitor was first tested using the enamel cell line LS8 cells. Ru265 prevented c Ca2+ clearance in permeabilized LS8 cells like ruthenium red, and it did not affect ΔΨm in intact cells. In primary ameloblasts, SOCE stimulation elicited a significantly higher m Ca2+ uptake in maturation ameloblasts. The uptake of Ca2+ into the mitochondria was dramatically decreased in the presence of Ru265. Combined, these results suggest an increased mitochondrial Ca2+ handling in maturation but only upon stimulation of Ca2+ influx via SOCE. These functional studies provide insights not only on the role of mitochondria in ameloblast Ca2+ physiology, but also advance the concept that SOCE and m Ca2+ uptake are complementary processes in biological mineralization.
PMID: 35084775
ISSN: 1530-6860
CID: 5157132

Mugharet el'Aliya: Affinities of an enigmatic north African Aterian maxillary fragment

Roeding, Carolin; Stringer, Chris; Lacruz, Rodrigo S.; Harvati, Katerina
ISSN: 2692-7691
CID: 5388662

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function

Souza Bomfim, Guilherme H; Mitaishvili, Erna; Aguiar, Talita Ferreira; Lacruz, Rodrigo S
Mibefradil is a tetralol derivative originally developed as an antagonist of T-type voltage-gated calcium (Ca2+) channels to treat hypertension when used at nanomolar dosage. More recently, its therapeutic application in hypertension has declined and has been instead repurposed as a treatment of cancer cell proliferation and solid tumor growth. Beyond its function as a Cav blocker, the micromolar concentration of mibefradil can stimulate a rise in [Ca2+]cyt although the mechanism is poorly known. The chanzyme TRPM7 (transient receptor potential melastanin 7), the release of intracellular Ca2+ pools, and Ca2+ influx by ORAI channels have been associated with the increase in [Ca2+]cyt triggered by mibefradil. This study aims to investigate the cellular targets and pathways associated with mibefradil's effect on [Ca2+]cyt. To address these questions, we monitored changes in [Ca2+]cyt in the specialized mouse epithelial cells (LS8 and ALC) and the widely used HEK-293 cells by stimulating these cells with mibefradil (0.1 μM to 100 μM). We show that mibefradil elicits an increase in [Ca2+]cyt at concentrations above 10 μM (IC50 around 50 μM) and a fast Ca2+ increase capacity at 100 μM. We found that inhibiting IP3 receptors, depleting the ER-Ca2+ stores, or blocking phospholipase C (PLC), significantly decreased the capacity of mibefradil to elevate [Ca2+]cyt. Moreover, the transient application of 100 μM mibefradil triggered Ca2+ influx by store-operated Ca2+ entry (SOCE) mediated by the ORAI channels. Our findings reveal that IP3R and PLC are potential new targets of mibefradil offering novel insights into the effects of this drug.
PMID: 35006468
ISSN: 2662-8651
CID: 5118402

Calcium Transport in Specialized Dental Epithelia and Its Modulation by Fluoride

Costiniti, Veronica; Bomfim, Guilherme H; Mitaishvili, Erna; Son, Ga-Yeon; Li, Yi; Lacruz, Rodrigo S
Most cells use calcium (Ca2+) as a second messenger to convey signals that affect a multitude of biological processes. The ability of Ca2+ to bind to proteins to alter their charge and conformation is essential to achieve its signaling role. Cytosolic Ca2+ (cCa2+) concentration is maintained low at ~100 nM so that the impact of elevations in cCa2+ is readily sensed and transduced by cells. However, such elevations in cCa2+ must be transient to prevent detrimental effects. Cells have developed a variety of systems to rapidly clear the excess of cCa2+ including Ca2+ pumps, exchangers and sequestering Ca2+ within intracellular organelles. This Ca2+ signaling toolkit is evolutionarily adapted so that each cell, tissue, and organ can fulfill its biological function optimally. One of the most specialized cells in mammals are the enamel forming cells, the ameloblasts, which also handle large quantities of Ca2+. The end goal of ameloblasts is to synthesize, secrete and mineralize a unique proteinaceous matrix without the benefit of remodeling or repair mechanisms. Ca2+ uptake into ameloblasts is mainly regulated by the store operated Ca2+ entry (SOCE) before it is transported across the polarized ameloblasts to reach the insulated enamel space. Here we review the ameloblasts Ca2+ signaling toolkit and address how the common electronegative non-metal fluoride can alter its function, potentially addressing the biology of dental fluorosis.
PMID: 34456880
ISSN: 1664-2392
CID: 5431152

A comprehensive survey of Retzius periodicities in fossil hominins and great apes

Hogg, Russell; Lacruz, Rodrigo; Bromage, Timothy G; Dean, M Christopher; Ramirez-Rozzi, Fernando; Girimurugan, Senthil Balaji; McGrosky, Amanda; Schwartz, Gary T
Recent studies have provided great insight into hominin life history evolution by utilizing incremental lines found in dental tissues to reconstruct and compare the growth records of extant and extinct humans versus other ape taxa. Among the hominins, studies that have examined Retzius periodicity (RP) variation have come to contradictory conclusions in some instances. To clarify RP variation among hominins and better place this variation in its broader evolutionary context, we conduct the most comprehensive analysis of published RP values for hominins and great apes to date. We gathered all available data from the literature on RP data from extant humans, great apes, and fossil hominins and assessed their variation using parametric and nonparametric analyses of variance. We also performed phylogenetic generalized least-squares regressions of RP data for these taxa as well as a larger set of hominoids for which RP data have been published against data for body mass, encephalization, and mean semicircular canal radius (a proxy for metabolic rate). Our results show that modern humans have a mean RP significantly differing from that of other hominins. Pongo also is significantly different from nearly all other taxa in all analyses. Our results also demonstrate that RP variation among hominins scales with respect to body mass, encephalization, and semicircular canal radius similarly to other hominids but that modern humans and Pongo stand out in this regard. Operating within the hypothesis that RP reflects autonomic biorhythms that regulate multiple life history variables, our results reinforce the idea that Homo sapiens has evolved a life history distinct from other hominins, even from other members of Homo, and suggest that many of these life history differences may be driven by hypothalamic output from the brain.
PMID: 33069911
ISSN: 1095-8606
CID: 4641882