Recent origin of low trabecular bone density in modern humans

Humans are unique, compared with our closest living relatives (chimpanzees) and early fossil hominins, in having an enlarged body size and lower limb joint surfaces in combination with a relatively gracile skeleton (i.e., lower bone mass for our body size). Some analyses have observed that in at least a few anatomical regions modern humans today appear to have relatively low trabecular density, but little is known about how that density varies throughout the human skeleton and across species or how and when the present trabecular patterns emerged over the course of human evolution. Here, we test the hypotheses that (i) recent modern humans have low trabecular density throughout the upper and lower limbs compared with other primate taxa and (ii) the reduction in trabecular density first occurred in early Homo erectus, consistent with the shift toward a modern human locomotor anatomy, or more recently in concert with diaphyseal gracilization in Holocene humans. We used peripheral quantitative CT and microtomography to measure trabecular bone of limb epiphyses (long bone articular ends) in modern humans and chimpanzees and in fossil hominins attributed to Australopithecus africanus, Paranthropus robustus/early Homo from Swartkrans, Homo neanderthalensis, and early Homo sapiens. Results show that only recent modern humans have low trabecular density throughout the limb joints. Extinct hominins, including pre-Holocene Homo sapiens, retain the high levels seen in nonhuman primates. Thus, the low trabecular density of the recent modern human skeleton evolved late in our evolutionary history, potentially resulting from increased sedentism and reliance on technological and cultural innovations

The Locomotion of Babakotia radofilai Inferred From Epiphyseal and Diaphyseal Morphology of the Humerus and Femur

Palaeopropithecids, or “sloth lemurs,” are a diverse clade of large-bodied Malagasy subfossil primates characterized by their inferred suspensory positional behavior. The most recently discovered genus of the palaeopropithecids is Babakotia, and it has been described as more arboreal than Mesopropithecus, but less than Palaeopropithecus. In this article, the withinbone and between-bones articular and cross-sectional diaphyseal proportions of the humerus and femur of Babakotia were compared to extant lemurs, Mesopropithecus and Palaeopropithecus in order to further understand its arboreal adaptations. Additionally, a sample of apes and sloths (Choloepus and Bradypus) are included as functional outgroups composed of suspensory adapted primates and non-primates. Results show that Babakotia and Mesopropithecus both have high humeral/femoral shaft strength proportions, similar to extant great apes and sloths and indicative of forelimb suspensory behavior, with Babakotia more extreme in this regard. All three subfossil taxa have relatively large femoral heads, also associated with suspension in modern taxa. However, Babakotia and Mesopropithecus (but not Palaeopropithecus) have relatively small femoral head surface area to shaft strength proportions suggesting that hind-limb positioning in these taxa during climbing and other behaviors was different than in extant great apes, involving less mobility. Knee and humeral articular dimensions relative to shaft strengths are small in Babakotia and Mesopropithecus, similar to those found in modern sloths and divergent from those in extant great apes and lemurs, suggesting more sloth-like use of these joints during locomotion. Mesopropithecus and Babakotia are more similar to Choloepus in humerofemoral head and length proportions while Palaeopropithecus is more similar to Bradypus. These results provide further evidence of the suspensory adaptations of Babakotia and further highlight similarities to both extant suspensory primates and non-primate slow arboreal climbers and hangers

Differential Susceptibility to Hypertension Is Due to Selection during the Out-of-Africa Expansion

Hypertension is a leading cause of stroke, heart disease, and kidney failure. The genetic basis of blood pressure variation is largely unknown but is likely to involve genes that influence renal salt handling and arterial vessel tone. Here we argue that susceptibility to hypertension is ancestral and that differential susceptibility to hypertension is due to differential exposure to selection pressures during the out-of-Africa expansion. The most important selection pressure was climate, which produced a latitudinal cline in heat adaptation and, therefore, hypertension susceptibility. Consistent with this hypothesis, we show that ecological variables, such as latitude, temperature, and rainfall, explain worldwide variation in heat adaptation as defined by seven functional alleles in five genes involved in blood pressure regulation. The latitudinal cline in heat adaptation is consistent worldwide and is largely unmatched by latitudinal clines in short tandem repeat markers, control single nucleotide polymorphisms, or non-functional single nucleotide polymorphisms within the five genes. In addition, we show that latitude and one of these alleles, GNB3 (G protein β3 subunit) 825T, account for a major portion of worldwide variation in blood pressure. These results suggest that the current epidemic of hypertension is due to exposures of the modern period interacting with ancestral susceptibility. Modern populations differ in susceptibility to these new exposures, however, such that those from hot environments are more susceptible to hypertension than populations from cold environments. This differential susceptibility is likely due to our history of adaptation to climate

Bioarchaeology of Neolithic Çatalhöyük Reveals Fundamental Transitions in Health, Mobility, and Lifestyle in Early Farmers

The transition from a human diet based exclusively on wild plants and animals to one involving dependence on domesticated plants and animals beginning 10,000 to 11,000 y ago in Southwest Asia set into motion a series of profound health, lifestyle, social, and economic changes affecting human populations throughout most of the world. However, the social, cultural, behavioral, and other factors surrounding health and lifestyle associated with the foraging-to-farming transition are vague, owing to an incomplete or poorly understood contextual archaeological record of living conditions. Bioarchaeological investigation of the extraordinary record of human remains and their context from Neolithic Çatalhöyük (7100–5950 cal BCE), a massive archaeological site in south-central Anatolia (Turkey), provides important perspectives on population dynamics, health outcomes, behavioral adaptations, interpersonal conflict, and a record of community resilience over the life of this single early farming settlement having the attributes of a protocity. Study of Çatalhöyük human biology reveals increasing costs to members of the settlement, including elevated exposure to disease and labor demands in response to community dependence on and production of domesticated plant carbohydrates, growing population size and density fueled by elevated fertility, and increasing stresses due to heightened workload and greater mobility required for caprine herding and other resource acquisition activities over the nearly 12 centuries of settlement occupation. These changes in life conditions foreshadow developments that would take place worldwide over the millennia following the abandonment of Neolithic Çatalhöyük, including health challenges, adaptive patterns, physical activity, and emerging social behaviors involving interpersonal violence

Body mass estimation from footprint size in hominins.

Although many studies relating stature to foot length have been carried out, the relationship between foot size and body mass remains poorly understood. Here we investigate this relationship in 193 adult and 50 juvenile habitually unshod/minimally shod individuals from five different populations-Machiguenga, Daasanach, Pumé, Hadzabe, and Samoans-varying greatly in body size and shape. Body mass is highly correlated with foot size, and can be predicted from foot area (maximum length × breadth) in the combined sample with an average error of about 10%. However, comparisons among populations indicate that body shape, as represented by the body mass index (BMI), has a significant effect on foot size proportions, with higher BMI samples exhibiting relatively smaller feet. Thus, we also derive equations for estimating body mass from both foot size and BMI, with BMI in footprint samples taken as an average value for a taxon or population, estimated independently from skeletal remains. Techniques are also developed for estimating body mass in juveniles, who have relatively larger feet than adults, and for converting between foot and footprint size. Sample applications are given for five Pliocene through Holocene hominin footprint samples from Laetoli (Australopithecus afarensis), Ileret (probable Homo erectus), Happisburgh (possible Homo antecessor), Le Rozel (archaic Homo sapiens), and Barcin Höyük (H. sapiens). Body mass estimates for Homo footprint samples appear reasonable when compared to skeletal estimates for related samples. However, estimates for the Laetoli footprint sample using the new formulae appear to be too high when compared to skeletal estimates for A. afarensis. Based on the proportions of A.L. 288-1, this is apparently a result of relatively large feet in this taxon. A different method using a ratio between body mass and foot area in A.L. 288-1 provides estimates more concordant with skeletal estimates and should be used for A. afarensis

Novel mesothelin antibodies enable crystallography of the intact mesothelin ectodomain and engineering of potent, T cell-engaging bispecific therapeutics

Mesothelin is a glypiated, cell-surface glycoprotein expressed at low levels on normal mesothelium but overexpressed by many cancers. Implicated in cell adhesion and multiple signaling pathways, mesothelin’s precise biological function and overall structure remain undefined. Antibodies targeting mesothelin have been engineered into immunotoxins, antibody-drug conjugates, CAR-T cells, or bispecific T cell engagers as candidate therapeutics but most face challenges, including binding epitopes that are not optimal for selected modalities. Here we describe the isolation and characterization of a novel anti-mesothelin antibody, 1A12, including crystallographic mapping of the 1A12 epitope in relation to other antibodies (amatuximab, anetumab). 1A12 possesses uniquely favorable properties, including a membrane-proximal epitope, and enabled structure determination of the complete mesothelin ectodomain. We incorporated 1A12 into two different bispecific T cell engaging architectures with various anti-CD3 co-targeting elements as candidate therapeutics, demonstrating in vitro functionality and potency

Growth Hormone Protects Against Ovariectomy-Induced Bone Loss in States of Low Circulating Insulin-like Growth Factor (IGF-1)*

Early after estrogen loss in postmenopausal women and ovariectomy (OVX) of animals, accelerated endosteal bone resorption leads to marrow expansion of long bone shafts that reduce mechanical integrity. Both growth hormone (GH) and insulin-like growth factor (IGF-1) are potent regulators of bone remodeling processes. To investigate the role of the GH/IGF-1 axis with estrogen deficiency, we used the liver IGF-1-deficient (LID) mouse. Contrary to deficits in controls, OVX of LID mice resulted in maintenance of cortical bone mechanical integrity primarily owing to an enhanced periosteal expansion affect on cross-sectional structure (total area and cortical width). The serum balance in LID that favors GH over IGF-1 diminished the effects of ablated ovarian function on numbers of osteoclast precursors in the marrow and viability of osteocytes within the cortical matrix and led to less endosteal resorption in addition to greater periosteal bone formation. Interactions between estrogen and the GH/IGF-1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture. © 2010 American Society for Bone and Mineral Researc

A causal account of the brain network computations underlying strategic social behavior

During competitive interactions, humans have to estimate the impact of their own actions on their opponent's strategy. Here we provide evidence that neural computations in the right temporoparietal junction (rTPJ) and interconnected structures are causally involved in this process. By combining inhibitory continuous theta-burst transcranial magnetic stimulation with model-based functional MRI, we show that disrupting neural excitability in the rTPJ reduces behavioral and neural indices of mentalizing-related computations, as well as functional connectivity of the rTPJ with ventral and dorsal parts of the medial prefrontal cortex. These results provide a causal demonstration that neural computations instantiated in the rTPJ are neurobiological prerequisites for the ability to integrate opponent beliefs into strategic choice, through system-level interaction within the valuation and mentalizing networks