Encoding of kinetic and kinematic movement parameters in the sensorimotor cortex: A Brain‐Computer Interface perspective

For severely paralyzed people, Brain‐Computer Interfaces (BCIs) can potentially replace lost motor output and provide a brain‐based control signal for augmentative and alternative communication devices or neuroprosthetics. Many BCIs focus on neuronal signals acquired from the hand area of the sensorimotor cortex, employing changes in the patterns of neuronal firing or spectral power associated with one or more types of hand movement. Hand and finger movement can be described by two groups of movement features, namely kinematics (spatial and motion aspects) and kinetics (muscles and forces). Despite extensive primate and human research, it is not fully understood how these features are represented in the SMC and how they lead to the appropriate movement. Yet, the available information may provide insight into which features are most suitable for BCI control. To that purpose, the current paper provides an in‐depth review on the movement features encoded in the SMC. Even though there is no consensus on how exactly the SMC generates movement, we conclude that some parameters are well represented in the SMC and can be accurately used for BCI control with discrete as well as continuous feedback. However, the vast evidence also suggests that movement should be interpreted as a combination of multiple parameters rather than isolated ones, pleading for further exploration of sensorimotor control models for accurate BCI control.     

Engraftable neural crest stem cells derived from cynomolgus monkey embryonic stem cells

Neural crest stem cells (NCSCs), a population of multipotent cells that migrate extensively and give rise to diverse derivatives, including peripheral and enteric neurons and glia, craniofacial cartilage and bone, melanocytes and smooth muscle, have great potential for regenerative medicine. Non-human primates provide optimal models for the development of stem cell therapies. Here, we describe the first derivation of NCSCs from cynomolgus monkey embryonic stem cells (CmESCs) at the neural rosette stage. CmESC-derived neurospheres replated on polyornithine/laminin-coated dishes migrated onto the substrate and showed characteristic expression of NCSC markers, including Sox10, AP2α, Slug, Nestin, p75, and HNK1. CmNCSCs were capable of propagating in an undifferentiated state in vitro as adherent or suspension cultures, and could be subsequently induced to differentiate towards peripheral nervous system lineages (peripheral sympathetic neurons, sensory neurons, and Schwann cells) and mesenchymal lineages (osteoblasts, adipocytes, chondrocytes, and smooth muscle cells). CmNCSCs transplanted into developing chick embryos or fetal brains of cynomolgus macaques survived, migrated, and differentiated into progeny consistent with a neural crest identity. Our studies demonstrate that CmNCSCs offer a new tool for investigating neural crest development and neural crest-associated human disease and suggest that this non-human primate model may facilitate tissue engineering and regenerative medicine efforts.     

From the Cover: Hominids adapted to metabolize ethanol long before human-directed fermentation

Paleogenetics is an emerging field that resurrects ancestral proteins from now-extinct organisms to test, in the laboratory, models of protein function based on natural history and Darwinian evolution. Here, we resurrect digestive alcohol dehydrogenases (ADH4) from our primate ancestors to explore the history of primate–ethanol interactions. The evolving catalytic properties of these resurrected enzymes show that our ape ancestors gained a digestive dehydrogenase enzyme capable of metabolizing ethanol near the time that they began using the forest floor, about 10 million y ago. The ADH4 enzyme in our more ancient and arboreal ancestors did not efficiently oxidize ethanol. This change suggests that exposure to dietary sources of ethanol increased in hominids during the early stages of our adaptation to a terrestrial lifestyle. Because fruit collected from the forest floor is expected to contain higher concentrations of fermenting yeast and ethanol than similar fruits hanging on trees, this transition may also be the first time our ancestors were exposed to (and adapted to) substantial amounts of dietary ethanol.One trend in modern medicine attributes diseases in humans to an incomplete adaptation of the human genome to new challenges presented by our changing cultural and demographic environment (1). This attribution is especially convincing for some “lifestyle” diseases. For example, the recent increase in sugar consumption (including sucrose and fructose) is associated with the emergence of obesity, diabetes, and hypertension (2). Under an evolutionary paradigm, an organism fully adapted to a sugar-rich diet would not be expected to become diseased by consuming sugars, suggesting that humankind has not had enough time to adapt to a modern diet rich in such sugars.It is unclear whether the human genome has had more time to adapt to dietary ethanol (“alcohol” in the vernacular), which also produces a disease spectrum (“alcoholism”) common today in many societies (3). In one historical model, ethanol was not a significant part of the hominin “Paleolithic diet” (4) and was also absent from the diets of earlier ancestors. Rather, the model holds that ethanol entered our diets in significant amounts only after humans began to store surplus food (possibly because of the advent of agriculture) and subsequently developed the ability to intentionally direct the fermentation of food (∼9,000 y ago (5), perhaps as a means of preservation (6). In this model, alcoholism as a disease reflects insufficient time since humans first encountered ethanol for their genome to have adapted completely to ethanol. As such, the allelic variants of enzymes in the ethanol metabolic pathway that disfavor ethanol consumption (e.g., ADH1B*47His and ALDH2*487Lys, both of which lead to an accumulation of acetaldehyde—a toxic intermediate that causes headache, nausea, and general discomfort) represent an early stage of adaptation, possibly in association with pathogenic infections (7–10).In an alternative model, primates may have ingested ethanol via frugivory as early as 80 million y ago (Ma), a time corresponding to the origin and diversification of primates (11) and when angiosperm plants first produced fleshy fruits that can become infected by yeast capable of the accumulating ethanol via fermentation (12). In one version of this model, small amounts of ethanol present in slightly fermenting fruit attached to trees attracted arboreal primates foraging in the trees. In this version, our contemporary attraction to ethanol is an “evolutionary hangover” that ceased to be beneficial once that attraction became redirected to beverages with high concentrations of ethanol (13), made possible only after humans developed the tools allowing them to intentionally direct fermentation (and enhanced with the advent of technology to distill ethanol to higher concentrations). Another version of the “ethanol early” model for ethanol exposure recognizes that ethanol itself, as well as the food naturally containing it, can be a significant source of nutrition. This model posits that any organism with metabolic adaptations that permit the exploitation of ethanolic food would have access to a specialized niche or important fallback foods unavailable to organisms without this metabolic capacity.Paleogenetics is an emerging field designed to address such natural historical hypotheses and, in particular, to distinguish between competing historical models (14). Here, to gain a genetic perspective on the natural history of the interaction between our human ancestors and ethanol, we examined the evolution of Class IV alcohol dehydrogenases (ADH4) (see SI Text for a discussion of the various synonyms used within the ADH family). These digestive enzymes are abundant in the stomach, esophagus, and tongue of primates and are active against a wide range of alcohols. Thus, ADH4 is the first alcohol-metabolizing enzyme to encounter ethanol that is imbibed (15), and several studies indicate that ADH4 contributes significantly to the first-pass metabolism of ethanol in humans (16).ADH4 is also active against retinol (in vitro), and ADH4’s high catalytic efficiency for retinol (as defined by its k_cat/K_M ratio) suggests it may play a role in retinoic acid biosynthesis (17). Mice with inactivated ADH4 genes, however, display few complications associated with retinoid metabolism except under extreme conditions of dietary retinol excess or dietary retinoid deficiency (18, 19). Further, dietary retinoids occur in the form of retinyl esters (from animal foods) or carotenoids (from plant foods); these forms of provitamin A are not substrates for ADH4 present in the upper gastrointestinal track and are converted into retinol only after entering the small intestines. Geraniol, however, is a monoterpenoid that is structurally similar to retinol and is commonly found in plants as an antifeedant, making it a physiologically relevant substrate for ADH4 in herbivorous primates.We therefore tested alternative models for the history of primate exposure to ethanol by comparing the enzymatic efficiencies of modern and ancestral ADH4 enzymes toward geraniol and ethanol. These comparisons identified a dramatic evolutionary transition from an ethanol-inactive ADH4 to an ethanol-active ADH4 in our hominin ancestors ∼10 million y ago.This study focuses on the evolution of one component of ethanol metabolism, ADH4. Ethanol metabolism is complex and involves other ethanol-metabolizing enzymes [e.g., ADH1, ADH2, and the microsomal ethanol oxidizing system (MEOS)], enzymes involved in the downstream metabolism of by-products from ethanol metabolism (e.g., ALDH2, which oxidizes acetaldehyde created from ethanol), and enzymes indirectly affected by the by-products of ethanol metabolism (e.g., ALDH1). A more nuanced understanding of primate adaptation to ethanol will develop as future work examines these related enzymes.     

Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints

Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system.Oxytocin has crucial functions related to physiological processes and social behaviors in primates and other placental mammals. A nonapeptide (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly) (1), oxytocin (OXT-8Leu) is both a neurotransmitter released by neuronal cells in synapses and a hormone, activating receptors distant from the site of its synthesis through the circulatory system (2). In mammals, OXT acts as a hormone in uterine contraction during parturition and in milk ejection while lactating. It is also a key central nervous system neurotransmitter, regulating/modulating complex social and reproductive behaviors (i.e., pair bonding and parental care) (3–7).Until recently, it was believed that the OXT amino acid chain was the same in all placental mammals. However, Lee and colleagues (8) reported a T > C change in four New World monkeys (NWms), Saimiri sciureus, Cebus apella, Callithrix jacchus, and Aotus nancimae, substituting leucine to proline at position 8 (OXT-8Pro). This form was also found in Tupaia belangeri, a tree shrew species of Southeast Asia (8). OXT differs from its paralog vasopressin (AVP; Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) at positions 3 and 8. Variation at position 8 also identifies nonplacental OXT/AVP-like nonapeptides, such as mesotocin, present in some marsupials (7, 9). These findings dispel the notion of a universal OXT amino acid sequence for placental mammals. They also suggest that residue variability at position 8, in some cases associated with variations at positions 2–5, may be connected with the recognition, binding, and activation of receptors, potentially leading to species-specific functional changes (7, 10).OXT activity depends on adequate interaction with its unique receptor, OXTR, although it can also bind to the vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) with lower affinity (11–13). Similar to other receptors that use G proteins as transducer signals across the cell membranes, OXTR is composed of seven transmembrane (TM1–TM7), four extracellular (N-terminal tail-ECL3), and four intracellular (ICL1-C-terminal tail) domains. ECL and ICL are important for the interaction with OXT and G proteins, respectively, whereas TMs are connected with both functions (7, 11).In contrast to what is observed for placental mammal OXT, OXTR presents hundreds of variants in regulatory and coding regions, including at the intraspecific level. In humans, OXTR single-nucleotide polymorphisms have been associated with several social behavioral phenotypes (14).The presence of OXT-OXTR-related systems throughout the animal kingdom indicates that their typical roles in placental mammals are likely exaptations of ancient functions, such as regulation of fluid balance and egg-laying (15, 16). Studies have attempted to investigate both the interaction of OXT-OXTR-like systems and their coevolution (11, 17). However, our knowledge about this nonapeptide-receptor system, including the extent of its variability in the primate order, remains limited.NWm emerged ∼30 million years ago. They are classified into 16 genera and ∼75 species and present a wide range of reproductive and social behaviors (18, 19), but little is known about their genetic variability and concurrent phenotypic variation (20).The present study reports results about OXT and OXTR diversity in 29 primate species, including 20 NWm species. These analyses include original OXT and OXTR sequences for 16 and 12 NWm species, respectively. We discuss details about the coevolution of these systems, as well as possible connections among reported genetic variability, positive selection, and some key species-specific biologic traits.     

Pig-to-baboon lung xenotransplantation: Extended survival with targeted genetic modifications and pharmacologic treatments

Galactosyl transferase knock-out pig lungs fail rapidly in baboons. Based on previously identified lung xenograft injury mechanisms, additional expression of human complement and coagulation pathway regulatory proteins, anti-inflammatory enzymes and self-recognition receptors, and knock-down of the β4Gal xenoantigen were tested in various combinations. Transient life-supporting GalTKO.hCD46 lung function was consistently observed in association with either hEPCR (n = 15), hTBM (n = 4), or hEPCR.hTFPI (n = 11), but the loss of vascular barrier function in the xenograft and systemic inflammation in the recipient typically occurred within 24 h. Co-expression of hEPCR and hTBM (n = 11) and additionally blocking multiple pro-inflammatory innate and adaptive immune mechanisms was more consistently associated with survival >1 day, with one recipient surviving for 31 days. Combining targeted genetic modifications to the lung xenograft with selective innate and adaptive immune suppression enables prolonged initial life-supporting lung function and extends lung xenograft recipient survival, and illustrates residual barriers and candidate treatment strategies that may enable the clinical application of other organ xenografts.