Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels.

Cardiac Nav1.5 and Kir2.1-2.3 channels generate Na (INa) and inward rectifier K (IK1) currents, respectively. The functional INa and IK1 interplay is reinforced by the positive and reciprocal modulation between Nav15 and Kir2.1/2.2 channels to strengthen the control of ventricular excitability. Loss-of-function mutations in the SCN5A gene, which encodes Nav1.5 channels, underlie several inherited arrhythmogenic syndromes, including Brugada syndrome (BrS). We investigated whether the presence of BrS-associated mutations alters IK1 density concomitantly with INa density. Results obtained using mouse models of SCN5A haploinsufficiency, and the overexpression of native and mutated Nav1.5 channels in expression systems - rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) - demonstrated that endoplasmic reticulum (ER) trafficking-defective Nav1.5 channels significantly decreased IK1, since they did not positively modulate Kir2.1/2.2 channels. Moreover, Golgi trafficking-defective Nav1.5 mutants produced a dominant negative effect on Kir2.1/2.2 and thus an additional IK1 reduction. Moreover, ER trafficking-defective Nav1.5 channels can be partially rescued by Kir2.1/2.2 channels through an unconventional secretory route that involves Golgi reassembly stacking proteins (GRASPs). Therefore, cardiac excitability would be greatly affected in subjects harboring Nav1.5 mutations with Golgi trafficking defects, since these mutants can concomitantly trap Kir2.1/2.2 channels, thus unexpectedly decreasing IK1 in addition to INa.

New radiocarbon dating and demographic insights into San Juan ante Portam Latinam, a possible Late Neolithic war grave in North-Central Iberia.

OBJECTIVES: San Juan ante Portam Latinam is one of a small number of European Neolithic sites meeting many of the archaeological criteria expected for a mass grave, and furthermore presents evidence for violent conflict. This study aims to differentiate between what is potentially a single episode of deposition, versus deposition over some centuries, or, alternatively, that resulting from a combination of catastrophic and attritional mortality. The criteria developed are intended to have wider applicability to other such proposed events. MATERIAL AND METHODS: Ten new AMS 14 C determinations on human bone from the site, together with previously available dates, are analyzed through Bayesian modeling to refine the site's chronology. This is used together with the population's demographic profile as the basis for agent-based demographic modeling. RESULTS: The new radiocarbon results, while improving the site's chronology, fail to resolve the question whether the burial represents a single event, or deposition over decades or centuries-primarily because the dates fall within the late fourth millennium BC plateau in the calibration curve. The demographic modeling indicates that the population's age and sex distribution fits neither a single catastrophic event nor a fully attritional mortality profile, but instead may partake of elements of both. DISCUSSION: It is proposed that San Juan ante Portam Latinam was used as burial place for the mainly adolescent and adult male dead of a particular or multiple violent engagements (e.g., battles), while previously or subsequently seeing use for attritional burial by other members of one or more surrounding communities dead over the course of a few generations. The overall bias towards males, particularly to the extent that many may represent conflict mortality, has implications for the structure of the surviving community, the members of which may have experienced increased vulnerability in the face of neighboring aggressors.

Living different lives: Early social differentiation identified through linking mortuary and isotopic variability in Late Neolithic/ Early Chalcolithic north-central Spain.

Variation in burial location and treatment is often observed in the prehistoric archaeological record, but its interpretation is usually highly ambiguous. Biomolecular approaches provide the means of addressing this variability in a way not previously possible, linking the lives of individuals to their funerary treatment. Here, we undertake stable carbon and nitrogen isotope analyses on a substantial sample of 166 individuals from a series of broadly contemporary Late Neolithic/ Early Chalcolithic (3500 to 2900 cal BC) mortuary monuments (El Sotillo, Alto de la Huesera, Chabola de la Hechicera and Longar) and caves (Las Yurdinas II, Los Husos I and Peña Larga) within a very spatially restricted area of north-central Spain, with sites separated by no more than 10 km on average. This spatial and temporal proximity allows us to focus on the question at the appropriate scale of analysis, avoiding confounding variables such as environmental change, diachronic trends in the subsistence economy, etc. The results demonstrate a statistically significant difference in human δ13C values between those interred in caves and those placed in monuments. The difference appears to be correlated with fine-grained environmental factors (elevation/ temperature/ precipitation), suggesting that use of the landscape was being divided at a very local scale. The reasons for this partitioning may involve differential social status (e.g. those interred in caves may be of lower standing with more restricted access to the valley's arable resources) or economic specialization (e.g. upland herding vs. valley farming) within the same community or, alternatively, different populations performing different funerary practices and following distinct subsistence economies in some respect. Our results contribute to a better understanding of the development of social differentiation and community specialisation on the scale of the immediate lived landscape.

Demographic differences between funerary caves and megalithic graves of northern Spanish Late Neolithic/Early Chalcolithic.

OBJECTIVES: The study focuses on the estimation of demographic parameters of Late Neolithic/Early Chalcolithic (mid 4th-early 3rd millenniums cal. BC) burial sites from the La Rioja region (Ebro valley, northern Spain) to identify demographic characteristics. MATERIALS AND METHODS: The human remains come from three caves (Las Yurdinas II, Peña Larga, and La Peña de Marañón) and three megalithic graves (Alto de la Huesera, San Martín, and Peña Guerra II). The total skeletal sample consists of a minimum of 261 individuals, 149 being buried in caves and 112 in megalithic graves. Data based on age and sex estimation are analyzed using abridged life tables, mortality rates, and sex ratios. RESULTS: A systematic bias against children under 5 years of age is detected both in caves (5 q0 = 187.92%) and megalithic graves (5 q0 = 71.43%) but also against some juveniles and adults compared with population models, though a statistically significant greater lack of infants is worth noting in the megaliths (t-test, P = 0.012). Moreover, a significant divergence in sex ratios (χ(2) , P = 0.002) is also identified between site types, clearly prioritizing women in caves (sex ratio = 0.45) and men in megalithic graves (sex ratio = 1.33). CONCLUSIONS: This evidence is interpreted as the result of different selective burial patterns. The mortuary variability could lie behind intragroup differential status relationships, though the hypothesis of two populations performing distinct funerary practices in a small region cannot be rejected at the present state of the research. Am J Phys Anthropol 160:284-297, 2016. © 2016 Wiley Periodicals, Inc.