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In northwestern Africa, lifestyle transitioned from foraging to food production around 7,400 years ago but what sparked that change remains unclear. Archaeological data support conflicting views: (1) that migrant European Neolithic farmers brought the new way of life to North Africa1–3or (2) that local hunter-gatherers adopted technological innovations4,5. The latter view is also supported by archaeogenetic data6. Here we fill key chronological and archaeogenetic gaps for the Maghreb, from Epipalaeolithic to Middle Neolithic, by sequencing the genomes of nine individuals (to between 45.8- and 0.2-fold genome coverage). Notably, we trace 8,000 years of population continuity and isolation from the Upper Palaeolithic, via the Epipaleolithic, to some Maghrebi Neolithic farming groups. However, remains from the earliest Neolithic contexts showed mostly European Neolithic ancestry. We suggest that farming was introduced by European migrants and was then rapidly adopted by local groups. During the Middle Neolithic a new ancestry from the Levant appears in the Maghreb, coinciding with the arrival of pastoralism in the region, and all three ancestries blend together during the Late Neolithic. Our results show ancestry shifts in the Neolithization of northwestern Africa that probably mirrored a heterogeneous economic and cultural landscape, in a more multifaceted process than observed in other regions.

Our previous studies with shishijimicin A resulted in the total synthesis of this scarce marine natural product and a number of its simpler analogues endowed with picomolar potencies against certain cancer cell lines. Herein, we describe the design, synthesis, and biological evaluation of four linker-drugs, anticipating the construction of antibody–drug conjugates (ADCs) as the ultimate goal of this research program. Using a common payload, the assembly of these linker-drugs utilized different linkers and attachment points, providing opportunities to probe the optimal molecular design of the intended ADCs as targeted cancer therapies. In the course of ADC generation and in vitro evaluation, we identified two linker-drugs with a promising in vitro plasma stability profile and excellent targeted cytotoxicity and specificity. Conjugation of shishijimicin A enediyne payloads through their phenolic moiety represents a novel approach to enediyne ADC creation, while the pharmacological profiles of at least two of the generated ADCs compare well with the profiles of the corresponding clinically approved ADC Kadcyla.

•Analysis of sexual dimorphism in the prehistoric burial site of Camino del Molino (southeastern Iberia).•First discriminant functions developed on a skeletal collection from the 3rd millennium BC.•The use of LDA and RF analysis has made it possible to compare different sexual diagnostic techniques on long bones and to test the validity of machine learning on prehistoric samples.•LDA and Random Forest agree that the epiphyses of the long bones are the regions with the highest power of sex accuracy.•These formulae can serve as an alternative/complementary sex estimation method in the CMOL disarticulated sample and possibly in other homogeneous prehistoric series.

Conventional antibody–drug conjugates (ADCs) are heterogeneous mixtures of chemically distinct molecules that vary in both drugs/antibody (DAR) and conjugation sites. Suboptimal properties of heterogeneous ADCs have led to new site-specific conjugation methods for improving ADC homogeneity. Most site-specific methods require extensive antibody engineering to identify optimal conjugation sites and introduce unique functional groups for conjugation with appropriately modified linkers. Alternative nonrecombinant methods have emerged in which bifunctional linkers are utilized to cross-link antibody interchain cysteines and afford ADCs containing four drugs/antibody. Although these methods have been shown to improve ADC homogeneity and stability in vitro, their effect on the pharmacological properties of ADCs in vivo is unknown. In order to determine the relative impact of interchain cysteine cross-linking on the therapeutic window and other properties of ADCs in vivo, we synthesized a derivative of the known ADC payload, MC-MMAF, that contains a bifunctional dibromomaleimide (DBM) linker instead of a conventional maleimide (MC) linker. The DBM-MMAF derivative was conjugated to trastuzumab and a novel anti-CD98 antibody to afford ADCs containing predominantly four drugs/antibody. The pharmacological properties of the resulting cross-linked ADCs were compared with analogous heterogeneous ADCs derived from conventional linkers. The results demonstrate that DBM linkers can be applied directly to native antibodies, without antibody engineering, to yield highly homogeneous ADCs via cysteine cross-linking. The resulting ADCs demonstrate improved pharmacokinetics, superior efficacy, and reduced toxicity in vivo compared to analogous conventional heterogeneous ADCs.

This article discusses the use of shades of red in Mexican fashion and design, with a particular focus on hot pink. The author comments on the influence of indigenous Mexican traditional clothing, which utilizes a variety of red shades. Fashion designer Ramón Valdiosera and actress Dolores del Río, both of whom became well-known for creating and wearing ethnic Mexican clothing featuring the color pink, are also highlighted.

1. The patterns of electrical activity and membrane characteristics of a population of neurosecretory-cell somata in the X-organ of the crayfish were investigated with microelectrodes and whole-cell, voltage-clamp techniques. Some neurons (56%) were silent but could be excited by intracellular current injection: other cells showed spontaneous tonic activity (35%), and some had spontaneous bursting activity (9%). The spiking activity was abolished by tetrodotoxin (TTX) exposure and by severing the axon near the cell body. After axotomy, only a small, slow, regenerative depolarization remained that could be blocked by Cd2+. 2. Under voltage clamp the steady-state I-V curve in low [Ca2+]i (9 X 10(-9) M) showed a slope conductance of 16.7 +/- 3.9 (SD) nS (n = 10) at -50 mV and zero current potential of -50.1 +/- 7.7 mV. In current-clamp mode these neurons were either silent or fired tonically. With high [Ca2+]i (1.7 X 10(-6) M) both the slope conductance and inward and outward currents were reduced. In some neurons high [Ca2+]i reveals a negative slope resistance in the range of -46 to -41 mV. It could be supressed by removing [Na+]o, but it was TTX insensitive. These are the neurons that under current clamp showed bursting activity. 3. The main inward current in cell somata was a Ca2+ current of 2 +/- 0.6 nA (n = 18), activated at -40 mV and peaking at 20 mV. It showed relaxation with prolonged pulses. No Na(+)-dependent, TTX-sensitive inward currents were recorded with short (100-ms) pulses in axotomized neurons. 4. Two outward currents could be distinguished.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between the fine structure, electric field equations, and electric circuit models of skeletal muscle fibers is discussed. Experimental evidence illustrates the profound variation of potential with circumferential position, even at low frequencies (100 Hz). Since one-dimensional cable theory cannot account for such variation, three-dimensional cable theory must be used. Several circuit models of a sarcomere are presented and plots are made of the predicted phase angle between sinusoidal applied current and potential. The circuit models are described by equations involving normalized variables, since they affect the phase plot in a relatively simple way. A method is presented for estimating the values of the circuit elements and the standard deviation of the estimates. The reliability of the estimates is discussed. An objective measure of fit, Hamilton's R test, is used to test the significance of different fits to data. Finally, it is concluded that none of the proposed circuit models provides an adequate description of the observed variation of phase angle with circumferential location. It is not clear whether the source of disagreement is inadequate measurements or inadequate theory.

The linear circuit parameters of 140 muscle fibers in nine solutions are determined from phase measurements fitted with three circuit models: the disk model, in which the resistance to radial current flow is in the lumen of the tubules; the lumped model, in which the resistance is at the mouth of the tubules; and the hybrid model, in which it is in both places. The lumped model fails to fit the data. The disk and hybrid model fit the data, but the optimal circuit values of the hybrid model seem more reasonable. The circuit values depend on sarcomere length. The conductivity of the lumen of the tubules is less than, and varies in a nonlinear manner with, the conductivity of the bathing solution, suggesting that the tubules are partially occluded by some material like basement membrane which restricts the mobility of ions and has fixed charge. The x2.5 hypertonic sucrose solution used in many voltage clamp experiments produces a large increase in the radial resistance, suggesting that control of the potential across the tubular membranes would be difficult to achieve. Glycerol-treated fibers have 90% of their tubular system insulated from the extracellular solution and 10% connected to the extracellular solution through a high resistance. We discuss the implications of our results for calculations of the nonlinear properties of muscle fibers, including the action potential and the radial spread of contraction.

Summary 1. Intracellular and voltage-clamp recordings were obtained from a selected population of neuroscretory (ns) cells in the X organ of the crayfish isolated eyestalk. Pulses of γ-aminobutyric acid (GABA) elicited depolarizing responses and bursts of action potentials in a dose-dependent manner. These effects were blocked by picrotoxin (50 µM) but not by bicuculline. Picrotoxin also suppressed spontaneous synaptic activity.

Molecular design, synthesis, and biological evaluation of tubulysin analogues, linker-drugs, and antibody–drug conjugates are described. Among the new discoveries reported is the identification of new potent analogues within the tubulysin family that carry a C11 alkyl ether substituent, rather than the usual ester structural motif at that position, a fact that endows the former with higher plasma stability than that of the latter. Also described herein are X-ray crystallographic analysis studies of two tubulin–tubulysin complexes formed within the α/β interface between two tubulin heterodimers and two highly potent tubulysin analogues, one of which exhibited a different binding mode to the one previously reported for tubulysin M. The X-ray crystallographic analysis-derived new insights into the binding modes of these tubulysin analogues explain their potencies and provide inspiration for further design, synthesis, and biological investigations within this class of antitumor agents. A number of these analogues were conjugated as payloads with appropriate linkers at different sites allowing their attachment onto targeting antibodies for cancer therapies. A number of such antibody–drug conjugates were constructed and tested, both in vivo and in vitro, leading to the identification of at least one promising ADC (Herceptin–LD3), warranting further investigations.

In this study, we have used a technique designed to target short fragments containing informative mitochondrial substitutions to extend the temporal limits of DNA recovery and study the molecular phylogeny of Ursus deningeri. We present a cladistic analysis using DNA recovered from 400kyr old U. deningeriremains, which demonstrates U. deningeri's relation to Ursus spelaeus. This study extends the limits of recovery from skeletal remains by almost 300kyr. Plant material from permafrost environments has yielded DNA of this age in earlier studies, and our data suggest that DNA in teeth from cave environments may be equally well preserved.