Palaeoloxodon and Human Interaction: Depositional Setting,Chronology and Archaeology at the Middle Pleistocene Ficoncella Site (Tarquinia,Italy)

The Ficoncella site in northern Latium (Italy) represents a unique opportunity to investigate the modalities of a short occupation in an alluvial setting during the Lower Palaeolithic. The small excavation area yielded a lithic assemblage, a carcass of Palaeoloxodon antiquus, and some other faunal remains. The main objectives of the study are to better characterize the depositional context where the Palaeoloxodon and the lithic assemblage occur, and to evaluate with greater precision the occupation dynamics. A 25 m-long well was drilled just above the top of the terrace of the Ficoncella site and faunal and lithic remains were analyzed with current and innovative techniques. The archaeological site contains floodplain deposits as it is located next to a small incised valley that feeds into a larger valley of the Mignone River. A tephra layer capping the site is ⁴⁰Ar/³⁹Ar dated to 441± 8 ka. Collectively, the geochronologic, tephrochronologic and geologic data, suggest the site was occupied during MIS 13. The new results should prompt further research at Ficoncella in order to improve our understanding of the dynamics of human settlement in Europe during the Early to Middle Pleistocene.     

Timescales and cultural process at 40,000 BP in the light of the Campanian Ignimbrite eruption, Western Eurasia

Significant new information shows that the Campanian Ignimbrite (CI) eruption from the Phlegrean Fields, southern Italy, was much larger than hitherto supposed and in fact one of the largest late Quaternary explosive events. The eruption can be dated to 40,000 calendar years ago, within the interval of the so-called Middle to Upper Paleolithic 'transition'. Its position can be precisely correlated with a number of other environmental events, including Heinrich Event 4 (HE4), the Laschamp excursion, and a particular cosmogenic nuclide peak. In view of this unique combination of factors, we studied the CI volcanic catastrophe with particular attention to its impact on climate and human ecosystems, including potential interference with ongoing processes of cultural evolution (biological evolution is best left aside for the moment). The contribution of this research is chronological and ecological. The CI volcanic event provides an unequalled means of correlating stratigraphic sequences across Western Eurasia, either directly or indirectly, and affords a unique opportunity to establish the age and climatic context of important archaeological sequences. Ecologically, the CI eruption inevitably interacted with the beginning of HE4 in terms of atmospheric feedback systems. Their combined forcing produced a sudden and at least hemispheric climatic deterioration; a 'volcanic winter' scenario cannot be ruled out. Paleolithic occupation was severely altered throughout the direct-impact zone of the eruption and likely along fringe areas in southern and southeastern Europe. The above observations call for a reconsideration of the processes and rhythms involved in the Middle to Upper Paleolithic 'transition'. A tentative model is suggested that links the exceptional environmental stress at 40,000 BP with processes already active in Paleolithic societies, leading to a period of accelerated change in cultural configurations. These eventually evolved into an Upper Paleolithic proper at a later date. The evidence to invoke allochthonous cultural input or invasionist scenarios is not considered compelling.     

Changes in the mechanical properties of the respiratory system during the development of interstitial lung edema

Background

Pulmonary edema induces changes in airway and lung tissues mechanical properties that can be measured by low-frequency forced oscillation technique (FOT). It is preceded by interstitial edema which is characterized by the accumulation of extravascular fluid in the interstitial space of the air-blood barrier. Our aim was to investigate the impact of the early stages of the development of interstitial edema on the mechanical properties of the respiratory system.

Methods

We studied 17 paralysed and mechanically ventilated closed-chest rats (325–375 g). Total input respiratory system impedance (Zrs) was derived from tracheal flow and pressure signals by applying forced oscillations with frequency components from 0.16 to 18.44 Hz distributed in two forcing signals. In 8 animals interstitial lung edema was induced by intravenous infusion of saline solution (0.75 ml/kg/min) for 4 hours; 9 control animals were studied with the same protocol but without infusion. Zrs was measured at the beginning and every 15 min until the end of the experiment.

Results

In the treated group the lung wet-to-dry weight ratio increased from 4.3 ± 0.72 to 5.23 ± 0.59, with no histological signs of alveolar flooding. Resistance (Rrs) increased in both groups over time, but to a greater extent in the treated group. Reactance (Xrs) did not change in the control group, while it decreased significantly at all frequencies but one in the treated. Significant changes in Rrs and Xrs were observed starting after ~135 min from the beginning of the infusion. By applying a constant phase model to partition airways and tissue mechanical properties, we observed a mild increase in airways resistance in both groups. A greater and significant increase in tissue damping (from 603.5 ± 100.3 to 714.5 ± 81.9 cmH₂O/L) and elastance (from 4160.2 ± 462.6 to 5018.2 ± 622.5 cmH₂O/L) was found only in the treated group.

Conclusion

These results suggest that interstitial edema has a small but significant impact on the mechanical features of lung tissues and that these changes begin at very early stages, before the beginning of accumulation of extravascular fluid into the alveoli.     

Structural analysis of the Sulfolobus solfataricus MCM protein N-terminal domain

The Mini-Chromosome Maintenance (MCM) proteins are candidates of replicative DNA helicase in eukarya and archaea. Here we report a 2.8 Å crystal structure of the N-terminal domain (residues 1–268) of the Sulfolobus solfataricus MCM (Sso MCM) protein. The structure reveals single-hexameric ring-like architecture, at variance from the protein of Methanothermobacter thermoautotrophicus (Mth). Moreover, the central channel in Sso MCM seems significantly narrower than the Mth counterpart, which appears to more favorably accommodate single-stranded DNA than double-stranded DNA, as supported by DNA-binding assays. Structural analysis also highlights the essential role played by the zinc-binding domain in the interaction with nucleic acids and allows us to speculate that the Sso MCM N-ter domain may function as a molecular clamp to grasp the single-stranded DNA passing through the central channel. On this basis possible DNA unwinding mechanisms are discussed.     

Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells

There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17βoxidation of T to Ad (cells: 28–77%; tissues: 35–50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5α-reductase enzyme products (18% and 15%, respectively), while 5β-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4–11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50–55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17βoxidation of T to Ad (35–50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24 h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5β-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients.     

Efficient algorithms to explore conformation spaces of flexible protein loops

Several applications in biology - e.g., incorporation of protein flexibility in ligand docking algorithms, interpretation of fuzzy X-ray crystallographic data, and homology modeling - require computing the internal parameters of a flexible fragment (usually, a loop) of a protein in order to connect its termini to the rest of the protein without causing any steric clash. One must often sample many such conformations in order to explore and adequately represent the conformational range of the studied loop. While sampling must be fast, it is made difficult by the fact that two conflicting constraints - kinematic closure and clash avoidance - must be satisfied concurrently. This paper describes two efficient and complementary sampling algorithms to explore the space of closed clash-free conformations of a flexible protein loop. The "seed sampling" algorithm samples broadly from this space, while the "deformation sampling" algorithm uses seed conformations as starting points to explore the conformation space around them at a finer grain. Computational results are presented for various loops ranging from 5 to 25 residues. More specific results also show that the combination of the sampling algorithms with a functional site prediction software (FEATURE) makes it possible to compute and recognize calcium-binding loop conformations. The sampling algorithms are implemented in a toolkit (LoopTK), which is available at https://simtk.org/home/looptk.     

Design of Supervisors to Avoid Deadlock in Flexible Assembly Systems

Modern production systems exhibit a high degree of resource sharing that can lead to deadlock conditions. Deadlock arises when some parts remain indefinitely blocked because each of them requests access to a resource held by some other parts. One of the tasks of the control system lies in preventing such situations from occurring by proper resource management. This article addresses the deadlock problem for an important class of production facilities, that is, flexible assembly systems, that can perform both manufacturing or assembly operations. In particular, we develop an approach to deadlock avoidance based on a supervisory control that works by inhibiting or enabling the events involving resource allocation. The article proposes two supervisors characterized by easy implementation, efficiency, and flexibility in resource management. The analysis of some case studies, performed by discrete event simulation, confirms the effectiveness of the approach.     

Effects of intermediates on aggregation of native bovine serum albumin

Protein aggregation has been recognized to be a pathological indicator for several fatal diseases, such as Alzheimer's disease, transmissible spongiform encephalopathies, Creutzfeldt-Jacob disease, etc. Aggregation usually involves conformational changes of proteins that have acquired an intermediate beta-structure-rich conformation and can occur even at low protein concentration. Recent work in our laboratory has shown that bovine serum albumin (BSA), even at low-concentration, exhibits self-association properties related to conformational changes, so providing a very convenient model system to study this class of problems. Here we report data (obtained by different experimental techniques) on a mixture of BSA in native and intermediate (beta-structure-rich) form. Results show that the interaction between the two species is responsible for a decrease in the thermodynamic stability of the solution. This occurs without requiring noticeable conformational changes of the native protein. Results presented here can provide new insight on the "protein only" hypothesis proposed for the formation of plaques involved in several neurodegenerative diseases.     

Intrasexual and intersexual dimorphisms of the red salmon prosencephalon

Intrasexual as well as intersexual dimorphisms were found in the prosencephalon and mesencephalon of adult Oncorhynchus nerka (red/sockeye salmon). These dimorphisms are concerned with the position of the preoptic nucleus, nucleus lateralis tuberis, habenula, third ventricle, tectal ventricles, preoptic recess, recessus lateralis, horizontal commissure, posterior commissure, and toral commissure. The intrasexual dimorphism was characterized by either a rostral ("r"-pattern) or a caudal ("c"-pattern) position of the preoptic region as well as varying locations of other structures within the prosencephalon. As compared to "c"-pattern fish, the preoptic nucleus and nucleus lateralis tuberis were located more rostral, and the habenula was positioned further caudal, in "r"-type animals. The intersexual dimorphism was also characterized by different positions of the structures listed above. With the exception of the preoptic nucleus, all of these were located further rostral in "r"-pattern females than in type "r" males. In "c"-pattern females, they were positioned further caudal than in type "c" males. The number of neurons in the parvocellular and in the magnocellular portion of the preoptic region differed in the two genders with respect to "r"- as well as "c"-pattern fish. Males had more neurons than females in both the magno- and the parvocellular subdivisions of the preoptic region. In "r"- and "c"-pattern fish, the average size of magnocellular preoptic neurons was larger in females than in males. The observed intersexual variations may reflect gender-specific differences in the control of the pituitary. Functional correlates of intrasexual dimorphism are obscure.     

Interaction of processes on different length scales in a bioelastomer capable of performing energy conversion

This work concerns the aggregation properties of (Gly-Val-Gly-Val-Pro)(251) rec, a polypentapeptide reflecting a highly conserved repetitive unit of the bioelastomer, elastin. On raising the temperature of aqueous solutions above 25 degrees C, this polypeptide was already known to undergo concurrent conformational changes (hydrophobic folding), phase separation, and self-assembly with formation of aggregated three-stranded filaments composed of dynamic polypeptide helices, called beta-spirals. Aggregates obtained from the solution can be shaped into bands that acquire entropic elastic properties upon gamma-irradiation and can perform a variety of energy conversions. Previous studies have shown that aggregation is prompted by the (diverging) critical fluctuations of concentration occurring in the solution, in vicinity of its spinodal line. Here, we present combined circular dicroism (CD) and light scattering experiments, and independent fittings of experimental data to the theoretical spinodal and binodal (coexistence) lines. Results show the following logical and causal sequence of processes: (a) Smooth and progressive conformational changes promoted by concentration fluctuations occurring as temperature is raised "pull down" (in the temperature scale) the instability region of the solution. (b) This further promotes critical fluctuations. (c) The related locally high concentration prompts a further substantial conformational change ending in triple-helix formation and coacervation. (d) This intertwining of processes, covering different length scales (from that of individual peptides to the mesoscopic one of demixed regions), is related to the fact that solvent-induced interactions play a strong role over the entire scale span. These results concur with other recent ones in pointing out that process interactions over many length-scales probably reflect a frequent if not ubiquitous pattern in protein aggregation. This may be highly relevant to the desirable deep understanding of such phenomenon, whose interests cover many fields.