Mediterranean winter rainfall in phase with African monsoons during the past 1.36 million years.

Mediterranean climates are characterized by strong seasonal contrasts between dry summers and wet winters. Changes in winter rainfall are critical for regional socioeconomic development, but are difficult to simulate accurately1 and reconstruct on Quaternary timescales. This is partly because regional hydroclimate records that cover multiple glacial-interglacial cycles2,3 with different orbital geometries, global ice volume and atmospheric greenhouse gas concentrations are scarce. Moreover, the underlying mechanisms of change and their persistence remain unexplored. Here we show that, over the past 1.36 million years, wet winters in the northcentral Mediterranean tend to occur with high contrasts in local, seasonal insolation and a vigorous African summer monsoon. Our proxy time series from Lake Ohrid on the Balkan Peninsula, together with a 784,000-year transient climate model hindcast, suggest that increased sea surface temperatures amplify local cyclone development and refuel North Atlantic low-pressure systems that enter the Mediterranean during phases of low continental ice volume and high concentrations of atmospheric greenhouse gases. A comparison with modern reanalysis data shows that current drivers of the amount of rainfall in the Mediterranean share some similarities to those that drive the reconstructed increases in precipitation. Our data cover multiple insolation maxima and are therefore an important benchmark for testing climate model performance.

1.36 million years of Mediterranean forest refugium dynamics in response to glacial-interglacial cycle strength.

The sediment record from Lake Ohrid (Southwestern Balkans) represents the longest continuous lake archive in Europe, extending back to 1.36 Ma. We reconstruct the vegetation history based on pollen analysis of the DEEP core to reveal changes in vegetation cover and forest diversity during glacial-interglacial (G-IG) cycles and early basin development. The earliest lake phase saw a significantly different composition rich in relict tree taxa and few herbs. Subsequent establishment of a permanent steppic herb association around 1.2 Ma implies a threshold response to changes in moisture availability and temperature and gradual adjustment of the basin morphology. A change in the character of G-IG cycles during the Early-Middle Pleistocene Transition is reflected in the record by reorganization of the vegetation from obliquity- to eccentricity-paced cycles. Based on a quantitative analysis of tree taxa richness, the first large-scale decline in tree diversity occurred around 0.94 Ma. Subsequent variations in tree richness were largely driven by the amplitude and duration of G-IG cycles. Significant tree richness declines occurred in periods with abundant dry herb associations, pointing to aridity affecting tree population survival. Assessment of long-term legacy effects between global climate and regional vegetation change reveals a significant influence of cool interglacial conditions on subsequent glacial vegetation composition and diversity. This effect is contrary to observations at high latitudes, where glacial intensity is known to control subsequent interglacial vegetation, and the evidence demonstrates that the Lake Ohrid catchment functioned as a refugium for both thermophilous and temperate tree species.

Chitosan Micro-Grooved Membranes with Increased Asymmetry for the Improvement of the Schwann Cell Response in Nerve Regeneration.

Peripheral nerve injuries are a common condition in which a nerve is damaged, affecting more than one million people every year. There are still no efficient therapeutic treatments for these injuries. Artificial scaffolds can offer new opportunities for nerve regeneration applications; in this framework, chitosan is emerging as a promising biomaterial. Here, we set up a simple and effective method for the production of micro-structured chitosan films by solvent casting, with high fidelity in the micro-pattern reproducibility. Three types of chitosan directional micro-grooved patterns, presenting different levels of symmetricity, were developed for application in nerve regenerative medicine: gratings (GR), isosceles triangles (ISO) and scalene triangles (SCA). The directional patterns were tested with a Schwann cell line. The most asymmetric topography (SCA), although it polarized the cell shaping less efficiently, promoted higher cell proliferation and a faster cell migration, both individually and collectively, with a higher directional persistence of motion. Overall, the use of micro-structured asymmetrical directional topographies may be exploited to enhance the nerve regeneration process mediated by chitosan scaffolds.

Cyclo His-Pro Attenuates Muscle Degeneration in Murine Myopathy Models.

Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in inflammation and fibrosis that ultimately affect the overall muscle biomechanics. At the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common condition that affects an increasing proportion of the elderly. Although characterized by different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. Here, the therapeutic effects of Cyclo Histidine-Proline (CHP) against DMD and sarcopenia are evaluated. In the mdx mouse model of DMD, it is shown that CHP restored muscle contractility and force production, accompanied by the reduction of fibrosis and inflammation in skeletal muscle. CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These findings from two different models of muscle dysfunction hence warrant further investigation into the effects of CHP on muscle pathologies in animal models and eventually in patients.

Systems genetics of metabolic health in the BXD mouse genetic reference population.

Susceptibility to metabolic syndrome (MetS) is dependent on genetics, environment, and gene-by-environment interactions, rendering the study of underlying mechanisms challenging. The majority of experiments in model organisms do not incorporate genetic variation and lack specific evaluation criteria for MetS. Here, we derived a continuous metric, the metabolic health score (MHS), based on standard clinical parameters and defined its molecular signatures in the liver and circulation. In human UK Biobank, the MHS associated with MetS status and was predictive of future disease incidence, even in individuals without MetS. Using quantitative trait locus analyses in mice, we found two MHS-associated genetic loci and replicated them in unrelated mouse populations. Through a prioritization scheme in mice and human genetic data, we identified TNKS and MCPH1 as candidates mediating differences in the MHS. Our findings provide insights into the molecular mechanisms sustaining metabolic health across species and uncover likely regulators. A record of this paper's transparent peer review process is included in the supplemental information.

Cyclo(His-Pro): A further step in the management of steatohepatitis.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) have become the world's most common liver diseases, placing a growing strain on healthcare systems worldwide. Nonetheless, no effective pharmacological treatment has been approved. The naturally occurring compound cyclo histidine-proline (His-Pro) (CHP) is an interesting candidate for NAFLD management, given its safety profile and anti-inflammatory effects. Methods: Two different mouse models of liver disease were used to evaluate protective effects of CHP on disease progression towards fibrosis: a model of dietary NAFLD/NASH, achieved by thermoneutral housing (TN) in combination with feeding a western diet (WD), and liver fibrosis caused by repeated injections with carbon tetrachloride (CCl4). Results: Treatment with CHP limited overall lipid accumulation, lowered systemic inflammation, and prevented hyperglycaemia. Histopathology and liver transcriptomics highlighted reduced steatosis and demonstrated remarkable protection from the development of inflammation and fibrosis, features which herald the progression of NAFLD. We identified the extracellular signal-regulated kinase (ERK) pathway as an early mediator of the cellular response to CHP. Conclusions: CHP was active in both the preventive and therapeutic setting, reducing liver steatosis, fibrosis, and inflammation and improving several markers of liver disease. Impact and implications: Considering the incidence and the lack of approved treatments, it is urgent to identify new strategies that prevent and manage NAFLD. CHP was effective in attenuating NAFLD progression in two animal models of the disease. Overall, our work points to CHP as a novel and effective strategy for the management of NAFLD, fuelling optimism for potential clinical studies.

Mid-late Holocene vegetation history of the Argive Plain (Peloponnese, Greece) as inferred from a pollen record from ancient Lake Lerna.

This study provides a high-resolution reconstruction of the vegetation of the Argive Plain (Peloponnese, Greece) covering 5000 years from the Early Bronze Age onwards. The well dated pollen record from ancient Lake Lerna has been interpreted in the light of archaeological and historical sources, climatic data from the same core and other regional proxies. Our results demonstrate a significant degree of human impact on the environments of the Argive Plain throughout the study period. During the Early Bronze Age evidence of a thermophilous vegetation is seen in the pollen record, representing the mixed deciduous oak woodland of the Peloponnesian uplands. The plain was mainly used for the cultivation of cereals, whereas local fen conditions prevailed at the coring site. Towards the end of this period an increasing water table is recorded and the fen turns into a lake, despite more arid conditions. In the Late Bronze Age, the presence of important palatial centres modified the landscape resulting in decrease of mixed deciduous oak woodland and increase in open land, partly used for grazing. Possibly, the human management produced a permanent hydrological change at Lake Lerna. From the Archaic period onwards the increasing human pressure in association with local drier conditions caused landscape instability, as attested by a dramatic alluvial event recorded in the Pinus curve at the end of the Hellenistic Age. Wet conditions coincided with Roman times and favoured a forest regeneration pattern in the area, at the same time as we see the most intensive olive cultivation in the pollen record. The establishment of an economic landscape primarily based on pastures is recorded in the Byzantine period and continues until modern times. Overgrazing and fires in combination with arid conditions likely caused degradation of the vegetation into garrigue, as seen in the area of the Argive Plain today.

Deep drilling reveals massive shifts in evolutionary dynamics after formation of ancient ecosystem.

The scarcity of high-resolution empirical data directly tracking diversity over time limits our understanding of speciation and extinction dynamics and the drivers of rate changes. Here, we analyze a continuous species-level fossil record of endemic diatoms from ancient Lake Ohrid, along with environmental and climate indicator time series since lake formation 1.36 million years (Ma) ago. We show that speciation and extinction rates nearly simultaneously decreased in the environmentally dynamic phase after ecosystem formation and stabilized after deep-water conditions established in Lake Ohrid. As the lake deepens, we also see a switch in the macroevolutionary trade-off, resulting in a transition from a volatile assemblage of short-lived endemic species to a stable community of long-lived species. Our results emphasize the importance of the interplay between environmental/climate change, ecosystem stability, and environmental limits to diversity for diversification processes. The study also provides a new understanding of evolutionary dynamics in long-lived ecosystems.

Chitosan films for regenerative medicine: fabrication methods and mechanical characterization of nanostructured chitosan films.

Regenerative medicine is continuously facing new challenges and it is searching for new biocompatible, green/natural polymer materials, possibly biodegradable and non-immunogenic. Moreover, the critical importance of the nano/microstructuring of surfaces is overall accepted for their full biocompatibility and in vitro/in vivo performances. Chitosan is emerging as a promising biopolymer for tissue engineering and its application can be further improved by exploiting its nano/microstructuration. Here, we report the state of the art of chitosan films and scaffolds nano/micro-structuration. We show that it is possible to obtain, by solvent casting, chitosan thin films with good mechanical properties and to structure them at the microscale and even nanoscale level, with resolutions down to 100 nm.

Modulation of the metastatic progression of breast cancer with an organometallic ruthenium compound.

The modulation of the metastatic progression of breast cancer has been evaluated in vitro and in vivo with RAPTA-T, [Ru(eta6-toluene)Cl2(PTA)], an organometallic ruthenium compound. In vitro RAPTA-T inhibits some steps of the metastatic process such as the detachment from the primary tumour, the migration/invasion and the re-adhesion to a new growth substrate. All these effects are boosted when cells grow on components of the extra cellular matrix such as collagen IV and fibronectin and minimized on the non-specific substrate poly-L-lysine and are more pronounced when experiments are performed with the highly invasive MDA-MB-231 cells than with the non-invasive MCF-7 or the non- tumourigenic HBL-100. In vivo RAPTA-T selectively reduces the growth of lung metastases, an effect that might be explained by the in vitro activity. The effect on tests requiring the interaction of the tumour cells with extra cellular matrix components, might suggest an interaction with cell surface molecules in the activity of this ruthenium compound.