A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Holocene climate dynamics and construction of the pesqueiras in the NW Iberian Lower Miño River: an OSL approach

Abstract In the Lower Miño River basin a 15-m thick sandy fluvial sequence is found at the town of Chan de Vide, some 55 km upstream from the Atlantic Ocean. The deposit is exceptional because it is the only known sandy deposit in the upstream reaches of the Lower Miño area, which is dominated by coarse gravel deposits. The deposit is probably preserved because of its location in a structurally-controlled bend of the Miño River, shielding the deposit from the high-energy, erosive currents of the Miño River. A total of 8 samples were OSL-dated in the upper 9 m of the deposit. The oldest age obtained at the base of the deposit centres around 3.1 ka ago and the youngest sample 2 m under the top around 200 years ago. A linear sedimentation rate is observed from 3.1 ka until 1.0 ka ago, but from 1.0 ka onwards the sedimentation rate increases significantly. The deposit could be the result of increasing sea level during the Holocene, but the lower part of the deposit needs to be dated to confirm the onset of sedimentation. The most important result is that the increase in sedimentation rate around 1.0 ka is probably the result of the construction of a series of dams (pesqueiras) used for fishing purposes, just downstream of the studied deposit, which were first described around the 12th century. It is a strong indication that the pesqueiras indeed originate from the Middle Ages and not from Roman times, as postulated by some authors. Keywords Minho, sea-level changes, damming, sediment, OSL-datin

Palaeofloods and ancient fishing weirs in NW Iberian rivers

A 15-m-thick, fluvial sedimentary record of the NW Iberian lower Miño River was studied. Grain-size analyses were performed and twelve samples were dated using optically stimulated luminescence dating techniques, documenting a 1300-yr-old reconstructed fluvial record that does not match with known climate fluctuations in the area, but is linked instead to the construction of a series of ancient fishing weirs (pesqueiras). The sedimentation phases are in agreement with known episodes of increased population density, which suggests active use of the pesqueiras. A number of sedimentation hiatuses in the fluvial record point towards damage to the pesqueiras during large-scale flooding in the Miño River basin, and a sudden drop in population probably due to the arrival of the plague in the 13th century AD. The oldest sedimentation phases started just after 700 AD, and we infer that the first pesqueiras were constructed around this time. This timing coincides with the transition of the NW Iberian landscape towards a more intensively used agricultural landscape, as evidenced from other geo-archeological investigations. The results demonstrate that the pesqueiras are several hundreds of years older than known from historical records, but not so old as to date back to the Roman occupation

Heinrich events and tectonic uplift as possible drivers for late Quaternary fluvial dynamics in the western Peruvian Andes

Late Quaternary fluvial valley development in Peru is considered to be driven by summer insolation maxima in the precession cycle, which coincide with increased precipitation and rising lake levels in the central Andes. Our literature review, however, indicates that fluvial aggradation does not always coincide with summer insolation maxima but may also occur during transitions between insolation maxima and minima or even during summer insolation minima. Tectonic uplift as a driver of fluvial incision has not been considered in the current terrace formation models, despite the Peruvian margin being located above an active subduction zone. We present new chronologic, stratigraphic and geomorphic data of the Cañete River valley over the past 102 ± 6 ka. We mapped its fluvial terraces (11.5°-13° southern latitude) along a 75-km long reach perpendicular to the strike of the Andes. Five fluvial terraces and one floodplain level were identified with relative elevations of up to 181.1 m above the floodplain. Thirty-three (pIR) IRSL ages of eight fluvial terraces and one alluvial fan sediment sample showed that their ages in part correspond to summer insolation maxima of the precession cycle, but that a better match exists with pluvial periods that coincided with Heinrich events of the northern hemisphere and rising lake levels in the Andes. The chronology of terraces of the Cañete River agrees with those of previously studied fluvial systems between 7° and 16° southern latitude in Peru, suggesting a regional-scale fluvial response possibly to the Heinrich events. Reconstructed longitudinal profiles and terrace ages were utilised to calculate vertical incision rates. We calculated a mean rate of 1.8 ± 0.10 mm a−1 over the last 102 ± 6 ka, but incision rates varied considerably within this time period possibly in response to changes in the Qs: Qw ratio as a consequence of increased sediment input during the wet Heinrich events. A set of 1338 GNSS measurements of daily, vertical crustal deformation of the years 2009–2015 showed a continuous and positive trend in interseismic, accumulative vertical crustal movements with a time-averaged, crustal uplift rate of 1.9 ± 3.6 mm a−1. The positive trend in vertical movements, together with data from literature suggest landscape rejuvenation along the forearc and western Cordillera in central Peru. It is proposed that maximally ∼0.5 mm a−1 of the total incision over the past 102 ka may possibly be related to nonrecoverable, interseismic deformation. Climate change-driven variations in the Qs:Qw ratio are superimposed on the long-term tectonic uplift trend, and both are considered the main drivers of fluvial incision. © 2022 Elsevier B.V

An alternative explanation for late Quaternary fluvial dynamics in the western Andes: the role of north Atlantic Heinrich events and nonrecoverable interseismic deformation

The formation of fluvial terraces in the western Peruvian Andes over the past 100 ka has commonly been associated to summer insolation maxima of the precession cycle which coincide with increased precipitation and fluvial aggradation. Fluvial incision is also thought to be a result of climate cyclicity, even though there is an ongoing debate about the exact details. Tectonic uplift is generally not considered to play a role as the western Andes attained its maximum elevation during the late Miocene after which mountain building shifted towards the eastern Andes and Subandine belt. Based on fluvial terrace mapping, longitudinal profile reconstructions and IRSL dating, we show that fluvial aggradation was more likely connected to increased precipitation as a result of the North Atlantic Heinrich events. Our dataset of >1300 days of GNSS-measured vertical crustal motions between the years of 2009 and 2015 shows that uplift is occurring with rates of 1.9 mm/yr during the interseismic cycle. We suggest that nonrecoverable, interseismic deformation is an important driver for tectonic uplift and fluvial incision over the 100-ka timescale contributing a maximum of 0.5 mm/yr to long-term uplift. Superimposed on tectonic uplift, changes in the discharge-to-sediment-load ratio of fluvial systems cause highly fluctuating, time-variable fluvial incision. The number of fluvial terraces, the timing of their formation and the reconstructed incisional dynamics in our study area shows strong parallels with those of other fluvial systems in Peru. We present therefore an alternative view of late Quaternary fluvial dynamics for the entire western Peruvian Andes

Comment on “A multidisciplinary overview of the lower Miño River terrace system (NW Iberian Peninsula)” by E. Méndez-Quintas et al

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A 0.65 Ma chronology and incision rate assessment of the NW Iberian Mino River terraces based on 10Be and luminescence dating

In this work a series of 5 luminescence and 10Be dated fluvial terraces of the Miño River (NW Iberian Atlantic Margin) is presented. The outcomes allowed answering the longstanding question whether the Miño valley infill has a fluvial or marine origin. The perfect exponential decrease in 10Be concentrations with depth and a progressive increase in age with terrace altitude indicate that the Miño terraces are fluvial terraces rather than terraces incised in older marine basin infill. Accurate dating of the terraces was difficult due to saturation of the luminescence signal and high inheritance of 10Be concentrations. Nevertheless, minimum ages of up to 650 ka could be determined and are very likely close to the real ages of the terraces. The age estimations and field evidence suggest that terrace formation and terrace incision occurred during eccentricity-forced cycles of glacio-eustatic sea level changes and tectonic uplift. The occurrence of a steep and narrow continental shelf probably favoured rapid and profound incision by the Miño River during periods of low sea levels. It is furthermore hypothesised that the transition periods between glacials and interglacials were especially important for terrace deposition and incision. Denudation rates of the terraces were calculated from the 10Be data and do not exceed 1.30 m Ma- 1. These extremely low rates are probably the result of a combination of factors that favoured terrace preservation. Large, flat terrace surfaces with high permeability and continuous vegetation cover during the Quaternary stabilised the terrace surfaces. Maximum incision rates, calculated from terrace age and altitude, are 0.07–0.09 m ka- 1. These values can be used as proxies for tectonic uplift rates. They are in agreement with published uplift rates along the northern Spanish coast and the westernmost termination of the Cordillera Cantabrica. This similarity most likely identifies a common tectonic regime leading to similar tectonic uplift rates. The results demonstrate that tectonic uplift occurs in a region that was until very recently considered as tectonically stable

The current treatment landscape: The need for antifungal stewardship programmes

There is increasing evidence supporting the need for antifungal stewardship (AFS) programmes in order to promote appropriate antifungal use, improve diagnosis and quality of care, and decrease the costs of antifungal treatment. AFS programmes delivered by experienced teams can be efficacious and cost effective. However, there are a variety of challenges often faced during the implementation of AFS programmes which can present barriers to their success. These can include lack of dedicated personnel, lack of investment in new diagnostic and prescription tools, and misperception by other physicians

Macrophage CD5L is a target for cancer immunotherapyResearch in context

Summary: Background: Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. Methods: Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. Findings: Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel–Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. Interpretation: CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. Funding: For a full list of funding bodies, please see the Acknowledgements