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Isotopes of dissolved inorganic carbon (DIC) are used to indicate both transit times and biogeochemical evolution of groundwaters. These signals can be complicated in carbonate aquifers, as both abiotic (i.e., carbonate equilibria) and biotic factors influence the δ13C and 14C of DIC. We applied a novel graphical method for tracking changes in the δ13C and 14C of DIC in two distinct aquifer complexes identified in the Hainich Critical Zone Exploratory (CZE), a platform to study how water transport links surface and shallow groundwaters in limestone and marlstone rocks in central Germany. For more quantitative estimates of contributions of different biotic and abiotic carbon sources to the DIC pool, we used the NETPATH geochemical modeling program, which accounts for changes in dissolved ions in addition to C isotopes. Although water residence times in the Hainich CZE aquifers based on hydrogeology are relatively short (years or less), DIC isotopes in the shallow, mostly anoxic, aquifer assemblage (HTU) were depleted in 14C compared to a deeper, oxic, aquifer complex (HTL). Carbon isotopes and chemical changes in the deeper HTL wells could be explained by interaction of recharge waters equilibrated with post-bomb 14C sources with carbonates. However, oxygen depletion and δ13C and 14C values of DIC below those expected from the processes of carbonate equilibrium alone indicate considerably different biogeochemical evolution of waters in the upper aquifer assemblage (HTU wells). Changes in 14C and 13C in the upper aquifer complexes result from a number of biotic and abiotic processes, including oxidation of 14C-depleted OM derived from recycled microbial carbon and sedimentary organic matter as well as water–rock interactions. The microbial pathways inferred from DIC isotope shifts and changes in water chemistry in the HTU wells were supported by comparison with in situ microbial community structure based on 16S rRNA analyses. Our findings demonstrate the large variation in the importance of biotic as well as abiotic controls on 13C and 14C of DIC in closely related aquifer assemblages. Further, they support the importance of subsurface-derived carbon sources like DIC for chemolithoautotrophic microorganisms as well as rock-derived organic matter for supporting heterotrophic groundwater microbial communities and indicate that even shallow aquifers have microbial communities that use a variety of subsurface-derived carbon sources.

Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling by the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues ( n =20) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by reverse transcriptase–PCR, western blots and immunohistochemistry. Cell growth, apoptosis, nuclear factor-κB (NF-κB) translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysaccharide (LPS) or paclitaxel (PTX). Culture supernatants were tested for cytokine levels. TLR4 was expressed in all tumors, tumor cell lines and normal epithelium. MyD88 was detectable in tumor tissues and in 3/5 OvCa lines but not in normal cells. In MyD88 + SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-κB pathway and promoted interleukin (IL)-8, IL-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88 neg A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect. Thus, TLR4/MyD88 signaling supports OvCa progression and chemoresistance, promoting immune escape.

Physical and photophysical properties of starch-based biopolymer films containing 5-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine (NTA) powder as a nanofiller were examined using atomic force microscopy (AFM), Fourier-transform infrared spectroscopy (FTIR), stationary UV-Vis and fluorescence spectroscopy as well as resonance light scattering (RLS) and time-resolved measurements, and where possible, analyzed with reference to pristine NTA solutions. AFM studies revealed that the addition of NTA into the starch biopolymer did not significantly affect surface roughness, with all examined films displaying similar Sq values ranging from 70.7 nm to 79.7 nm. Similarly, Young’s modulus measurements showed no significant changes after incorporating the 1,3,4-thiadiazole. Adhesion force and water contact angle assessments demonstrated that the films maintained high hydrophilicity (water wetting) across all examined films. Color analysis corroborated the anticipated trend, showing that increasing additive content resulted in decreased lightness and increased yellowness. Interestingly, however, while in polar isopropanol solvent at low concentration, NTA shows a typical single-band emission, centered at 410 nm and a slight enhancement of the band on the long-wavelength side around 530 nm, its incorporation into the biopolymer matrices results in the appearance of dual fluorescence signal with maxima at 430 and 530 nm. Concentration-dependence emission experiments, demonstrating that with even a slight increase of the amount of NTA in solution, an additional, weak long-wavelength emission band emerged within the spectral range corresponding to the intensive band in the biopolymer film, along with results of the performed quantum-chemical studies, including both the monomeric and aggregated (dimer and trimer) models, conclusively unveil that the dual fluorescence observed in starch/NTA films is due to molecular aggregation effects resulting in aggregation-induced emission. This study underscores the potential of NTA as an additive in biobased polymer films, furnishing them with new photophysical features without substantially altering their surface properties and thus enabling their extended applications.

Recent changes in CMOS device structures and materials motivated by impending atomistic and quantum-mechanical limitations have profoundly influenced the nature of delay and power variability. Variations in process, temperature, power supply, wear-out, and use history continue to strongly influence delay. The manner in which tolerance is specified and accommodated in high-performance design changes dramatically as CMOS technologies scale beyond a 90-nm minimum lithographic linewidth. In this paper, predominant contributors to variability in new CMOS devices are surveyed, and preferred approaches to mitigate their sources of variability are proposed. Process-, device-, and circuit-level responses to systematic and random components of tolerance are considered. Exploratory, novel structures emerging as evolutionary CMOS replacements are likely to change the nature of variability in the coming generations.

Background Aquagenic pruritus (AP), an intense sensation of scratching induced after water contact, is the most troublesome aspect of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Mostly described in polycythemia vera (PV, ~ 40%), it is also present in essential thrombocythemia (ET) and primary myelofibrosis (PMF) (10%). Even if this symptom can decrease or disappear under cytoreductive treatments, 30% of treated MPN patients still persist with a real impact on the quality of life (QoL). Because its pathophysiology is poorly understood, efficient symptomatic treatments of AP are missing. The neuropeptide substance P (SP) plays a crucial role in the induction of pruritus. Several studies showed the efficacy of aprepitant, an antagonist of SP receptor (NK-1R), in the treatment of chronic pruritus but never evaluated in AP. The objectives of APHYPAP are twofold: a clinical aim with the evaluation of the efficacy of two drugs in the treatment of a persistent AP for MPN patients and a biological aim to find clues to elucidate AP pathophysiology. Methods/design A multicentric, double-blind, double-placebo, randomized study will include 80 patients with MPN (PV or ET or PMF) treated since at least 6 months for their hemopathy but suffering from a persistent AP (VAS intensity ≥6/10). Patients will be randomized between aprepitant (80 mg daily) + placebo to match to hydroxyzine OR hydroxyzine (25 mg daily) + placebo to match to aprepitant for 14 days. At D0, baseline information will be collected and drugs dispense. Outcome measures will be assessed at D15, D30, D45, and D60. The primary study endpoint will be the reduction of pruritus intensity below (or equal) at 3/10 on VAS at D15. Secondary outcome measures will include the number of patients with a reduction or cessation of AP at D15 or D60; evaluation of QoL and AP characteristics at D0, D15, D30, D45, and D60 with MPN-SAF and AP questionnaires, respectively; modification of plasmatic concentrations of cytokines and neuropeptides at D0, D15, D30, and D60; and modification of epidermal innervation density and pruriceptor expression at D0 and D15. Discussion The APHYPAP trial will examine the efficacy of aprepitant vs hydroxyzine (reference treatment for AP) to treat persistent AP in MPN patients. The primary objective is to demonstrate the superiority of aprepitant vs hydroxyzine to treat persistent AP of MPN patients. The treatment received will be considered efficient if the AP intensity will be reduced at 3/10 or below on VAS after 14 days of treatment. The results of this study may provide a new treatment option for this troublesome symptom and also give us more insights in the pathophysiology understanding of AP. Trial registration APHYPAP. NCT03808805 , first posted: January 18, 2019; last update posted: June 10, 2021. EudraCT 2018-090426-66

Identifying the ways in which drugs interact with DNA is crucial from a pharmacological point of view, and therefore determining the binding mode of tacrine-coumarin derivatives with DNA is key to gaining a fuller understanding of the activity of these compounds. Seven tacrine-coumarin derivatives 1a − 1d and 2a − 2c have been evaluated for their binding affinity to calf thymus DNA (ctDNA) by a variety of spectroscopic techniques including UV–Vis absorbance, fluorescence and CD spectroscopy. The effect of 1a − 1d and 2a − 2c on thermal denaturation profiles of ctDNA was also studied. The binding constants for the ctDNA-drug complexes were determined on the basis of spectrophotometric and spectrofluorometric titrations. Evidence has been provided that the tacrine-coumarin hybrid molecules bind to ctDNA through a non-intercalative mode of interaction such as groove binding. For derivatives 1d and 2c molecular docking was performed for two different DNA conformations. The results of preliminary molecular docking show that the most favourable DNA binding mode of these derivatives is non-intercalative.

A survey of industry trends from the last two decades of scaling for CMOS logic is examined in an attempt to extrapolate practical directions for CMOS technology as lithography progresses toward the point at which CMOS is limited by the size of the silicon atom itself. Some possible directions for various specialized applications in CMOS logic are explored, and it is further conjectured that double-gate MOSFETs will prove to be the dominant device architecture for this last era of CMOS scaling.

Background Cerebral palsy (CP) causes motor, cognitive and sensory impairment at different extents. Many recent rehabilitation developments (therapies) have focused solely on the upper extremities (UE), although the lower extremities (LE) are commonly affected. Hand-arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) applies the concepts of motor skill learning and intensive training to both the UE and LE. It involves constant stimulation of the UE and LE, for several hours each day over a 2-week period. The effects of HABIT-ILE have never been evaluated in a large sample of young children. Furthermore, understanding of functional, neuroplastic and biomechanical changes in infants with CP is lacking. The aim of this study is to carry out a multi-center randomized controlled trial (RCT) to evaluate the effects of HABIT-ILE in pre-school children with unilateral CP on functional, neuroplastic and biomechanical parameters. Methods This multi-center, 3-country study will include 50 pre-school children with CP aged 1–4 years. The RCT will compare the effect of 50 h (two weeks) of HABIT-ILE versus usual motor activity, including regular rehabilitation. HABIT-ILE will be delivered in a day-camp setting, with structured activities and functional tasks that will be continuously progressed in terms of difficulty. Assessments will be performed at 3 intervals: baseline (T0), two weeks later and 3 months later. Primary outcomes will be the Assisting Hand Assessment; secondary outcomes include the Melbourne Assessment-2, executive function assessments, questionnaires ACTIVLIM-CP, Pediatric Evaluation of Disability Inventory, Young Children’s Participation and Environment Measure, Measure of the Process of Care, Canadian Occupational Performance Measure, as well as neuroimaging and kinematics measures. Discussion We expect that HABIT-ILE will induce functional, neuroplastic and biomechanical changes as a result of the intense, activity-based rehabilitation process and these changes will impact the whole developmental curve of each child, improving functional ability, activity and participation in the short-, mid- and long-term. Name of the registry: Changes Induced by Early HABIT-ILE in Pre-school Children With Uni- and Bilateral Cerebral Palsy (EarlyHABIT-ILE). Trial registration Trial registration number: NCT04020354 -Registration date on the International Clinical Trials Registry Platform (ICTRP): November 20th, 2018; Registration date on NIH Clinical Trials Registry: July 16th, 2019.

To quantify the contribution of autotrophic microorganisms to organic matter (OM) formation in soils, we investigated natural CO2 vents (mofettes) situated in a wetland in northwest Bohemia (Czech Republic). Mofette soils had higher soil organic matter (SOM) concentrations than reference soils due to restricted decomposition under high CO2 levels. We used radiocarbon (Δ14C) and stable carbon (δ13C) isotope ratios to characterize SOM and its sources in two mofettes and compared it with respective reference soils, which were not influenced by geogenic CO2.The geogenic CO2 emitted at these sites is free of radiocarbon and enriched in 13C compared to atmospheric CO2. Together, these isotopic signals allow us to distinguish C fixed by plants from C fixed by autotrophic microorganisms using their differences in 13C discrimination. We can then estimate that up to 27 % of soil organic matter in the 0–10 cm layer of these soils was derived from microbially assimilated CO2.Isotope values of bulk SOM were shifted towards more positive δ13C and more negative Δ14C values in mofettes compared to reference soils, suggesting that geogenic CO2 emitted from the soil atmosphere is incorporated into SOM. To distinguish whether geogenic CO2 was fixed by plants or by CO2 assimilating microorganisms, we first used the proportional differences in radiocarbon and δ13C values to indicate the magnitude of discrimination of the stable isotopes in living plants. Deviation from this relationship was taken to indicate the presence of microbial CO2 fixation, as microbial discrimination should differ from that of plants. 13CO2-labelling experiments confirmed high activity of CO2 assimilating microbes in the top 10 cm, whereδ13C values of SOM were shifted up to 2 ‰ towards more negative values. Uptake rates of microbial CO2 fixation ranged up to 1.59 ± 0.16 µg gdw-1 d-1. We inferred that the negative δ13C shift was caused by the activity of autotrophic microorganisms using the Calvin–Benson–Bassham (CBB) cycle, as indicated from quantification of cbbL/cbbM marker genes encoding for RubisCO by quantitative polymerase chain reaction (qPCR) and by acetogenic and methanogenic microorganisms, shown present in the mofettes by previous studies. Combined Δ14C and δ13C isotope mass balances indicated that microbially derived carbon accounted for 8–27 % of bulk SOM in this soil layer.The findings imply that autotrophic microorganisms can recycle significant amounts of carbon in wetland soils and might contribute to observed radiocarbon reservoir effects influencing Δ14C signatures in peat deposits.