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\"The pH scale measures how acidic or basic a substance is, ranging from 0 to 14. Readers will learn how certain substances rank on the pH scale, what happens when acids and bases are mixed, and how water can make a substance either acidic or basic. These significant science concepts are discussed in clear and approachable text and supported by motivating fact boxes, charts, and images and photographs.\"-- Provided by publisher.

Key Points The regulation of pH in tumours involves the interplay of several proteins, including: the carbonic anhydrases (EC 4.2.1.1) CA2, CA9 and CA12; the vacuolar ATPase (V-ATPase); anion exchangers AE1, AE2 and AE3; Na + /HCO 3 − co-transporters (NBCs); electroneutral Na + -driven Cl − /HCO 3 − exchanger (NDCBE); the monocarboxylate transporters MCT1, MCT2, MCT3 and MCT4; and Na + /H + exchanger 1, among others. The concerted action of these proteins maintains a slightly alkaline intracellular pH (pH i ) and an acidic extracellular pH (pH e ) within the tumours, which favours the growth and spread of the primary tumour, leading to the formation of metastases. The inhibition of one or more of these pH regulators with specific inhibitors causes both pH i and pH e values to return to normal, with the consequent impairment of tumour growth. This property represents an antitumour mechanism that is not exploited by the classical anticancer drugs. The inhibition of CA9 and/or CA12 with sulphonamide- or coumarin-based small-molecule inhibitors reverses the effects of tumour acidification, leading to inhibition of cancer cell growth in both primary tumours and metastases. Some of these compounds are in preclinical development. This effect can also be exploited for the imaging and treatment of tumours that overexpress CA9 or CA12. The same effect has been observed with antibodies targeting CA9 (and, more recently, also CA12). Some of these antibodies (for example, cG250) are in Phase III clinical development as antitumour and diagnostic agents. Some sulphonamides also inhibit anion exchangers, whereas proton pump inhibitors of the omeprazole type show antitumour effects by inhibiting V-ATPase, thus interfering with other tumour pH regulators. Potent, specific and non-toxic compounds as well as antibodies that interfere with these proteins may represent valuable new antitumour drugs. Changes in pH i towards basic values lead to the production of splice isoforms of extracellular matrix components at the tumour site, which are ideal targets for antibody-based pharmacodelivery strategies. The ability of tumour cells to maintain a slightly alkaline intracellular pH and an acidic extracellular pH aids the growth of primary tumours and the formation of metastases. Inhibiting pH-regulating proteins in tumours represents a novel therapeutic strategy that is not exploited by the classical anticancer drugs. The high metabolic rate of tumours often leads to acidosis and hypoxia in poorly perfused regions. Tumour cells have thus evolved the ability to function in a more acidic environment than normal cells. Key pH regulators in tumour cells include: isoforms 2, 9 and 12 of carbonic anhydrase, isoforms of anion exchangers, Na + /HCO 3 − co-transporters, Na + /H + exchangers, monocarboxylate transporters and the vacuolar ATPase. Both small molecules and antibodies targeting these pH regulators are currently at various stages of clinical development. These antitumour mechanisms are not exploited by the classical cancer drugs and therefore represent a new anticancer drug discovery strategy.

In a porcine cystic fibrosis model, lack of cystic fibrosis transmembrane conductance regulator (CFTR) is shown to result in acidification of airway surface liquid (ASL), and this decrease in pH reduces the ability of ASL to kill bacteria; the findings directly link loss of the CFTR anion channel to impaired defence against bacterial infection. Lung susceptibility to bacterial infection in cystic fibrosis The discovery of a link between cystic fibrosis and mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene has stimulated two decades of extensive research. As a result, the genetic, functional and cellular aspects of CFTR are well known. But despite these advances, it has proved impossible to relate the pathogenesis of bacterial lung infection, the major cause of morbidity and mortality in the disease, to the basic physiological abnormality — the loss of CFTR anion channels. The experiments reported here show that without CFTR, when airway epithelial HCO 3 secretion is defective, the pH of the airway surface liquid falls and inhibits antimicrobial function. This impairs the killing of bacteria that enter the lungs. Reducing the pH of the airway surface layer diminished bactericidal activity in wild-type pigs, whereas increasing the pH restored antimicrobial activity in pigs lacking CFTR . These findings link CFTR mutations to defective bacterial eradication, and suggest that increasing the pH of the airway surface liquid might prevent the initial infection in patients with cystic fibrosis. Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene 1 . Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain 2 , 3 , 4 , 5 , 6 . To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease 7 , 8 . At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria 8 . Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo , when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO 3 − transport 9 , 10 , 11 , 12 , 13 . Without CFTR, airway epithelial HCO 3 − secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.

Hydrogen is a key product of rumen fermentation and has been suggested to thermodynamically control the production of the various volatile fatty acids (VFA). Previous studies, however, have not accounted for the fact that only thermodynamic near-equilibrium conditions control the magnitude of reaction rate. Furthermore, the role of NAD, which is affected by hydrogen partial pressure (PH2), has often not been considered. The aim of this study was to quantify the control of PH2 on reaction rates of specific fermentation pathways, methanogenesis and NADH oxidation in rumen microbes. The control of PH2 was quantified using the thermodynamic potential factor (FT), which is a dimensionless factor that corrects a predicted kinetic reaction rate for the thermodynamic control exerted. Unity FT was calculated for all glucose fermentation pathways considered, indicating no inhibition of PH2 on the production of a specific type of VFA (e.g., acetate, propionate and butyrate) in the rumen. For NADH oxidation without ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity to zero for different NAD+ to NADH ratios and pH of 6.2 and 7.0, which indicates thermodynamic control of PH2. For NADH oxidation with ferredoxin oxidation, increasing PH2 within the rumen physiological range decreased FT from unity at pH of 7.0 only. For the acetate to propionate conversion, FT increased from 0.65 to unity with increasing PH2, which indicates thermodynamic control. For propionate to acetate and butyrate to acetate conversions, FT decreased to zero below the rumen range of PH2, indicating full thermodynamic suppression. For methanogenesis by archaea without cytochromes, FT differed from unity only below the rumen range of PH2, indicating no thermodynamic control. This theoretical investigation shows that thermodynamic control of PH2 on individual VFA produced and associated yield of hydrogen and methane cannot be explained without considering NADH oxidation.

Aerosol acidity (pH) affects aerosol composition and properties, and therefore climate, human health and ecosystems. Fine aerosol acidity and its seasonal variation at 6 sites (Finokalia, Patras, Thissio, Ioannina, Thessaloniki, and Xanthi) in Greece were investigated during 2019-2020. The thermodynamic model ISORROPIA-lite was used to calculate aerosol water and acidity based on measurements of the chemical composition of PM.sub.2.5 and available gas-phase concentrations of HNO.sub.3, NH.sub.3, and HCl. During winter the fine aerosols were acidic to moderately acidic throughout Greece with an overall mean aerosol pH of 3.57±0.44 in urban areas and 3.05±0.50 in remote locations. The highest aerosol pH (4.08±0.42) in January 2020 was found in Ioannina due to, among others, high K.sup.+ levels from biomass burning emissions. Aerosols in Xanthi were the most acidic due to high sulfate levels. Similar seasonal profiles of aerosol pH were observed at all sites studied with different factors contributing to this seasonality. During the summer PM.sub.2.5 at Thissio, Ioannina and Finokalia was acidic with a mean aerosol pH across all three sites of 1.76±0.40. During this season, sulfates were the driver of the higher acidity conditions at Thissio and Finokalia, with other factors such as the semivolatiles and temperature contributing to a lesser extent. At Ioannina, temperature along with the total ammonia and nitrate were the main contributors to the seasonal difference of the aerosol pH, while some of the nonvolatile species also contributed. In most cases, the importance of organics for aerosol pH was small.

There has been significant progress in the last few decades in addressing the biomedical applications of polymer hydrogels. Particularly, stimuli responsive hydrogels have been inspected as elegant drug delivery systems capable to deliver at the appropriate site of action within the specific time. The present work describes the synthesis of pH responsive semi-interpenetrating network (semi-IPN) hydrogels of N-succinyl-chitosan (NSC) via Schiff base mechanism using glutaraldehyde as a crosslinking agent and Poly (acrylamide-co-acrylic acid)(Poly (AAm-co-AA)) was embedded within the N-succinyl chitosan network. The physico-chemical interactions were characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscope (FESEM). The synthesized hydrogels constitute porous structure. The swelling ability was analyzed in physiological mediums of pH 7.4 and pH 1.2 at 37°C. Swelling properties of formulations with various amounts of NSC/ Poly (AAm-co-AA) and crosslinking agent at pH 7.4 and pH 1.2 were investigated. Hydrogels showed higher swelling ratios at pH 7.4 while lower at pH 1.2. Swelling kinetics and diffusion parameters were also determined. Drug loading, encapsulation efficiency, and in vitro release of 5-fluorouracil (5-FU) from the synthesized hydrogels were observed. In vitro release profile revealed the significant influence of pH, amount of NSC, Poly (AAm-co-AA), and crosslinking agent on the release of 5-FU. Accordingly, rapid and large release of drug was observed at pH 7.4 than at pH 1.2. The maximum encapsulation efficiency and release of 5-FU from SP2 were found to be 72.45% and 85.99%, respectively. Kinetics of drug release suggested controlled release mechanism of 5-FU is according to trend of non-Fickian. From the above results, it can be concluded that the synthesized hydrogels have capability to adapt their potential exploitation as targeted oral drug delivery carriers.

Humic acids derived from Chinese weathered coal were oxidized with hydrogen peroxide (H2O2) under various conditions, and their chemical composition and structure were examined. The raw material humic acids (HA) and oxidized humic acids (OHAs) were characterized by elemental analysis and ultraviolet visible (UV-Vis), Fourier transform infrared (FTIR), and solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Our results show that aromatic functional groups accounted for more than 70% of the HA and OHAs and there were significant differences in their structures and compositions. Compared to the HA, the average H and N contents of the OHAs decreased by 5.15% and 2.52%, respectively, and the average O content of those of the OHAs increased by 5.30%. The hydrophobicity index (HI) of HA is higher than those of the OHAs. Importantly, in the hypothesis test between the properties and preparation conditions of humic acid using SPSS, the partial η2 of the temperature, hydrogen peroxide concentration, liquid-solid ratio, and time were 0.809, 0.771, 0.748 and 0.729, respectively; thus, among the preparation conditions, temperature is the most important factor affecting the humic acids properties.

Pentavalent methylated arsenic (As) species such as monomethylarsonic acid [MMA(V)] and dimethylarsinic acid [DMA(V)] are used as herbicides or pesticides, and can also be synthesized by soil microorganisms or algae through As methylation. The mechanism of MMA(V) and DMA(V) uptake remains unknown. Recent studies have shown that arsenite is taken up by rice (Oryza sativa) roots through two silicon transporters, Lsi1 (the aquaporin NIP2;1) and Lsi2 (an efflux carrier). Here we investigated whether these two transporters also mediate the uptake of MMA(V) and DMA(V). MMA(V) was partly reduced to trivalent MMA(III) in rice roots, but only MMA(V) was translocated to shoots. DMA(V) was stable in plants. The rice lsi1 mutant lost about 80% and 50% of the uptake capacity for MMA(V) and DMA(V), respectively, compared with the wild-type rice, whereas Lsi2 mutation had little effect. The short-term uptake kinetics of MMA(V) can be described by a Michaelis-Menten plus linear model, with the wild type having 3.5-fold higher Vmax than the lsi1 mutant. The uptake kinetics of DMA(V) were linear with the slope being 2.8-fold higher in the wild type than the lsi1 mutant. Heterologous expression of Lsi1 in Xenopus laevis oocytes significantly increased the uptake of MMA(V) but not DMA(V), possibly because of a very limited uptake of the latter. Uptake of MMA(V) and DMA(V) by wild-type rice was increased as the pH of the medium decreased, consistent with an increasing proportion of the undissociated species. The results demonstrate that Lsi1 mediates the uptake of undissociated methylated As in rice roots.

Long-distance transport of nitrate requires xylem loading and unloading, a successive process that determines nitrate distribution and subsequent assimilation efficiency. Here, we report the functional characterization of NRT1.8, a member of the nitrate transporter (NRT1) family in Arabidopsis thaliana. NRT1.8 is upregulated by nitrate. Histochemical analysis using promoter-β-glucuronidase fusions, as well as in situ hybridization, showed that NRT1.8 is expressed predominantly in xylem parenchyma cells within the vasculature. Transient expression of the NRT1.8:enhanced green fluorescent protein fusion in onion epidermal cells and Arabidopsis protoplasts indicated that NRT1.8 is plasma membrane localized. Electrophysiological and nitrate uptake analyses using Xenopus laevis oocytes showed that NRT1.8 mediates low-affinity nitrate uptake. Functional disruption of NRT1.8 significantly increased the nitrate concentration in xylem sap. These data together suggest that NRT1.8 functions to remove nitrate from xylem vessels. Interestingly, NRT1.8 was the only nitrate assimilatory pathway gene that was strongly upregulated by cadmium (Cd²⁺) stress in roots, and the nrt1.8-1 mutant showed a nitrate-dependent Cd²⁺-sensitive phenotype. Further analyses showed that Cd²⁺ stress increases the proportion of nitrate allocated to wild-type roots compared with the nrt1.8-1 mutant. These data suggest that NRT1.8-regulated nitrate distribution plays an important role in Cd²⁺ tolerance.

Papain-like cysteine proteases (PLCPs) are a large class of proteolytic enzymes associated with development, immunity, and senescence. Although many properties have been described for individual proteases, the distribution of these characteristics has not been studied collectively. Here, we analyzed 723 plant PLCPs and classify them into nine subfamilies that are present throughout the plant kingdom. Analysis of these subfamilies revealed previously unreported distinct subfamily-specific functional and structural characteristics. For example, the NPIR and KDEL localization signals are distinctive for subfamilies, and the carboxyl-terminal granulin domain occurs in two PLCP subfamilies, in which some individual members probably evolved by deletion of the granulin domains. We also discovered a conserved double cysteine in the catalytic site of SAG12-like proteases and two subfamily-specific disulfides in RD19A-like proteases. Protease activity profiling of representatives of the PLCP subfamilies using novel fluorescent probes revealed striking polymorphic labeling profiles and remarkably distinct pH dependency. Competition assays with peptide-epoxide scanning libraries revealed common and unique inhibitory fingerprints. Finally, we expand the detection of PLCPs by identifying common and organ-specific protease activities and identify previously undetected proteases upon labeling with cell-penetrating probes in vivo. This study provides the plant protease research community with tools for further functional annotation of plant PLCPs.