scholarly journals Monodeuterated Methane, an Isotopic Tool To Assess Biological Methane Metabolism Rates

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Jeffrey J. Marlow ◽  
Joshua A. Steele ◽  
Wiebke Ziebis ◽  
Silvan Scheller ◽  
David Case ◽  
...  
Keyword(s):  
Methane Oxidation ◽  
Type I ◽  
Hydrogen Atoms ◽  
Natural Systems ◽  
Methane Consumption ◽  
Oxidation Rates ◽  
Carbon Isotopic ◽  
Wide Range ◽  
Methane Metabolism ◽  
Aerobic And Anaerobic

ABSTRACTBiological methane oxidation is a globally relevant process that mediates the flux of an important greenhouse gas through both aerobic and anaerobic metabolic pathways. However, measuring these metabolic rates presents many obstacles, from logistical barriers to regulatory hurdles and poor precision. Here we present a new approach for investigating microbial methane metabolism based on hydrogen atom dynamics, which is complementary to carbon-focused assessments of methanotrophy. The method uses monodeuterated methane (CH3D) as a metabolic substrate, quantifying the aqueous D/H ratio over time using off-axis integrated cavity output spectroscopy. This approach represents a nontoxic, comparatively rapid, and straightforward approach that supplements existing radiotopic and stable carbon isotopic methods; by probing hydrogen atoms, it offers an additional dimension for examining rates and pathways of methane metabolism. We provide direct comparisons between the CH3D procedure and the well-established14CH4radiotracer method for several methanotrophic systems, including type I and II aerobic methanotroph cultures and methane-seep sediment slurries and carbonate rocks under anoxic and oxic incubation conditions. In all applications tested, methane consumption values calculated via the CH3D method were directly and consistently proportional to14C radiolabel-derived methane oxidation rates. We also employed this method in a nontraditional experimental setup, using flexible, gas-impermeable bags to investigate the role of pressure on seep sediment methane oxidation rates. Results revealed an 80% increase over atmospheric pressure in methanotrophic rates the equivalent of ~900-m water depth, highlighting the importance of this parameter on methane metabolism and exhibiting the flexibility of the newly described method.IMPORTANCEMicrobial methane consumption is a critical component of the global carbon cycle, with wide-ranging implications for climate regulation and hydrocarbon exploitation. Nonetheless, quantifying methane metabolism typically involves logistically challenging methods and/or specialized equipment; these impediments have limited our understanding of methane fluxes and reservoirs in natural systems, making effective management difficult. Here, we offer an easily implementable, precise method using monodeuterated methane (CH3D) that advances three specific aims. First, it allows users to directly compare methane consumption rates between different experimental treatments of the same inoculum. Second, by empirically linking the CH3D procedure with the well-established14C radiocarbon approach, we determine absolute scaling factors that facilitate rate measurements for several aerobic and anaerobic systems of interest. Third, CH3D represents a helpful tool in evaluating the relationship between methane activation and full oxidation in methanotrophic metabolisms. The procedural advantages, consistency, and novel research questions enabled by the CH3D method should prove useful in a wide range of culture-based and environmental microbial systems to further elucidate methane metabolism dynamics.

scholarly journals Monodeuterated methane: an isotopic probe to measure biological methane metabolism rates and track catabolic exchange reactions

2016 ◽  
Author(s):  
Jeffrey J. Marlow ◽  
Joshua A. Steele ◽  
Wiebke Ziebis ◽  
Silvan Scheller ◽  
David Case ◽  
...  
Keyword(s):  
Methane Oxidation ◽  
Type I ◽  
Branch Points ◽  
Exchange Reactions ◽  
Oxidation Rates ◽  
Carbon Isotopic ◽  
Isotopic Methods ◽  
Wide Range ◽  
Experimental Treatments ◽  
Methane Metabolism

Abstract. Biological methane oxidation is a globally relevant process that mediates the flux of an important greenhouse gas through both aerobic and anaerobic metabolic pathways. However, measuring the rates of these metabolisms presents many obstacles, from logistical barriers to regulatory hurdles and poor precision. Here we present a new approach for measuring rates of microbial methane metabolism that is non-toxic, rapid, and relatively high throughput, alleviating some of the current methodological challenges. Specifically, we tested the potential for using monodeuterated methane (CH3D) as a metabolic substrate for measuring the rate of methane activation by quantifying the change in the aqueous D / H ratio over time using a water isotope analyzer. This method represents a non-toxic, comparatively rapid and straightforward approach that is complementary to existing radio (14C)- and stable (13C) carbon isotopic methods; by probing hydrogen atom dynamics, it offers an additional dimension through which to examine the rates and pathways of methane metabolism. We provide direct comparisons between the CH3D procedure and the well-established 14CH4 radiotracer approach for several methanotrophic systems, including type I and type II aerobic methanotroph cultures, and methane seep sediment and carbonate rocks under anoxic and oxic incubation conditions. We also employ this method to investigate the role of pressure on methane oxidation rates in anoxic seep sediment, revealing an 80 % increase at the equivalent of ~ 900 m water depth (40 MPa). The monodeuterated methane approach offers a procedurally straightforward, reliable method that advances three specific aims: 1) the direct comparison of methane oxidation rates between different experimental treatments of the same inoculum; 2) the determination of an absolute scaling factor using paired CH3D and 14C-radiocarbon procedures for new systems of interest; and 3) a continued evaluation of C- and H-atom tracking through methanotrophic metabolisms, with specific foci on enzyme reversibility and anabolic/catabolic branch points. The procedural advantages, consistency, and novel research questions enabled by the monodeuterated methane method should prove useful in a wide range of culture-based and environmental microbial systems to further elucidate methane metabolism dynamics.

UK landfill methane emissions: Use of mobile plume measurements and carbon isotopic characterisation to reassess oxidation rates for open and closed sites 

2021 ◽  
Author(s):  
Semra Bakkaloglu ◽  
Dave Lowry ◽  
Rebecca Fisher ◽  
James France ◽  
Euan Nisbet
Keyword(s):  
Methane Oxidation ◽  
Mole Fraction ◽  
Oxidation Rate ◽  
Methane Emissions ◽  
Isotopic Signature ◽  
Oxidation Rates ◽  
Landfill Cover ◽  
Carbon Isotopic ◽  
Landfill Sites ◽  
The Impact

<p>Biological methane oxidation in landfill cover material can be characterised using stable isotopes. Methane oxidation fraction is calculated from the carbon isotopic signature of emitted CH<sub>4</sub>, with enhanced microbial consumption of methane in the aerobic portion of the landfill cover indicated by a shift to less depleted isotopic values in the residual methane emitted to air. This study was performed at four southwest England landfill sites. Mobile mole fraction measurement at the four sites was coupled with Flexfoil bag sampling of air for high-precision isotope analysis. Gas well samples collected from the pipeline systems and downwind plume air samples were utilized to estimate methane oxidation rate for whole sites. This work was designed to assess the impact on carbon isotopic signature and oxidation rate as UK landfill practice and waste streams have changed in recent years.</p><p>The landfill status such as closed and active, seasonal variation, cap stripping and site closure impact on landfill isotopic signature and oxidation rate were evaluated. The isotopic signature of <sup>13</sup>C-CH<sub>4</sub> values of emissions varied between -60 and -54‰, with an averaged value of -57 +- 2‰ for methane from closed and active landfill sites. Methane emissions from older, closed landfill sites were typically more enriched in <sup>13</sup>C than emissions from active sites. This study found that the isotopic signature of <sup>13</sup>C-CH<sub>4</sub> of fugitive methane did not show a seasonal trend, and there was no plume observed from a partial cap stripping process to assess changes in <sup>13</sup>C-CH<sub>4</sub>  isotopic signatures of emitted methane. Also, the closure of an active landfill cell caused a significant decrease in mole fraction of measured CH<sub>4</sub>, which was less depleted <sup>13</sup>C in the emitted plume due to a higher oxidation rate. Methane oxidation, estimated from the isotope fractionation, ranged from 3 to 27%, with mean values of 7% and 15% for active and closed landfills, respectively. These results indicate that the oxidation rate is highly site specific.</p><p> </p>

scholarly journals Abundance and Activity of Methanotrophic Bacteria in Littoral and Profundal Sediments of Lake Constance (Germany)

2008 ◽  
Vol 75 (1) ◽  
pp. 119-126 ◽  
Author(s):  
M. Rahalkar ◽  
J. Deutzmann ◽  
B. Schink ◽  
I. Bussmann
Keyword(s):  
Methane Oxidation ◽  
Lake Constance ◽  
Type I ◽  
Sediment Depth ◽  
Oxidation Activity ◽  
Oxidation Rates ◽  
Methane Oxidizing Bacteria ◽  
Littoral Sediment ◽  
Sediment Layers

ABSTRACT The abundances and activities of aerobic methane-oxidizing bacteria (MOB) were compared in depth profiles of littoral and profundal sediments of Lake Constance, Germany. Abundances were determined by quantitative PCR (qPCR) targeting the pmoA gene and by fluorescence in situ hybridization (FISH), and data were compared to methane oxidation rates calculated from high-resolution concentration profiles. qPCR using type I MOB-specific pmoA primers indicated that type I MOB represented a major proportion in both sediments at all depths. FISH indicated that in both sediments, type I MOB outnumbered type II MOB at least fourfold. Results obtained with both techniques indicated that in the littoral sediment, the highest numbers of methanotrophs were found at a depth of 2 to 3 cm, corresponding to the zone of highest methane oxidation activity, although no oxygen could be detected in this zone. In the profundal sediment, highest methane oxidation activities were found at a depth of 1 to 2 cm, while MOB abundance decreased gradually with sediment depth. In both sediments, MOB were also present at high numbers in deeper sediment layers where no methane oxidation activity could be observed.

Low-Btu gas mixtures—I. Methane oxidation rates for a wide range of equivalence ratios

Energy ◽  
1977 ◽  
Vol 2 (2) ◽  
pp. 197-205 ◽  
Author(s):  
S.S. Penner ◽  
W.M. Heffington ◽  
G.E. Parks ◽  
K.G.P. Sulzmann
Keyword(s):  
Methane Oxidation ◽  
Gas Mixtures ◽  
Oxidation Rates ◽  
Wide Range

scholarly journals Active Methanotrophs and Their Response to Temperature in Marine Environments: An Experimental Study

2021 ◽  
Vol 9 (11) ◽  
pp. 1261
Author(s):  
Jing Li ◽  
Xiaoqing Xu ◽  
Changling Liu ◽  
Nengyou Wu ◽  
Zhilei Sun ◽  
...  
Keyword(s):  
Methane Oxidation ◽  
East China Sea ◽  
East China ◽  
Bohai Bay ◽  
Type I ◽  
Marine Environments ◽  
Ch4 Oxidation ◽  
China Sea ◽  
Oxidation Rates ◽  
Response To Temperature

Aerobic methane (CH4) oxidation plays a significant role in marine CH4 consumption. Temperature changes resulting from, for example, global warming, have been suggested to be able to influence methanotrophic communities and their CH4 oxidation capacity. However, exact knowledge regarding temperature controls on marine aerobic methane oxidation is still missing. In this study, CH4 consumption and the methanotrophic community structure were investigated by incubating sediments from shallow (Bohai Bay) and deep marine environments (East China Sea) at 4, 15, and 28 °C for up to 250 days. The results show that the abundance of the methanotrophic population, dominated by the family Methylococcaceae (type I methanotrophs), was significantly elevated after all incubations and that aerobic methane oxidation for both areas had a strong temperature sensitivity. A positive correlation between the CH4 oxidation rate and temperature was witnessed in the Bohai Bay incubations, whereas for the East China Sea incubations, the optimum temperature was 15 °C. The systematic variations of pmoA OTUs between the Bohai Bay and East China Sea incubations indicated that the exact behaviors of CH4 oxidation rates with temperature are related to the different methanotrophic community structures in shallow and deep seas. These results are of great significance for quantitatively evaluating the biodegradability of CH4 in different marine environments.

scholarly journals Analysis of Methane Monooxygenase Genes in Mono Lake Suggests That Increased Methane Oxidation Activity May Correlate with a Change in Methanotroph Community Structure

2005 ◽  
Vol 71 (10) ◽  
pp. 6458-6462 ◽  
Author(s):  
Ju-Ling Lin ◽  
Samantha B. Joye ◽  
Johannes C. M. Scholten ◽  
Hendrik Schäfer ◽  
Ian R. McDonald ◽  
...  
Keyword(s):  
Methane Oxidation ◽  
Gel Electrophoresis ◽  
Denaturing Gradient Gel Electrophoresis ◽  
Mono Lake ◽  
Hypersaline Lake ◽  
Type I ◽  
Type Ii ◽  
Oxidation Activity ◽  
Oxidation Rates ◽  
Gradient Gel Electrophoresis

ABSTRACT Mono Lake is an alkaline hypersaline lake that supports high methane oxidation rates. Retrieved pmoA sequences showed a broad diversity of aerobic methane oxidizers including the type I methanotrophs Methylobacter (the dominant genus), Methylomicrobium, and Methylothermus, and the type II methanotroph Methylocystis. Stratification of Mono Lake resulted in variation of aerobic methane oxidation rates with depth. Methanotroph diversity as determined by analysis of pmoA using new denaturing gradient gel electrophoresis primers suggested that variations in methane oxidation activity may correlate with changes in methanotroph community composition.

scholarly journals Anaerobic methane oxidation in an East African great lake (Lake Kivu)

2016 ◽  
Author(s):  
Fleur A. E. Roland ◽  
François Darchambeau ◽  
Cédric Morana ◽  
Sean A. Crowe ◽  
Bo Thamdrup ◽  
...  
Keyword(s):  
Methane Oxidation ◽  
Anaerobic Methane Oxidation ◽  
Ch4 Oxidation ◽  
Oxidation Rates ◽  
Anoxic Waters ◽  
Nitrate Consumption ◽  
Lake Kivu ◽  
Consumption Rates ◽  
Field Campaigns ◽  
Aerobic And Anaerobic

Abstract. This study investigates methane (CH4) oxidation in the water column of Lake Kivu, a deep meromictic tropical lake containing large quantities of CH4 in the anoxic deep waters. Depth profiles of dissolved gases (CH4 and nitrous oxide (N2O)) and of the different potential electron acceptors for anaerobic methane oxidation (AOM) (nitrate, sulfate, iron and manganese) were determined during six field campaigns between June 2011 and August 2014. Bacterial abundance all along the vertical profiles was also determined by flow cytometry during three field campaigns, and denitrification measurements based on stable isotopes were performed twice. Incubation experiments were performed to quantify CH4 oxidation and nitrate consumption rates, with a focus on AOM, without and with an inhibitor of sulfate-reducing bacteria activity (molybdate). Nitrate consumption rates were measured in these incubations. Substantial CH4 oxidation activity was observed in oxic and anoxic waters, and in the upper anoxic waters of Lake Kivu, CH4 is a major electron donor to sustain anaerobic metabolic processes coupled to AOM. The maximum aerobic and anaerobic CH4 oxidation rates were estimated to 27 ± 2 and 16 ± 8 µmol L−1 d−1, respectively. We observed a decrease of AOM rates when molybdate was added for half of the measurements, strongly suggesting the occurrence of AOM linked to sulfate reduction, but an increase of AOM rates was observed for the other half. Nitrate reduction rates and dissolved manganese production rates tended to be higher with the addition of molybdate, but the maximum rates of 0.6 ± 0.02 and 11 ± 2 µmol L−1 d−1, respectively, were never high enough to explain AOM rates observed at the same depths. We also put in evidence a difference in relative importance of aerobic and anaerobic CH4 oxidation between the seasons, with a higher importance of aerobic oxidation when the oxygenated layer was thicker (in dry season).

scholarly journals Evidence of Intense Archaeal and Bacterial Methanotrophic Activity in the Black Sea Water Column

2005 ◽  
Vol 71 (12) ◽  
pp. 8099-8106 ◽  
Author(s):  
Edith Durisch-Kaiser ◽  
Lucia Klauser ◽  
Bernhard Wehrli ◽  
Carsten Schubert
Keyword(s):  
Water Column ◽  
Methane Oxidation ◽  
Black Sea ◽  
Sea Water ◽  
Single Cells ◽  
Carbon Isotopic Composition ◽  
The Black Sea ◽  
Type I ◽  
Oxidation Rates ◽  
Cell Counts

ABSTRACT In the northwestern Black Sea, methane oxidation rates reveal that above shallow and deep gas seeps methane is removed from the water column as efficiently as it is at sites located off seeps. Hence, seeps should not have a significant impact on the estimated annual flux of ∼4.1 × 109 mol methane to the atmosphere [W. S. Reeburgh, B. B. Ward, S. C. Wahlen, K. A. Sandbeck, K. A. Kilatrick, and L. J. Kerkhof, Deep-Sea Res. 38(Suppl. 2):S1189-S1210, 1991]. Both the stable carbon isotopic composition of dissolved methane and the microbial community structure analyzed by fluorescent in situ hybridization provide strong evidence that microbially mediated methane oxidation occurs. At the shelf, strong isotope fractionation was observed above high-intensity seeps. This effect was attributed to bacterial type I and II methanotrophs, which on average accounted for 2.5% of the DAPI (4′,6′-diamidino-2-phenylindole)-stained cells in the whole oxic water column. At deep sites, in the oxic-anoxic transition zone, strong isotopic fractionation of methane overlapped with an increased abundance of Archaea and Bacteria, indicating that these organisms are involved in the oxidation of methane. In underlying anoxic water, we successfully identified the archaeal methanotrophs ANME-1 and ANME-2, eachof which accounted for 3 to 4% of the total cell counts. ANME-1 and ANME-2 appear as single cells in anoxicwater, compared to the sediment, where they may form cell aggregates with sulfate-reducing bacteria (A. Boetius, K. Ravenschlag, C. J. Schubert, D. Rickert, F. Widdel, A. Giesecke, R. Amann, B. B. Jørgensen, U. Witte, and O. Pfannkuche, Nature 407:623-626, 2000; V. J. Orphan, C. H. House, K.-U. Hinrichs, K. D. McKeegan, and E. F. DeLong, Proc. Natl. Acad. Sci. USA 99:7663-7668, 2002).

Search for mutations of the interferon-induced transmembrane protein 5 (IFITM5) gene in patients with osteogenesis imperfecta

2019 ◽  
pp. 21-29
Author(s):  
А.Р. Зарипова ◽  
Л.Р. Нургалиева ◽  
А.В. Тюрин ◽  
И.Р. Минниахметов ◽  
Р.И. Хусаинова
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Transmembrane Protein ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Heterozygous Mutation ◽  
Type I ◽  
New Genes ◽  
Wide Range ◽  
Type V

Проведено исследование гена интерферон индуцированного трансмембранного белка 5 (IFITM5) у 99 пациентов с несовершенным остеогенезом (НО) из 86 неродственных семей. НО - клинически и генетически гетерогенное наследственное заболевание соединительной ткани, основное клиническое проявление которого - множественные переломы, начиная с неонатального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам НО относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушения роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. НО встречается как у мужчин, так и у женщин. До сих пор не определена степень генетической гетерогенности заболевания. На сегодняшний день известно 20 генов, вовлеченных в патогенез НО, и исследователи разных стран продолжают искать новые гены. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-сцепленные мутации в широком спектре генов, кодирующих белки, которые участвуют в синтезе коллагена I типа, его процессинге, секреции и посттрансляционной модификации, а также в белках, которые регулируют дифференцировку и активность костеобразующих клеток, вызывают НО. Мутации в гене IFITM5, также называемом BRIL (bone-restricted IFITM-like protein), участвующем в формировании остеобластов, приводят к развитию НО типа V. До 5% пациентов имеют НО типа V, который характеризуется образованием гиперпластического каллуса после переломов, кальцификацией межкостной мембраны предплечья и сетчатым рисунком ламелирования, наблюдаемого при гистологическом исследовании кости. В 2012 г. гетерозиготная мутация (c.-14C> T) в 5’-нетранслируемой области (UTR) гена IFITM5 была идентифицирована как основная причина НО V типа. В представленной работе проведен анализ гена IFITM5 и идентифицирована мутация c.-14C>T, возникшая de novo, у одного пациента с НО, которому впоследствии был установлен V тип заболевания. Также выявлены три известных полиморфных варианта: rs57285449; c.80G>C (p.Gly27Ala) и rs2293745; c.187-45C>T и rs755971385 c.279G>A (p.Thr93=) и один ранее не описанный вариант: c.128G>A (p.Ser43Asn) AGC>AAC (S/D), которые не являются патогенными. В статье уделяется внимание особенностям клинических проявлений НО V типа и рекомендуется определение мутации c.-14C>T в гене IFITM5 при подозрении на данную форму заболевания. A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

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