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1.
Adv Mater ; : e2308823, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38531078

ABSTRACT

Organic electrochemical transistors (OECTs) are one of the promising building blocks to realize next-generation bioelectronics. To date, however, the performance and signal processing capabilities of these devices remain limited by their stability and speed. Herein, the authors demonstrate stable and fast n-type organic electrochemical transistors based on a side-chain-free ladder polymer, poly(benzimidazoanthradiisoquinolinedione). The device demonstrated fast normalized transient speed of 0.56 ± 0.17 ms um-2 and excellent long-term stability in aqueous electrolytes, with no significant drop in its doping current after 50 000 successive doping/dedoping cycles and 2-month storage at ambient conditions. These unique characteristics make this polymer especially suitable for bioelectronics, such as being used as a pull-down channel in a complementary inverter for long-term stable detection of electrophysiological signals. Moreover, the developed device shows a reversible anti-ambipolar behavior, enabling reconfigurable electronics to be realized using a single material. These results go beyond the conventional OECT and demonstrate the potential of OECTs to exhibit dynamically configurable functionalities for next-generation reconfigurable electronics.

2.
Nanotechnology ; 35(4)2023 Nov 06.
Article in English | MEDLINE | ID: mdl-37848022

ABSTRACT

In the dynamic landscape of the Internet of Things (IoT), where smart devices are reshaping our world, nanomaterials can play a pivotal role in ensuring the IoT's sustainability. These materials are poised to redefine the development of smart devices, not only enabling cost-effective fabrication but also unlocking novel functionalities. As the IoT is set to encompass an astounding number of interconnected devices, the demand for environmentally friendly nanomaterials takes center stage. ThisFocus Issuespotlights cutting-edge research that explores the intersection of nanomaterials and sustainability. The collection delves deep into this critical nexus, encompassing a wide range of topics, from fundamental properties to applications in devices (e.g. sensors, optoelectronic synapses, energy harvesters, memory components, energy storage devices, and batteries), aspects concerning circularity and green synthesis, and an array of materials comprising organic semiconductors, perovskites, quantum dots, nanocellulose, graphene, and two-dimensional semiconductors. Authors not only showcase advancements but also delve into the sustainability profile of these materials, fostering a responsible endeavour toward a green IoT future.

3.
Int J Sports Physiol Perform ; 18(1): 61-68, 2023 Jan 01.
Article in English | MEDLINE | ID: mdl-36460002

ABSTRACT

PURPOSE: To examine the longitudinal relationships between shoulder internal and external rotation (IR and ER) strength, maturity status, and swim performance (aim 1). To determine whether maturity status mediated (partially/fully) the relationship between shoulder IR/ER strength and performance in age-group swimmers (aim 2). METHODS: Using a repeated-measures design, anthropometrics, maturity status, shoulder IR/ER strength, and 200-m front-crawl velocity were assessed over 3 competition seasons in N = 82 Australian male competitive swimmers (10-15 y). For aim 1, linear mixed models examined longitudinal relationships between assessed variables. For aim 2, causal mediation analyses examined proportional (in)direct contributions of maturity status between shoulder IR strength and swim performance. RESULTS: For aim 1, linear mixed models identified a significant relationship between shoulder IR strength and swim performance over time (F1,341.25 = 16.66, P < .001, marginal R2 = .13, conditional R2 = .91). However, maturity status was influential (ΔAkaike information criterion = -75.8, χ2 = 19.98, P < .001), suggesting removal of the shoulder IR strength-swim velocity relationship (F1,214.1 = 0.02, P = .88). For aim 2, mediation analyses identified maturity status as fully mediating the shoulder IR strength-swim velocity relationship (92.30%, P < .001). CONCLUSIONS: Shoulder IR and ER strength did not account for variance in longitudinal age-group swim performance independent of maturity status. Interindividual differences in maturity status fully explained the relationship between shoulder IR/ER strength and swim performance. For practitioners, findings promote the need to account for maturation status and question the rationale for upper-limb strength assessment during maturational years.


Subject(s)
Shoulder Joint , Shoulder , Humans , Male , Adolescent , Australia , Swimming , Range of Motion, Articular
4.
Adv Mater ; 34(42): e2206118, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36008368

ABSTRACT

The rapid development of organic electrochemical transistor (OECTs)-based circuits brings new opportunities for next-generation integrated bioelectronics. The all-polymer bulk-heterojunction (BHJ) offers an attractive, inexpensive alternative to achieve efficient ambipolar OECTs, and building blocks of logic circuits constructed from them, but have not been investigated to date. Here, the first all-polymer BHJ-based OECTs are reported, consisting of a blend of new p-type ladder conjugated polymer and a state-of-the-art n-type ladder polymer. The whole ladder-type polymer BHJ also proves that side chains are not necessary for good ion transport. Instead, the polymer nanostructures play a critical role in the ion penetration and transportation and thus in the device performance. It also provides a facile strategy and simplifies the fabrication process, forgoing the need to pattern multiple active layers. In addition, the development of complementary metal-oxide-semiconductor (CMOS)-like OECTs allows the pursuit of advanced functional logic circuitry, including inverters and NAND gates, as well as for amplifying electrophysiology signals. This work opens a new approach to the design of new materials for OECTs and will contribute to the development of organic heterojunctions for ambipolar OECTs toward high-performing logic circuits.

5.
ACS Nano ; 16(8): 12049-12060, 2022 08 23.
Article in English | MEDLINE | ID: mdl-35939084

ABSTRACT

Organic electrochemical transistors (OECTs) have recently attracted attention due to their high transconductance and low operating voltage, which makes them ideal for a wide range of biosensing applications. Poly-3,4-ethylenedioxythiophene:poly-4-styrenesulfonate (PEDOT:PSS) is a typical material used as the active channel layer in OECTs. Pristine PEDOT:PSS has poor electrical conductivity, and additives are typically introduced to improve its conductivity and OECT performance. However, these additives are mostly either toxic or not proven to be biocompatible. Herein, a biocompatible ionic liquid [MTEOA][MeOSO3] is demonstrated to be an effective additive to enhance the performance of PEDOT:PSS-based OECTs. The influence of [MTEOA][MeOSO3] on the conductivity, morphology, and redox process of PEDOT:PSS is investigated. The PEDOT:PSS/[MTEOA][MeOSO3]-based OECT exhibits high transconductance (22.3 ± 4.5 mS µm-1), high µC* (the product of mobility µ and volumetric capacitance C*) (283.80 ± 29.66 F cm-1 V-1 s-1), fast response time (∼40.57 µs), and excellent switching cyclical stability. Next, the integration of sodium (Na+) and potassium (K+) ion-selective membranes with the OECTs is demonstrated, enabling selective ion detection in the physiological range. In addition, flexible OECTs are designed for electrocardiography (ECG) signal acquisition. These OECTs have shown robust performance against physical deformation and successfully recorded high-quality ECG signals.


Subject(s)
Biosensing Techniques , Ionic Liquids , Polystyrenes , Electric Capacitance , Ions
6.
Clin Otolaryngol ; 47(6): 620-627, 2022 11.
Article in English | MEDLINE | ID: mdl-35916238

ABSTRACT

INTRODUCTION: Recent guidelines suggest obstructive sleep apnoea (OSA) is not an absolute contraindication for same day discharge following surgery. The aim of this systematic review was to examine the feasibility and safety of day case nasal and/or palatopharyngeal surgery in patients with OSA. METHODS: We performed a systematic search of PubMed, EMBASE and the Cochrane library. Quality assessment of included studies was performed. The protocol of this systematic review was registered with PROSPERO (CRD42021273451). RESULTS: A total of 1836 patients from 10 observational studies were included. There were 268 (15.4%) nasal surgeries, 738 palatopharyngeal surgeries (42.4%) and 735 (42.2%) combined nasal and palatopharyngeal surgery. The majority of patients had moderate to severe OSA. A total of 860 patients (49.8%) were successfully discharged as day cases. There were no standard criteria for daycase surgery. Post-anaesthetic respiratory events were reported in 86/1750 (4.9%) patients. Oxygen desaturation was the most common respiratory event (83.7%, n = 72). There was no mortality reported. CONCLUSION: Current data suggests day surgery is feasible in carefully selected patients with OSA undergoing nasal and/or palatopharyngeal surgery. Further well-designed prospective studies with an emphasis on the systematic assessment of complications are required to establish safety and daycase criteria.


Subject(s)
Sleep Apnea, Obstructive , Feasibility Studies , Humans , Oxygen , Pharyngeal Muscles , Prospective Studies , Sleep Apnea, Obstructive/surgery
7.
Micromachines (Basel) ; 13(8)2022 Aug 12.
Article in English | MEDLINE | ID: mdl-36014224

ABSTRACT

In this work, a composite strain sensor is fabricated by synthesizing MXene and deposition of polypyrrole on top of the flexible electrospun PVDF nanofibers. The fabricated sensor exhibits a conductive network constructed with MXene and polypyrrole of microcracks network structure, demonstrating its strain sensing properties. The presence of these microcracks serves as mechanical weak points, which leads to sensitivity enhancement, while the electrospun fiber substrate act as a cushion for strain loading under large deformations. The as-prepared MXene@Polypyrrole PVDF sensor has a gauge factor range of 78-355 with a sensing range between 0-100%. Besides strain deformations, the sensor can operate in torsional deformation and human motion, indicating the sensor's potential as a wearable health monitoring device.

8.
Mater Horiz ; 9(9): 2408-2415, 2022 08 30.
Article in English | MEDLINE | ID: mdl-35801931

ABSTRACT

Poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) based organic electrochemical transistors (OECTs) have proven to be one of the most versatile platforms for various applications including bioelectronics, neuromorphic computing and soft robotics. The use of PEDOT:PSS for OECTs originates from its ample mixed ionic-electronic conductivity, which in turn depends on the microscale phase separation and morphology of the polymer. Thus, modulation of the microstructure of PEDOT:PSS film enables us to tune the operation and device characteristics of the resulting OECT. Herein we report enhanced transconductance (20 mS), fast switching (32 µs) and stable operation (10 000 cycles) of modified PEDOT:PSS based OECTs using 15-crown-5 as an additive. Four probe measurements reveal an increased electronic conductivity of the modified PEDOT:PSS film (∼450 S cm-1) while tapping mode atomic force microscopy shows an increased phase separation. Further detailed characterization using spectroelectrochemistry, X-ray photoelectron spectroscopy (XPS) and grazing incidence wide-angle X-ray diffraction (GIWAXS) provides insight into the microstructural changes brought about by the crown ether additive that result in the desirable characteristics of the modified PEDOT:PSS film.


Subject(s)
Crown Ethers , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Electronics , Ions , Polymers/chemistry
9.
Eur Respir J ; 60(6)2022 12.
Article in English | MEDLINE | ID: mdl-35896203

ABSTRACT

BACKGROUND: There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease. METHOD: We measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore. RESULTS: The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sd z-score: FEV1 -0.94±1.05, FVC -0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03±0.99, FVC 0.04±0.97, FEV1/FVC -0.03±0.99) and external validation (z-scores: FEV1 0.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia. CONCLUSION: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.


Subject(s)
Asian People , Lung , Male , Female , Humans , Adolescent , Adult , Nutrition Surveys , Reference Values , Spirometry , Forced Expiratory Volume , India , Vital Capacity
10.
Clin Otolaryngol ; 47(5): 553-560, 2022 09.
Article in English | MEDLINE | ID: mdl-35603525

ABSTRACT

OBJECTIVES: Obstructive sleep apnoea (OSA) is a common indication for adenoidectomy and tonsillectomy in children. Traditional practice involves overnight admission to monitor for respiratory complications. However, there is a shift towards same-day discharge in selected patients. This systematic review aims to critically evaluate day-case criteria and safety in children with OSA undergoing adenotonsillectomy. DESIGN: We performed a systematic search of EMBASE, Medline and the Cochrane library. All data collected were independently validated for accuracy. Quality assessment of included articles was performed. The protocol was registered with PROSPERO. RESULTS: A total of 15 studies were included (10 731 patients). There was heterogeneity in methods used to ascertain OSA, day-case discharge criteria and lack of prospective discharge protocol. The proportion of children considered for planned day-case surgery ranged from 28.7%-100% based on individual criteria, with an average rate of successful same-day discharge of 96.1% in these patients. The reported rates of post-operative respiratory adverse events and need for airway intervention were 0%-27.3% and 0.4%-6.8%, respectively. There was no reported mortality. The studies were considered low to medium on quality assessment. CONCLUSION: There is a lack of prospective data on day-case criteria and systematic assessment of post-operative complications in children with OSA undergoing adenoidectomy and tonsillectomy. However, current literature suggests that day-case surgery is safe in carefully selected patients. Better characterisation of patient-specific risk factors is needed to develop an optimal criteria-based timeline for safe discharge. This has the potential to improve confidence and uptake across units.


Subject(s)
Sleep Apnea, Obstructive , Tonsillectomy , Adenoidectomy/adverse effects , Adenoidectomy/methods , Ambulatory Surgical Procedures , Child , Humans , Patient Discharge , Sleep Apnea, Obstructive/etiology , Sleep Apnea, Obstructive/surgery , Tonsillectomy/adverse effects , Tonsillectomy/methods
11.
Adv Mater ; 34(19): e2200682, 2022 May.
Article in English | MEDLINE | ID: mdl-35305267

ABSTRACT

A stretchable and self-healable conductive material with high conductivity is critical to high-performance wearable electronics and integrated devices for applications where large mechanical deformation is involved. While there has been great progress in developing stretchable and self-healable conducting materials, it remains challenging to concurrently maintain and recover such functionalities before and after healing. Here, a highly stretchable and autonomic self-healable conducting film consisting of a conducting polymer (poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), PEDOT:PSS) and a soft-polymer (poly(2-acrylamido-2-methyl-1-propanesulfonic acid), PAAMPSA) is reported. The optimal film exhibits outstanding stretchability as high as 630% and high electrical conductivity of 320 S cm-1 , while possessing the ability to repair both mechanical and electrical breakdowns when undergoing severe damage at ambient conditions. This polymer composite film is further utilized in a tactile sensor, which exhibits good pressure sensitivity of 164.5 kPa-1 , near hysteresis-free, an ultrafast response time of 19 ms, and excellent endurance over 1500 consecutive presses. Additionally, an integrated 5 × 4 stretchable and self-healable organic electrochemical transistor (OECT) array with great device performance is successfully demonstrated. The developed stretchable and autonomic self-healable conducting film significantly increases the practicality and shelf life of wearable electronics, which in turn, reduces maintenance costs and build-up of electronic waste.

12.
J Phys Chem B ; 126(9): 2073-2085, 2022 Mar 10.
Article in English | MEDLINE | ID: mdl-35200014

ABSTRACT

Conjugated polymers are promising materials for thermoelectrics as they offer good performances at near ambient temperatures. The current focus on polymer thermoelectric research mainly targets a higher power factor (PF; a product of the conductivity and square of the Seebeck coefficient) through improving the charge mobility. This is usually accomplished via structural modification in conjugated polymers using different processing techniques and doping. As a result, the structure-charge transport relationship in conjugated polymers is generally well-established. In contrast, the relationship between the structure and the Seebeck coefficient is poorly understood due to its complex nature. A theoretical framework by David Emin (Phys. Rev. B, 1999, 59, 6205-6210) suggests that the Seebeck coefficient can be enhanced via carrier-induced vibrational softening, whose magnitude is governed by the size of the polaron. In this work, we seek to unravel this relationship in conjugated polymers using a series of highly identical pro-quinoid polymers. These polymers are ideal to test Emin's framework experimentally as the quinoid character and polaron delocalization in these polymers can be well controlled even by small atomic differences (<10 at. % per repeating unit). By increasing the polaron delocalization, that is, the polaron size, we demonstrate that both the conductivity and the Seebeck coefficient (and hence PF) can be increased simultaneously, and the latter is due to the increase in the polaron's vibrational entropy. By using literature data, we also show that this phenomenon can be observed in two closely related diketopyrrolopyrrole-conjugated polymers as well as in p-doped P3HT and PANI systems with an increasing molecular order.

13.
Malays Fam Physician ; 17(3): 84-88, 2022 Nov 30.
Article in English | MEDLINE | ID: mdl-36606176

ABSTRACT

Introduction: Psoriasis affects approximately 2-3% of the population worldwide, although the overall prevalence in Asia is <0.5%. Scalp psoriasis is a common initial presentation of psoriasis, which affects almost 80% of patients with psoriasis. Method: This retrospective descriptive study investigated 1,671 patients with psoriasis with scalp involvement registered with the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. Results: A total of 21,859 patients with psoriasis were registered with the MPR during the study period; among them, scalp involvement was seen in 7.6% (n= 1,671). Female sex preponderance (61%) was observed in the majority of Malay patients (58.5%), followed by the Chinese (16.9%), Indian (17.1%) and other ethnic patients (7.5%). A positive family history of psoriasis was identified in 22.7% (n=380). Approximately 34.8% (n=581) and 11% (n=172) of the patients had nail changes and psoriatic arthropathy, respectively. The mainstay treatment modality was topical treatment (93.6%), followed by systemic therapy (10%) and phototherapy (0.5%). The comorbidities found among the patients with scalp psoriasis included hypertension (27.9%), obesity (26%), dyslipidaemia (21%), diabetes mellitus (18.4%), ischaemic heart disease (5.4%) and cerebrovascular disease (1.3%). Approximately 23% reported a Dermatology Life Quality Index (DLQI) of >10, which indicated moderate-to-severe impairment. Conclusion: The proportion of patients with psoriasis with scalp involvement in our study (7.6%) is much lower than previous reports. Scalp psoriasis markedly negatively impacts the DLQI.

14.
Sci Rep ; 11(1): 23621, 2021 Dec 08.
Article in English | MEDLINE | ID: mdl-34880283

ABSTRACT

The past few decades have seen an uptick in the scope and range of device applications of organic semiconductors, such as organic field-effect transistors, organic photovoltaics and light-emitting diodes. Several researchers have studied electrical transport in these materials and proposed physical models to describe charge transport with different material parameters, with most disordered semiconductors exhibiting hopping transport. However, there exists a lack of a consensus among the different models to describe hopping transport accurately and uniformly. In this work, we first evaluate the efficacy of using a purely data-driven approach, i.e., symbolic regression, in unravelling the relationship between the measured field-effect mobility and the controllable inputs of temperature and gate voltage. While the regressor is able to capture the scaled mobility well with mean absolute error (MAE) ~ O(10-2), better than the traditionally used hopping transport model, it is unable to derive physically interpretable input-output relationships. We then examine a physics-inspired renormalization approach to describe the scaled mobility with respect to a scale-invariant reference temperature. We observe that the renormalization approach offers more generality and interpretability with a MAE of the ~ O(10-1), still better than the traditionally used hopping model, but less accurate as compared to the symbolic regression approach. Our work shows that physics-based approaches are powerful compared to purely data-driven modelling, providing an intuitive understanding of data with extrapolative ability.

15.
Nanomaterials (Basel) ; 11(11)2021 Nov 09.
Article in English | MEDLINE | ID: mdl-34835769

ABSTRACT

Nanocelluloses are promising bio-nano-materials for use as water treatment materials in environmental protection and remediation. Over the past decades, they have been integrated via novel nanoengineering approaches for water treatment processes. This review aims at giving an overview of nanocellulose requirements concerning emerging nanotechnologies of waster treatments and purification, i.e., adsorption, absorption, flocculation, photocatalytic degradation, disinfection, antifouling, ultrafiltration, nanofiltration, and reverse osmosis. Firstly, the nanocellulose synthesis methods (mechanical, physical, chemical, and biological), unique properties (sizes, geometries, and surface chemistry) were presented and their use for capturing and removal of wastewater pollutants was explained. Secondly, different chemical modification approaches surface functionalization (with functional groups, polymers, and nanoparticles) for enhancing the surface chemistry of the nanocellulose for enabling the effective removal of specific pollutants (suspended particles, microorganisms, hazardous metals ions, organic dyes, drugs, pesticides fertilizers, and oils) were highlighted. Thirdly, new fabrication approaches (solution casting, thermal treatment, electrospinning, 3D printing) that integrated nanocelluloses (spherical nanoparticles, nanowhiskers, nanofibers) to produce water treatment materials (individual composite nanoparticles, hydrogels, aerogels, sponges, membranes, and nanopapers) were covered. Finally, the major challenges and future perspectives concerning the applications of nanocellulose based materials in water treatment and purification were highlighted.

16.
Nano Lett ; 21(21): 9262-9269, 2021 Nov 10.
Article in English | MEDLINE | ID: mdl-34719932

ABSTRACT

Conductive filaments (CFs) play a critical role in the mechanism of resistive random-access memory (ReRAM) devices. However, in situ detection and visualization of the precise location of CFs are still key challenges. We demonstrate for the first time the use of a π-conjugated molecule which can transform between its twisted and planar states upon localized Joule heating generated within filament regions, thus reflecting the locations of the underlying CFs. Customized patterns of CFs were induced and observed by the π-conjugated molecule layer, which confirmed the hypothesis. Additionally, statistical studies on filaments distribution were conducted to study the effect of device sizes and bottom electrode heights, which serves to enhance the understanding of switching behavior and their variability at device level. Therefore, this approach has great potential in aiding the development of ReRAM technology.

17.
Adv Mater ; 33(49): e2101874, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34606146

ABSTRACT

Organic electrochemical transistors (OECTs) are presently a focus of intense research and hold great potential in expanding the horizons of the bioelectronics industry. The notable characteristics of OECTs, including their electrolyte-gating, which offers intimate interfacing with biological environments, and aqueous stability, make them particularly suitable to be operated within a living organism (in vivo). Unlike the existing in vivo bioelectronic devices, mostly based on rigid metal electrodes, OECTs form a soft mechanical contact with the biological milieu and ensure a high signal-to-noise ratio because of their powerful amplification capability. Such features make OECTs particularly desirable for a wide range of in vivo applications, including electrophysiological recordings, neuron stimulation, and neurotransmitter detection, and regulation of plant processes in vivo. In this review, a systematic compilation of the in vivo applications is presented that are addressed by the OECT technology. First, the operating mechanisms, and the device design and materials design principles of OECTs are examined, and then multiple examples are provided from the literature while identifying the unique device properties that enable the application progress. Finally, one critically looks at the future of the OECT technology for in vivo bioelectronic applications.


Subject(s)
Biosensing Techniques , Transistors, Electronic , Electrodes , Electrolytes
18.
Acta Pharm Sin B ; 11(7): 2059-2069, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34386338

ABSTRACT

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

19.
Cell Metab ; 33(5): 1027-1041.e8, 2021 05 04.
Article in English | MEDLINE | ID: mdl-33770508

ABSTRACT

Mitochondria have an independent genome (mtDNA) and protein synthesis machinery that coordinately activate for mitochondrial generation. Here, we report that the Krebs cycle intermediate fumarate links metabolism to mitobiogenesis through binding to malic enzyme 2 (ME2). Mechanistically, fumarate binds ME2 with two complementary consequences. First, promoting the formation of ME2 dimers, which activate deoxyuridine 5'-triphosphate nucleotidohydrolase (DUT). DUT fosters thymidine generation and an increase of mtDNA. Second, fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production. Methylation of the ME2-fumarate binding site by protein arginine methyltransferase-1 inhibits fumarate signaling to constrain mitobiogenesis. Notably, acute myeloid leukemia is highly dependent on mitochondrial function and is sensitive to targeting of the fumarate-ME2 axis. Therefore, mitobiogenesis can be manipulated in normal and malignant cells through ME2, an unanticipated governor of mitochondrial biomass production that senses nutrient availability through fumarate.


Subject(s)
Fumarates/metabolism , Malate Dehydrogenase/metabolism , Mitochondria/metabolism , Animals , Cell Line , Citric Acid Cycle , DNA, Mitochondrial/metabolism , Dimerization , Humans , Leukemia/pathology , Leukemia/veterinary , Malate Dehydrogenase/antagonists & inhibitors , Malate Dehydrogenase/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mitochondria/genetics , Protein Binding , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism , Pyrophosphatases/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Ribosomal Proteins/metabolism , Thymidine/metabolism
20.
Haematologica ; 106(6): 1545-1558, 2021 06 01.
Article in English | MEDLINE | ID: mdl-32414855

ABSTRACT

Aldehyde dehydrogenases (ALDHs) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of T-cell acute lymphoblastic leukemia (T-ALL) cases. However, its molecular function and role in T-ALL pathogenesis are largely unknown. ChIP-seq and RNA-seq analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In T-ALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the TCA cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species (ROS), while ROS levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish T-ALL model. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes.


Subject(s)
Aldehyde Dehydrogenase , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Aldehyde Dehydrogenase/genetics , Animals , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , T-Cell Acute Lymphocytic Leukemia Protein 1 , T-Lymphocytes , Transcription Factors , Zebrafish
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