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1.
J Oncol Pharm Pract ; : 10781552241235573, 2024 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-38404003

RESUMO

INTRODUCTION: Drug-drug interactions (DDIs) pose a significant threat to patients with cancer, resulting in several adverse events in an oncology setting. Our study aims to identify potential DDIs in inpatient oncology wards, assess their severity, and provide recommendations to avoid these interactions. MATERIALS AND METHODS: This prospective study was conducted in 79 hospitalized cancer patients over a period of 9 months (from August 2021 to May 2022) at the Amrita Institute of Medical Sciences, Kochi receiving at least two oncological or non-oncological drugs for 5 days. RESULTS: Significant differences were found in drug count (61.6% vs. 38.4%), hospitalization duration (63.1% vs. 36.9%), and medications for comorbidities (63% vs. 37%) between patients with and without DDIs (p < 0.001, <0.001, and 0.01, respectively). The study identified 321 DDIs, with 14 (4.4%) X interactions, 93 (30%) D interactions, 161 (50%) C interactions, and 53 (15.6%) B interactions. Severity-wise, 76 (23.7%) were major, 190 (59.1%) were moderate, and 55 (17.2%) were minor. CONCLUSION: Our study showed that drug count, medications for comorbidities, and hospitalization duration significantly increase the risk of DDIs in hospitalized oncology patients. Around 96.4% of recommendations for potential interactions were accepted and implemented, highlighting the huge opportunities and requirements for improvement, implementation, and management of drug interactions in oncology settings.

2.
Chemosphere ; 351: 141220, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38224749

RESUMO

Hydrogen (H2) generation by electrochemical water splitting is a key technique for sustainable energy applications. Two-dimensional (2D) transition-metal dichalcogenide (MoS2) and silver phosphate (Ag3PO4) possess excellent electrochemical hydrogen evolution reaction (HER) properties when they are combined together as a composite rather than individuals. Reports examining the HER activity by using Ag3PO4, especially, in combination with the 2D layered MoS2 are limited in literature. The weight fraction of MoS2 in Ag3PO4 is optimized for 1, 3, and 5 wt%. The Ag3PO4/1 wt % MoS2 combination exhibits enhanced HER activity with least overpotential of 235 mV among the other samples in the acidic medium. The synergistic effect of optimal nano-scale 2D layered MoS2 structure and Ag3PO4 is essential for creating higher electrochemical active surface area of 217 mF/cm2, and hence this leads to faster reaction kinetics in the HER. This work suggests the advantages of Ag3PO4/1 wt % MoS2 heterogeneous composite catalyst for electrochemical analysis and HER indicating lower resistivity and low Tafel slope value (179 mV/dec) among the prepared catalysts making it a promising candidate for its use in practical energy applications.


Assuntos
Molibdênio , Nanoestruturas , Humanos , Hidrogênio , Cinética , Física
3.
J Thorac Oncol ; 19(1): 94-105, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37595684

RESUMO

INTRODUCTION: With global adoption of computed tomography (CT) lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open-source, cloud-based, globally distributed, screening CT imaging data set and computational environment that are compliant with the most stringent international privacy regulations that also protect the intellectual properties of researchers, the International Association for the Study of Lung Cancer sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be used for clinically relevant AI research. METHODS: In this second phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans. RESULTS: A total of 1394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness more than or equal to 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high-quality CT scans. CONCLUSIONS: These initial experiments revealed that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based data sets.


Assuntos
Aprendizado Profundo , Enfisema , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patologia , Inteligência Artificial , Detecção Precoce de Câncer , Pulmão/patologia , Enfisema/patologia
4.
Quant Imaging Med Surg ; 13(9): 6193-6204, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37711774

RESUMO

Background: A calibration phantom-based method has been developed for predicting small lung nodule volume measurement bias and precision that is specific to a particular computed tomography (CT) scanner and acquisition protocol. Methods: The approach involves CT scanning a simple reference object with a specific acquisition protocol, analyzing the scan to estimate the fundamental imaging properties of the CT acquisition system, generating numerous simulated images of a target geometry using the fundamental imaging properties, measuring the simulated images with a standard nodule volume segmentation algorithm, and calculating bias and precision performance statistics from the resulting volume measurements. We evaluated the ability of this approach to predict volume measurement bias and precision of Teflon spheres (diameters =4.76, 6.36, and 7.94 mm) placed within an anthropomorphic chest phantom when using 3M Scotch Magic™ tape as the reference object. CT scanning of the spheres was performed with 0.625, 1.25, and 2.5 mm slice thickness and spacing. Results: The study demonstrated good agreement between predicted volumetric performance and observed volume measurement performance for both volumetric measurement bias and precision. The predicted and observed volume mean for all slice thicknesses was found to be 28% and 13% lower on average than the manufactured sphere volume, respectively. When restricted to 0.625 and 1.25 mm slice thickness scans, which are recommended for small lung nodule volume measurement, we found that the difference between predicted and observed volume coefficient of variation was less than 1.0 %. The approach also showed a resilience to varying CT image acquisition protocols, a critical capability when deploying in a real-world clinical setting. Conclusions: This is the first report of a calibration phantom-based method's ability to predict both small lung nodule volume measurement bias and precision. Volume measurement bias and precision for small lung nodules can be predicted using simple low-cost reference objects to estimate fundamental CT image characteristics and modeling and simulation techniques. The approach demonstrates an improved method for predicting task specific, clinically relevant measurement performance using advanced and fully automated image analysis techniques and low-cost reference objects.

5.
Biomolecules ; 13(5)2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37238689

RESUMO

D-serine is an important signalling molecule, which activates N-methyl D-aspartate receptors (NMDARs) in conjunction with its fellow co-agonist, the neurotransmitter glutamate. Despite its involvement in plasticity and memory related to excitatory synapses, its cellular source and sink remain a question. We hypothesise that astrocytes, a type of glial cell that surrounds synapses, are likely candidates to control the extracellular concentration of D-Serine by removing it from the synaptic space. Using in situ patch clamp recordings and pharmacological manipulation of astrocytes in the CA1 region of the mouse hippocampal brain slices, we investigated the transport of D-serine across the plasma membrane. We observed the D-serine-induced transport-associated currents upon puff-application of 10 mM D-serine on astrocytes. Further, O-benzyl-L-serine and trans-4-hydroxy-proline, known substrate inhibitors of the alanine serine cysteine transporters (ASCT), reduced D-serine uptake. These results indicate that ASCT is a central mediator of astrocytic D-serine transport and plays a role in regulating its synaptic concentration by sequestration into astrocytes. Similar results were observed in astrocytes of the somatosensory cortex and Bergmann glia in the cerebellum, indicative of a general mechanism expressed across a range of brain areas. This removal of synaptic D-serine and its subsequent metabolic degradation are expected to reduce its extracellular availability, influencing NMDAR activation and NMDAR-dependent synaptic plasticity.


Assuntos
Astrócitos , Potenciação de Longa Duração , Camundongos , Animais , Potenciação de Longa Duração/fisiologia , Astrócitos/metabolismo , Sinapses/metabolismo , Hipocampo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Encéfalo/metabolismo
6.
HSS J ; 18(1): 78-82, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35087336

RESUMO

Background: Assessing the extent and specific location of brachial plexus injuries can be difficult given the variety of mechanisms of injury and anatomic complexity of the plexus. We developed a program to accurately assess the location of a patient's neurologic injury based on electromyographic data. Purpose: We sought to test our hypothesis that the location of traumatic brachial plexopathies could be accurately assessed with a novel program that processed electromyogram (EMG) and mechanism of injury data. Methods: This retrospective diagnostic cohort study was carried out with a novel diagnostic algorithm developed with the Python programming language. The program accepts user input of muscles demonstrating decreased motor unit recruitment, positive sharp waves, or fibrillation potentials. The testing data set was derived from a registry of brachial plexus injuries treated at our center. The primary outcome was the percent concordance of the algorithm's diagnosis with the surgical diagnosis. Results: Ninety-five cases met the inclusion criteria. Median time from injury onset to EMG examination was 4 months; median time from EMG examination to surgery was 1.2 months. The program diagnosis matched the surgical diagnosis in 92 out of 95 (97%) of cases, including cases with multilevel injuries and additional peripheral nerve injuries. Conclusion: This program accurately localized brachial plexopathies in nearly all cases, including those involving polytrauma or complex patterns of injury. This algorithm may be valuable as an aid to complete electrodiagnostic examinations, a diagnostic adjunct when planning treatment of severe plexus palsies, or an educational tool.

7.
Recent Pat Biotechnol ; 15(4): 266-285, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34602042

RESUMO

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS), also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins, Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-Gilford progeria syndrome and its therapy in the current article. METHODS: The goal of the present review article is to provide information about Hutchinson- Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS. RESULTS: The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients. CONCLUSION: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.


Assuntos
Progéria , Sistemas CRISPR-Cas , Terapia Genética , Humanos , Patentes como Assunto , Progéria/genética , Tecnologia
8.
J Hand Surg Am ; 46(9): 812.e1-812.e5, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33487489

RESUMO

PURPOSE: The purpose of the study was to evaluate the utility of the levator scapulae motor nerve (LSN) as a donor nerve for brachial plexus nerve transfer. We hypothesized that the LSN could be transferred to the suprascapular nerve (SSN) or long thoracic nerve (LTN) with a reliable tension-free coaptation and appropriate donor-to-recipient axon count ratio. METHODS: Twelve brachial plexus dissections were performed on 6 adult cadavers, bilaterally. We identified the LSN, spinal accessory nerve (SAN), SSN, and LTN. Each nerve was prepared for transfer and nerve redundancies were calculated. Cross-sections of each nerve were examined histologically, and axons counted. We transferred the LSN to target first the SSN and then the LTN, in a tension-free coaptation. For reference, we transferred the distal SAN to target the SSN and LTN and compared transfer parameters. RESULTS: Three cadavers demonstrated 2 LSN branches supplying the levator scapulae. The axon count ratio of donor-to-recipient nerve was 1:4.0 (LSN:SSN) and 1:2.1 (LSN:LTN) for a single LSN branch and 1:3.0 (LSN:SSN) and 1:1.6 (LSN:LTN) when 2 LSN branches were available. Comparatively, the axon count ratio of donor-to-recipient nerve was 1:2.5 and 1:1.3 for the SAN to the SSN and the LTN, respectively. The mean redundancy from the LSN to the SSN and the LTN was 1.7 cm (SD, 3.1 cm) and 2.9 cm (SD, 2.8 cm), and the redundancy from the SAN to the SSN and the LTN was 4.5 (SD, 0.7 cm) and 0.75 cm (SD, 1.0 cm). CONCLUSIONS: These data support the use of the LSN as a potential donor for direct nerve transfer to the SSN and LTN, given its adequate redundancy and size match. CLINICAL RELEVANCE: The LSN should be considered as an alternative nerve donor source for brachial plexus reconstruction, especially in 5-level injuries with scarce donor nerves. If used in lieu of the SAN during primary nerve reconstruction, trapezius tendon transfer for improved external rotation would be enabled.


Assuntos
Neuropatias do Plexo Braquial , Plexo Braquial , Transferência de Nervo , Músculos Superficiais do Dorso , Nervo Acessório/cirurgia , Adulto , Plexo Braquial/cirurgia , Neuropatias do Plexo Braquial/cirurgia , Cadáver , Humanos
9.
Abdom Radiol (NY) ; 46(4): 1651-1658, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33098478

RESUMO

PURPOSE: To develop and externally validate a multivariate prediction model for the prediction of acute kidney injury (AKI) in COVID-19, based on baseline renal perfusion from contrast-enhanced CT together with clinical and laboratory parameters. METHODS: In this retrospective IRB-approved study, we identified COVID-19 patients who had a standard-of-care contrast-enhanced abdominal CT scan within 5 days of their COVID-19 diagnosis at our institution (training set; n = 45, mean age 65 years, M/F 23/22) and at a second institution (validation set; n = 41, mean age 61 years, M/F 22/19). The CT renal perfusion parameter, cortex-to-aorta enhancement index (CAEI), was measured in both sets. A multivariate logistic regression model for predicting AKI was constructed from the training set with stepwise feature selection with CAEI together with demographical and baseline laboratory/clinical data used as input variables. Model performance in the training and validation set was evaluated with ROC analysis. RESULTS: AKI developed in 16 patients (35.6%) of the training set and in 6 patients (14.6%) of the validation set. Baseline CAEI was significantly lower in the patients that ultimately developed AKI (P = 0.003). Logistic regression identified a model combining baseline CAEI, blood urea nitrogen, and gender as most significant predictor of AKI. This model showed excellent diagnostic performance for prediction of AKI in the training set (AUC = 0.89, P < 0.001) and good performance in the validation set (AUC 0.78, P = 0.030). CONCLUSION: Our results show diminished renal perfusion preceding AKI and a promising role of CAEI, combined with laboratory and demographic markers, for prediction of AKI in COVID-19.


Assuntos
Injúria Renal Aguda , COVID-19 , Injúria Renal Aguda/diagnóstico por imagem , Idoso , Teste para COVID-19 , Humanos , Laboratórios , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Tomografia Computadorizada por Raios X
10.
J Hand Surg Am ; 46(1): 43-53, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32868098

RESUMO

PURPOSE: Wide variability in the recovery of patients affected by neuralgic amyotrophy (NA) is recognized, with up to 30% experiencing residual motor deficits. Using magnetic resonance imaging and ultrasound (US), we identified hourglass constrictions (HGCs) in all affected nerves of patients with chronic motor paralysis from NA. We hypothesized that chronic NA patients undergoing microsurgical epineurolysis and perineurolysis of constrictions would experience greater recovery compared with patients managed nonsurgically. METHODS: We treated 24 patients with chronic motor palsy from NA and HGCs identified on magnetic resonance imaging and US either with microsurgical epineurolysis and perineurolysis of HGCs (11 of 24) or nonsurgically (13 of 24). Muscle strength (both groups) and electrodiagnostic testing (EDX) (operative group) was performed before and after surgery. Preoperative EDX confirmed muscle denervation in the distribution of affected nerve(s). All patients met criteria for microneurolysis: 12 months without improvement since onset or failure of clinical and EDX improvement after 6 months documented by 3 successive examinations, each at least 6 weeks apart. RESULTS: Mean time from onset to surgery was 12.5 ± 4.0 months. Average time to most recent post-onset follow-up occurred at 27.3 months (range, 18-42 months; 15 nerves). Average time to latest follow-up among nonsurgical patients was 33.6 months (range, 18-108 months; 16 nerves). Constrictions involved individual fascicular groups (FCs) of the median nerve and the suprascapular, axillary and radial nerves proper (HGCs). Nine of 11 operative patients experienced clinical recovery compared with 3 of 13 nonsurgical patients. EMG revealed significant motor unit recovery from axonal regeneration in the operative group. CONCLUSIONS: Microsurgical epineurolysis and perineurolysis of FCs and HGCs was associated with significantly improved clinical and nerve regeneration at an average follow-up of 14.8 months compared with nonsurgical management. We recommend microneurolysis of HGCs and FCs as a treatment option for patients with chronic NA who have failed to improve with nonsurgical treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.


Assuntos
Neurite do Plexo Braquial , Neurite do Plexo Braquial/terapia , Constrição , Humanos , Imageamento por Ressonância Magnética , Nervo Mediano , Ultrassonografia
11.
RSC Adv ; 11(38): 23400-23408, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35479807

RESUMO

The difference in resistive switching characteristics by modifying the device configuration provides a unique operating principle, which is essential for both fundamental studies and the development of future memory devices. Here, we demonstrate the poly(methyl methacrylate) (PMMA)-based resistive switching characteristics using four different combinations of electrode/electrolyte arrangement in the device geometry. From the current-voltage (I-V) measurements, all the PMMA-based devices revealed nonvolatile memory behavior with a higher ON/OFF resistance ratio (∼105-107). Significantly, the current conduction in the filament and resistive switching behavior depend majorly on the presence of Al electrode and electrochemically active silver (Ag) element in the PMMA matrix. A trap-controlled space charge limited conduction (SCLC) mechanism constitutes the resistive switching in the Al/PMMA/Al device, whereas the current conduction governed by ohmic behavior influences the resistive switching in the Ag-including devices. The depth-profiling X-ray photoelectron spectroscopy (XPS) study evidences the conducting filament formation processes in the PMMA-based devices. These results with different conduction mechanisms provide further insights into the understanding of the resistive switching behavior in the polymer-based devices by simply rearranging the device configuration.

12.
ACS Pharmacol Transl Sci ; 3(5): 948-964, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33073193

RESUMO

Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC50s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIß). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIIIß. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIIIß with an IC50 of 2.0 ± 0.30 nM. Together the results demonstrate that Pf PI4KIIIß is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.

13.
HSS J ; 16(3): 280-287, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33088241

RESUMO

BACKGROUND: Injuries to the hand and wrist constitute up to 25% of all athletic injuries, yet not much information is available on the effects of such injuries on the careers of professional athletes. Understanding whether elite athletes can return to sport and at what level has value for athletes, coaches, managers, and others, including athletes at other levels of play. QUESTIONS/PURPOSES: The purpose of this study was to systematically review the literature on injuries of the hand and wrist in professional athletes to determine the prevalence and types of injuries sustained in professional sports, the management and clinical outcomes of such injuries, and the statistics regarding return to play. METHODS: A systematic review was conducted of PubMed/MEDLINE and the Cochrane Central Register of Controlled Trials to identify all studies reporting on hand and wrist injuries in professional athletes that were published between January 1970 and April 2019. Inclusion criteria were injuries of the upper extremity distal to the elbow that occurred in professional athletes during athletic competition, English language, and a study cohort consisting of four or more subjects. Details of injury sustained, sport, treatment, clinical outcome, and return to sport were extracted. RESULTS: We identified 32 nonoverlapping studies involving a total of 4299 hand and wrist injuries. The most common sport studied was baseball (eight studies), followed by football (seven), boxing (six), and basketball (five). Specific injury type was included in 29 of 32 studies and totaled 792 injuries. Metacarpal fractures were the most common injuries (n = 273; 34.5%), followed by thumb collateral ligament injuries (n = 110; 13.9%), phalangeal fractures (n = 87; 11.0%), and scaphoid fractures (n = 56; 7.1%). The overall operative rate was 18.3% (n = 708 of 3867). One-half of the studies reported the return to play (average, 2.8 months; range, 0.5 to 9 months). Seven studies reported sport-specific objective performance measures, with six describing consistent return to preinjury levels of performance among athletes. CONCLUSIONS: Based on the available evidence, a large majority of hand and wrist injuries in professional athletes are treated conservatively. Athletes frequently return to preinjury levels of performance after surgery. Additionally, return to play after a hand injury appears to be faster than that after other bony injuries. Further research is needed into the impact of these injuries on athletic performance, as well as how surgical intervention affects validated patient-reported outcome measures in professional athletes.

14.
JBJS Rev ; 8(9): e2000011, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32890049

RESUMO

Anterior interosseous nerve syndrome (AINS) represents a form of neuralgic amyotrophy (Parsonage-Turner syndrome). AINS does not originate from external compression of the AIN in the forearm. Fascicular constrictions (FCs) of the median nerve are identified within the anterior interosseous fascicular group at or above the medial epicondyle. Spontaneous recovery is not ensured, leaving up to 30% of patients with permanent weakness or palsy. Fascicular microneurolysis of the median nerve, performed at or above the elbow, is a treatment option for patients who do not recover spontaneously.


Assuntos
Neurite do Plexo Braquial/etiologia , Neurite do Plexo Braquial/diagnóstico , Neurite do Plexo Braquial/cirurgia , Humanos , Procedimentos Neurocirúrgicos
16.
mBio ; 11(3)2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487759

RESUMO

Many species of pathogenic fungi deploy the unfolded protein response (UPR) to expand the folding capacity of the endoplasmic reticulum (ER) in proportion to the demand for virulence-related proteins that traffic through the secretory pathway. Although Ca2+ plays a pivotal role in ER function, the mechanism by which transcriptional upregulation of the protein folding machinery is coordinated with Ca2+ homeostasis is incompletely understood. In this study, we investigated the link between the UPR and genes encoding P-type Ca2+-ATPases in the human-pathogenic mold Aspergillus fumigatus We demonstrate that acute ER stress increases transcription of the srcA gene, encoding a member of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) family, as well as that of pmrA, encoding a secretory pathway Ca2+-ATPase (SPCA) in the Golgi membrane. Loss of the UPR transcription factor HacA prevented the induction of srcA and pmrA transcription during ER stress, defining these ER/Golgi Ca2+ pumps as novel downstream targets of this pathway. While deletion of srcA alone caused no major deficiencies, a ΔsrcA/ΔpmrA mutant displayed a severe polarity defect, was hypersensitive to ER stress, and showed attenuated virulence. In addition, cell wall analyses revealed a striking reduction in mannose levels in the absence of both Ca2+ pumps. The ΔhacA mutant was hypersensitive to agents that block calcineurin-dependent signaling, consistent with a functional coupling between the UPR and Ca2+ homeostasis. Together, these findings demonstrate that the UPR integrates the need for increased levels of chaperone and folding enzymes with an influx of Ca2+ into the secretory pathway to support fungal growth, stress adaptation, and pathogenicity.IMPORTANCE The UPR is an intracellular signal transduction pathway that maintains homeostasis of the ER. The pathway is also tightly linked to the expression of virulence-related traits in diverse species of human-pathogenic and plant-pathogenic fungal species, including the predominant mold pathogen infecting humans, Aspergillus fumigatus Despite advances in the understanding of UPR signaling, the linkages and networks that are governed by this pathway are not well defined. In this study, we revealed that the UPR is a major driving force for stimulating Ca2+ influx at the ER and Golgi membranes and that the coupling between the UPR and Ca2+ import is important for virulence, cell wall biosynthesis, and resistance to antifungal compounds that inhibit Ca2+ signaling.


Assuntos
Adenosina Trifosfatases/metabolismo , Aspergillus fumigatus/enzimologia , Aspergillus fumigatus/patogenicidade , Parede Celular/fisiologia , Estresse do Retículo Endoplasmático , Resposta a Proteínas não Dobradas , Células A549 , Células Epiteliais Alveolares/microbiologia , Animais , Aspergillus fumigatus/genética , Cálcio/metabolismo , Retículo Endoplasmático/enzimologia , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Complexo de Golgi/enzimologia , Humanos , Masculino , Camundongos , Transdução de Sinais , Virulência
17.
J Nanosci Nanotechnol ; 20(5): 2893-2901, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31635626

RESUMO

Manipulation of ionic transport in the self-assembled polymer thin films using nanoarchitectonics approach can open the door for the development of novel electronic devices with ultrafast operation and low-power consumption. Here, we demonstrate a highly sensitive and ultrafast responsive flexible humidity sensor for human respiration monitoring. Humidity sensing behavior of the polymerbased planar devices, in which a polyethylene oxide-phosphotungstic acid (PEO-PWA) thin film is placed between an opposing inert electrodes, have been investigated by optimizing the device configuration and PWA salt concentration in the PEO matrix. The ultrafast response (~50 ms) and recovery (~52 ms) of the humidity sensor enabled us to study the real-time human respiration monitoring. Using morphological analysis, it is proposed that the ultrafast response-recovery time for this sensor is ascribed to their self-assembled lamellar-like structures of the PEO-PWA matrix polymer, which provides long-range continuous proton transport path in the polymer interface.


Assuntos
Polímeros , Respiração , Humanos , Umidade
18.
RSC Adv ; 10(73): 45019-45027, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-35516246

RESUMO

The detailed understanding and control of ionic transport pathways in the electrode/electrolyte interface is vital for realizing micro-scale energy storage devices and formulating adequate design principles. A planar device geometry with nanostructured thin solid polymer electrolyte (SPE) and potassium hydroxide (KOH) incorporated poly(N-vinyl imidazole) (PVI) is demonstrated for micro-supercapacitors (MSCs). The adsorption/desorption kinetics of ionic charges in the interfacial regime of ITO/PVI-KOH has been investigated for electrical double layer capacitance (EDLC) characteristics. A single-cell of ITO/PVI-KOH/ITO planar MSC shows the large variation in volumetric capacitance and capacitance retention characteristics when the thickness of PVI-KOH approaches the characteristic nanoscale. Moreover, ITO/PVI-KOH/ITO planar MSC consisting of five series-cells exhibits the maximum operating cell voltage of 5.0 V with maximum volumetric energy and power density of 0.056 mW h cm-3 and 6.89 mW cm-3, respectively. The electrochemical properties of planar MSC have been systematically studied so as to confirm how the anions and cations are separated at electrode/electrolyte interfaces by means of an electromotive force. Significantly, the hydrated PVI enables charge migration and separation of cations and anions at the electrode/electrolyte interfaces.

19.
J Oral Microbiol ; 10(1): 1487743, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29988788

RESUMO

Background: Bacteria use two-component signal transduction systems (among others) to perceive and respond to environmental changes. Within the genus Porphyromonas, we observed degeneration of these systems, as exemplified by the loss of RprX, the sensor kinase partner of the RprY. Objective: The purpose of this study was to investigate modulation of RprY function by acetylation. Design: The transcriptional activity of the rprY-pat genes were measured by RT-PCR and 5'-RACE. The acetylation of RprY were detected by western blotting. Electromobility shift and in vitro ChIP assays were used to measure the DNA binding activity of RprY. The expression of RprY target genes was measured by qRT-PCR. Effects of acetylation on phosphorylation of RprY were measured by Phos-tag gels. Results: The rprY gene is cotranscribed with pat. RprY is acetylated in vivo, and autoacetylated in vitro in a reaction that is enhanced by Pat; the CobB sirtuin deacetylates RprY. Acetylation reduced the DNA binding of RprY. Induced oxidative stress decreased production of RprY in vivo, increased its acetylation and increased expression of nqrA. Conclusions: We propose that to compensate for the loss of RprX, P. gingivalis has evolved a novel mechanism to inactivate RprY through acetylation.

20.
Tomography ; 4(1): 33-41, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29984312

RESUMO

A challenge in multicenter trials that use quantitative positron emission tomography (PET) imaging is the often unknown variability in PET image values, typically measured as standardized uptake values, introduced by intersite differences in global and resolution-dependent biases. We present a method for the simultaneous monitoring of scanner calibration and reconstructed image resolution on a per-scan basis using a PET/computed tomography (CT) "pocket" phantom. We use simulation and phantom studies to optimize the design and construction of the PET/CT pocket phantom (120 × 30 × 30 mm). We then evaluate the performance of the PET/CT pocket phantom and accompanying software used alongside an anthropomorphic phantom when known variations in global bias (±20%, ±40%) and resolution (3-, 6-, and 12-mm postreconstruction filters) are introduced. The resulting prototype PET/CT pocket phantom design uses 3 long-lived sources (15-mm diameter) containing germanium-68 and a CT contrast agent in an epoxy matrix. Activity concentrations varied from 30 to 190 kBq/mL. The pocket phantom software can accurately estimate global bias and can detect changes in resolution in measured phantom images. The pocket phantom is small enough to be scanned with patients and can potentially be used on a per-scan basis for quality assurance for clinical trials and quantitative PET imaging in general. Further studies are being performed to evaluate its performance under variations in clinical conditions that occur in practice.

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