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1.
J Neurogenet ; : 1-8, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38975939

RESUMO

Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.

2.
Elife ; 122024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904665

RESUMO

In their folded state, biomolecules exchange between multiple conformational states that are crucial for their function. Traditional structural biology methods, such as X-ray crystallography and cryogenic electron microscopy (cryo-EM), produce density maps that are ensemble averages, reflecting molecules in various conformations. Yet, most models derived from these maps explicitly represent only a single conformation, overlooking the complexity of biomolecular structures. To accurately reflect the diversity of biomolecular forms, there is a pressing need to shift toward modeling structural ensembles that mirror the experimental data. However, the challenge of distinguishing signal from noise complicates manual efforts to create these models. In response, we introduce the latest enhancements to qFit, an automated computational strategy designed to incorporate protein conformational heterogeneity into models built into density maps. These algorithmic improvements in qFit are substantiated by superior Rfree and geometry metrics across a wide range of proteins. Importantly, unlike more complex multicopy ensemble models, the multiconformer models produced by qFit can be manually modified in most major model building software (e.g., Coot) and fit can be further improved by refinement using standard pipelines (e.g., Phenix, Refmac, Buster). By reducing the barrier of creating multiconformer models, qFit can foster the development of new hypotheses about the relationship between macromolecular conformational dynamics and function.


Assuntos
Microscopia Crioeletrônica , Modelos Moleculares , Conformação Proteica , Microscopia Crioeletrônica/métodos , Cristalografia por Raios X/métodos , Proteínas/química , Software , Algoritmos , Biologia Computacional/métodos
3.
South Asian J Cancer ; 13(2): 132-141, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38919665

RESUMO

Atreye MajumdarSambit K. MohantyObjective This article identifies and evaluates the frequency of mutations in the BCR-ABL1 kinase domain (KD) of chronic myeloid leukemia (CML) patients who showed suboptimal response to their current tyrosine kinase inhibitor (TKI) regime and assesses their clinical value in further treatment decisions. Materials and Methods Peripheral and/or bone marrow were collected from 791 CML patients. Ribonucleic acid was extracted, reverse transcribed, and Sanger sequencing method was utilized to detect single-nucleotide variants (SNVs) in BCR-ABL1 KD. Results Thirty-eight different SNVs were identified in 29.8% ( n = 236/791) patients. T315I, E255K, and M244V were among the most frequent mutations detected. In addition, one patient harbored a novel L298P mutation. A subset of patients from the abovementioned harbored compound mutations (13.3%, n = 33/236). Follow-up data was available in 28 patients that demonstrated the efficacy of TKIs in correlation with mutation analysis and BCR-ABL1 quantitation. Molecular response was attained in 50% patients following an appropriate TKI shift. A dismal survival rate of 40% was observed in T315I-harboring patients on follow-up. Conclusion This study shows the incidence and pattern of mutations in one of the largest sets of Indian CML patients. In addition, our findings strengthen the prognostic value of KD mutation analysis among strategies to overcome TKI resistance.

4.
Nature ; 630(8017): 654-659, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38839965

RESUMO

Emissions reduction and greenhouse gas removal from the atmosphere are both necessary to achieve net-zero emissions and limit climate change1. There is thus a need for improved sorbents for the capture of carbon dioxide from the atmosphere, a process known as direct air capture. In particular, low-cost materials that can be regenerated at low temperatures would overcome the limitations of current technologies. In this work, we introduce a new class of designer sorbent materials known as 'charged-sorbents'. These materials are prepared through a battery-like charging process that accumulates ions in the pores of low-cost activated carbons, with the inserted ions then serving as sites for carbon dioxide adsorption. We use our charging process to accumulate reactive hydroxide ions in the pores of a carbon electrode, and find that the resulting sorbent material can rapidly capture carbon dioxide from ambient air by means of (bi)carbonate formation. Unlike traditional bulk carbonates, charged-sorbent regeneration can be achieved at low temperatures (90-100 °C) and the sorbent's conductive nature permits direct Joule heating regeneration2,3 using renewable electricity. Given their highly tailorable pore environments and low cost, we anticipate that charged-sorbents will find numerous potential applications in chemical separations, catalysis and beyond.


Assuntos
Dióxido de Carbono , Dióxido de Carbono/análise , Dióxido de Carbono/química , Dióxido de Carbono/isolamento & purificação , Adsorção , Eletrodos , Hidróxidos/química , Atmosfera/química , Carbonatos/química , Ar , Temperatura , Carvão Vegetal/química , Porosidade , Carbono/química
5.
Bone ; 185: 117126, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38777312

RESUMO

Chronic kidney disease-induced secondary hyperparathyroidism (CKD-SHPT) heightens fracture risk through impaired mineral homeostasis and elevated levels of uremic toxins (UTs), which in turn enhance bone remodeling. Etelcalcetide (Etel), a calcium-sensing receptor (CaSR) agonist, suppresses parathyroid hormone (PTH) in hyperparathyroidism to reduce excessive bone resorption, leading to increased bone mass. However, Etel's effect on bone quality, chemical composition, and strength is not well understood. To address these gaps, we established a CKD-SHPT rat model and administered Etel at a human-equivalent dose concurrently with disease induction. The effects on bone and mineral homeostasis were compared with a CKD-SHPT (vehicle-treated group) and a control group (rats without SHPT). Compared with vehicle-treated CKD-SHPT rats, Etel treatment improved renal function, reduced circulating UT levels, improved mineral homeostasis parameters, decreased PTH levels, and prevented mineralization defects. The upregulation of mineralization-promoting genes by Etel in CKD-SHPT rats might explain its ability to prevent mineralization defects. Etel preserved both trabecular and cortical bones with attendant suppression of osteoclast function, besides increasing mineralization. Etel maintained the number of viable osteocytes to the control level, which could also contribute to its beneficial effects on bone. CKD-SHPT rats displayed increased carbonate substitution of matrix and mineral, decreased crystallinity, mineral-to-matrix ratio, and collagen maturity, and these changes were mitigated by Etel. Further, Etel treatment prevented CKD-SHPT-induced deterioration in bone strength and mechanical behavior. Based on these findings, we conclude that in CKD-SHPT rats, Etel has multiscale beneficial effects on bone that involve remodeling suppression, mineralization gene upregulation, and preservation of osteocytes.


Assuntos
Osso e Ossos , Calcimiméticos , Hiperparatireoidismo Secundário , Peptídeos , Ratos Sprague-Dawley , Insuficiência Renal Crônica , Animais , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/patologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Peptídeos/farmacologia , Calcimiméticos/farmacologia , Calcimiméticos/uso terapêutico , Ratos , Hormônio Paratireóideo/farmacologia , Masculino , Calcificação Fisiológica/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos
6.
Cureus ; 16(4): e58339, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38752080

RESUMO

Membranous nephropathy (MN) is an autoimmune condition that is a common cause of nephrotic syndrome in nondiabetic adults. In this study, we highlight a case of a 22-year-old male with a past medical history of arthrogryposis multiplex congenita (AMC) who initially presented with right flank pain and hematuria. Subsequent workup revealed significant proteinuria with biopsy-proven primary MN. Early detection of the disease is critical to establish treatment promptly and prevent complications such as those resulting from a hypercoagulable state.

7.
J Family Med Prim Care ; 13(3): 869-874, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38736837

RESUMO

Introduction: Efficient care by labour monitoring tools manages labour, identifies the abnormalities and avoids the fatalities. Various studies are being undertaken by the researchers to understand the limited use of these therapeutic tools. The present study aimed to develop a novel labour monitoring instrument after understanding the barriers and enablers of the currently used tools and using it in the health setting for improving clinical outcomes. Materials and Methods: Methodological research design was adopted to develop the novel tool. Item pool was generated by literature review, focus group discussions and retrospective observations of the partographs. Developed tool was evaluated by various experts by undergoing three rounds and was found to be reliable in terms of stability and equivalency. After undergoing pilot runs by researcher and nurses, tool was found to be feasible and understandable. The developed novel labour monitoring tool was used on 200 intranatal women. Results: Focus group discussions revealed various barriers in the current labour tools, such as lack of clarity, complexity, staff shortage, workload etc. Retrospective observation of filled partographs revealed the incomplete recording of the components of the partograph. The prepared first draft underwent rigorous review by the experts. The prepared novel tool, after being used on 200 intranatal women resulted in 90% of normal vaginal deliveries. Duration of 1st stage of labour was around 5 hours. Conclusion: A novel labour monitoring tool was developed after methodological approach resulting in adequate monitoring and improved labour outcomes.

8.
Int Microbiol ; 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740653

RESUMO

The current study was aimed for the generation of Pleurotus extracellular extract-mediated selenium and zinc-oxide nanoparticles (NPs). The Pleurotus djamor (PD) and Pleurotus sajor-caju (PSC) extracts were incubated with different concentrations of sodium selenate and zinc acetate to yield BioSeNPs and BioZnONPs. The NPs formation led to visual color change (brick-red and white for Se and Zn nanosols, respectively). The synthesized NPs were spherical with size of 124 and 68 nm and 84 and 91 nm for PD and PSC BioSeNPs and BioZnONPs respectively. The UV absorbance peaks were recorded at 293.2 and 292.2 nm and 365.9 and 325.5 nm for BioSeNPs and BioZnONPs derived from PD and PSC respectively. FT-IR spectroscopy indicated specific functional group adoration on metal-based NPs. On supplementation in straw, these NPs improved the fruit body yield besides enhancing their protein and Se/ Zn contents. These biofortified mushrooms could be potential dietary supplement/ nutraceutical.

9.
Commun Med (Lond) ; 4(1): 77, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654117

RESUMO

BACKGROUND: Bloodstream infections (BSIs) are a life-threatening acute medical condition and current diagnostics for BSIs suffer from long turnaround time (TAT). Here we show the validation of a rapid detection-analysis platform (RDAP) for the diagnosis of BSIs performed on clinical blood samples METHODS: The validation was performed on a cohort of 59 clinical blood samples, including positive culture samples, which indicated confirmed bloodstream infections, and negative culture samples. The bacteria in the positive culture samples included Gram-positive and Gram-negative pathogenic species. RDAP is based on an electrochemical sandwich immunoassay with voltage-controlled signal amplification, which provides an ultra-low limit of detection (4 CFU/mL), allowing the platform to detect and identify bacteria without requiring culture and perform phenotypic antibiotic susceptibility testing (AST) with only 1-2 h of antibiotic exposure. The preliminary diagnostic performance of RDAP was compared with that of standard commercial diagnostic technologies. RESULTS: Using a typical clinical microbiology laboratory diagnostic workflow that involved sample culture, agar plating, bacteria identification using matrix-assisted laser desorption ionization time-of-flight (MALDI TOF) mass spectrometry, and AST using MicroScan as a clinical diagnostic reference, RDAP showed diagnostic accuracy of 93.3% and 95.4% for detection-identification and AST, respectively. However, RDAP provided results at least 15 h faster. CONCLUSIONS: This study shows the preliminary feasibility of using RDAP to rapidly diagnose BSIs, including AST. Limitations and potential mitigation strategies for clinical translation of the present RDAP prototype are discussed. The results of this clinical feasibility study indicate an approach to provide near real-time diagnostic information for clinicians to significantly enhance the treatment outcome of BSIs.


Effective treatment of bloodstream infections (BSIs), a life-threatening acute medical condition, requires rapid diagnosis. Current diagnostic methods involve culturing the bacteria from the patient's blood, which requires typically 16­48 h to produce a diagnosis. Here, we demonstrate the feasibility of using a culture-free platform to perform rapid diagnosis of BSIs. We tested the diagnostic platform on a cohort of clinical blood samples. The bacteria contained in the samples covered a representative range of bacteria that cause BSIs. The culture-free platform produced diagnosis in about 15 hours faster than standard commercial diagnostic technologies and  the diagnostic results were in good agreement with that of standard technologies. The results of this study indicate an approach to providing near real-time diagnostic information for clinicians to significantly enhance the treatment outcome of BSIs.

10.
Epilepsy Behav ; 153: 109703, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452517

RESUMO

BACKGROUND: Neuropsychological Rehabilitation (NR) helps manage cognitive deficits in epilepsy. As internationally developed programs have limited applicability to resource-limited countries, we developed a program to bridge this gap. This 6-week caregiver-assisted, culturally suitable program has components of (1) psychoeducation, (2) compensatory training, and, (3) cognitive retraining and is called EMPOWER (Indigenized Home Based Attention and Memory Rehabilitation Program for Adult Patients with Drug Refractory Epilepsy). Its efficacy needs to be determined. METHODS: We carried out an open-label parallel randomized controlled trial. Adults aged 18-45 years with Drug Refractory Epilepsy (DRE), fluency in Hindi and or English, with impaired attention or memory (n = 28) were randomized to Intervention Group (IG) and Control Group (CG). The primary outcomes were objective memory (Auditory Verbal Learning Test), patient and caregiver reported everyday memory difficulties (Everyday Memory Questionnaire-Revised), number of memory aids in use, depression (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) and quality of life (Quality of Life in Epilepsy-31). Intention to treat was carried out for group analysis. In the absence of norms necessary for computing Reliable Change Indices (RCIs), a cut-off of +1.0 Standard Deviation (SD) was utilized to identify clinically meaningful changes in the individual analysis of objective memory. A cut-off of 11.8 points was used for quality of life. Feedback and program evaluation responses were noted. RESULTS: The majority of the sample comprised DRE patients with temporal lobe epilepsy who had undergone epilepsy surgery. Group analysis indicated improved learning (p = 0.013), immediate recall (p = 0.001), delayed recall (p < 0.001), long-term retention (p = 0.031), patient-reported everyday memory (p < 0.001), caregiver-reported everyday memory (p < 0.001), anxiety (p = 0.039) and total quality of life (p < 0.001). Individual analysis showed improvement in 50 %, 64 %, 71 %, 57 %, and 64 % of patients on learning, immediate recall, delayed recall, long-term retention, and total quality of life respectively. Despite improvements, themes indicative of a lack of awareness and understanding of cognitive deficits were identified. Overall, the program was rated favorably by patients and caregivers alike. CONCLUSION: NR shows promise for patients with DRE, however larger studies are warranted. The role of cognition in epilepsy needs to be introduced at the time of diagnosis to help lay the foundation for education and acceptance.


Assuntos
Epilepsia Resistente a Medicamentos , Epilepsia , Adulto , Humanos , Qualidade de Vida/psicologia , Testes Neuropsicológicos , Epilepsia/psicologia , Memória de Curto Prazo
11.
Cureus ; 16(2): e54382, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38505454

RESUMO

We outline the presentation of a 68-year-old woman who received a chest radiograph due to her insurance requirements, resulting in the discovery of a left-sided pleural effusion. The effusion was further characterized as loculated on subsequent imaging. Thoracentesis yielded exudative fluid, leading to the patient undergoing video-assisted thoracoscopic surgery (VATS). During this procedure, a cystic mass was visualized, with the conversion of the operation to an open thoracotomy and left lower lobe lobectomy. Pathology was positive for spindle cell sarcoma. A thorough history of the patient revealed a decades-long occupational exposure to asbestos. The significance of this report is to illustrate the clinical presentation, immunohistochemical characteristics, and management of a rare spindle cell malignancy. Our case also raises the importance of screening patients on an individualized, shared decision-making basis.

12.
Int Microbiol ; 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38506949

RESUMO

Essential oils are highly complex volatile chemical compounds utilized for food preservation. The present study compares the antibacterial, and antibiofilm activities of essential oils (EOs) and their blends. Three EOs-basil, clove, and lemongrass-and their blends were evaluated against five food-borne bacterial pathogens. A concentration-dependent effect with maximum inhibition at minimum inhibitory concentration values was recorded while no synergistic activity was observed on blending of EOs. The mechanism of antibacterial action was identified as ROS burst, leakage of cytoplasmic content, and DNA degradation through fluorescence microscopy, electrical conductivity, and DNA cleavage studies. The role of EOs on biofilm growth was deciphered with lemongrass EO being most effective as it curbed biofilm formation on the surface of corn-starch packaging films. This work highlights the antibacterial action mechanism of EOs and their potential role in curtailing biofilm growth on food-grade packaging material.

13.
iScience ; 27(3): 109280, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38444606

RESUMO

Chitinases and ecdysteroid hormones are vital for insect development. Crosstalk between chitin and ecdysteroid metabolism regulation is enigmatic. Here, we examined chitinase inhibition effect on Spodoptera frugiperda ecdysteroid metabolism. In vitro studies suggested that berberine inhibits S. frugiperda chitinase 5 (SfCht5). The Berberine feeding resulted in defective S. frugiperda development. Berberine-fed insects showed higher SfCht5 and Chitinase 7 expression and cumulative chitinase activity. Chitinase inhibition led to overexpression of chitinases, ecdysteroid biosynthesis, and responsive genes. SfCht5 silencing and overexpression resulted in ecdysone receptor deregulation. Transcription factors, like Broad Complex Z4, regulate the ecdysteroid metabolism and showed high expression upon berberine ingestion. Broad Complex Z4 binding in 5' UTR of Ecdysone receptor, SfCht5, Chitinase 7, Phantom, Neverland, and other ecdysteroid biosynthesis genes might lead to their upregulation in berberine-fed insects. As a result, berberine-fed insects showed ecdysone overaccumulation. These findings underscore chitinase activity's impact on ecdysone biosynthesis and its transcriptional crosstalk.

14.
Sci Rep ; 14(1): 5264, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438596

RESUMO

We present a temporary keyword search over sensitive and confidential health data in a cloud environment. The cloud constitutes a semi-trusted domain, making it necessary for data owners to secure their data before outsourcing it through techniques like encryption. Attribute-based keyword search techniques tend to perform a search operation using a search token generated by an authorized user. These search tokens can lead to serious privacy threats, as they can extract all ciphertexts that may have been generated along with their keyword. Therefore, restricting search tokens to extract ciphertexts generated within a time interval is a more promising solution. In this paper, we present a novel ciphertext policy fine-grained temporary keyword that prevents the misuse of these search tokens. Further, it mitigates the risk of insider threats within healthcare organizations by limiting the window of opportunity for unauthorized access to minimum. To assess the security, our proposed scheme is formally proven to be secure against Selectively Chosen Keyword Attacks in the generic bilinear group model. Additionally, we demonstrate that the encryption algorithm's complexity is linear in relation to the number of attributes. Our scheme's significance and practicality are revealed by the performance evaluation.

15.
J Endocrinol ; 261(2)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38492310

RESUMO

Estrogen deficiency is one of the main causes for postmenopausal osteoporosis. Current osteoporotic therapies are of high cost and associated with serious side effects. So there is an urgent need for cost-effective anti-osteoporotic agents. Anti-osteoporotic activity of Litsea glutinosa extract (LGE) is less explored. Moreover, its role in fracture healing and mechanism of action is still unknown. In the present study we explore the osteoprotective potential of LGE in osteoblast cells and fractured and ovariectomized (Ovx) mice models. Alkaline phosphatase (ALP), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and mineralization assays revealed that LGE treatment increased osteoblast cell differentiation, viability and mineralization. LGE treatment at 0.01 µg increased the expression of BMP2, PSMAD, RUNX2 and type 1 col. LGE also mitigated RANKL-induced osteoclastogenesis. Next, drill hole injury Balb/C mice model was treated with LGE for 12 days. Micro-CT analysis and Calcein labeling at the fracture site showed that LGE (20 mg/kg) enhanced new bone formation and bone regeneration, also increased expression of BMP2/SMAD1 signaling genes at fracture site. Ovx mice were treated with LGE for 1 month. µCT analysis indicated that the treatment of LGE at 20 mg/kg dose prevented the alteration in bone microarchitecture and maintained bone mineral density and bone mineral content. Treatment also increased bone strength and restored the bone turnover markers. Furthermore, in bone samples, LGE increased osteogenesis by enhancing the expression of BMP2/SMAD1 signaling components and decreased osteoclast number and surface. We conclude that LGE promotes osteogenesis via modulating the BMP2/SMAD1 signaling pathway. The study advocates the therapeutic potential of LGE in osteoporosis treatment.


Assuntos
Doenças Ósseas Metabólicas , Litsea , Camundongos , Animais , Feminino , Humanos , Consolidação da Fratura , Osteogênese , Doenças Ósseas Metabólicas/metabolismo , Transdução de Sinais , Osteoblastos/metabolismo , Diferenciação Celular , Ovariectomia , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/farmacologia
17.
J Cell Physiol ; 239(5): e31217, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38327035

RESUMO

A few ubiquitin ligases have been shown to target Runx2, the key osteogenic transcription factor and thereby regulate bone formation. The regulation of Runx2 expression and function are controlled both at the transcriptional and posttranslational levels. Really interesting new gene (RING) finger ubiquitin ligases of which RNF138 is a member are important players in the ubiquitin-proteasome system, contributing to the regulation of protein turnover and cellular processes. Here, we demonstrated that RNF138 negatively correlated with Runx2 protein levels in osteopenic ovariectomized rats which implied its role in bone loss. Accordingly, RNF138 overexpression potently inhibited osteoblast differentiation of mesenchyme-like C3H10T1/2 as well primary rat calvarial osteoblast (RCO) cells in vitro, whereas overexpression of catalytically inactive mutant RNF138Δ18-58 (lacks RING finger domain) had mild to no effect. Contrarily, RNF138 depletion copiously enhanced endogenous Runx2 levels and augmented osteogenic differentiation of C3H10T1/2 as well as RCOs. Mechanistically, RNF138 physically associates within multiple regions of Runx2 and ubiquitinates it leading to its reduced protein stability in a proteasome-dependent manner. Moreover, catalytically active RNF138 destabilized Runx2 which resulted in inhibition of its transactivation potential and physiological function of promoting osteoblast differentiation leading to bone loss. These findings underscore the functional involvement of RNF138 in bone formation which is primarily achieved through its modulation of Runx2 by stimulating ubiquitin-mediated proteasomal degradation. Thus, our findings indicate that RNF138 could be a promising novel target for therapeutic intervention in postmenopausal osteoporosis.


Assuntos
Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core , Osteoblastos , Osteogênese , Ubiquitina-Proteína Ligases , Ubiquitinação , Animais , Feminino , Humanos , Camundongos , Ratos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células HEK293 , Osteoblastos/metabolismo , Ovariectomia , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Ratos Sprague-Dawley , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética
18.
Am J Case Rep ; 25: e942030, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38310350

RESUMO

BACKGROUND Three driver mutations have been identified in patients with essential thrombocythemia - JAK2 V617F, CALR, and MPL. Out of these, JAK2 V617F is mostly common. These mutations are thought to be mutually exclusive; therefore, the initial workup may not include the identification of all mutations separately. CASE REPORT We present a case of a 55-year-old woman who was referred to the hematology clinic for an elevated platelet count noted when she was hospitalized for a renal stone. The patient was asymptomatic. A workup was initiated for essential thrombocythemia, and she was tested for JAK2 V617F mutation using an allele-specific polymerase chain reaction (AS-PCR) test in peripheral blood, which came back positive. The variant allele frequency was 2%. She underwent a bone marrow biopsy, and next-generation sequencing (NGS) showed a CALR mutation. A 52 bp deletion-type mutation was detected in the CALR gene on exon 9, with a variant allele frequency of 7%. The NGS did not detect JAK2 mutation due to its low sensitivity. She was started on aspirin alone as she was less than 60 years old and had no history of thrombotic events. The patient has been following up with the hematology clinic for the last 2 years and has not had any thrombotic events. CONCLUSIONS We propose that in patients with a low JAK2 V617 allele variant, testing for other driver mutations should be performed. In our patient, JAK2 mutation could be clonal hematopoiesis of indeterminate potential; therefore, the dominant mutation (CALR) would determine the disease phenotype.


Assuntos
Trombocitemia Essencial , Trombose , Feminino , Humanos , Pessoa de Meia-Idade , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Mutação , Éxons , Reação em Cadeia da Polimerase , Janus Quinase 2/genética
19.
J Ren Care ; 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38341770

RESUMO

BACKGROUND: Depression is common in people with chronic kidney disease, yet little is known about how depression is identified and managed as part of routine kidney care. OBJECTIVES: The primary objective was to survey all UK adult kidney centres to understand how depression is identified and managed. A secondary objective was to broadly describe the variability in psychosocial care. DESIGN: Online survey. METHODS: The survey comprised of three sections: (1) general kidney care, (2) psychological provision and (3) social work provision. RESULTS: 48/68 (71%) of centres responded to the general survey with 20 and 13 responses from psychological and social work module respectively. Only 31.4% reported having both in centre psychological and social work practitioners. Three centres reported no access to psychosocial provision. Of the 25 centres who reported on pathways, 36.0% reported having internal pathways for the identification and management of depression. Within services with psychological provision, screening for depression varied across modality/group (e.g., 7.1% in mild/moderate chronic kidney disease vs. 62.5% in kidney donors). Cognitive Behavioural Therapy and Acceptance and Commitment Therapy were the most common interventions offered. Most psychosocial services were aware of the National Institute for Health and Care Excellence guidelines for managing depression in long-term conditions (n = 18, 94.7%) yet few fully utilised (n = 6, 33.3%). Limited workforce capacity was evident. CONCLUSIONS: There is considerable variability in approaches taken to identify and treat depression across UK kidney services, with few services having specific pathways designed to detect and manage depression. Workforce capacity remains a significant issue.

20.
J Fluoresc ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38411860

RESUMO

Iron, an essential trace element exhibits detrimental effects on human health when present at higher or lower concentration than the required. Therefore, there is a pressing demand for sensitive and selective detection of Fe3+ in water, food etc. Unfortunately, in several instances, the traditional approaches suffer from a number of shortcomings like complicated procedures, limited sensitivity, poor selectivity and more expensive and time consuming. The scope of optical tuning and excellent photophysical properties of carbon- based nanomaterials like carbon dots (C-dots) and graphene dots (g-dots) have made them promising optical sensors of metal ions. Moreover, high surface area, superior stability of such materials contributes towards the fruitful development of sensors. The present review offered critical information on the fabrication and fluorimetric applications of these functional nanomaterials for sensitive and selective detection of Fe3+. An in-depth discussion on fluorescent C-dots made from naturally occurring materials and chemical techniques were presented. Effect of doping in C-dots was also highlighted in terms of improved fluorescence response and selectivity. In a similar approach g-dots were also discussed. Many of these sensors exhibited great selectivity, superior sensitivity, high quantum yield, robust chemical and photochemical stability and real-time applicability. Further improvement in these factors can be targeted to develop new sensors.

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