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1.
EJIFCC ; 35(1): 23-30, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38706736

RESUMO

Introduction: As Artificial Intelligence (AI) technology continues to assimilate into various industries, there is a huge scope in the healthcare industry specifically in clinical laboratories. The perspective of the laboratory professionals can give valuable insight on the ideal path to take for AI implementation. Methods: The study utilized a cross-sectional survey design and was conducted at the section of Chemical Pathology, Department of Pathology and Laboratory Medicine, the Aga Khan University (AKU), Karachi, Pakistan in collaboration with Consultant Pathologists of 9 clinical laboratories associated with teaching hospitals across Pakistan from October-November 2023. The survey was for a duration of 2 weeks and was circulated to all working laboratory technical staff after informed consent. Results: A total of 351 responses were received, of which 342 (male=146, female=196) responses were recorded after exclusion. Respondents ranged from technologists, faculty, residents, and coordinators, and were from different sections (chemical pathology, microbiology, haematology, histopathology, POCT). Out of the total 312 (91.2%) of respondents stated that they were at least somewhat familiar with AI technology. Experts in AI were only 2.0% (n=7) of all respondents, but 90% (n=6) of these were < 30 years old. 76.3% (n=261) of the respondents felt the need to implement more AI technology in the laboratories, with time saving (26.1%) and improving performances of tests (17.7%) cited to be the greatest benefits of AI. Security concerns (n=144) and a fear of decreasing personal touch (n=143) were the main concerns of the respondents while the younger employees had an increased fear of losing their jobs. 76.3% were in favour of an increase in AI usage in the laboratories. Conclusion: This study highlights a favourable perspective among laboratory professionals, acknowledging the potential of AI to enhance both the efficiency and quality of laboratory practices. However, it underscores the importance of addressing their concerns in the thoughtful implementation of this emerging technology.

2.
Cureus ; 16(4): e57615, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38707031

RESUMO

Ovarian granulosa cell tumors (GCTs) are rare neoplasms with a unique incidence pattern peaking in postmenopausal women. This case report presents two instances of stage 4 recurrent adult GCTs with a prolonged 20-year follow-up. Patient 1, diagnosed at 54 years, experienced multiple recurrences managed through surgery, hormonal therapy, and chemotherapy, culminating in hepatocellular carcinoma. Patient 2, diagnosed at 67 years, underwent various treatments, including surgery, chemotherapy, and hormonal therapy, demonstrating disease stability. Despite the generally favorable prognosis, these cases highlight the challenges of managing recurrent GCTs, emphasizing the need for tailored therapeutic approaches.

4.
ACS Omega ; 9(17): 19261-19271, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38708274

RESUMO

Magnesium hydride (MgH2) is a promising hydrogen storage candidate due to its large capacity; however, high dehydrogenation temperature and slow kinetic rates are the main bottlenecks. Herein, we proposed a strategy for designing nitrogen-doped graphene-supported Ni nanoparticles (NPs) (Ni@NC) to tackle these problems. The results showed that the MgH2 + 15 wt % Ni@NC nanocomposite reduced the on-set dehydrogenation temperature to 195 °C, which was 175 °C lower than pristine MgH2. In addition, MgH2 + 15 wt % Ni@NC achieved 1.7 and 6.5 wt % desorption capacities at 225 and 300 °C, respectively, while absorbing 5.5 wt % hydrogen at 100 °C. The MgH2 + 15 wt % Ni@NC nanocomposite showed high cyclic stability, achieving 98.0% capacity retention after 100 cycles at 270 °C with negligible loss in capacity. This remarkable hydrogen storage performance can be attributed to the homogeneous distribution of Ni NPs on N-doped graphene layers, in situ formed Mg2NiH2 NPs, and multiphasic regions, promoting the nucleation and growth process during hydrogenation/dehydrogenation, which stabilized and improved the cyclic stability. This strategy paves the way to developing high-performance MgH2 for large-scale applications.

6.
Artigo em Inglês | MEDLINE | ID: mdl-38726701

RESUMO

Fish substitution in fish products is an important issue in fish markets, as it is a widespread practice. An authentication protocol for Rohu, Thaila and Tilapia was developed by multiplex PCR. Three species-specific and one degenerate common forward primer were designed using the Cytb gene of the mitochondrial genome. These primers for Labeo rohita, Labeo catla and Oreochromis niloticus showed the fragment size of 235 bp, 186 bp and 506 bp on the agarose gel, respectively. The primers for L. rohita and L. catla were sensitive to 0.1 ng of DNA template, while for O. niloticus this value was 1 ng of DNA template. A total of 230 commercial samples (160 fried and 70 processed fish products) were screened, where 60% mislabeling in fried and 30% mislabeling in processed fish were found. This multiplex PCR protocol could give useful insights for food inspection and enforcement of regulatory food control.

7.
Front Immunol ; 15: 1352821, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711517

RESUMO

Pancreatic cancer is a significant cause of cancer-related mortality and often presents with limited treatment options. Pancreatic tumors are also notorious for their immunosuppressive microenvironment. Irreversible electroporation (IRE) is a non-thermal tumor ablation modality that employs high-voltage microsecond pulses to transiently permeabilize cell membranes, ultimately inducing cell death. However, the understanding of IRE's impact beyond the initiation of focal cell death in tumor tissue remains limited. In this study, we demonstrate that IRE triggers a unique mix of cell death pathways and orchestrates a shift in the local tumor microenvironment driven, in part, by reducing the myeloid-derived suppressor cell (MDSC) and regulatory T cell populations and increasing cytotoxic T lymphocytes and neutrophils. We further show that IRE drives induce cell cycle arrest at the G0/G1 phase in vitro and promote inflammatory cell death pathways consistent with pyroptosis and programmed necrosis in vivo. IRE-treated mice exhibited a substantial extension in progression-free survival. However, within a span of 14 days, the tumor immune cell populations reverted to their pre-treatment composition, which resulted in an attenuation of the systemic immune response targeting contralateral tumors and ultimately resulting in tumor regrowth. Mechanistically, we show that IRE augments IFN- Î³ signaling, resulting in the up-regulation of the PD-L1 checkpoint in pancreatic cancer cells. Together, these findings shed light on potential mechanisms of tumor regrowth following IRE treatment and offer insights into co-therapeutic targets to improve treatment strategies.


Assuntos
Modelos Animais de Doenças , Eletroporação , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Camundongos , Linhagem Celular Tumoral , Células Supressoras Mieloides/imunologia , Camundongos Endogâmicos C57BL , Humanos , Linfócitos T Reguladores/imunologia , Feminino
8.
J Mol Model ; 30(5): 159, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700555

RESUMO

CONTEXT: Depletion of natural resources, responsible for energy production, is a serious concern for researchers to develop alternate energy resources or materials. Scientists have proposed various energy materials which are based on semiconductors and their underlying physics. Cerium oxide (CeO2) is a versatile energy material which receives much attention owing to excellent photocatalytic, photonic, thermal stability, and optoelectronic applications. Even though CeO2 exhibited remarkable physical properties, but yet, they can be enhanced upon suitable doping. Focus on current research is to dope group V elements into CeO2 in order to enhance its electronic and optical response. The density of states (DOS) and band gaps of proposed materials are calculated, and significant improvement is noted after applying TB-mbj method. Optical absorption spectra of V/Nb/Ta-doped CeO2 show blueshift and decrease in reflectivity along with the presence of magnetism illustrate potential uses of these materials in future UV optoelectronics, spintronics, sensing, and energy harvesting devices. METHODS: This research is based on computational work carried using Wien2k code where PBE-GGA approximation is used to approximate exchange and correlation potentials. Supercells of vanadium/niobium/tantalum-doped CeO2 are constructed, and spin-polarized density of states (DOS) along with optical constant are calculated. TB-mbj method is used to bring improvements in DOS and band gaps of proposed materials. Iterations are conducted using convergence criterion, and non-relativistic calculations are performed.

9.
Contemp Nurse ; : 1-30, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38805602

RESUMO

BACKGROUND: Globally, nurses and midwives have a higher rate of being overweight/obese than the general population, influenced by workplace environments that impact dietary habits. OBJECTIVE: This systematic review aimed to identify barriers/facilitators to healthy eating among nurses in clinical settings. DESIGN: This systematic review followed Joanna Briggs Institute's guidelines for qualitative systematic reviews. METHODS: Eight electronic databases: PROQUEST CENTRAL, SCIENCEDIRECT, MEDLINE, CINAHL, PsycINFO, WEB SCIENCE, PUB MED, and SCOPUS were searched. Articles were screened using JBI SUMARI®, and quality assessment was done using the JBI critical appraisal checklist. Data were extracted using the JBI data extraction tool. RESULTS: Nine qualitative studies were reviewed, involving 488 nurses, concluding 37 distinct findings. Two synthesised findings emerged: barriers, and facilitators to healthy eating, related to organisational (shift work/long working hours), personal, physical workplace environment, and social factors. CONCLUSIONS: The review emphasises the necessity of promoting attainable healthy eating practices at organisational, personal, environmental, and social levels within the workplace. REGISTRATION: PROSPERO International prospective register of systematic reviews, ID: CRD42022309259.

10.
Artigo em Inglês | MEDLINE | ID: mdl-38806330

RESUMO

INTRODUCTION: Chest radiotherapy has been utilized to treat intra-thoracic and mediastinal tumors. Chest wall irradiation (C-XRT) survivors frequently develop valvular disease, including aortic stenosis, which eventually requires valve replacement. Previous trials have shown worse outcomes with surgical aortic valve replacement. However, transcatheter aortic valve replacement (TAVR) outcomes-related data in patients with C-XRT is limited. METHODS: The national inpatient sample (NIS) database was queried from 2016 to 2020 to identify adult hospitalizations with TAVR, which were dichotomized based on a history of C-XRT using ICD-10-CM codes. Propensity score matching was performed to derive age, sex, hospital characteristics, and co-morbidities matched controls without a history of C-XRT. The outcomes studied were inpatient mortality and complications, mean length of stay (LOS), and total hospital charge (THC). Multivariate logistic and linear regression were used to analyze the outcomes. RESULTS: Of 296,670 patients who underwent TAVR between 2016 and 2020, 515 had a history of C-XRT. Upon propensity score matching in patients undergoing TAVR, Patients with a history of C-XRT showed significantly lower adjusted odds of in-hospital mortality (adjusted odd ratio [aOR] 0.04, 95 % CI [0.003-0.57], p = 0.017), lower mean LOS by 1.6 days (-1.88 to -1.26 days, p < 0.001) and reduced mean THC (-$74,720, [-$88,784 to -$60,655], p < 0.001). Additionally, patients with C-XRT had significantly lower adjusted odds of inpatient complications, mainly acute myocardial infarction, cerebrovascular events, acute respiratory failure, acute kidney injury, need for vasopressors and cardiopulmonary resuscitation, whereas similar odds of complications, including a requirement of intubation, mechanical ventilation, hemodialysis, and cardiogenic shock. CONCLUSION: Our analysis showed reduced adjusted odds of in-hospital mortality, length of stay, total hospital charges, and inpatient complications in patients undergoing TAVR with a history of C-XRT. TAVR appears to be a safe and viable alternative in this population subgroup.

11.
J Dent ; : 105096, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38796090

RESUMO

OBJECTIVES: When dental practitioners encounter a defective restoration, they are faced with a crucial decision whether to repair or replace it. This study aims to explore international preferences for repair procedures and the clinical steps taken during the repair process. METHOD: An 11-question survey was distributed to dentists across 21 countries via different platforms. The survey comprised two sections: the first included five questions aimed at gathering demographic information, while the second consisted of six questions focusing on participants' practices related to the repair of composite or amalgam restorations A meta-analysis was employed to ascertain the pooled odds ratio of repairing versus replacement. The statistical analysis was carried out using the RevMan 5.3 program and forest plots were generated using the same program to visualize the results. RESULTS: The survey was completed by 3680 dental practitioners. The results indicated a strong tendency to repair defective composite restorations (OR: 14.23; 95% CI: 7.40, 27.35, p<0.001). In terms of amalgam, there was a significant tendency to replace the restorations (OR: 0.19; 95% CI: 0.12, 0.30, p<0.001). When repairing restorations, the most common protocols were etching with orthophosphoric acid and creating an enamel bevel, regardless of the restorative material used. CONCLUSION: The findings of this study indicate that there exists a knowledge gap among dental practitioners regarding restoration repair. It is imperative that dental practitioners receive proper education and training on restoration repair, to ensure the usage of adequate protocols and restoration survival.

12.
Fungal Biol ; 128(3): 1771-1779, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38796261

RESUMO

Phaseolus vulgaris L., commonly known as the common bean, is a highly nutritious crop often called the "poor man's meat". However, it is susceptible to various diseases throughout the cropping season, with anthracnose caused by Colletotrichum lindemuthianum being a significant threat that leads to substantial losses. There is still a lack of understanding about the molecular basis of C. lindemuthianum pathogenicity. The first step in understanding this is to identify pathogenicity genes that express more during infection of common beans. A reverse transcription quantitative real-time PCR (qPCR) method can be used for virulence gene expression. However, this approach requires selecting appropriate reference genes to normalize relative gene expression data. Currently, there is no reference gene available for C. lindemuthianum. In this study, we selected eight candidate reference genes from the available genome of C. lindemuthianum to bridge the gap. These genes were ACT (Actin), ß-tub (ß-tubulin), EF (Elongation Factor), Cyt C (Cytochrome C), His H3 (Histone H3), CHS1 (Chitin synthetase), GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) and abfA (Alpha-l-Arabinofuranosidase A). The primers for these candidate reference genes were able to amplify cDNA only from the pathogen, demonstrating their specificity. The qPCR efficiency of the primers ranged from 80% to 103%. We analyzed the stability of gene expression in C. lindemuthianum by exposing the mycelium to nine different stress conditions. We employed algorithms, such as GeNorm, NormFinder, BestKeeper, and RefFinder tools, to identify the most stable gene. The analysis using these tools revealed that EF, GAPDH, and ß-tub most stable genes, while ACT and CHS1 showed relatively low expression stability. A large number of potential effector genes have been identified through bioinformatics analysis in C. lindemuthianum. The stable genes for qPCR (EF and GAPDH) discovered in this study will aid the scientific community in determining the relative expression of C. lindemuthianum effector genes.


Assuntos
Colletotrichum , Phaseolus , Doenças das Plantas , Reação em Cadeia da Polimerase em Tempo Real , Padrões de Referência , Colletotrichum/genética , Phaseolus/microbiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/normas , Doenças das Plantas/microbiologia , Perfilação da Expressão Gênica , Genes Fúngicos
14.
Transplant Direct ; 10(6): e1633, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38807861

RESUMO

Background: Ex vivo kidney perfusion is an evolving platform that demonstrates promise in preserving and rehabilitating the kidney grafts. Despite this, there is little consensus on the optimal perfusion conditions. Hypothermic perfusion offers limited functional assessment, whereas normothermic perfusion requires a more complex mechanical system and perfusate. Subnormothermic machine perfusion (SNMP) has the potential to combine the advantages of both approaches but has undergone limited investigation. Therefore, the present study sought to determine the suitability of SNMP for extended kidney preservation. Methods: SNMP at 22-25 °C was performed on a portable device for 24 h with porcine kidneys. Graft assessment included measurement of mechanical parameters and biochemical analysis of the perfusate using point-of-care tests. To investigate the viability of kidneys preserved by SNMP, porcine kidney autotransplants were performed in a donation after circulatory death (DCD) model. SNMP was also compared with static cold storage (SCS). Finally, follow-up experiments were conducted in a subset of human kidneys to test the translational significance of findings in porcine kidneys. Results: In the perfusion-only cohort, porcine kidneys all displayed successful perfusion for 24 h by SNMP, evidenced by stable mechanical parameters and biological markers of graft function. Furthermore, in the transplant cohort, DCD grafts with 30 min of warm ischemic injury demonstrated superior posttransplant graft function when preserved by SNMP in comparison with SCS. Finally, human kidneys that underwent 24-h perfusion exhibited stable functional and biological parameters consistent with observations in porcine organs. Conclusions: These observations demonstrate the suitability and cross-species generalizability of subnormothermic machine perfusion to maintain stable kidney perfusion and provide foundational evidence for improved posttransplant graft function of DCD kidneys after SNMP compared with SCS.

15.
Prostate Cancer ; 2024: 1588891, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38783970

RESUMO

Prostate cancer is a common cancer with significant implications for global health. Prompt and precise identification is crucial for efficient treatment strategizing and enhanced patient results. This research study investigates the utilization of machine learning techniques to diagnose prostate cancer. It emphasizes utilizing deep learning models, namely VGG16, VGG19, ResNet50, and ResNet50V2, to extract relevant features. The random forest approach then uses these features for classification. The study begins by doing a thorough comparison examination of the deep learning architectures outlined above to evaluate their effectiveness in extracting significant characteristics from prostate cancer imaging data. Key metrics such as sensitivity, specificity, and accuracy are used to assess the models' efficacy. With an accuracy of 99.64%, ResNet50 outperformed other tested models when it came to identifying important features in images of prostate cancer. Furthermore, the analysis of understanding factors aims to offer valuable insights into the decision-making process, thereby addressing a critical problem for clinical practice acceptance. The random forest classifier, a powerful ensemble learning method renowned for its adaptability and ability to handle intricate datasets, then uses the collected characteristics as input. The random forest model seeks to identify patterns in the feature space and produce precise predictions on the presence or absence of prostate cancer. In addition, the study tackles the restricted availability of datasets by utilizing transfer learning methods to refine the deep learning models using a small amount of annotated prostate cancer data. The objective of this method is to improve the ability of the models to generalize across different patient populations and clinical situations. This study's results are useful because they show how well VGG16, VGG19, ResNet50, and ResNet50V2 work for extracting features in the field of diagnosing prostate cancer, when used with random forest's classification abilities. The results of this work provide a basis for creating reliable and easily understandable machine learning-based diagnostic tools for detecting prostate cancer. This will enhance the possibility of an early and precise diagnosis in clinical settings such as index terms deep learning, machine learning, prostate cancer, cancer identification, and cancer classification.

16.
Cureus ; 16(4): e58820, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38784341

RESUMO

INTRODUCTION: The challenges posed by high altitude are particularly significant in terms of cardiovascular health. There are currently no data available on acute coronary syndrome (ACS) among Amarnath pilgrims. The objective of this study was to investigate the clinical and angiographic profiles of ACS among Amarnath pilgrims, focusing on demographic characteristics, risk factors, types of ACS, clinical presentation, angiographic findings, and in-hospital outcomes. By examining these aspects, we aimed to provide insights into the unique challenges faced by pilgrims during their spiritual journey and to identify potential strategies for improving the prevention and management of ACS in this population.  Methods: This was a hospital-based, prospective, observational study that included patients who had participated in the pilgrimage and presented with ACS between 2022 and 2023.  Results: Sixty patients were recruited for the study, with a mean age of 51.19 ± 11.17 years. Of these, 43 (71.7%) were male. Risk factors identified in the study included hypertension in 35 (58.3%), smoking in 23 (38.3%), diabetes mellitus in 18 (30%), and dyslipidemia in 25 (41.6%) patients. ST-elevation myocardial infarction (STEMI) was present in 46 (76.66%) patients, Anterior wall myocardial infarction (AWMI) occurred in 29 (48.3%), inferior wall myocardial infarction (IWMI) in 15 (25%), and high lateral wall myocardial infarction (HLWMI) in two (3.3%) patients. Of the 60 patients, 19 (31.6%) were in Killip class I, 16 (26.6%) were in class II, and 25 (41.6%) were in classes III or IV. The average time from the onset of symptoms to hospitalization was 7.6 ± 3.1 hours, significantly higher in those with Killip class III or IV (9.3 ± 3.6 vs. 5.4 ± 2.7 hours, p = 0.01). There were nine (15%) in-hospital deaths, and in the multivariate analysis, advanced Killip class (p = 0.04) and delays in hospitalization of more than six hours (p = 0.03) were found to be significant predictors of mortality. CONCLUSION: In conclusion, 40% of patients presented in the advanced Killip class, and 15% experienced in-hospital mortality. The average time from the onset of symptoms to hospitalization was significantly higher for those categorized in the advanced Killip classes. Our study highlights a significant association between advanced Killip class, delay in hospitalization, and in-hospital mortality among Amarnath pilgrims with ACS, underscoring the importance of timely intervention. It is recommended that appropriate measures be taken to improve patient outcomes in these cases.

17.
RSC Adv ; 14(24): 16661-16677, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38784421

RESUMO

This study explores the iodine and nickel-doped cobalt hydroxide (I & Ni-co-doped-Co(OH)2) as a potential material for energy storage and conversion applications owing to its excellent electrochemical characteristics. According to our analysis, it was revealed that this material exhibits pseudocapacitive-like behavior, as evident from distinct redox peaks observed in cyclic voltammetry, which confirms its ability to store charges. The diffusion coefficient analysis reveals that this material possesses conductivity and rapid diffusion kinetics, making it particularly advantageous compared to materials synthesized in previous studies. Charge-discharge measurements were performed to analyze the charge storage capacity and stability of this material after 3000 consecutive cycles, showing its excellent stability with minimum loss of capacitance. Furthermore, its anodic and cathodic linear sweep voltammetry curves were measured to evaluate its oxygen evolution and hydrogen evolution reaction performance. The results showed that the material exhibited an excellent water splitting performance, which suggests its potential practical application for hydrogen production. This increased activity was attributed to the doping of α-Co(OH)2, which improved its structural stability, electrical conductivity, and charge transfer efficiency. Thus, I & Ni-co-doped-Co(OH)2 possesses enhanced properties that make it an excellent material for both energy storage and hydrogen generation applications.

18.
Comput Biol Chem ; 111: 108097, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38772048

RESUMO

A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC50 values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC50 = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC50 values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC50 = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.

19.
Clin Genet ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38774940

RESUMO

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease-causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population.

20.
bioRxiv ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38766217

RESUMO

Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species modulate crucial cellular processes within MΦ, including phagocytosis, and host cell defenses, to establish an intracytosolic replication niche, remain poorly defined. In this study, we describe a previously unappreciated mechanism, in which pathogenic rickettsiae infection is mediated by the phosphatidylserine (PS)-binding receptor, CD300f. We found that CD300f -/- mice but not wild-type (WT) C57BL/6J mice were protected against R. typhi - or R. rickettsii [ Shelia Smith ]-induced fatal rickettsiosis. Adoptative transfer studies further revealed that CD300f-expressing bone marrow-derived macrophages (BMDMΦ) are important mediators to control rickettsiosis in WT mice. Mechanistical analysis, using WT or CD300f -/- BMDMΦ, showed that CD300f facilitates the engulfment of both pathogenic R. typhi and R. rickettsii species, likely via a PS-mediated mechanism. Furthermore, CD300f was involved in the intracytosolic replication of both pathogenic rickettsiae by differentially modulating the anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1ß cytokine responses. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment and the intracellular survival of pathogenic rickettsiae within the host. Significance Statement: Vector-borne diseases, which are transmitted by hematophagous arthropods, like ticks and fleas, present a perilous threat to public health. In fact, tick- and flea-borne rickettsial diseases are on the rise globally and our current inadequate understanding on how Rickettsia interacts with their mammalian host has significantly impaired the development of effective interventions against pathogenic rickettsial infections. Here, we identified the phosphatidylserine (PS)-receptor, CD300f, as an important mediator of pathogenic rickettsiae infection in vivo and in vitro . Specifically, we showed that CD300f-expressing macrophages facilitate rickettsial infection by differentially modulating anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1ß cytokine responses. In sum, our data described CD300f as an important regulator of rickettsial infection and may present a target for therapeutic intervention.

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