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The world urgently needs new sources of clean energy due to a growing global population, rising energy use, and the effects of climate change. Nuclear energy is one of the most promising solutions for meeting the world's energy needs now and in the future. One type of nuclear energy, Low Energy Nuclear Reactions (LENR), has gained interest as a potential clean energy source. Recent AI advancements create new ways to help research LENR and to comprehensively analyze the relationships between experimental parameters, materials, and outcomes across diverse LENR research endeavors worldwide. This study explores and investigates the effectiveness of modern AI capabilities leveraging embedding models and topic modeling techniques, including Latent Dirichlet Allocation (LDA), BERTopic, and Top2Vec, in elucidating the underlying structure and prevalent themes within a large LENR research corpus. These methodologies offer unique perspectives on understanding relationships and trends within the LENR research landscape, thereby facilitating advancements in this crucial energy research area. Furthermore, the study presents LENRsim, an experimental machine learning tool to identify similar LENR studies, along with a user-friendly web interface for widespread adoption and utilization. The findings contribute to the understanding and progression of LENR research through data-driven analysis and tool development, enabling more informed decision-making and strategic planning for future research in this field. The insights derived from this study, along with the experimental tools we developed and deployed, hold the potential to significantly aid researchers in advancing their studies of LENR.
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INTRODUCTION: Laparoscopic Complete Mesocolic Excision (CME) with Central Vascular Ligation (CVL) in colon cancer surgery has not been broadly adopted in part because of safety concerns. Pre-operative 3-D virtual modelling (3DVM) may help but needs validation. METHODS: 3DVM were routinely constructed from CT mesenteric angiograms (CTMA) using a commercial service (Visible Patient, Strasbourg, France) for consecutive patients during our CMECVL learning curve over three years. 3DVMs were independently checked versus CTMA and operative findings. CMECVL outcomes were compared versus other patients undergoing standard mesocolic excision (SME) surgery laparoscopically in the same hospital as control. Stakeholders were studied regarding 3DVM use and usefulness (including detail retention) versus CTMA and a physical 3D-printed model. RESULTS: 26 patients underwent 3DVM with intraoperative display during laparoscopic CMECVL within existing workflows. 3DVM accuracy was 96 % re arteriovenous variations at patient level versus CTMA/intraoperative findings including accessory middle colic artery identification in three patients. Twenty-two laparoscopic CMECVL with 3DVM cases were compared with 49 SME controls (age 69 ± 10 vs 70.9 ± 11 years, 55 % vs 53 % males). There were no intraoperative complications with CMECVL and similar 30-day postoperative morbidity (30 % vs 29 %), hospital stay (9 ± 3 vs 12 ± 13 days), 30-day readmission (6 % vs 4 %) and reoperation (0 % vs 4 %) rates. Intraoperative times were longer (215.7 ± 43.9 vs 156.9 ± 52.9 min, p=<0.01) but decreased significantly over time. 3DVM surveys (n = 98, 20 surgeons, 48 medical students, 30 patients/patient relatives) and comparative study revealed majority endorsement (90 %) and favour (87 %). CONCLUSION: 3DVM use was positively validated for laparoscopic CMECVL and valued by clinicians, students, and patients alike.
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Resveratrol, a stilbene, particularly trans-isomer, shows significant osteogenic potential but experiences high instability and poor bioavailability. However, cis-isomer (cRes) is not explored yet due to its instability. Our study investigates the osteoinductive potential of cRes for the first time by stabilizing it onto the surface of gold nanoparticles. cRes capped GNPs (cRGNPs) presented no toxic effects on the MC3T3-E1 cells with increased levels of alkaline phosphatase and calcium deposition. The nanoparticles presented a 2.6-fold increase in cell number compared to the control. The pro-migratory effect of the cRGNPs was also significantly higher (97.21 ± 0.99 % migration) in 4 days. The osteoinductivity was further confirmed by enhanced expression of osteoblastic genes like RUNX2, OPN, OCN, BMP, OPG, and Col1A. The stability provided to cRes upon conjugating to GNPs allowed exploration of its potential in aiding proliferation, migration, and differentiation of the pre-osteoblasts, which will be beneficial in repairing bone defects.
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Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist. The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses. Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited. In our study, we engineered a recombinant prefusion-stabilized trimeric spike protein antigen, IMT-CVAX, encoded by the IMT-C20 gene. This antigen was expressed utilizing a suspension mammalian cell line (CHO-S). The establishment of a stable cell line expressing IMT-CVAX involved the integration of the gene into the CHO genome, followed by the expression, purification, and characterization of the protein. To gauge the vaccine potential of adjuvanted IMT-CVAX, we conducted assessments in small animals. Analyses of blood collected from immunized animals included measurements of anti-spike IgG, SARS-CoV-2 neutralization, and responses from GC-B and Tfh cells. Furthermore, the protective efficacy of IMT-CVAX was evaluated using a Hamster challenge model. Our findings indicate that adjuvanted IMT-CVAX elicits an excellent immune response in both mice and hamsters. Notably, sera from animals immunized with IMT-CVAX effectively neutralize a diverse range of SARS-CoV-2 variants. Moreover, IMT-CVAX immunization conferred complete protection to hamsters against SARS-CoV-2 infection. In hACE2 transgenic mice, IMT-CVAX vaccination induced a robust response from GC-B and Tfh cells. Based on our preclinical model assessments, adjuvanted IMT-CVAX emerges as a highly efficacious vaccine candidate. This protein-subunit-based vaccine exhibits promise for clinical development, offering an affordable solution for both primary and heterologous immunization against SARS-CoV-2 variants.
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Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Vacunas contra la COVID-19/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/prevención & control , COVID-19/inmunología , Ratones , Cricetinae , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Cricetulus , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Células CHO , Femenino , Humanos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/genética , Adyuvantes Inmunológicos/administración & dosificaciónRESUMEN
Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV.
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Antivirales , Autofagia , Quinolinas , Replicación Viral , Infección por el Virus Zika , Virus Zika , Virus Zika/efectos de los fármacos , Virus Zika/fisiología , Autofagia/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Humanos , Antivirales/farmacología , Antivirales/síntesis química , Antivirales/química , Quinolinas/farmacología , Quinolinas/química , Quinolinas/síntesis química , Infección por el Virus Zika/tratamiento farmacológico , Infección por el Virus Zika/virología , Línea Celular , Chlorocebus aethiops , Animales , Células VeroRESUMEN
In bacteria, peptidyl-tRNA hydrolase (Pth, E.C. 3.1.1.29) is a ubiquitous and essential enzyme for preventing the accumulation of peptidyl-tRNA and sequestration of tRNA. Pth is an esterase that cleaves the ester bond between peptide and tRNA. Here, we present the crystal structure of Pth from Enterococcus faecium (EfPth) at a resolution of 1.92 Å. The two molecules in the asymmetric unit differ in the orientation of sidechain of N66, a conserved residue of the catalytic site. Enzymatic hydrolysis of substrate α-N-BODIPY-lysyl-tRNALys (BLT) by EfPth was characterized by Michaelis-Menten parameters KM 163.5 nM and Vmax 1.9 nM/s. Compounds having pyrrolinone scaffold were tested for inhibition of Pth and one compound, 1040-C, was found to have IC50 of 180 nM. Antimicrobial activity profiling was done for 1040-C. It exhibited equipotent activity against drug-susceptible and resistant S. aureus (MRSA and VRSA) and Enterococcus (VSE and VRE) with MICs 2-8 µg/mL. 1040-C synergized with gentamicin and the combination was effective against the gentamicin resistant S. aureus strain NRS-119. 1040-C was found to reduce biofilm mass of S. aureus to an extent similar to Vancomycin. In a murine model of infection, 1040-C was able to reduce bacterial load to an extent comparable to Vancomycin.
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Hidrolasas de Éster Carboxílico , Enterococcus faecium , Enterococcus faecium/enzimología , Enterococcus faecium/efectos de los fármacos , Animales , Ratones , Hidrolasas de Éster Carboxílico/química , Hidrolasas de Éster Carboxílico/metabolismo , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Antibacterianos/farmacología , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Pirrolidinonas/química , Pirrolidinonas/farmacología , Modelos Moleculares , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Dominio Catalítico , Hidrólisis , Biopelículas/efectos de los fármacosRESUMEN
BACKGROUND: Intravascular hemolysis is associated with massive release of hemoglobin and consequently labile heme into the blood, resulting in prothrombotic and proinflammatory events in patients. Though heme is well-known to participate in these adverse effects, it is not monitored. Instead, haptoglobin and hemoglobin serve as clinical biomarkers. The quantification of labile heme together with hemoglobin, however, should be considered in clinical diagnosis as well, to obtain a complete picture of the hemolytic state in patients. So far, quantification techniques for labile heme were not yet systematically analyzed and compared for their clinical application potential, especially in the presence of hemoglobin. RESULTS: Two commercial assays (Heme Assay Kit®, Hemin Assay Kit®) and five common approaches (pyridine hemochromogen assay, apo-horseradish peroxidase-based assay, UV/Vis spectroscopy, HPLC, mass spectrometry) were analyzed concerning their linearity, accuracy, and precision, as well as their ability to distinguish between hemoglobin-bound heme and labile heme. Further, techniques for the quantification of hemoglobin (Harboe method, SLS method, Hemastix®) were included to study their selectivity for hemoglobin and potential interference by the presence of labile heme. Both, indirect and direct approaches were suitable for the determination of a wide concentration of heme (â¼0.02-45 µM) and hemoglobin (â¼0.002-17 µM). A clear distinction between hemoglobin-bound heme and labile heme with one method was not possible. Thus, a novel combined approach is presented and applied to human and porcine plasma samples for the determination of hemoglobin and labile heme. SIGNIFICANCE: Our results demonstrate the need to develop improved techniques to differentiate labile and protein-bound heme for early detection of intravascular hemolysis. Here, we present a novel strategy by combining two spectroscopic methods, which is most reliable as an easy-to-use tool for the determination of hemoglobin and heme levels in plasma samples for the diagnosis of intravascular hemolysis and in basic biomedical research.
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Hemo , Hemoglobinas , Hemólisis , Hemo/química , Hemo/análisis , Hemoglobinas/análisis , Humanos , Animales , Porcinos , Cromatografía Líquida de Alta PresiónRESUMEN
Background: The healing of burn wounds is a complicated physiological process that involves several stages, including haemostasis, inflammation, proliferation, and remodelling to rebuild the skin and subcutaneous tissue integrity. Recent advancements in nanomaterials, especially nanofibers, have opened a new way for efficient healing of wounds due to burning or other injuries. Methods: This study aims to develop and characterize collagen-decorated, bilayered electrospun nanofibrous mats composed of PVP and PVA loaded with Resveratrol (RSV) and Ampicillin (AMP) to accelerate burn wound healing and tissue repair. Results: Nanofibers with smooth surfaces and web-like structures with diameters ranging from 200 to 400 nm were successfully produced by electrospinning. These fibres exhibited excellent in vitro properties, including the ability to absorb wound exudates and undergo biodegradation over a two-week period. Additionally, these nanofibers demonstrated sustained and controlled release of encapsulated Resveratrol (RSV) and Ampicillin (AMP) through in vitro release studies. The zone of inhibition (ZOI) of PVP-PVA-RSV-AMP nanofibers against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was found 31±0.09 mm and 12±0.03, respectively, which was significantly higher as compared to positive control. Similarly, the biofilm study confirmed the significant reduction in the formation of biofilms in nanofiber-treated group against both S. aureus and E. coli. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analysis proved the encapsulation of RSV and AMP successfully into nanofibers and their compatibility. Haemolysis assay (%) showed no significant haemolysis (less than 5%) in nanofiber-treated groups, confirmed their cytocompatibility with red blood cells (RBCs). Cell viability assay and cell adhesion on HaCaT cells showed increased cell proliferation, indicating its biocompatibility as well as non-toxic properties. Results of the in-vivo experiments on a burn wound model demonstrated potential burn wound healing in rats confirmed by H&E-stained images and also improved the collagen synthesis in nanofibers-treated groups evidenced by Masson-trichrome staining. The ELISA assay clearly indicated the efficient downregulation of TNF-alpha and IL-6 inflammatory biomarkers after treatment with nanofibers on day 10. Conclusion: The RSV and AMP-loaded nanofiber mats, developed in this study, expedite burn wound healing through their multifaceted approach.
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Ampicilina , Quemaduras , Colágeno , Escherichia coli , Nanofibras , Alcohol Polivinílico , Povidona , Resveratrol , Staphylococcus aureus , Cicatrización de Heridas , Resveratrol/farmacología , Resveratrol/química , Resveratrol/administración & dosificación , Resveratrol/farmacocinética , Nanofibras/química , Quemaduras/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Animales , Colágeno/química , Povidona/química , Staphylococcus aureus/efectos de los fármacos , Alcohol Polivinílico/química , Humanos , Escherichia coli/efectos de los fármacos , Ampicilina/farmacología , Ampicilina/química , Ampicilina/farmacocinética , Ampicilina/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Ratas , Biopelículas/efectos de los fármacos , MasculinoRESUMEN
A coating that can be activated by moisture found in respiratory droplets could be a convenient and effective way to control the spread of airborne pathogens and reduce fomite transmission. Here, the ability of a novel 6-hydroxycatechol-containing polymer to function as a self-disinfecting coating on the surface of polypropylene (PP) fabric was explored. Catechol is the main adhesive molecule found in mussel adhesive proteins. Molecular oxygen found in an aqueous solution can oxidize catechol and generate a known disinfectant, hydrogen peroxide (H2O2), as a byproduct. However, given the limited amount of moisture found in respiratory droplets, there is a need to enhance the rate of catechol autoxidation to generate antipathogenic levels of H2O2. 6-Hydroxycatechol contains an electron donating hydroxyl group on the 6-position of the benzene ring, which makes catechol more susceptible to autoxidation. 6-Hydroxycatechol-coated PP generated over 3000 µM of H2O2 within 1 h when hydrated with a small amount of aqueous solution (100 µL of PBS). The generated H2O2 was three orders of magnitude higher when compared to the amount generated by unmodified catechol. 6-Hydroxycatechol-containing coating demonstrated a more effective antimicrobial effect against both Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria when compared to unmodified catechol. Similarly, the self-disinfecting coating reduced the infectivity of both bovine viral diarrhea virus and human coronavirus 229E by as much as a 2.5 log reduction value (a 99.7% reduction in viral load). Coatings containing unmodified catechol did not generate sufficient H2O2 to demonstrate significant virucidal effects. 6-Hydroxycatechol-containing coating can potentially function as a self-disinfecting coating that can be activated by the moisture present in respiratory droplets to generate H2O2 for disinfecting a broad range of pathogens.
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Catecoles , Peróxido de Hidrógeno , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Catecoles/química , Catecoles/farmacología , Humanos , Staphylococcus aureus/efectos de los fármacos , Desinfectantes/farmacología , Desinfectantes/química , Polipropilenos/química , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/efectos de los fármacosRESUMEN
Pilonidal disease and hidradenitis suppurativa affect healthy young adults, causing discomfort and pain that leads to loss of work productivity and should be approached in a personalized manner. Patients with pilonidal disease should engage in hair removal to the sacrococcygeal region and surgical options considered. Hidradenitis suppurativa can be a morbid and challenging disease process. Medical management with topical agents, antibiotics, and biologics should be used initially but wide local excision should be considered in severe or refractory cases of the disease.
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Hidradenitis Supurativa , Seno Pilonidal , Humanos , Hidradenitis Supurativa/terapia , Hidradenitis Supurativa/cirugía , Hidradenitis Supurativa/complicaciones , Hidradenitis Supurativa/diagnóstico , Seno Pilonidal/cirugía , Seno Pilonidal/terapia , Seno Pilonidal/diagnóstico , Remoción del Cabello/métodosRESUMEN
Introduction In modern dentistry, the focus is more on preventing caries than on treating it, which helps preserve the tooth structure. Pit and fissure sealants (PFS) are the most effective methods for providing a mechanical barrier and avoiding the accumulation of dental plaque in deep pits and fissures, thereby preventing occlusal caries. The present study was conducted to compare the efficiency of dentin bonding agents (DBA) with or without fissurotomy in reducing microleakage before PFS placement. Materials and methods A total of 48 freshly extracted premolars were randomly divided into four groups as follows: Group 1, the conventional technique of PFS (Clinpro, 3M ESPE sealant); Group 2, fissurotomy performed before PFS placement; Group 3, Scotchbond Universal Adhesive (3M ESPE DBA) applied before PFS placement; and Group 4, fissurotomy along with DBA was used before PFS placement. The teeth were subjected to thermocycling followed by dye penetration using a 1% solution of methylene blue for 24 hours. All teeth were then assessed for microleakage by a qualitative method using a stereomicroscope at 40X and depth of dye penetration by image analysis. The Kruskal-Wallis test followed by Dunn's test was used for intergroup comparisons of microleakage scores, and ANOVA followed by Tukey's test was used for intergroup comparisons of the depth of dye penetration. These analyses were conducted using statistical software (SPSS version 22, Chicago, IL, USA). Results Statistically significant differences were observed between the groups in terms of the microleakage scores and depth of dye penetration (p<0.05). The group 4 showed a minimum microleakage score (0.50±0.52), and maximum scores were observed in Group 1 (2.16±0.71). Group 2 showed insignificant differences with groups 3 and 4 for depth of dye penetration (p>0.05). Statistically significant differences were observed between groups 1 and 2, groups 1 and 4, and groups 3 and 4 for the microleakage score (p<0.05). Conclusion Fissurotomy with or without DBA significantly reduced microleakage before the PFS placement. Prior use of fourth-generation DBA significantly reduced microleakage compared with PFS placement without the use of DBA.
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Pseudohypoaldosteronism type II (PHA II) or Gordon syndrome is characterized by hyperkalemia, hypertension, hyperchloremic metabolic acidosis, low plasma renin activity, and normal kidney function. We report a rare case of a young adult female patient presenting with abdominal pain, diarrhea, and vomiting. She was hypertensive during the presentation. Blood work showed mild anemia, hyperkalemia, hyperchloremia, and metabolic acidosis, with normal renal function and liver function. Plasma renin activity and aldosterone levels were low-normal. These findings were suggestive of PHA II or Gordon syndrome. It is a rare familial disease, with a non-specific presentation and no specific diagnostic criteria, and physicians should suspect it in patients with hyperkalemia in the setting of normal glomerular filtration, along with hypertension (which can be absent), metabolic acidosis, hyperchloremia, low plasma renin activity, and relatively suppressed aldosterone.
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Zika virus (ZIKV) infection during pregnancy causes severe neurological and ocular abnormalities in infants, yet no vaccine or antivirals are available. Our transcriptomic analysis of ZIKV-infected retinal pigment epithelial (RPE) cells revealed alterations in the cholesterol pathway. Thus, we investigated the functional roles of ATP binding cassette transporter G1 (ABCG1) and sterol response element binding protein 2 (SREPB-2), two key players in cholesterol metabolism, during ocular ZIKV infection. Our in vitro data showed that increased ABCG1 activity via liver X receptors (LXRs), reduced ZIKV replication, while ABCG1 knockdown increased replication with elevated intracellular cholesterol. Conversely, inhibiting SREBP-2 or its knockdown reduced ZIKV replication by lowering cholesterol levels. In vivo, LXR agonist or SREBP-2 inhibitor treatment mitigated ZIKV-induced chorioretinal lesions in mice, concomitant with decreased expression of inflammatory mediators and increased activation of antiviral response genes. In summary, our study identifies ABCG1's antiviral role and SREBP-2's proviral effects in ocular ZIKV infection, offering cholesterol metabolism as a potential target to develop antiviral therapies.
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Recurrent hyperparathyroidism (HPT) after initial parathyroid surgery occurs rarely in an ectopic location. The rare phenomenon of parathyromatosis may be the cause of this. We present the case of a 59-year-old woman with recurrent HPT, which presented as a new ectopic mediastinal parathyroid gland 13 years after initial 3.5 gland parathyroidectomy. A 1.5 × 1.3 cm lesion was discovered as an incidental finding in the pretracheal region, closely abutting the aortic arch. An aspirate revealed oncocytic cells, which were positive for parathyroid hormone, confirming a mediastinal parathyroid nodule. Sestamibi scan confirmed an avid nodule in the mediastinum. This patient had multiple co-morbidities but was asymptomatic of HPT. It was therefore decided at multi-disciplinary team discussion that she should undergo surveillance. To our knowledge, no such presentations have been reported in the literature. Thus, our case report is a unique addition of an atypical presentation of HPT.
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Sound absorption below 1000 Hz has been extremely difficult through traditional barriers and absorbers, but it is required for noise control of appliances and machineries. Existing passive acoustic metamaterials attenuate low-frequency noise but with narrow bandwidths and bulky sizes. Hence, this paper proposes an acoustic metamaterial with enclosed symmetrical labyrinthine air channels and two micro-slits (configuration 1, identical slits; configuration 2, unequal length slits) at the end channels. Its theoretical model is established by acoustic impedance analysis using electro-acoustic analogy and validated numerically and experimentally. Sound absorption is found to happen as a result of impedance matching, Fabry-Perot-like labyrinthine resonances, and thermo-viscous losses in micro-slits. Parametric investigations reveal that increase in the number of channels, channel length, total height, and outer panel thickness shifts sound absorption peak to lower frequency but also decreases the magnitude and frequency range of absorption. Decreasing the channel width and slit width increases the sound absorption magnitude without changing absorption frequencies. Interestingly, unequal slit lengths perform better than equal slits by giving a lower frequency sound absorption with increased magnitude and frequency range, which is unlike that in existing labyrinthine metamaterials. Therefore, the proposed unequal slit metamaterial has enhanced low-frequency sound absorption and can be applied to appliances and machineries.
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BACKGROUND: The characterization of inherited mild factor XIII deficiency is more imprecise than its rare, inherited severe forms. It is known that heterozygosity at FXIII genetic loci results in mild FXIII deficiency, characterized by circulating FXIII activity levels ranging from 20% to 60%. There exists a gap in information on 1) how genetic heterozygosity renders clinical bleeding manifestations among these individuals and 2) the reversal of unexplained bleeding upon FXIII administration in mild FXIII-deficient individuals. OBJECTIVES: To assess the prevalence and burden of mild FXIII deficiency among the apparently healthy German-Caucasian population and correlate it with genetic heterozygosity at FXIII and fibrinogen gene loci. METHODS: Peripheral blood was collected from 752 donors selected from the general population with essentially no bleeding complications to ensure asymptomatic predisposition. These were assessed for FXIII and fibrinogen activity, and FXIII and fibrinogen genes were resequenced using next-generation sequencing. For comparison, a retrospective analysis was performed on a cohort of mild inherited FXIII deficiency patients referred to us. RESULTS: The prevalence of mild FXIII deficiency was high (â¼0.8%) among the screened German-Caucasian population compared with its rare-severe forms. Although no new heterozygous missense variants were found, certain combinations were relatively dominant/prevalent among the mild FXIII-deficient individuals. CONCLUSION: This extensive, population-based quasi-experimental approach revealed that the burden of heterozygosity in FXIII and fibrinogen gene loci causes the clinical manifestation of inherited mild FXIII deficiency, resulting in ''unexplained bleeding'' upon provocation.
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Deficiencia del Factor XIII , Factor XIII , Hemostáticos , Humanos , Factor XIII/genética , Deficiencia del Factor XIII/diagnóstico , Deficiencia del Factor XIII/genética , Fibrinógeno/genética , Hemorragia/diagnóstico , Hemorragia/genética , Estudios RetrospectivosRESUMEN
The sixth family phosphodiesterases (PDE6) are principal effector enzymes of the phototransduction cascade in rods and cones. Maturation of nascent PDE6 protein into a functional enzyme relies on a coordinated action of ubiquitous chaperone HSP90, its specialized cochaperone aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), and the regulatory Pγ-subunit of PDE6. Deficits in PDE6 maturation and function underlie severe visual disorders and blindness. Here, to elucidate the roles of HSP90, AIPL1, and Pγ in the maturation process, we developed the heterologous expression system of human cone PDE6C in insect cells allowing characterization of the purified enzyme. We demonstrate that in the absence of Pγ, HSP90, and AIPL1 convert the inactive and aggregating PDE6C species into dimeric PDE6C that is predominantly misassembled. Nonetheless, a small fraction of PDE6C is properly assembled and fully functional. From the analysis of mutant mice that lack both rod Pγ and PDE6C, we conclude that, in contrast to the cone enzyme, no maturation of rod PDE6AB occurs in the absence of Pγ. Co-expression of PDE6C with AIPL1 and Pγ in insect cells leads to a fully mature enzyme that is equivalent to retinal PDE6. Lastly, using immature PDE6C and purified chaperone components, we reconstituted the process of the client maturation in vitro. Based on this analysis we propose a scheme for the PDE6 maturation process.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6 , Células Fotorreceptoras Retinianas Conos , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ceguera/genética , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/deficiencia , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Mutación , Multimerización de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/deficiencia , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Células Fotorreceptoras Retinianas Conos/química , Células Fotorreceptoras Retinianas Conos/metabolismoRESUMEN
Malaria is still a complex and lethal parasitic infectious disease, despite the availability of effective antimalarial drugs. Resistance of malaria parasites to current treatments necessitates new antimalarials targeting P. falciparum proteins. The present study reported the design and synthesis of a series of a 2-(4-substituted piperazin-1-yl)-N-(5-((naphthalen-2-yloxy)methyl)-1,3,4-thiadiazol-2-yl)acetamide hybrids for the inhibition of Plasmodium falciparum dihydrofolate reductase (PfDHFR) using computational biology tools followed by chemical synthesis, structural characterization, and functional analysis. The synthesized compounds were evaluated for their in vitro antimalarial activity against CQ-sensitive PfNF54 and CQ-resistant PfW2 strain. Compounds T5 and T6 are the most active compounds having anti-plasmodial activity against PfNF54 with IC50 values of 0.94 and 3.46 µM respectively. Compound T8 is the most active against the PfW2 strain having an IC50 of 3.91 µM. Further, these active hybrids (T5, T6, and T8) were also evaluated for enzyme inhibition assay against PfDHFR. All the tested compounds were non-toxic against the Hek293 cell line with good selectivity indices. Hemolysis assay also showed non-toxicity of these compounds on normal uninfected human RBCs. In silico molecular docking studies were carried out in the binding pocket of both the wild-type and quadruple mutant Pf-DHFR-TS to gain further insights into probable modes of action of active compounds. ADME prediction and physiochemical properties support their drug-likeness. Additionally, they were screened for antileishmanial activity against L. donovani promastigotes to explore broader applications. Thus, this study provides molecular frameworks for developing potent antimalarials and antileishmanial agents.
RESUMEN
Extensive vascular leakage and shock is a major cause of dengue-associated mortality. At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine-1-phosphate receptors (S1PR1-S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)-infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier-protective S1P receptors, without targeting S1PR2. In the present study, we explored whether FTY720 treatment can alleviate DENV-induced endothelial hyperpermeability. In functional assays, in both in vitro systems and in AG129 animal models, FTY720 treatment was found effective. Upon treatment, there was complete restoration of the monolayer integrity in DENV serotype 2-infected human microvascular endothelial cells (HMEC-1). At the molecular level, the treatment reversed activation of the S1P pathway. It significantly reduced the phosphorylation of the key molecules such as PTEN, RhoA, and VE-Cadherin; and also, the expression levels of S1PR2. In DENV2-infected AG129 mice treated with FTY720, there was significant improvement in weight gain, in overall clinical symptoms, and in survival. Whereas 100% of the DENV2-infected, untreated animals died by day-10 post-infection, 70% of the FTY720-treated animals were alive; and at the end of the 15-day post-infection observation period, 30% of them were still surviving. There was a significant reduction in the Evan's-blue dye permeability in the organs of FTY720-treated, DENV-2 infected animals; and also improvement in the hemogram, with complete restoration of thrombocytopenia and hepatic function. Our results show that the FDA-approved molecule Fingolimod (FTY720) is a promising therapeutic intervention in severe dengue.