RESUMO
BACKGROUND: Accurate genetic diagnosis of end-stage renal disease patients with a family history of renal dysfunction is very essential. It not only helps in proper prognosis, but becomes crucial in designating donor for live related renal transplant. We here present a case of family with deleterious mutations in INF2 and ROBO2 and its importance of genetic testing before preparing for kidney transplantation. CASE PRESENTATION: We report the case of a 29-year-female with end-stage renal disease and rapidly progressive renal failure. Mutational analysis revealed an Autosomal Dominant inheritance pattern and mutation in exon 4 of the INF2 gene (p. Thr215Ser) and exon 26 of the ROBO2 gene (p. Arg1371Cys). Her mother was diagnosed for CKD stage 4 with creatinine level of 4.3 mg/dL. Genetic variants (INF2 and ROBO2) identified in proband were tested in her sisters and mother. Her elder sister was positive for both heterozygous variants (INF2 and ROBO2). Her mother was positive for mutation in INF2 gene, and her donor elder sister did not showed mutation in INF2 gene and had mutation in ROBO2 gene without any clinical symptoms. CONCLUSION: This case report emphasize that familial genetic screening has allowed us in allocating the donor selection in family where family member had history of genetic defect of Chronic Kidney Disease. Information of the causative renal disorder is extremely valuable for risk-assessment and planning of kidney transplantation.
Assuntos
Glomerulosclerose Segmentar e Focal , Falência Renal Crônica , Transplante de Rim , Humanos , Feminino , Idoso , Forminas/genética , Seguimentos , Glomerulosclerose Segmentar e Focal/genética , Mutação , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Falência Renal Crônica/cirurgia , Linhagem , Proteínas Roundabout , Receptores Imunológicos/genéticaRESUMO
PURPOSE: AI has shown promise in automating and improving various tasks, including medical image analysis. Distal humerus fractures are a critical clinical concern that requires early diagnosis and treatment to avoid complications. The standard diagnostic method involves X-ray imaging, but subtle fractures can be missed, leading to delayed or incorrect diagnoses. Deep learning, a subset of artificial intelligence, has demonstrated the ability to automate medical image analysis tasks, potentially improving fracture identification accuracy and reducing the need for additional and cost-intensive imaging modalities (Schwarz et al. 2023). This study aims to develop a deep learning-based diagnostic support system for distal humerus fractures using conventional X-ray images. The primary objective of this study is to determine whether deep learning can provide reliable image-based fracture detection recommendations for distal humerus fractures. METHODS: Between March 2017 and March 2022, our tertiary hospital's PACS data were evaluated for conventional radiography images of the anteroposterior (AP) and lateral elbow for suspected traumatic distal humerus fractures. The data set consisted of 4931 images of patients seven years and older, after excluding paediatric images below seven years due to the absence of ossification centres. Two senior orthopaedic surgeons with 12 + years of experience reviewed and labelled the images as fractured or normal. The data set was split into training sets (79.88%) and validation tests (20.1%). Image pre-processing was performed by cropping the images to 224 × 224 pixels around the capitellum, and the deep learning algorithm architecture used was ResNet18. RESULTS: The deep learning model demonstrated an accuracy of 69.14% in the validation test set, with a specificity of 95.89% and a positive predictive value (PPV) of 99.47%. However, the sensitivity was 61.49%, indicating that the model had a relatively high false negative rate. ROC analysis showed an AUC of 0.787 when deep learning AI was the reference and an AUC of 0.580 when the most senior orthopaedic surgeon was the reference. The performance of the model was compared with that of other orthopaedic surgeons of varying experience levels, showing varying levels of diagnostic precision. CONCLUSION: The developed deep learning-based diagnostic support system shows potential for accurately diagnosing distal humerus fractures using AP and lateral elbow radiographs. The model's specificity and PPV indicate its ability to mark out occult lesions and has a high false positive rate. Further research and validation are necessary to improve the sensitivity and diagnostic accuracy of the model for practical clinical implementation.
Assuntos
Fraturas Ósseas , Fraturas Distais do Úmero , Humanos , Criança , Inteligência Artificial , Fraturas Ósseas/diagnóstico por imagem , Radiografia , Algoritmos , Estudos RetrospectivosRESUMO
Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.
Assuntos
Aldeído Desidrogenase , Inibidores Enzimáticos , Isatina , Simulação de Acoplamento Molecular , Humanos , Isatina/química , Isatina/farmacologia , Aldeído Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura MolecularRESUMO
Omicron derived lineages viz. BA.2, BA.3, BA.4 BA.5, BF.7 and XBBs show prominence with improved immune escape, transmissibility, infectivity, and pathogenicity in general. Sub-variants, XBB.1.5 and XBB.1.16 have shown rapid spread, with mutations embedded throughout the viral genome, including the spike protein. Changing atomic landscapes in spike contributes significantly to modulate host pathogen interactions and infections thereof. In the present work, we computationally analyzed the binding affinities of spike receptor binding domains (RBDs) of XBB.1.5 and XBB.1.16 towards human angiotensin-converting enzyme 2 (hACE2) compared to Omicron. We have employed simulations and binding energy estimation of molecular complexes of spike-hACE2 to assess the interplay of interaction pattern and effect of mutations if any in the binding mode of the RBDs of these novel mutants. We calculated the binding free energy (BFE) of the RBD of the Omicron, XBB.1.5 and XBB.1.16 spike protein to hACE2. We showed that XBB.1.5 and XBB.1.16 can bind to human cells more strongly than Omicron due to the increased charge of the RBD, which enhances the electrostatic interactions with negatively charged hACE2. The per-residue decompositions further show that the Asp339His, Asp405Asn and Asn460Lys mutations in the XBBs RBD play a crucial role in enhancing the electrostatic interactions, by acquiring positively charged residues, thereby influencing the formation/loss of interfacial bonds and thus strongly affecting the spike RBD-hACE2 binding affinity. Simulation results also indicate less interference of heterogeneous glycans of XBB.1.5 spike RBD towards binding to hACE2. Moreover, despite having less interaction at the three interfacial contacts between XBB S RBD and hACE2 compared to Omicron, variants XBB.1.5 and XBB.1.16 had higher total binding free energies (ΔGbind) than Omicron due to the contribution of non-interfacial residues to the free energy, providing insight into the increased binding affinity of XBB1.5 and XBB.1.16. Furthermore, the presence of large positively charged surface patches in the XBBs act as drivers of electrostatic interactions, thus support the possibility of a higher binding affinity to hACE2.
Assuntos
Simulação de Dinâmica Molecular , Glicoproteína da Espícula de Coronavírus , Humanos , Glicoproteína da Espícula de Coronavírus/genética , Mutação , Polissacarídeos , Software , Ligação ProteicaRESUMO
Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones' hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton's Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones' interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/química , Tirosina Quinase da Agamaglobulinemia/metabolismo , Biomarcadores Tumorais , Medula Óssea/metabolismo , Medula Óssea/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/etiologia , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Relação Estrutura-Atividade , Microambiente Tumoral/efeitos dos fármacosRESUMO
As clinical applications for chimeric antigen receptor T cell (CART) therapy extend beyond early phase trials, commercial manufacture incorporating cryopreservation steps becomes a logistical necessity. The effect of cryopreservation on CART characteristics is unclear. We retrospectively evaluated the effect of cryopreservation on product release criteria and in vivo characteristics in 158 autologous CART products from 6 single-center clinical trials. Further, from 3 healthy donor manufacturing runs, we prospectively identified differentially expressed cell surface markers and gene signatures among fresh versus cryopreserved CARTs. Within 2 days of culture initiation, cell viability of the starting fraction (peripheral blood mononuclear cells [PBMNCs]) decreased significantly in the cryo-thawed arm compared to the fresh arm. Despite this, PBMNC cryopreservation did not affect final CART fold expansion, transduction efficiency, CD3%, or CD4:CD8 ratios. In vivo CART persistence and clinical responses did not differ among fresh and cryopreserved final products. In healthy donors, compared to fresh CARTs, early apoptotic cell-surface markers were significantly elevated in cryo-thawed CARTs. Cryo-thawed CARTs also demonstrated significantly elevated expression of mitochondrial dysfunction, apoptosis signaling, and cell cycle damage pathways. Cryopreservation during CART manufacture is a viable strategy, based on standard product release parameters. The clinical impact of cryopreservation-related subtle micro-cellular damage needs further study.
Assuntos
Autoantígenos/imunologia , Criopreservação/métodos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Adolescente , Adulto , Idoso , Apoptose , Relação CD4-CD8 , Ciclo Celular , Sobrevivência Celular , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Adulto JovemRESUMO
Poly(A) polymerases (PAPs) are found in most living organisms and have important roles in RNA function and metabolism. Here, we report the crystal structure of human PAPD1, a noncanonical PAP that can polyadenylate RNAs in the mitochondria (also known as mtPAP) and oligouridylate histone mRNAs (TUTase1). The overall structure of the palm and fingers domains is similar to that in the canonical PAPs. The active site is located at the interface between the two domains, with a large pocket that can accommodate the substrates. The structure reveals the presence of a previously unrecognized domain in the N-terminal region of PAPD1, with a backbone fold that is similar to that of RNP-type RNA binding domains. This domain (named the RL domain), together with a ß-arm insertion in the palm domain, contributes to dimerization of PAPD1. Surprisingly, our mutagenesis and biochemical studies show that dimerization is required for the catalytic activity of PAPD1.
Assuntos
RNA Polimerases Dirigidas por DNA/química , Proteínas Mitocondriais/química , Multimerização Proteica , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/metabolismo , Humanos , Proteínas Mitocondriais/metabolismo , Dados de Sequência Molecular , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Alinhamento de Sequência , Especificidade por SubstratoRESUMO
People suffering from malnutrition become susceptible to the infection like Leishmania sp., as it results in a compromised immune response. Retinoic acid (RA), an important constituent of nutrition, shows an immune-modulatory activity. However, its role in the containment of infection is not yet ascertained, particularly in case of visceral leishmaniasis (VL). VL patients (n = 10) and healthy endemic controls (n = 9) were recruited to measure the serum levels of RA. An in vitro model of Leishmania infection using the murine mφ cell line J774.1 was used to investigate the RA-synthesizing enzymes (RALDH-1 and RALDH-2). Parasite loads among infected mφ were measured by quantitative expression of kDNA in the presence of an inhibitor of the RALDH-2 enzyme. We found a significant decrease in the serum levels of RA in VL cases. Importantly, we observed decreased levels of RALDH-1 and RALDH-2 among L. donovani-infected mφ along with simultaneous decrease as well as increase in the Th-1 and Th-2-associated factors, respectively. Furthermore, the pretreatment of mφ with an RALDH-2 inhibitor improved parasite in vitro infection. Our findings show impaired RA pathway among infected mφ and indicate that an intact RA pathway is critical for anti-Leishmania immune response. Graphical abstract á .
Assuntos
Fatores Imunológicos/sangue , Leishmania donovani/fisiologia , Leishmaniose Visceral/parasitologia , Macrófagos/parasitologia , Retinal Desidrogenase/metabolismo , Tretinoína/sangue , Animais , Linhagem Celular , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Leishmaniose Visceral/sangue , Leishmaniose Visceral/imunologia , Macrófagos/enzimologia , Masculino , Camundongos , Tretinoína/imunologia , Tretinoína/metabolismoRESUMO
BACKGROUND: There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India. METHODS: We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12 months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (≥10 000 copies/mL) detected ≥2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction. RESULTS: All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12 months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6 months. Nine (14.5%) patients had SSBKV. There was no biopsy-proven BKVAN. At the end of 1 year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV. CONCLUSION: Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6 months. Most clear their viremia by 12 months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients.
Assuntos
Nefropatias/epidemiologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Viremia/epidemiologia , Adulto , Vírus BK/isolamento & purificação , Biópsia , Monitoramento Epidemiológico , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/virologia , Humanos , Imunossupressores/uso terapêutico , Incidência , Índia/epidemiologia , Nefropatias/sangue , Nefropatias/patologia , Nefropatias/virologia , Transplante de Rim/métodos , Doadores Vivos , Masculino , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/virologia , Estudos Prospectivos , Transplantados/estatística & dados numéricos , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia , Viremia/virologia , Adulto JovemRESUMO
The Staphylococcus aureus agr quorum-sensing system plays a major role in the transition from the persistent to the virulent phenotype. S. aureus agr type I to IV strains are characterized by mutations in the sensor domain of the histidine kinase AgrC and differences in the sequences of the secreted autoinducing peptides (AIP). Here we demonstrate that interactions between the cytosolic domain of AgrC (AgrCCyto) and the response regulator domain of AgrA (AgrARR) dictate the spontaneity of the cellular response to AIP stimuli. The crystal structure of AgrCCyto provided a basis for a mechanistic model of AgrC-AgrA interactions. This model enabled an analysis of the biochemical and biophysical parameters of AgrC-AgrA interactions in the context of the conformational features of the AgrC-AgrA complex. This analysis revealed distinct sequence and conformational features that determine the affinity, specificity, and kinetics of the phosphotransfer reaction. This step, which governs the response time for transcriptional reengineering triggered by an AIP stimulus, is independent of the agr type and similar for agonist and antagonist stimuli. These experimental data could serve as a basis on which to validate simulations of the quorum-sensing response and for strategies that employ the agr quorum-sensing system to combat biofilm formation in S. aureus infections.
Assuntos
Proteínas de Bactérias/metabolismo , Percepção de Quorum/fisiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Biofilmes , Cristalografia , Citosol/metabolismo , Dimerização , Humanos , Cinética , Modelos Biológicos , Modelos Moleculares , Peptídeos Cíclicos/química , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/metabolismo , Fenótipo , Fosforilação , Ligação Proteica , Conformação Proteica , Proteínas Quinases/química , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes , Staphylococcus aureus/genética , Fatores de TempoRESUMO
Gain-of-function mutations in the calcium channel TRPC6 lead to autosomal dominant focal segmental glomerulosclerosis and podocyte expression of TRPC6 is increased in some acquired human glomerular diseases, particularly in membranous nephropathy. These observations led to the hypothesis that TRPC6 overactivation is deleterious to podocytes through pathological calcium signaling, both in genetic and acquired diseases. Here, we show that the effects of TRPC6 on podocyte function are context-dependent. Overexpression of TRPC6 alone did not directly affect podocyte morphology and cytoskeletal structure. Unexpectedly, however, overexpression of TRPC6 protected podocytes from complement-mediated injury, whereas genetic or pharmacological TRPC6 inactivation increased podocyte susceptibility to complement. Mechanistically, this effect was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation. Podocyte-specific TRPC6 transgenic mice showed stronger CaMKII activation, reduced podocyte foot process effacement and reduced levels of proteinuria during nephrotoxic serum nephritis, whereas TRPC6 null mice exhibited reduced CaMKII activation and higher levels of proteinuria compared with wild type littermates. Human membranous nephropathy biopsy samples showed podocyte staining for active CaMKII, which correlated with the degree of TRPC6 expression. Together, these data suggest a dual and context dependent role of TRPC6 in podocytes where acute activation protects from complement-mediated damage, but chronic overactivation leads to focal segmental glomerulosclerosis.
Assuntos
Proteínas do Sistema Complemento/metabolismo , Glomerulosclerose Segmentar e Focal/metabolismo , Podócitos/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Ativação Enzimática , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Podócitos/patologia , Proteinúria/metabolismo , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6RESUMO
Plasmodium falciparum origin recognition complex 1 (ORC1) protein has been implicated in DNA replication and silencing var gene family. However, the mechanism and the domain structure of ORC1 related to the regulation of var gene family are unknown. Here we show that the unique N-terminus of PfORC1 (PfORC1N(1-238)) is targeted to the nuclear periphery in vivo and this region binds to the telomeric DNA in vitro due to the presence of a leucine heptad repeats. Like PfORC1N(1-238), endogenous full length ORC1, was found to be associated with sub telomeric repeat regions and promoters of various var genes. Additionally, binding and propagation of ORC1 to telomeric and subtelomeric regions was severely compromised in PfSir2 deficient parasites suggesting the dependence of endogenous ORC1 on Sir2 for var gene regulation. This feature is not previously described for Plasmodium ORC1 and contrary to yeast Saccharomyces cerevisiae where ORC function as a landing pad for Sir proteins. Interestingly, the overexpression of ORC1N(1-238) compromises the binding of Sir2 at the subtelomeric loci and var gene promoters consistent with de-repression of some var genes. These results establish role of the N-terminus of PfORC1 in heterochromatin formation and regulation of var gene expression in co-ordination with Sir2 in P. falciparum.
Assuntos
Inativação Gênica , Complexo de Reconhecimento de Origem/química , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Telômero/metabolismo , Núcleo Celular/metabolismo , DNA/metabolismo , Dimerização , Complexo de Reconhecimento de Origem/metabolismo , Complexo de Reconhecimento de Origem/fisiologia , Plasmodium falciparum/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Sequências Repetitivas de Aminoácidos , Sequências Repetitivas de Ácido Nucleico , Sirtuína 2/metabolismoRESUMO
Plasmodium falciparum, one of the deadliest parasites on earth causes human malaria resulting one million deaths annually. Central to the parasite pathogenicity and morbidity is the switching of parasite virulence (var) gene expression causing host immune evasion. The regulation of Plasmodium var gene expression is poorly understood. The complex life cycle of Plasmodium and mutually exclusive expression pattern of var genes make this disease difficult to control. Recent studies have demonstrated the pivotal role of epigenetic mechanism for control of coordinated expression of var genes, important for various clinical manifestations of malaria. In this review, we discuss about different Plasmodium histones and their various modifications important for gene expression and gene repression.Contribution of epigenetic mechanism to understand the var gene expression is also highlighted. We also describe in details P. falciparum nuclear architecture including heterochromatin, euchromatin and telomeric regions and their importance in subtelomeric and centrally located var gene expression. Finally, we explore the possibility of using Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC)inhibitors against multi-drug resistance malaria parasites to provide another line of treatment for malaria.
Assuntos
Antimaláricos/uso terapêutico , Epigênese Genética , Regulação da Expressão Gênica , Malária Falciparum/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Acetilação , Animais , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Resistência a Medicamentos/genética , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/virologia , Fenótipo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Processamento de Proteína Pós-Traducional , Virulência/genéticaRESUMO
Drug-resistant Staphylococcus aureus strains are global health concerns. Several studies have shown that these strains can develop defences against cell wall antibiotics such as ß-lactams, glycopeptides and daptomycin which target cell wall biosynthesis. The coordination of these responses have been associated with two component system (TCS) regulated by histidine kinase protein (VraS) and its cognate regulator VraR which influences the target DNA upon signal recognition. Computer-based screening methods, predictions and simulations have emerged as more efficient and quick ways to identify promising new compound leads from large databases against emerging drug targets thus allowing prediction of small select set of molecules for further validations. These combined approaches conserve valuable time and resources. Due to methicillin resistance, sulfonamide-derivative medications have been found to be effective treatment strategy to treat S. aureus infections. The current study used ligand-based virtual screening (LBVS) to identify powerful sulfonamide derivative inhibitors from an antibacterial compound library against VraSR signaling components, VraS and VraR. We identified promising sulfonamide derivative [compound 5: (4-[(1-{[(3,5-Dimethoxyphenyl)Carbamoyl]Methyl}-2,4-Dioxo-1,2,3,4-Tetrahydroquinazolin-3-Yl)Methyl]-N-[(Furan-2-Yl)Methyl]Benzamide)] with reasonable binding parameters of -31.38 kJ/mol and ΔGbind score of -294.32 kJ/mol against ATP binding domain of sensor kinase VraS. We further identified four compounds N1 (PCID83276726), N3 (PCID83276757), N9 (PCID3672584), and N10 (PCID20900589) against VraR DNA binding domain (VraRC) with ΔGbind energies of -190.27, -237.54, -165.21, and -190.88 kJ/mol, respectively. Structural and simulation analyses further suggest their stable interactions with DNA interacting residues and potential to disrupt DNA binding domain dimerization; therefore, it is prudent to further investigate and characterize them as VraR dimer disruptors and inhibit other promoter binding site. Interestingly, the discovery of drugs that target VraS and VraR may open new therapeutic avenues for drug-resistant S. aureus. These predictions based on screening, simulations and binding affinities against VraSR components hold promise for opening novel therapeutic avenues against drug-resistant S. aureus and present opportunities for repositioning efforts. These efforts aim to create analogs with enhanced potency and selectivity against two-component signaling systems that significantly contribute to virulence in MRSA or VRSA. These analyses contribute valuable insights into potential avenues for combating antibiotic-resistant S. aureus through computationally driven drug discovery strategies.Communicated by Ramaswamy H. Sarma.
RESUMO
Two component signaling system ArlRS (Autolysis-related locus) regulates adhesion, biofilm formation and virulence in methicillin resistant Staphylococcus aureus. It consists of a histidine kinase ArlS and response regulator ArlR. ArlR is composed of a N-terminal receiver domain and DNA-binding effector domain at C-terminal. ArlR receiver domain dimerizes upon signal recognition and activates DNA binding by effector domain and subsequent virulence expression. In silico simulation and structural data suggest that coumestrol, a phytochemical found in Pueraria montana, forges a strong intermolecular interaction with residues involved in dimer formation and destabilizes ArlR dimerization, an essential conformational switch required for downstream effector domain to bind to virulent loci. Structural and energy profiles of simulated ArlR-coumestrol complexes suggest lower affinity between ArlR monomers due to structural rigidity at the dimer interface hindering the conformational rearrangements relevant for dimer formation. These analyses could be an attractive strategy to develop therapeutics and potent leads molecules response regulators of two component systems in which are involved in MRSA virulence as well as other drug-resistant pathogens.Communicated by Ramaswamy H. Sarma.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/metabolismo , Virulência , Staphylococcus aureus , Cumestrol/farmacologia , Cumestrol/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas Quinases/metabolismo , DNA/metabolismoRESUMO
Quinoline or 1-aza-naphthalene is a weak tertiary base. Quinoline ring has been found to possess antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti-inflammatory, and analgesic activity. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. The article aims at highlighting these very diversities of the ring.
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Fear of a fresh infection wave and a global health issue in the ongoing COVID-19 pandemic have been rekindled by the appearance of two new novel variants BF.7 and BA.4/5 of Omicron lineages. Predictions of increased antibody evasion capabilities and transmissibility have been recognised in addition to the existing lineages (BA.1.1, BA.2, BA.2.12.1 and BA.3) as cause for worry. In comparison to Omicron, BA.4 and BF.7 share nine mutations in the spike protein, Leu371Phe, Thr376Ala, Asp405Asn, Arg408Ser, Ser446Gly, Leu452Arg, Phe486Val, Arg493Gln, Ser496Gly, whereas BF.7 contains an additional mutation, Arg346Thr, in the receptor binding domain (RBD) region. Due to the critical need for analysis and data on the BA.4 and BF.7 variants, we have computationally analyzed the interaction pattern between the Omicron, BA.4 and BF.7 RBD and angiotensin-converting enzyme 2 (ACE2) to determine the influence of these unique mutations on the structures, functions, and binding affinity of RBD towards ACE2. These analyses also allow to compare molecular models to previously reported data to evaluate the robustness of our methods for quick prediction of emerging future variants. The docking results reveal that BA.4 and BF.7 have particularly strong interactions with ACE2 when compared to Omicron, as shown by several parameters such as salt bridge, hydrogen bond, and non-bonded interactions. In addition, the estimations of binding free energy corroborated the findings further. BA.4 and BF.7 were found to bind to ACE2 with similar affinities (-72.14 and - 71.54 kcal/mol, respectively) and slightly stronger than Omicron (-70.04 kcal/mol). The differences in the binding pattern between the Omicron, BA.4 and BF.7 variant complexes indicated that the BA.4 and BF.7 RBD substitutions Asp405Asn, Ser446Gly, Leu452Arg, Phe486Val and Arg493Gln caused additional interactions with ACE2. In addition, normal mode analyses also indicate more stable conformations of BA.4 and BF.7 RBDs against human ACE2. Based on these structural and simulation analyses, we hypothesized that these changes may affect the binding affinity of BA.4 and BF.7 with ACE2.
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Enzima de Conversão de Angiotensina 2 , COVID-19 , Humanos , Enzima de Conversão de Angiotensina 2/genética , Pandemias , Projetos de Pesquisa , Simulação por Computador , Mutação , Ligação ProteicaRESUMO
Mycobacterium tuberculosis is leading cause of death worldwide. NAD participates in a host of redox reactions in energy landscape of organisms. Several studies implicate surrogate energy pathways involving NAD pools as important in survival of active as well as dormant mycobacteria. One of the NAD metabolic pathway enzyme, nicotinate mononucleotide adenylyltransferase (NadD) is indispensable in mycobacterial NAD metabolism and is perceived as an attractive drug target in pathogen. In this study, we have employed in silico screening, simulation and MM-PBSA strategies to identify potentially important alkaloid compounds against mycobacterial NadD for structure-based inhibitor development. We have performed an exhaustive structure-based virtual screening of an alkaloid library, ADMET, DFT profiling followed by Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation to identify 10 compounds which exhibit favourable drug like properties and interactions. Interaction energies of these 10 alkaloid molecules range between -190 kJ/mol and -250 kJ/mol. These compounds could be promising starting point in the development of selective inhibitors against Mycobacterium tuberculosis.
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Alcaloides , Antineoplásicos , Mycobacterium tuberculosis , NAD , Simulação de Dinâmica Molecular , Alcaloides/farmacologia , Simulação de Acoplamento MolecularRESUMO
Background: Bibliometric analysis is an approach adopted by researchers to understand the various analytics such as year-wise publications, their citations, most impactful authors and their contributions, identification of emerging keywords, multiple themes (niche, motor, basic, and emerging or declining) etc. F1000Research is one of the Q1 category journals that publishes articles in various domains, but a detailed journal analysis is yet to be done. Methods: This study is an effort to extract the F1000Research journey information through bibliometric analysis using VOS-viewer and Biblioshiny (R-studio) interface. The F1000Research journal started its journey in 2012; since then, 5767 articles have been published until the end of 2022. Most of the published articles are from medical science, covering Biochemistry, Genetics & Molecular Biology, Immunology & Pharmacology, Toxicology & Pharmaceutics. To understand the research journey, various analyses such as publication & citation trends, leading authors, institutions, countries, most frequent keywords, bibliographic coupling between authors, countries and documents, emerging research themes, and trending keywords were performed. Results: The United States is the biggest contributor, and COVID-19 is the most commonly occurred keyword. Conclusions: The present study may help future researchers to understand the emerging medical science domain. It will also help the editors and journal to focus more on developing or emerging areas and to understand their importance towards society. Future researchers can contribute their quality research studies, focusing on emerging themes. These authors' research can guide future researchers to develop their research area around the most impacted articles. They can collaborate with them to bring that emerging theme forward.
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COVID-19 , Estados Unidos , Humanos , Bibliometria , PublicaçõesRESUMO
Background and aim: To evaluate the association between severe early childhood caries (S-ECC), dietary preferences, and 2nd digit-4th digit (2D:4D) ratio. The objective is to contrast the detection and prevalence of dental caries in children with different sensitivity levels to the bitter taste of 6-n-propylthiouracil (PROP) and its association with 2D:4D. Materials and methods: A total of 300 children below 71 months of age were assigned to two study groups-group I (caries-free) and group II (caries). PROP sensitivity test was carried out to determine the inherent genetic ability to taste a bitter or sweet substance. Evaluation of dietary preferences was carried out using a food preference questionnaire, which was completed by the parents of the children to know the child's dietary habits and their sweet, sour, and strong taste preferences. The length of the index (2D) and ring (4D) finger was measured with the help of digital vernier caliper to record the 2D:4D ratio. The data obtained was subjected to statistical analysis using Pearson's Chi-squared test and one-way analysis of variance (ANOVA). Results: The results suggested a positive association between S-ECC and dietary preferences but could not establish a straightforward 1:1 relation between 2D:4D ratio and S-ECC. Conclusion: An individual considered as nontaster by PROP test was a sweet liker with low 2D:4D ratio having high caries index. The association between 2D:4D ratio and S-ECC should further be explored by taking other influencing factors into consideration before arriving at a definitive conclusion. How to cite this article: Srivastava SK, Garg N, Pathivada L, et al. Association between Severe Early Childhood Caries, Dietary Preferences, and 2nd Digit-4th Digit (2D:4D) Ratio. Int J Clin Pediatr Dent 2023;16(5):740-744.