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1.
Microbiol Spectr ; : e0231121, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35579429

RESUMO

The modulators of severe COVID-19 have emerged as the most intriguing features of SARS-CoV-2 pathogenesis. This is especially true as we are encountering variants of concern (VOC) with increased transmissibility and vaccination breakthroughs. Microbial co-infections are being investigated as one of the crucial factors for exacerbation of disease severity and complications of COVID-19. A key question remains whether early transcriptionally active microbial signature/s in COVID-19 patients can provide a window for future disease severity susceptibility and outcome? Using complementary metagenomics sequencing approaches, respiratory virus oligo panel (RVOP) and Holo-seq, our study highlights the possible functional role of nasopharyngeal early resident transcriptionally active microbes in modulating disease severity, within recovered patients with sub-phenotypes (mild, moderate, severe) and mortality. The integrative analysis combines patients' clinical parameters, SARS-CoV-2 phylogenetic analysis, microbial differential composition, and their functional role. The clinical sub-phenotypes analysis led to the identification of transcriptionally active bacterial species associated with disease severity. We found significant transcript abundance of Achromobacter xylosoxidans and Bacillus cereus in the mortality, Leptotrichia buccalis in the severe, Veillonella parvula in the moderate, and Actinomyces meyeri and Halomonas sp. in the mild COVID-19 patients. Additionally, the metabolic pathways, distinguishing the microbial functional signatures between the clinical sub-phenotypes, were also identified. We report a plausible mechanism wherein the increased transcriptionally active bacterial isolates might contribute to enhanced inflammatory response and co-infections that could modulate the disease severity in these groups. Current study provides an opportunity for potentially using these bacterial species for screening and identifying COVID-19 patient sub-groups with severe disease outcome and priority medical care. IMPORTANCE COVID-19 is invariably a disease of diverse clinical manifestation, with multiple facets involved in modulating the progression and outcome. In this regard, we investigated the role of transcriptionally active microbial co-infections as possible modulators of disease pathology in hospital admitted SARS-CoV-2 infected patients. Specifically, can there be early nasopharyngeal microbial signatures indicative of prospective disease severity? Based on disease severity symptoms, the patients were segregated into clinical sub-phenotypes: mild, moderate, severe (recovered), and mortality. We identified significant presence of transcriptionally active isolates, Achromobacter xylosoxidans and Bacillus cereus in the mortality patients. Importantly, the bacterial species might contribute toward enhancing the inflammatory responses as well as reported to be resistant to common antibiotic therapy, which together hold potential to alter the disease severity and outcome.

2.
PLoS One ; 17(3): e0264785, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35298502

RESUMO

The variability of clinical course and prognosis of COVID-19 highlights the necessity of patient sub-group risk stratification based on clinical data. In this study, clinical data from a cohort of Indian COVID-19 hospitalized patients is used to develop risk stratification and mortality prediction models. We analyzed a set of 70 clinical parameters including physiological and hematological for developing machine learning models to identify biomarkers. We also compared the Indian and Wuhan cohort, and analyzed the role of steroids. A bootstrap averaged ensemble of Bayesian networks was also learned to construct an explainable model for discovering actionable influences on mortality and days to outcome. We discovered blood parameters, diabetes, co-morbidity and SpO2 levels as important risk stratification features, whereas mortality prediction is dependent only on blood parameters. XGboost and logistic regression model yielded the best performance on risk stratification and mortality prediction, respectively (AUC score 0.83, AUC score 0.92). Blood coagulation parameters (ferritin, D-Dimer and INR), immune and inflammation parameters IL6, LDH and Neutrophil (%) are common features for both risk and mortality prediction. Compared with Wuhan patients, Indian patients with extreme blood parameters indicated higher survival rate. Analyses of medications suggest that a higher proportion of survivors and mild patients who were administered steroids had extreme neutrophil and lymphocyte percentages. The ensemble averaged Bayesian network structure revealed serum ferritin to be the most important predictor for mortality and Vitamin D to influence severity independent of days to outcome. The findings are important for effective triage during strains on healthcare infrastructure.


Assuntos
COVID-19/mortalidade , Hospitalização/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , COVID-19/epidemiologia , COVID-19/etiologia , Criança , China/epidemiologia , Feminino , Humanos , Índia/epidemiologia , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Medição de Risco/métodos , Fatores de Risco , Adulto Jovem
3.
Front Microbiol ; 13: 763169, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308382

RESUMO

Vaccine development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been of primary importance to contain the ongoing global pandemic. However, studies have demonstrated that vaccine effectiveness is reduced and the immune response is evaded by variants of concern (VOCs), which include Alpha, Beta, Delta, and, the most recent, Omicron. Subsequently, several vaccine breakthrough (VBT) infections have been reported among healthcare workers (HCWs) due to their prolonged exposure to viruses at healthcare facilities. We conducted a clinico-genomic study of ChAdOx1 (Covishield) VBT cases in HCWs after complete vaccination. Based on the clinical data analysis, most of the cases were categorized as mild, with minimal healthcare support requirements. These patients were divided into two sub-phenotypes based on symptoms: mild and mild plus. Statistical analysis showed a significant correlation of specific clinical parameters with VBT sub-phenotypes. Viral genomic sequence analysis of VBT cases revealed a spectrum of high- and low-frequency mutations. More in-depth analysis revealed the presence of low-frequency mutations within the functionally important regions of SARS-CoV-2 genomes. Emphasizing the potential benefits of surveillance, low-frequency mutations, D144H in the N gene and D138Y in the S gene, were observed to potentially alter the protein secondary structure with possible influence on viral characteristics. Substantiated by the literature, our study highlights the importance of integrative analysis of pathogen genomic and clinical data to offer insights into low-frequency mutations that could be a modulator of VBT infections.

4.
Brief Funct Genomics ; 21(2): 90-102, 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-34402498

RESUMO

Infectious diseases are potential drivers for human evolution, through a complex, continuous and dynamic interaction between the host and the pathogen/s. It is this dynamic interaction that contributes toward the clinical outcome of a pathogenic disease. These are modulated by contributions from the human genetic variants, transcriptional response (including noncoding RNA) and the pathogen's genome architecture. Modern genomic tools and techniques have been crucial for the detection and genomic characterization of pathogens with respect to the emerging infectious diseases. Aided by next-generation sequencing (NGS), risk stratification of host population/s allows for the identification of susceptible subgroups and better disease management. Nevertheless, many challenges to a general understanding of host-pathogen interactions remain. In this review, we elucidate how a better understanding of the human host-pathogen interplay can substantially enhance, and in turn benefit from, current and future applications of multi-omics based approaches in infectious and rare diseases. This includes the RNA-level response, which modulates the disease severity and outcome. The need to understand the role of human genetic variants in disease severity and clinical outcome has been further highlighted during the Coronavirus disease 2019 (COVID-19) pandemic. This would enhance and contribute toward our future pandemic preparedness.


Assuntos
COVID-19 , COVID-19/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Pandemias
5.
Pathogens ; 10(11)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34832622

RESUMO

Since the time when detection of gene expression in single cells by microarrays to the Next Generation Sequencing (NGS) enabled Single Cell Genomics (SCG), it has played a pivotal role to understand and elucidate the functional role of cellular heterogeneity. Along this journey to becoming a key player in the capture of the individuality of cells, SCG overcame many milestones, including scale, speed, sensitivity and sample costs (4S). There have been many important experimental and computational innovations in the efficient analysis and interpretation of SCG data. The increasing role of AI in SCG data analysis has further enhanced its applicability in building models for clinical intervention. Furthermore, SCG has been instrumental in the delineation of the role of cellular heterogeneity in specific diseases, including cancer and infectious diseases. The understanding of the role of differential immune responses in driving coronavirus disease-2019 (COVID-19) disease severity and clinical outcomes has been greatly aided by SCG. With many variants of concern (VOC) in sight, it would be of great importance to further understand the immune response specificity vis-a-vis the immune cell repertoire, the identification of novel cell types, and antibody response. Given the potential of SCG to play an integral part in the multi-omics approach to the study of the host-pathogen interaction and its outcomes, our review attempts to highlight its strengths, its implications for infectious disease biology, and its current limitations. We conclude that the application of SCG would be a critical step towards future pandemic preparedness.

6.
Front Immunol ; 12: 738093, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777349

RESUMO

Disease caused by SARS-CoV-2 coronavirus (COVID-19) led to significant morbidity and mortality worldwide. A systemic hyper-inflammation characterizes severe COVID-19 disease, often associated with acute respiratory distress syndrome (ARDS). Blood biomarkers capable of risk stratification are of great importance in effective triage and critical care of severe COVID-19 patients. Flow cytometry and next-generation sequencing were done on peripheral blood cells and urokinase-type plasminogen activator receptor (suPAR), and cytokines were measured from and mass spectrometry-based proteomics was done on plasma samples from an Indian cohort of COVID-19 patients. Publicly available single-cell RNA sequencing data were analyzed for validation of primary data. Statistical analyses were performed to validate risk stratification. We report here higher plasma abundance of suPAR, expressed by an abnormally expanded myeloid cell population, in severe COVID-19 patients with ARDS. The plasma suPAR level was found to be linked to a characteristic plasma proteome, associated with coagulation disorders and complement activation. Receiver operator characteristic curve analysis to predict mortality identified a cutoff value of suPAR at 1,996.809 pg/ml (odds ratio: 2.9286, 95% confidence interval 1.0427-8.2257). Lower-than-cutoff suPAR levels were associated with a differential expression of the immune transcriptome as well as favorable clinical outcomes, in terms of both survival benefit (hazard ratio: 0.3615, 95% confidence interval 0.1433-0.912) and faster disease remission in our patient cohort. Thus, we identified suPAR as a key pathogenic circulating molecule linking systemic hyperinflammation to the hypercoagulable state and stratifying clinical outcomes in severe COVID-19 patients with ARDS.


Assuntos
COVID-19/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , SARS-CoV-2 , Adulto , Idoso , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/imunologia , Proteínas Sanguíneas/análise , COVID-19/imunologia , Citocinas/sangue , Humanos , Inflamação/sangue , Inflamação/imunologia , Pessoa de Meia-Idade , Células Mieloides/imunologia , Proteoma/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/imunologia , Índice de Gravidade de Doença , Adulto Jovem
7.
Pathogens ; 10(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34578142

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests a broad spectrum of clinical presentations, varying in severity from asymptomatic to mortality. As the viral infection spread, it evolved and developed into many variants of concern. Understanding the impact of mutations in the SARS-CoV-2 genome on the clinical phenotype and associated co-morbidities is important for treatment and preventionas the pandemic progresses. Based on the mild, moderate, and severe clinical phenotypes, we analyzed the possible association between both, the clinical sub-phenotypes and genomic mutations with respect to the severity and outcome of the patients. We found a significant association between the requirement of respiratory support and co-morbidities. We also identified six SARS-CoV-2 genome mutations that were significantly correlated with severity and mortality in our cohort. We examined structural alterations at the RNA and protein levels as a result of three of these mutations: A26194T, T28854T, and C25611A, present in the Orf3a and N protein. The RNA secondary structure change due to the above mutations can be one of the modulators of the disease outcome. Our findings highlight the importance of integrative analysis in which clinical and genetic components of the disease are co-analyzed. In combination with genomic surveillance, the clinical outcome-associated mutations could help identify individuals for priority medical support.

8.
Nature ; 599(7883): 114-119, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34488225

RESUMO

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.


Assuntos
Evasão da Resposta Imune , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/imunologia , Replicação Viral/imunologia , Anticorpos Neutralizantes/imunologia , Vacinas contra COVID-19/imunologia , Fusão Celular , Linhagem Celular , Feminino , Pessoal de Saúde , Humanos , Índia , Cinética , Masculino , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinação
9.
Front Microbiol ; 12: 664386, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295314

RESUMO

Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.

10.
Front Microbiol ; 12: 653399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122366

RESUMO

Co-infection with ancillary pathogens is a significant modulator of morbidity and mortality in infectious diseases. There have been limited reports of co-infections accompanying SARS-CoV-2 infections, albeit lacking India specific study. The present study has made an effort toward elucidating the prevalence, diversity and characterization of co-infecting respiratory pathogens in the nasopharyngeal tract of SARS-CoV-2 positive patients. Two complementary metagenomics based sequencing approaches, Respiratory Virus Oligo Panel (RVOP) and Holo-seq, were utilized for unbiased detection of co-infecting viruses and bacteria. The limited SARS-CoV-2 clade diversity along with differential clinical phenotype seems to be partially explained by the observed spectrum of co-infections. We found a total of 43 bacteria and 29 viruses amongst the patients, with 18 viruses commonly captured by both the approaches. In addition to SARS-CoV-2, Human Mastadenovirus, known to cause respiratory distress, was present in a majority of the samples. We also found significant differences of bacterial reads based on clinical phenotype. Of all the bacterial species identified, ∼60% have been known to be involved in respiratory distress. Among the co-pathogens present in our sample cohort, anaerobic bacteria accounted for a preponderance of bacterial diversity with possible role in respiratory distress. Clostridium botulinum, Bacillus cereus and Halomonas sp. are anaerobes found abundantly across the samples. Our findings highlight the significance of metagenomics based diagnosis and detection of SARS-CoV-2 and other respiratory co-infections in the current pandemic to enable efficient treatment administration and better clinical management. To our knowledge this is the first study from India with a focus on the role of co-infections in SARS-CoV-2 clinical sub-phenotype.

11.
Brief Funct Genomics ; 20(1): 28-41, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33491070

RESUMO

The human genome has an almost equal distribution of unique and transposable genetic elements. Although at the transcriptome level, a relatively higher contribution from transposable elements derived RNA has been reported. This is further highlighted with evidence from pervasive transcription. Of the total RNA, noncoding RNAs (ncRNAs) are significant contributors to the transcriptome pool with sizeable fraction from repetitive elements of the human genome, inclusive of Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). ncRNAs are increasingly being implicated in diverse functional roles especially during conditions of stress. These stress responses are driven through diverse mediators, inclusive of long and short ncRNAs. ncRNAs such as MALAT1, GAS5, miR-204 and miR-199a-5p have been functionally involved during oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Also, within SINEs, Alu RNAs derived from primate-specific Alu repeats with ~11% human genome contribution, playing a significant role. Pathogenic diseases, including the recent COVID-19, leads to differential regulation of ncRNAs. Although, limited evidence suggests the need for an inquest into the role of ncRNAs in determining the host response towards pathogen challenge.


Assuntos
Infecções/genética , RNA não Traduzido/fisiologia , COVID-19/genética , COVID-19/virologia , Citocinas/fisiologia , Estresse do Retículo Endoplasmático , Interações Hospedeiro-Patógeno , Humanos , Infecções/metabolismo , Elementos Nucleotídeos Longos e Dispersos , Estresse Oxidativo , RNA não Traduzido/genética , SARS-CoV-2/isolamento & purificação , Elementos Nucleotídeos Curtos e Dispersos , Resposta a Proteínas não Dobradas
12.
Vaccines (Basel) ; 10(1)2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-35062715

RESUMO

This study elucidated the clinical, humoral immune response and genomic analysis of vaccine breakthrough (VBT) infections after ChAdOx1 nCoV-19/Covishield vaccine in healthcare workers (HCWs). Amongst 1858 HCWs, 1639 had received either two doses (1346) or a single dose (293) of ChAdOx1 nCoV-19 vaccine. SARS-CoV-2 IgG antibodies and neutralizing antibodies were measured in the vaccinated group and the development of SARS-CoV-2 infection was monitored.Forty-six RT-PCR positive samples from the 203 positive samples were subjected to whole genome sequencing (WGS). Of the 203 (10.92%) infected HCWs, 21.46% (47/219) were non-vaccinated, which was significantly more than 9.52% (156/1639) who were vaccinated and infection was higher in doctors and nurses. Unvaccinated HCWs had 1.57 times higher risk compared to partially vaccinated HCWs and 2.49 times higher risk than those who were fully vaccinated.The partially vaccinated were at higher risk than the fully vaccinated (RR 1.58). Antibody non-response was seen in 3.44% (4/116), low antibody levels in 15.51% (18/116) and medium levels were found in 81.03% (94/116). Fully vaccinated HCWs had a higher antibody response at day 42 than those who were partially vaccinated (8.96 + 4.00 vs. 7.17 + 3.82). Whole genome sequencing of 46 samples revealed that the Delta variant (B.1.617.2) was predominant (69.5%). HCWs who had received two doses of vaccine showed better protection from mild, moderate, or severe infection, with a higher humoral immune response than those who had received a single dose. The genomic analysis revealed the predominance of the Delta variant (B.1.617.2) in the VBT infections.

13.
Front Cell Infect Microbiol ; 11: 783961, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35047415

RESUMO

The global coronavirus disease 2019 (COVID-19) pandemic has demonstrated the range of disease severity and pathogen genomic diversity emanating from a singular virus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2). This diversity in disease manifestations and genomic mutations has challenged healthcare management and resource allocation during the pandemic, especially for countries such as India with a bigger population base. Here, we undertake a combinatorial approach toward scrutinizing the diagnostic and genomic diversity to extract meaningful information from the chaos of COVID-19 in the Indian context. Using methods of statistical correlation, machine learning (ML), and genomic sequencing on a clinically comprehensive patient dataset with corresponding with/without respiratory support samples, we highlight specific significant diagnostic parameters and ML models for assessing the risk of developing severe COVID-19. This information is further contextualized in the backdrop of SARS-CoV-2 genomic features in the cohort for pathogen genomic evolution monitoring. Analysis of the patient demographic features and symptoms revealed that age, breathlessness, and cough were significantly associated with severe disease; at the same time, we found no severe patient reporting absence of physical symptoms. Observing the trends in biochemical/biophysical diagnostic parameters, we noted that the respiratory rate, total leukocyte count (TLC), blood urea levels, and C-reactive protein (CRP) levels were directly correlated with the probability of developing severe disease. Out of five different ML algorithms tested to predict patient severity, the multi-layer perceptron-based model performed the best, with a receiver operating characteristic (ROC) score of 0.96 and an F1 score of 0.791. The SARS-CoV-2 genomic analysis highlighted a set of mutations with global frequency flips and future inculcation into variants of concern (VOCs) and variants of interest (VOIs), which can be further monitored and annotated for functional significance. In summary, our findings highlight the importance of SARS-CoV-2 genomic surveillance and statistical analysis of clinical data to develop a risk assessment ML model.


Assuntos
COVID-19 , SARS-CoV-2 , Genômica , Humanos , Mutação , Medição de Risco
14.
ACS Omega ; 5(27): 16395-16405, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32685802

RESUMO

We report here the preparation of an aminoxy amide-based pseudopeptide-derived building block using furanoid sugar molecules. Through the cyclo-oligomerization reaction, we generate a hybrid triazole/aminoxy amide macrocycle using the as-prepared building block. The novel conformation of the macrocycle has been characterized using NMR and molecular modeling studies, which show a strong resemblance of our synthesized compound to d-,l-α-aminoxy acid-based cyclic peptides that contain uniform backbone chirality. We observe that the macrocycle can efficiently and selectively bind Cl- ion and transport Cl- ion across a lipid bilayer. 1H NMR anion binding studies suggest a coherent relationship between the acidity of aminoxy amide N-H and triazole C-H proton binding strength. Using time-based fluorescence assay, we show that the macrocycle acts as a mobile transporter and follows an antiport mechanism. Our synthesized macrocycle imposes cancer cell death by disrupting ionic homeostasis through Cl- ion transport. The macrocycle induced cytochrome c leakage and changes in mitochondrial membrane potential along with activation of family of caspases, suggesting that the cellular apoptosis occurs through a caspase-dependent intrinsic pathway. The present results suggest the possibility of using the macrocycle as a biological tool of high therapeutic value.

15.
Cerebellum ; 15(2): 213-32, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25823827

RESUMO

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.


Assuntos
Ataxia Cerebelar/fisiopatologia , Cerebelo/fisiopatologia , Consenso , Encefalite/fisiopatologia , Doença de Hashimoto/fisiopatologia , Neuroimunomodulação/fisiologia , Animais , Ataxia Cerebelar/diagnóstico , Glutens/metabolismo , Humanos
16.
Org Lett ; 16(12): 3196-9, 2014 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-24896843

RESUMO

A tandem macro-dimerization reaction via a Cu(I) catalyzed azide/alkyne cycloaddition reaction has been employed to construct triazole/urea based peptidomimetic macrocycles considered as pseudocyclo-ß-peptides. Introduction of one particular chirality in the peptide backbone can alter the conformation as well as nature of self-assembly from cyclic D-,L-,α-peptide to cyclo-ß-peptide. One of them (16a) forms antiparallel dimers while the other (16b) undergoes higher order aggregation to form a nanorod structure.


Assuntos
Alcinos/química , Peptídeos Cíclicos/síntese química , Triazóis/química , Ureia/química , Azidas/química , Cobre/química , Dimerização , Iodetos/química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nanotubos/química , Peptídeos Cíclicos/química , Peptidomiméticos , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
17.
Alzheimer Dis Assoc Disord ; 28(3): 283-90, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24077017

RESUMO

BACKGROUND: The amyloid precursor protein intracellular domain (AICD) is an intrinsically unstructured molecule with functional promiscuity that plays an important role in determining the fate of the neurons during its degeneration. Its association with Alzheimer disease (AD) recently played a key role in propelling scientists to choose AICD as a major molecule of interest. Although several studies have been conducted elucidating AICD's participation in inducing neurodegenerative outcomes in AD condition, much remains to be deciphered regarding the linkage of AICD with cellular pathways in the AD scenario. RESULTS: In the present study, we have pulled down interactors of nonphosphorylated AICD from the cerebrospinal fluid of AD subjects, identified them by matrix assisted laser desorption ionization mass spectrometry, and subsequently studied the differential expression of these interactors in AD and control cases by 2-dimensional difference gel electrophoresis. The study has yielded some AICD-interactors that are differentially expressed in the AD cases and are involved in diverse cellular functions. CONCLUSIONS: This proteomic-based approach highlights the first step in finding the possible cellular pathways engaged in AD pathophysiology on the basis of interaction of one or more of their members with AICD.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/patologia , Western Blotting , Eletroforese em Gel Bidimensional , Feminino , Humanos , Imunoprecipitação , Masculino , Fosforilação , Estrutura Terciária de Proteína , Proteômica , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
18.
Chem Commun (Camb) ; 48(98): 11975-7, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23128360

RESUMO

Two peptidomimetic macrocycles, regioisomeric in terms of the position of triazole/amide, have been synthesized. Both undergo self-assembly in a parallel manner but in solvents of opposite polarity, ascribed to (ß, ß) and (ß-D, ß-L) hydrogen bonding leading to formation of two different unique classes of organic nanostructures.


Assuntos
Compostos Macrocíclicos/síntese química , Peptoides/síntese química , Triazóis/química , Amidas/química , Ligação de Hidrogênio , Compostos Macrocíclicos/química , Modelos Moleculares , Conformação Molecular , Peptoides/química , Estereoisomerismo
19.
J Org Chem ; 77(12): 5399-405, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22647142

RESUMO

Based on "amide-triazole bioequivalence" principle, 1,2,3-triazole-fused chiral medium ring benzo-heterocycles capable of mimicking benzolactams were designed. Their syntheses were accomplished by cycloaddition of different sugar-derived azidoalkynes. While triazole-fused eight-membered benzo-heterocycles were formed by exclusive intramolecuclar [3 + 2] cycloaddition, attempted preparation of seven-membered analogues led to some intermolecular cycloaddition resulting in a dimeric macrocyclic product, in addition to intramolecular cycloaddition furnishing the expected heterocycle.


Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/síntese química , Triazóis/química , Triazóis/síntese química , Ciclização , Estrutura Molecular , Estereoisomerismo
20.
J Assoc Physicians India ; 60: 26-32, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23547410

RESUMO

OBJECTIVE: Measure carotid intima-medial thickness (CIMT), its variability, risk factors, their correlation, in type 2 diabetic (DM), pre-diabetic (PDM) and non-diabetic (NDM) acute strokes. METHODS: Twenty four DM and a matched population of 14 patients each of PDM and NDM strokes were studied. Each group was compared as whole and by gender and stroke segregation. Study parameters were right and left CIMTs (CIMTR, CIMTL), insulin resistance (IR), age, BMI and lipids, correlations between CIMTs and CIMTs with risk markers. RESULTS: CIMTR was higher in DM and PDM compared to NDM, but CIMTLs did not differ. CIMTs were similar in genders and stroke types of each group. The IR was significantly high only in DM. Age and BMI correlations were predominantly positive and lipids variable except in PDM. Age and IR had better impacts on CIMTs in DM while BMI was poor. Females and infarcts had a more congruous CIMT increment in DM and PDM but male and haemorrhage in NDM. CONCLUSION: With similar levels of risk markers, their impacts on the CIMTs are highly variable at various levels of glycaemia. CIMTs were similar in the genders and stroke types of each group, irrespective of the glycemic status. The pre-diabetes group had distinct features.


Assuntos
Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2/complicações , Estado Pré-Diabético/complicações , Acidente Vascular Cerebral/diagnóstico , Adulto , Fatores Etários , Idoso , Biomarcadores/sangue , Glicemia/análise , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/fisiopatologia , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Índia/epidemiologia , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/diagnóstico por imagem , Estado Pré-Diabético/epidemiologia , Valor Preditivo dos Testes , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Ultrassonografia Doppler
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