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1.
Brief Bioinform ; 25(1)2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-38243695

RESUMO

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of muscle disorders including adult and juvenile dermatomyositis, polymyositis, immune-mediated necrotising myopathy and sporadic inclusion body myositis, all of which present with variable symptoms and disease progression. The identification of effective biomarkers for IIMs has been challenging due to the heterogeneity between IIMs and within IIM subgroups, but recent advances in machine learning (ML) techniques have shown promises in identifying novel biomarkers. This paper reviews recent studies on potential biomarkers for IIM and evaluates their clinical utility. We also explore how data analytic tools and ML algorithms have been used to identify biomarkers, highlighting their potential to advance our understanding and diagnosis of IIM and improve patient outcomes. Overall, ML techniques have great potential to revolutionize biomarker discovery in IIMs and lead to more effective diagnosis and treatment.


Assuntos
Doenças Autoimunes , Dermatomiosite , Miosite , Adulto , Humanos , Miosite/diagnóstico , Miosite/terapia , Dermatomiosite/diagnóstico , Biomarcadores , Progressão da Doença
2.
Nat Immunol ; 14(7): 699-705, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23666294

RESUMO

Activating and inhibitory receptors on natural killer (NK) cells have a crucial role in innate immunity, although the basis of the engagement of activating NK cell receptors is unclear. The activating receptor Ly49H confers resistance to infection with murine cytomegalovirus by binding to the 'immunoevasin' m157. We found that m157 bound to the helical stalk of Ly49H, whereby two m157 monomers engaged the Ly49H dimer. The helical stalks of Ly49H lay centrally across the m157 platform, whereas its lectin domain was not required for recognition. Instead, m157 targeted an 'aromatic peg motif' present in stalks of both activating and inhibitory receptors of the Ly49 family, and substitution of this motif abrogated binding. Furthermore, ligation of m157 to Ly49H or Ly49C resulted in intracellular signaling. Accordingly, m157 has evolved to 'tackle the legs' of a family of NK cell receptors.


Assuntos
Infecções por Herpesviridae/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Muromegalovirus/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Motivos de Aminoácidos/imunologia , Sequência de Aminoácidos , Animais , Cristalografia por Raios X , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Dados de Sequência Molecular , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos , Ressonância de Plasmônio de Superfície
3.
Nucleic Acids Res ; 51(14): 7269-7287, 2023 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-37334829

RESUMO

Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.


Assuntos
Microftalmia , Distrofia Muscular Facioescapuloumeral , Humanos , Distrofia Muscular Facioescapuloumeral/genética , Crista Neural/metabolismo , Microftalmia/genética , Eucromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , Músculo Esquelético/metabolismo , Fenótipo , Cromatina/genética
4.
Clin Gastroenterol Hepatol ; 22(3): 552-561.e4, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37871841

RESUMO

BACKGROUND & AIMS: Thermal treatment of the defect margin after endoscopic mucosal resection (EMR) of large nonpedunculated colorectal lesions reduces the recurrence rate. Both snare tip soft coagulation (STSC) and argon plasma coagulation (APC) have been used for thermal margin treatment, but there are few data directly comparing STSC with APC for this indication. METHODS: We performed a randomized 3-arm trial in 9 US centers comparing STSC with APC with no margin treatment (control) of defects after EMR of colorectal nonpedunculated lesions ≥15 mm. The primary end point was the presence of residual lesion at first follow-up. RESULTS: There were 384 patients and 414 lesions randomized, and 308 patients (80.2%) with 328 lesions completed ≥1 follow-up. The proportion of lesions with residual polyp at first follow-up was 4.6% with STSC, 9.3% with APC, and 21.4% with control subjects (no margin treatment). The odds of residual polyp at first follow-up were lower for STSC and APC when compared with control subjects (P = .001 and P = .01, respectively). The difference in odds was not significant between STSC and APC. STSC took less time to apply than APC (median, 3.35 vs 4.08 minutes; P = .019). Adverse event rates were low, with no difference between arms. CONCLUSIONS: In a randomized trial STSC and APC were each superior to no thermal margin treatment after EMR. STSC was faster to apply than APC. Because STSC also results in lower cost and plastic waste than APC (APC requires an additional device), our study supports STSC as the preferred thermal margin treatment after colorectal EMR. (Clinicaltrials.gov, Number NCT03654209.).


Assuntos
Pólipos do Colo , Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Humanos , Pólipos do Colo/patologia , Colonoscopia/métodos , Coagulação com Plasma de Argônio , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/etiologia , Ressecção Endoscópica de Mucosa/métodos
5.
J Autoimmun ; 142: 103150, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38043487

RESUMO

OBJECTIVES: Inclusion body myositis (IBM) is a progressive inflammatory-degenerative muscle disease of older individuals, with some patients producing anti-cytosolic 5'-nucleotidase 1A (NT5C1A, aka cN1A) antibodies. Human Leukocyte Antigens (HLA) is the highest genetic risk factor for developing IBM. In this study, we aimed to further define the contribution of HLA alleles to IBM and the production of anti-cN1A antibodies. METHODS: We HLA haplotyped a Western Australian cohort of 113 Caucasian IBM patients and 112 ethnically matched controls using Illumina next-generation sequencing. Allele frequency analysis and amino acid alignments were performed using the Genentech/MiDAS bioinformatics package. Allele frequencies were compared using Fisher's exact test. Age at onset analysis was performed using the ggstatsplot package. All analysis was carried out in RStudio version 1.4.1717. RESULTS: Our findings validated the independent association of HLA-DRB1*03:01:01 with IBM and attributed the risk to an arginine residue in position 74 within the DRß1 protein. Conversely, DRB4*01:01:01 and DQA1*01:02:01 were found to have protective effects; the carriers of DRB1*03:01:01 that did not possess these alleles had a fourteenfold increased risk of developing IBM over the general Caucasian population. Furthermore, patients with the abovementioned genotype developed symptoms on average five years earlier than patients without. We did not find any HLA associations with anti-cN1A antibody production. CONCLUSIONS: High-resolution HLA sequencing more precisely characterised the alleles associated with IBM and defined a haplotype linked to earlier disease onset. Identification of the critical amino acid residue by advanced biostatistical analysis of immunogenetics data offers mechanistic insights and future directions into uncovering IBM aetiopathogenesis.


Assuntos
Miosite de Corpos de Inclusão , Miosite , Humanos , Miosite de Corpos de Inclusão/genética , Genótipo , Haplótipos , Arginina , Austrália , Antígenos HLA , Cadeias HLA-DRB1/genética , Alelos
6.
Mol Cell Proteomics ; 21(1): 100178, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798331

RESUMO

MS-based immunopeptidomics is maturing into an automatized and high-throughput technology, producing small- to large-scale datasets of clinically relevant major histocompatibility complex (MHC) class I-associated and class II-associated peptides. Consequently, the development of quality control (QC) and quality assurance systems capable of detecting sample and/or measurement issues is important for instrument operators and scientists in charge of downstream data interpretation. Here, we created MhcVizPipe (MVP), a semiautomated QC software tool that enables rapid and simultaneous assessment of multiple MHC class I and II immunopeptidomic datasets generated by MS, including datasets generated from large sample cohorts. In essence, MVP provides a rapid and consolidated view of sample quality, composition, and MHC specificity to greatly accelerate the "pass-fail" QC decision-making process toward data interpretation. MVP parallelizes the use of well-established immunopeptidomic algorithms (NetMHCpan, NetMHCIIpan, and GibbsCluster) and rapidly generates organized and easy-to-understand reports in HTML format. The reports are fully portable and can be viewed on any computer with a modern web browser. MVP is intuitive to use and will find utility in any specialized immunopeptidomic laboratory and proteomics core facility that provides immunopeptidomic services to the community.


Assuntos
Antígenos de Histocompatibilidade Classe I , Software , Peptídeos , Proteômica , Controle de Qualidade
7.
Nucleic Acids Res ; 50(W1): W744-W752, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35524567

RESUMO

In recent years great progress has been made in identification of structural variants (SV) in the human genome. However, the interpretation of SVs, especially located in non-coding DNA, remains challenging. One of the reasons stems in the lack of tools exclusively designed for clinical SVs evaluation acknowledging the 3D chromatin architecture. Therefore, we present TADeus2 a web server dedicated for a quick investigation of chromatin conformation changes, providing a visual framework for the interpretation of SVs affecting topologically associating domains (TADs). This tool provides a convenient visual inspection of SVs, both in a continuous genome view as well as from a rearrangement's breakpoint perspective. Additionally, TADeus2 allows the user to assess the influence of analyzed SVs within flaking coding/non-coding regions based on the Hi-C matrix. Importantly, the SVs pathogenicity is quantified and ranked using TADA, ClassifyCNV tools and sampling-based P-value. TADeus2 is publicly available at https://tadeus2.mimuw.edu.pl.


Assuntos
Cromatina , DNA , Humanos , Cromatina/genética , Cromossomos , Genoma Humano
8.
Ann Surg Oncol ; 30(6): 3681-3689, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36800129

RESUMO

BACKGROUND: Outcomes of unplanned excisions of extremity soft tissue sarcomas (STSE) range from poor to even superior compared with planned excisions in developed countries. However, little is known regarding outcomes in low-to-middle-income countries. This study aimed to determine whether definitively treated STSE patients with a previous unplanned excision have poorer oncologic outcomes compared with those with planned excisions. PATIENTS AND METHODS: Using the database of a single sarcoma practice, we reviewed 148 patients with STSE managed with definitive surgery-78 with previous unplanned excisions (UE) and 70 with planned excisions (PE). RESULTS: Median follow-up was 4.4 years. UE patients had more surgeries overall and plastic reconstructions (P < 0.001). On multivariate analysis, overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were not worse among UE patients compared with PE patients. Negative predictors for LRFS were high tumor grade (P = 0.031) and an R1 surgical margin (P < 0.001). High grade (P <0.001), local recurrence (P = 0.001), and planned excisions (P = 0.009) predicted poorer DMFS, while age over 65 years (P = 0.011) and distant metastasis predicted poorer OS (P < 0.001). CONCLUSIONS: We recommend systematic re-excision for patients with unplanned excisions. Our study shows that STSE patients with UE, when subjected to re-excision with appropriate surgical margins, can achieve oncologic results similar to those for PE patients. However, there is an associated increased number of surgeries and plastic reconstruction for UE patients. This underscores the need, especially in a resource-limited setting, for education and collaborative policies to raise awareness about STSE among patients and physicians.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Idoso , Resultado do Tratamento , Estudos Retrospectivos , Extremidades/cirurgia , Extremidades/patologia , Reoperação , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Margens de Excisão , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/patologia
9.
J Anat ; 243(5): 813-825, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37391270

RESUMO

The locus coeruleus (LC) provides the principal supply of noradrenaline (NA) to the brain, thereby modulating an array of brain functions. The release of NA, and therefore its impact on the brain, is governed by LC neuronal excitability. Glutamatergic axons, from various brain regions, topographically innervate different LC sub-domains and directly alter LC excitability. However, it is currently unclear whether glutamate receptor sub-classes, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, are divergently expressed throughout the LC. Immunohistochemistry and confocal microscopy were used to identify and localise individual GluA subunits in the mouse LC. Whole-cell patch clamp electrophysiology and subunit-preferring ligands were used to assess their impact on LC spontaneous firing rate (FR). GluA1 immunoreactive clusters were associated with puncta immunoreactive for VGLUT2 on somata, and VGLUT1 on distal dendrites. GluA4 was associated with these synaptic markers only in the distal dendrites. No specific signal was detected for the GluA2-3 subunits. The GluA1/2 receptor agonist (S)-CPW 399 increased LC FR, whilst the GluA1/3 receptor antagonist philanthotoxin-74 decreased it. 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), a positive allosteric modulator of GluA3/4 receptors, had no significant effect on spontaneous FR. The data suggest distinct AMPA receptor subunits are targeted to different LC afferent inputs and have contrasting effects on spontaneous neuronal excitability. This precise expression profile could be a mechanism for LC neurons to integrate diverse information contained in various glutamate afferents.

10.
Immunity ; 41(4): 646-56, 2014 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-25367576

RESUMO

Natural killer (NK) cells have been reported to control adaptive immune responses that occur in lymphoid organs at the early stages of immune challenge. The physiological purpose of such regulatory activity remains unclear, because it generally does not confer a survival advantage. We found that NK cells specifically eliminated activated CD4(+) T cells in the salivary gland during chronic murine cytomegalovirus (MCMV) infection. This was dependent on TNF-related apoptosis inducing ligand (TRAIL) expression by NK cells. Although NK cell-mediated deletion of CD4(+) T cells prolonged the chronicity of infection, it also constrained viral-induced autoimmunity. In the absence of this activity, chronic infection was associated with a Sjogren's-like syndrome characterized by focal lymphocytic infiltration into the glands, production of autoantibodies, and reduced saliva and tear secretion. Thus, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.


Assuntos
Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/imunologia , Muromegalovirus/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Transferência Adotiva , Animais , Apoptose/imunologia , Doença Crônica , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/transplante , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Glândulas Salivares/imunologia , Glândulas Salivares/patologia , Glândulas Salivares/virologia
11.
Surg Endosc ; 37(11): 8785-8790, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37580579

RESUMO

BACKGROUND: There is a significant, unmet need for endoscopy services in rural Uganda. With limited diagnostic and therapeutic interventions, patients in these communities often present with advanced disease. Practicing surgeons must continually adapt to new techniques to meet the needs of their patient populations. Here, we present a remotely proctored endoscopy training program for a surgeon practicing in an area devoid of endoscopic capabilities. METHODS: This was a retrospective case series conducted between February 2020 and December 2022 at Kyabirwa Surgical Center (KSC). After a 1-week in-person training camp, one surgeon performed endoscopy under guidance of a remote proctor. Patient data and outcomes were collected retrospectively. RESULTS: The previously endoscopic naïve practicing Ugandan surgeon was remotely proctored for 139 endoscopic cases and he subsequently independently performed 167 diagnostic colonoscopies and 425 upper endoscopies. Therapeutic endoscopy was conducted under remote guidance after proficiency in diagnostic endoscopy. A total of 43 therapeutic procedures were performed, including 29 esophageal stent placements, 5 variceal bandings, and 9 foreign body retrievals. All procedures were completed without complication. CONCLUSION: Our center developed a remotely proctored endoscopy program that allowed for training of practicing surgeons in an area lacking endoscopic services. Despite its limitations, remotely proctored endoscopy serves as a unique but highly valuable method of expanding access to endoscopy, particularly in areas that lack adequate training opportunities.


Assuntos
Endoscopia Gastrointestinal , Cirurgiões , Masculino , Humanos , Estudos Retrospectivos , Uganda , Endoscopia/educação , Colonoscopia
12.
Proc Natl Acad Sci U S A ; 117(41): 25344-25351, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-32989149

RESUMO

The large concentrations of ultrafine particles consistently observed at high altitudes over the tropics represent one of the world's largest aerosol reservoirs, which may be providing a globally important source of cloud condensation nuclei. However, the sources and chemical processes contributing to the formation of these particles remain unclear. Here we investigate new particle formation (NPF) mechanisms in the Amazon free troposphere by integrating insights from laboratory measurements, chemical transport modeling, and field measurements. To account for organic NPF, we develop a comprehensive model representation of the temperature-dependent formation chemistry and thermodynamics of extremely low volatility organic compounds as well as their roles in NPF processes. We find that pure-organic NPF driven by natural biogenic emissions dominates in the uppermost troposphere above 13 km and accounts for 65 to 83% of the column total NPF rate under relatively pristine conditions, while ternary NPF involving organics and sulfuric acid dominates between 8 and 13 km. The large organic NPF rates at high altitudes mainly result from decreased volatility of organics and increased NPF efficiency at low temperatures, somewhat counterbalanced by a reduced chemical formation rate of extremely low volatility organic compounds. These findings imply a key role of naturally occurring organic NPF in high-altitude preindustrial environments and will help better quantify anthropogenic aerosol forcing from preindustrial times to the present day.

13.
Genome Res ; 29(10): 1622-1634, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537639

RESUMO

How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in humans and other animals are strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene-gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene bodies and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand-specific non-CpG methylation, its dynamic regulation, and its impact on the polycistronic mitochondrial transcript processing.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , DNA Mitocondrial/genética , Epigenoma/genética , Animais , Ilhas de CpG/genética , DNA Metiltransferase 3A , Regulação da Expressão Gênica/genética , Humanos , Mitocôndrias/genética
14.
Cell Mol Neurobiol ; 42(7): 2357-2377, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34101068

RESUMO

Duchenne muscular dystrophy (DMD) patients, having mutations of the DMD gene, present with a range of neuropsychiatric disorders, in addition to the quintessential muscle pathology. The neurobiological basis remains poorly understood because the contributions of different DMD gene products (dystrophins) to the different neural networks underlying such symptoms are yet to be fully characterised. While full-length dystrophin clusters in inhibitory synapses, with inhibitory neurotransmitter receptors, the precise subcellular expression of truncated DMD gene products with excitatory synapses remains unresolved. Furthermore, inflammation, involving P2X purinoceptor 7 (P2RX7) accompanies DMD muscle pathology, yet any association with brain dystrophins is yet to be established. The aim of this study was to investigate the comparative expression of different dystrophins, alongside ionotropic glutamate receptors and P2RX7s, within the cerebellar circuitry known to express different dystrophin isoforms. Immunoreactivity for truncated DMD gene products was targeted to Purkinje cell (PC) distal dendrites adjacent to, or overlapping with, signal for GluA1, GluA4, GluN2A, and GluD2 receptor subunits. P2X7R immunoreactivity was located in Bergmann glia profiles adjacent to PC-dystrophin immunoreactivity. Ablation of all DMD gene products coincided with decreased mRNA expression for Gria2, Gria3, and Grin2a and increased GluD2 immunoreactivity. Finally, dystrophin-null mice showed decreased brain mRNA expression of P2rx7 and several inflammatory mediators. The data suggest that PCs target different dystrophin isoforms to molecularly and functionally distinct populations of synapses. In contrast to muscle, dystrophinopathy in brain leads to the dampening of the local immune system.


Assuntos
Distrofina , Receptores Purinérgicos P2X7 , Animais , Cerebelo , Mediadores da Inflamação , Camundongos , Camundongos Endogâmicos mdx , Isoformas de Proteínas , RNA Mensageiro , Sinapses
15.
Surg Endosc ; 36(12): 9123-9128, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35920904

RESUMO

BACKGROUND: The introduction of new technologies in endoscopy has been met with uncertainty, skepticism, and lack of standardization or training parameters, particularly when disruptive devices or techniques are involved. The widespread availability of a novel endoscopic suturing device (OverStitch™) for tissue apposition has enabled the development of applications of endoscopic suturing. METHODS: The American Gastroenterological Association partnered with Apollo Endosurgery to develop a registry to capture in a pragmatic non-randomized study the safety, effectiveness, and durability of endoscopic suturing in approximating tissue in the setting of bariatric revision and fixation of endoprosthetic devices. RESULTS: We highlight the challenges of the adoption of novel techniques by examining the process of developing and executing this multicenter registry to assess real-world use of this endoscopic suturing device. We also present our preliminary data on the safety and effectiveness of the novel device as it is applied in the treatment of obesity. CONCLUSIONS: The Prospective Registry for Trans-Orifice Endoscopic Suturing Applications (ES Registry) was an effective Phase 4, postmarketing registry aimed at capturing pragmatic, real-world use of a novel device. These findings serve to solidify the role of endoscopic suturing in clinical practice.


Assuntos
Técnicas de Sutura , Suturas , Humanos , Endoscopia Gastrointestinal/métodos , Obesidade , Sistema de Registros
16.
Mol Cell Proteomics ; 19(1): 31-49, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31744855

RESUMO

The science that investigates the ensembles of all peptides associated to human leukocyte antigen (HLA) molecules is termed "immunopeptidomics" and is typically driven by mass spectrometry (MS) technologies. Recent advances in MS technologies, neoantigen discovery and cancer immunotherapy have catalyzed the launch of the Human Immunopeptidome Project (HIPP) with the goal of providing a complete map of the human immunopeptidome and making the technology so robust that it will be available in every clinic. Here, we provide a long-term perspective of the field and we use this framework to explore how we think the completion of the HIPP will truly impact the society in the future. In this context, we introduce the concept of immunopeptidome-wide association studies (IWAS). We highlight the importance of large cohort studies for the future and how applying quantitative immunopeptidomics at population scale may provide a new look at individual predisposition to common immune diseases as well as responsiveness to vaccines and immunotherapies. Through this vision, we aim to provide a fresh view of the field to stimulate new discussions within the community, and present what we see as the key challenges for the future for unlocking the full potential of immunopeptidomics in this era of precision medicine.


Assuntos
Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/química , Peptídeos/imunologia , Alelos , Estudos de Coortes , Humanos , Imunoterapia , Infecções/diagnóstico , Infecções/terapia , Espectrometria de Massas , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisão , Prognóstico
17.
J Public Health (Oxf) ; 44(1): e141-e148, 2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-33140080

RESUMO

BACKGROUND: The Canadian province of Alberta released the ABTraceTogether smartphone app in May 2020 to assist in contact tracing during the SARS-CoV-2 pandemic. Public engagement with this public health tool has been low, limiting the effectiveness of the intervention. This study examines physician knowledge of the app and practice patterns in relation to the app. METHODS: We conducted a cross-sectional self-administered online English language survey of physicians and medical students in Alberta, Canada. The survey link was sent to all registered members of the College of Physicians and Surgeons of Alberta and was distributed by other provincial physician organizations and health zone leaders. RESULTS: The survey received 317 responses. 96% of participants were aware of the app but only 27% had recommended the app to patients. The most common reason provided for not downloading or recommending the app was that participants had security concerns about the app. 23% of participants indicated they did not believe they had a responsibility to recommend the app to others. CONCLUSIONS: Our study provides insights into participants' knowledge and beliefs about the ABTraceTogether app. This information may be valuable to public health officials who wish to engage physicians in future public health campaigns.


Assuntos
COVID-19 , Aplicativos Móveis , Médicos , Alberta , COVID-19/epidemiologia , Busca de Comunicante , Estudos Transversais , Humanos , SARS-CoV-2 , Inquéritos e Questionários
18.
J Nurs Scholarsh ; 54(6): 772-786, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35607898

RESUMO

INTRODUCTION: COVID-19 can be considered a unique and complex form of trauma with potentially devastating consequences for nurses in general and new nurses specifically. Few studies have been published that explain how relatively new nurses were prepared for COVID-19 in terms of knowledge and skill and how these nurses fared physically and emotionally. DESIGN: A qualitative descriptive design utilizing purposive sampling to recruit a diverse group of nurses who were within 2 years post-graduation from nursing school. METHODS: In-depth interviews of 29 nurses were conducted using a semi-structured interview guide to elicit data, which was coded and analyzed using thematic analysis. RESULTS: Six main themes and multiple subthemes were identified in the data. The main themes were: "We were not prepared," "I was just thrown in," "Avoiding infection," "It was so sad," "We did the best we could," and "I learned so much." CONCLUSION: The nurses who participated in this study expressed fear, weariness, exhaustion, isolation, and distress, observations echoed by studies from other countries. Retention of new nurses in acute care settings has always been a concern. In the recent Current Population Survey, a 4% reduction in nurses under 35 years of age has been reported, imperiling the retention of an effective workforce for decades to come. CLINICAL RELEVANCE: A recent report suggests that a larger than expected number of young nurses have left the profession in the wake of the pandemic. Staff shortages threaten the ability of the remaining nurses to do their jobs. This is the time to listen to the needs of new nurses to retain them in the profession and to avoid an even greater shortage in the near future.


Assuntos
COVID-19 , Enfermeiras e Enfermeiros , Humanos , COVID-19/epidemiologia , COVID-19/enfermagem , Enfermeiras e Enfermeiros/psicologia , Enfermeiras e Enfermeiros/estatística & dados numéricos , Pandemias , Pesquisa Qualitativa , Mão de Obra em Saúde
19.
Genes Dev ; 28(22): 2464-76, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25403178

RESUMO

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for "telomere position effect over long distances." Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.


Assuntos
Regulação da Expressão Gênica , Encurtamento do Telômero/genética , Telômero/genética , Telômero/metabolismo , Células Cultivadas , Cromatina/metabolismo , Perfilação da Expressão Gênica , Humanos , Mioblastos/citologia
20.
Arch Psychiatr Nurs ; 40: 77-83, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36064249

RESUMO

PURPOSE: Stigmatized attitudes towards people with mental illness from healthcare providers continues to be a problem affecting recovery in people with mental illness. The process of recovery was explored through digital stories created by service users, with support from nursing students. Stigmatized attitudes in nursing students and stigma resistance in service users were also investigated. DESIGN AND METHODS: A quasi-experimental, mixed-methods, pilot study in which service users/nursing student teams created digital stories. Surveys testing stigmatized attitudes and stigma resistance were employed. FINDINGS: Statistical significance was not found, however, qualitative analysis revealed recovery elements and greater appreciation of individuals with mental illness by the nursing students. PRACTICE IMPLICATIONS: Digital story-telling assists service users in doing the internal work of making meaning from experience. Nursing students benefit from involvement in the activity.


Assuntos
Transtornos Mentais , Recuperação da Saúde Mental , Estudantes de Enfermagem , Atitude do Pessoal de Saúde , Humanos , Transtornos Mentais/psicologia , Projetos Piloto , Estigma Social , Estudantes de Enfermagem/psicologia
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