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Neuroimaging, across positron emission tomography (PET), electroencephalography (EEG), and magnetic resonance imaging (MRI), has been a mainstay of clinical neuroscience research for decades, yet has penetrated little into psychiatric drug development beyond often underpowered phase 1 studies, or into clinical care. Simultaneously, there is a pressing need to improve the probability of success in drug development, increase mechanistic diversity, and enhance clinical efficacy. These goals can be achieved by leveraging neuroimaging in a precision psychiatry framework, wherein effects of drugs on the brain are measured early in clinical development to understand dosing and indication, and then in later-stage trials to identify likely drug responders and enrich clinical trials, ultimately improving clinical outcomes. Here we examine the key variables important for success in using neuroimaging for precision psychiatry from the lens of biotechnology and pharmaceutical companies developing and deploying new drugs in psychiatry. We argue that there are clear paths for incorporating different neuroimaging modalities to de-risk subsequent development phases in the near to intermediate term, culminating in use of select neuroimaging modalities in clinical care for prescription of new precision drugs. Better outcomes through neuroimaging biomarkers, however, require a wholesale commitment to a precision psychiatry approach and will necessitate a cultural shift to align biopharma and clinical care in psychiatry to a precision orientation already routine in other areas of medicine.
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Translational control in pathogenic bacteria is fundamental to gene expression and affects virulence and other infection phenotypes. We used an enhanced ribosome profiling protocol coupled with parallel transcriptomics to capture accurately the global translatome of two evolutionarily distant pathogenic bacteria-the Gram-negative bacterium Salmonella and the Gram-positive bacterium Listeria. We find that the two bacteria use different mechanisms to translationally regulate protein synthesis. In Salmonella, in addition to the expected correlation between translational efficiency and cis-regulatory features such as Shine-Dalgarno (SD) strength and RNA secondary structure around the initiation codon, our data reveal an effect of the 2nd and 3rd codons, where the presence of tandem lysine codons (AAA-AAA) enhances translation in both Salmonella and E. coli. Strikingly, none of these features are seen in efficiently translated Listeria transcripts. Instead, approximately 20% of efficiently translated Listeria genes exhibit 70 S footprints seven nt upstream of the authentic start codon, suggesting that these genes may be subject to a novel translational initiation mechanism. Our results show that SD strength is not a direct hallmark of translational efficiency in all bacteria. Instead, Listeria has evolved additional mechanisms to control gene expression level that are distinct from those utilised by Salmonella and E. coli.
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Listeria , Biossíntese de Proteínas , Biossíntese de Proteínas/genética , Escherichia coli/genética , Escherichia coli/metabolismo , RNA Mensageiro/metabolismo , Listeria/genética , Códon/metabolismo , Códon de Iniciação/metabolismo , Bactérias/genética , Iniciação Traducional da Cadeia Peptídica/genéticaRESUMO
BACKGROUND: The genomes of indigenous African cattle are composed of components with Middle Eastern (taurine) and South Asian (indicine) origins, providing a valuable model to study hybridization and to identify genetic barriers to gene flow. In this study, we analysed indigenous African cattle breeds as models of hybrid zones, considering taurine and indicine samples as ancestors. In a genomic cline analysis of whole-genome sequence data, we considered over 8 million variants from 144 animals, which allows for fine-mapping of potential genomic incompatibilities at high resolution across the genome. RESULTS: We identified several thousand variants that had significantly steep clines ('SCV') across the whole genome, indicating restricted introgression. Some of the SCV were clustered into extended regions, with the longest on chromosome 7, spanning 725 kb and including 27 genes. We found that variants with a high phenotypic impact (e.g. indels, intra-genic and missense variants) likely represent greater genetic barriers to gene flow. Furthermore, our findings provide evidence that a large proportion of breed differentiation in African cattle could be linked to genomic incompatibilities and reproductive isolation. Functional evaluation of genes with SCV suggest that mitonuclear incompatibilities and genes associated with fitness (e.g. resistance to paratuberculosis) could account for restricted gene flow in indigenous African cattle. CONCLUSIONS: To our knowledge, this is the first time genomic cline analysis has been applied to identify restricted introgression in the genomes of indigenous African cattle and the results provide extended insights into mechanisms (e.g. genomic incompatibilities) contributing to hybrid differentiation. These results have important implications for our understanding of genetic incompatibilities and reproductive isolation and provide important insights into the impact of cross-breeding cattle with the aim of producing offspring that are both hardy and productive.
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Genoma , Genômica , Animais , Bovinos/genética , Hibridização Genética , Fluxo Gênico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Understanding the variation between well and poorly adapted cattle breeds to local environments and pathogens is essential for breeding cattle with improved climate and disease-resistant phenotypes. Although considerable progress has been made towards identifying genetic differences between breeds, variation at the epigenetic and chromatin levels remains poorly characterized. Here, we generate, sequence and analyse over 150 libraries at base-pair resolution to explore the dynamics of DNA methylation and chromatin accessibility of the bovine immune system across three distinct cattle lineages. RESULTS: We find extensive epigenetic divergence between the taurine and indicine cattle breeds across immune cell types, which is linked to the levels of local DNA sequence divergence between the two cattle sub-species. The unique cell type profiles enable the deconvolution of complex cellular mixtures using digital cytometry approaches. Finally, we show distinct sub-categories of CpG islands based on their chromatin and methylation profiles that discriminate between classes of distal and gene proximal islands linked to discrete transcriptional states. CONCLUSIONS: Our study provides a comprehensive resource of DNA methylation, chromatin accessibility and RNA expression profiles of three diverse cattle populations. The findings have important implications, from understanding how genetic editing across breeds, and consequently regulatory backgrounds, may have distinct impacts to designing effective cattle epigenome-wide association studies in non-European breeds.
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Cromatina , Epigenoma , Animais , Bovinos/genética , Fenótipo , Ilhas de CpG , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Marine Spatial Planning (MSP) provides a process that uses spatial data and models to evaluate environmental, social, economic, cultural, and management trade-offs when siting (i.e., strategically locating) ocean industries. Aquaculture is the fastest-growing food sector in the world. The United States (U.S.) has substantial opportunity for offshore aquaculture development given the size of its exclusive economic zone, habitat diversity, and variety of candidate species for cultivation. However, promising aquaculture areas overlap many protected species habitats. Aquaculture siting surveys, construction, operations, and decommissioning can alter protected species habitat and behavior. Additionally, aquaculture-associated vessel activity, underwater noise, and physical interactions between protected species and farms can increase the risk of injury and mortality. In 2020, the U.S. Gulf of Mexico was identified as one of the first regions to be evaluated for offshore aquaculture opportunities as directed by a Presidential Executive Order. We developed a transparent and repeatable method to identify aquaculture opportunity areas (AOAs) with the least conflict with protected species. First, we developed a generalized scoring approach for protected species that captures their vulnerability to adverse effects from anthropogenic activities using conservation status and demographic information. Next, we applied this approach to data layers for eight species listed under the Endangered Species Act, including five species of sea turtles, Rice's whale, smalltooth sawfish, and giant manta ray. Next, we evaluated four methods for mathematically combining scores (i.e., Arithmetic mean, Geometric mean, Product, Lowest Scoring layer) to generate a combined protected species data layer. The Product approach provided the most logical ordering of, and the greatest contrast in, site suitability scores. Finally, we integrated the combined protected species data layer into a multi-criteria decision-making modeling framework for MSP. This process identified AOAs with reduced potential for protected species conflict. These modeling methods are transferable to other regions, to other sensitive or protected species, and for spatial planning for other ocean-uses.
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Ecossistema , Elasmobrânquios , Animais , Aquicultura , Conservação dos Recursos Naturais/métodos , Espécies em Perigo de Extinção , Golfo do MéxicoRESUMO
East Coast fever, a tick-borne cattle disease caused by the Theileria parva parasite, is among the biggest natural killers of cattle in East Africa, leading to over 1 million deaths annually. Here we report on the genetic analysis of a cohort of Bos indicus (Boran) cattle demonstrating heritable tolerance to infection with T. parva (h2 = 0.65, s.e. 0.57). Through a linkage analysis we identify a 6 Mb genomic region on bovine chromosome 15 that is significantly associated with survival outcome following T. parva exposure. Testing this locus in an independent cohort of animals replicates this association with survival following T. parva infection. A stop gained variant in a paralogue of the FAF1 gene in this region was found to be highly associated with survival across both related and unrelated animals, with only one of the 20 homozygote carriers (T/T) of this change succumbing to the disease in contrast to 44 out of 97 animals homozygote for the reference allele (C/C). Consequently, we present a genetic locus linked to tolerance of one of Africa's most important cattle diseases, raising the promise of marker-assisted selection for cattle that are less susceptible to infection by T. parva.
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Doenças dos Bovinos , Theileria parva , Theileria , Theileriose , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Animais , Proteínas Reguladoras de Apoptose/genética , Bovinos , Doenças dos Bovinos/genética , Humanos , Theileria/genética , Theileria parva/genética , Theileriose/genética , Theileriose/parasitologiaRESUMO
Objective: To provide normative data and examine form equivalency of the Brief Visuospatial Memory Test-Revised (BVMT-R) in a sample of 9th decade adults. Method: The sample was comprised of 90 healthy individuals ages 80-84 (n = 42) and 85-89 (n = 48). The average years of education was 14.8 (2.4). The BVMT-R Forms 1 and 4 were administered in a counterbalanced order, one week apart. Form equivalency was conducted utilizing Analysis of Variance (ANOVA). Results: There were no significant gender, education, or MMSE differences between the two age groups or between the counterbalanced subgroups. There were no significant differences between Forms 1 and 4 for the 80-84 age group. However, BVMT-R Form 1 Trial 1 and Total Recall raw scores were significantly higher than those for Form 4 in the 85-89 age group. Conclusions: Individuals in their early 80s obtained comparable scores on Forms 1 and 4 of the BVMT-R; however, individuals in their late 80 s showed more difficulty learning and recalling information presented in Form 4 compared to Form 1. It is recommended that clinicians consider form-specific normative data with this population.
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Memória , Rememoração Mental , Adulto , Idoso de 80 Anos ou mais , Cognição , Humanos , Testes NeuropsicológicosRESUMO
The CD4+/CD8+ ratio is used as a marker of the immune regulation of T cell balance. When the ratio in peripheral blood is less than 1, this is considered an indication of immune suppression in an individual. Previous work on bovine Peripheral Blood Mononuclear Cells (PBMC) has consistently reported a ratio ≥1 as seen in other mammalian hosts, i.e. higher circulating CD4+ cell numbers than CD8+ cell numbers. However, a consistent inverted CD4+/CD8+ ratio (<1) was observed in Boran cattle, an African Bos indicus breed. The T cell populations were characterized in Boran cattle (nâ¯=â¯52), revealing higher percentages of circulating CD8+ cells (31.9 % average) than CD4+ cells (19.1 % average), thus resulting in the inversion of the expected T cell homeostasis in these animals. The results show that this inversion is not an effect of age or relatedness of the cattle, rather, it was shared by almost all Boran cattle used in this study. Despite this inversion being a feature shared by both males and females, the female cattle had significantly higher CD4+/CD8+ ratios than the male Boran. This paper describes the characteristics of the T cell fractions in the study animals and compares the findings to those of other Boran cattle in Kenya, and four other cattle breeds representing African indicine, African taurine, Brazilian indicine and European taurine cattle. We demonstrate that the consistent observation of inverted CD4+/CD8+ cell ratio was restricted to the Boran.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Bovinos/imunologia , Animais , Peso Corporal , Contagem de Células , Feminino , Quênia , Leucócitos Mononucleares/imunologia , MasculinoRESUMO
Invasive streptococcal disease (ISD) and toxic shock syndrome (STSS) result in over 160,000 deaths each year. We modelled these in HLA-transgenic mice infected with a clinically lethal isolate expressing Streptococcal pyrogenic exotoxin (Spe) C and demonstrate that both SpeC and streptococcal M protein, acting cooperatively, are required for disease. Vaccination with a conserved M protein peptide, J8, protects against STSS by causing a dramatic reduction in bacterial burden associated with the absence of SpeC and inflammatory cytokines in the blood. Furthermore, passive immunotherapy with antibodies to J8 quickly resolves established disease by clearing the infection and ablating the inflammatory activity of the M protein, which is further enhanced by addition of SpeC antibodies. Analysis of 77 recent isolates of Streptococcus pyogenes causing ISD, demonstrated that anti-J8 antibodies theoretically recognize at least 73, providing strong support for using antibodies to J8, with or without antibodies to SpeC, as a therapeutic approach.
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Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Exotoxinas/imunologia , Antígenos HLA/imunologia , Choque Séptico/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Superantígenos/imunologia , Animais , Antígenos HLA/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Choque Séptico/genética , Infecções Estreptocócicas/genéticaRESUMO
This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I-olfactory bulb only; 15.4% IIa-brainstem predominant; 13.6% IIb-limbic predominant; 31.8% III-brainstem and limbic; and 30.7% IV-neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.
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Encéfalo/patologia , Disfunção Cognitiva/diagnóstico , Corpos de Lewy/patologia , Doença por Corpos de Lewy/diagnóstico , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Masculino , Índice de Gravidade de DoençaRESUMO
Cardiac rehabilitation has significant benefits for patients with cardiovascular disease in terms of physical health and psychosocial well-being. Comprehensive cardiac rehabilitation programmes comprise graduated exercise, health education, psychological support, advice on preventive medicines, and stress management. However, service provision in the UK is inconsistent. Not all eligible patients are referred to cardiac rehabilitation programmes, and there are inequities in patient access linked to socio-economic status, gender, ethnic background, mental health issues, age and frailty. A person-centred approach would improve equity of access to cardiac rehabilitation programmes and ensure that all patients receive a programme of cardiac rehabilitation that is tailored to their needs and preferences. This article outlines the core components of a cardiac rehabilitation programme, discusses inequities in patient access, and suggests person-centred approaches that nurses can use in cardiac rehabilitation and other healthcare settings.
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Reabilitação Cardíaca , Reabilitação Cardíaca/estatística & dados numéricos , Aconselhamento , Exercício Físico , Acessibilidade aos Serviços de Saúde , Humanos , Reino UnidoRESUMO
BACKGROUND: The continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has thus far been disappointing, sparking renewed interest in the whole parasite vaccine approach. We previously showed that a chemically attenuated whole parasite asexual blood-stage vaccine induced CD4+ T cell-dependent protection against challenge with homologous and heterologous parasites in rodent models of malaria. METHODS: In this current study, we evaluated the immunogenicity and safety of chemically attenuated asexual blood-stage Plasmodium falciparum (Pf) parasites in eight malaria-naïve human volunteers. Study participants received a single dose of 3 × 107 Pf pRBC that had been treated in vitro with the cyclopropylpyrolloindole analogue, tafuramycin-A. RESULTS: We demonstrate that Pf asexual blood-stage parasites that are completely attenuated are immunogenic, safe and well tolerated in malaria-naïve volunteers. Following vaccination with a single dose, species and strain transcending Plasmodium-specific T cell responses were induced in recipients. This included induction of Plasmodium-specific lymphoproliferative responses, T cells secreting the parasiticidal cytokines, IFN-γ and TNF, and CD3+CD45RO+ memory T cells. Pf-specific IgG was not detected. CONCLUSIONS: This is the first clinical study evaluating a whole parasite blood-stage malaria vaccine. Following administration of a single dose of completely attenuated Pf asexual blood-stage parasites, Plasmodium-specific T cell responses were induced while Pf-specific antibodies were not detected. These results support further evaluation of this chemically attenuated vaccine in humans. TRIAL REGISTRATION: Trial registration: ACTRN12614000228684 . Registered 4 March 2014.
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Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Vacinas Atenuadas/imunologia , Adulto , Animais , Anticorpos Antiprotozoários/imunologia , Humanos , Imunidade Celular/imunologia , Masculino , Projetos Piloto , Plasmodium falciparum/imunologia , Linfócitos T/imunologia , Vacinação/métodosRESUMO
Peptide-based vaccines have the potential to overcome the limitations of classical vaccines; however, their use is hampered by a lack of carriers and adjuvants suitable for human use. In this study, an efficient self-adjuvanting peptide vaccine delivery system was developed based on the ionic interactions between cationic trimethyl chitosan (TMC) and a peptide antigen coupled with synthetically defined anionic α-poly-(l-glutamic acid) (PGA). The antigen, possessing a conserved B-cell epitope derived from the group A streptococcus (GAS) pathogen and a universal T-helper epitope, was conjugated to PGA using cycloaddition reaction. The produced anionic conjugate formed nanoparticles (NP-1) through interaction with cationic TMC. These NP-1 induced higher systemic and mucosal antibody titers compared to antigen adjuvanted with standard mucosal adjuvant cholera toxin B subunit or antigen mixed with TMC. The produced serum antibodies were also opsonic against clinically isolated GAS strains. Further, a reduction in bacterial burden was observed in nasal secretions, pharyngeal surface and nasopharyngeal-associated lymphoid tissue of mice immunized with NP-1 in GAS challenge studies. Thus, conjugation of defined-length anionic polymer to peptide antigen as a means of formulating ionic interaction-based nanoparticles with cationic polymer is a promising strategy for peptide antigen delivery. STATEMENT OF SIGNIFICANCE: A self-adjuvanting delivery system is required for peptide vaccines to enhance antigen delivery to immune cells and generate systemic and mucosal immunity. Herein, we developed a novel self-adjuvanting nanoparticulate delivery system for peptide antigens by combining polymer-conjugation and complexation strategies. We conjugated peptide antigen with anionic α-poly-(l-glutamic acid) that in turn, formed nanoparticles with cationic trimethyl chitosan by ionic interactions, without using external crosslinker. On intranasal administration to mice, these nanoparticles induced systemic and mucosal immunity, at low dose. Additionally, nanoparticles provided protection to vaccinated mice against group A streptococcus infection. Thus, this concept should be particularly useful in developing nanoparticles for the delivery of peptide antigens.
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Quitosana/química , Imunidade , Nanopartículas/administração & dosagem , Ácido Poliglutâmico/química , Streptococcus pyogenes/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Administração Intranasal , Animais , Anticorpos Antibacterianos/imunologia , Formação de Anticorpos , Diferenciação Celular , Quitosana/síntese química , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Proteínas Opsonizantes/metabolismo , Ácido Poliglutâmico/síntese química , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/prevenção & controleRESUMO
BACKGROUND: The closure of obstetrics (OB) units at rural hospitals is thought to have implications for access to prenatal care (PNC) and infant mortality rate (IMR). The objective of this study was to determine whether local availability of PNC and OB services, specifically as provided by family physicians (FPs), would be associated with a lower IMR in 1 rural Alabama county. METHODS: Data from 1986 to 2013 from Pickens County was compared with data from 2 sets of control counties: Clarke/Monroe (full OB care) and Coosa/Conecuh (no local OB care). RESULTS: From 1986 to 1991 (no local OB services; period 1), Pickens County's IMR was 17.9, which fell to 7.2 from 1993 to 2001 (with local services; period 2). After the county's OB unit closed, IMR rose to 16.0 from 2005 to 2013 (period 3). In Clarke/Monroe (continuous OB service), the IMR fell from 14.5 to 9.9 from period 1 to period 3. Coosa/Conecuh (no OB service) exhibited a consistent IMR ranging from 10.9 to 14.4. CONCLUSION: OB services provided by FPs in Pickens County resulted in improvement of the county's IMR. Local PNC was associated with a lower IMR.
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Medicina de Família e Comunidade/organização & administração , Mortalidade Infantil/tendências , Cuidado Pré-Natal/organização & administração , Serviços de Saúde Rural/organização & administração , População Rural/estatística & dados numéricos , Adolescente , Adulto , Alabama/epidemiologia , Criança , Medicina de Família e Comunidade/estatística & dados numéricos , Feminino , Acessibilidade aos Serviços de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Obstetrícia/educação , Médicos de Família/educação , Médicos de Família/estatística & dados numéricos , Gravidez , Cuidado Pré-Natal/estatística & dados numéricos , Serviços de Saúde Rural/estatística & dados numéricos , População Rural/tendências , Adulto JovemRESUMO
Antigenic diversity of the M protein is a major constraint to the development of immunity to group A streptococcus (GAS). We demonstrate that a conserved cryptic epitope that is unrecognized by the host immune system following infection can protect mice following vaccination, and that immunity is strengthened and broadened following successive infections. The observation that infection can boost and broaden, but cannot prime immunity to a cryptic epitope, may be exploited for vaccines for other pathogens.
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In addition to immune barriers, molecular incompatibilities between species are predicted to limit pig liver survival in primate xenotransplantation models. Assessment and measurement of synthetic function of genetically modified porcine livers after ex vivo perfusion with human blood have not previously been described. Eight porcine livers from α1,3-galactosyl transferase knockout and human membrane cofactor (GalTKO.hCD46), six livers from GalTKO.hCD46 and N-glycolylneuraminic acid knockout (GalTKO.hCD46.Neu5GcKO), and six livers from GalTKO.hCD46 with humanized decay-accelerating factor (hCD55), endothelial protein C receptor (hEPCR), tissue factor pathway inhibitor (hTFPI), and integrin-associated protein (hCD47) (GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47) pigs were perfused with human blood under physiologic conditions. Timed blood samples were tested for liver enzymes and for pig-specific albumin production via Western blot. Porcine albumin levels increased with time in all experiments. By densitometry, GalTKO.hCD46.Neu5GcKO livers had the highest albumin levels, measured both as total produced, and when controlled for perfusion duration, compared to GalTKO.hCD46 (P = .068) and GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47 livers (P = .04). Porcine livers perfused with human blood demonstrated the synthetic ability to produce albumin in all cases. GalTKO.hCD46.Neu5GcKO pig livers demonstrated the most robust albumin production. This suggests that the Neu5GcKO phenotype provides a protective effect on the graft due to decreased human antibody recognition and graft injury.