Fishery science and management are concerned with both positive, what happens in a fishery system, and normative, what management should do, questions. Rarely are normative criteria discussed as ...openly and transparently as the positive techniques and assumptions. Instead, normative criteria are often held implicitly, and often goals, and objectives are defined without careful thought about the normative criteria from which such goals, and objectives derive. Management involves three components: system attributes and dynamics, management options and goals and objectives that stem from normative criteria by which outcomes are judged. There is a need to consider normative frameworks and criteria carefully because normative criteria are intrinsic to any management process. This paper motivates the need to consider normative frameworks and criteria carefully, explores issues associated with developing normative frameworks and criteria that articulate positive science, discusses specific issues to consider when developing normative frameworks for recreational fisheries and provides the bioeconomic framework as an example of a normative framework useful for recreational fisheries.
Scientific advances over the last century have generated compelling evidence of the primary and secondary effects of gestational, infant, and childhood conditions. These early environmental ...influences have the potential not only to impact an individual's health outcomes, such as heart disease, type 2 diabetes, and cancer, but also to confer various protections and risks to that individual's descendants. The immediate and extended ramifications of early environmental exposure bring an understanding of epidemiological impact on disease states and a hope for prevention. This review highlights the contributions of several key population studies and briefly explores specific environmental influences, including nutritional deficiencies, exposure to substances and infections, and adverse childhood experiences. Mechanisms of these influences (e.g. stress and epigenetics) are discussed, as well as possible means of mitigating their negative consequences.
What this paper adds
Substance exposures in utero are associated with epigenetic changes and negative outcomes.
Adverse childhood experiences in early childhood can induce HPA and epigenetic changes.
Resumen
Influencias ambientales en la salud y el desarrollo: nutrición, exposición a sustancias y experiencias adversas en la infancia
Los avances científicos en el último siglo han generado pruebas convincentes de los efectos primarios y secundarios de las condiciones de la gestación, el infante y la infancia. Estas influencias ambientales tempranas tienen el potencial no solo de afectar los resultados de salud de una persona, como la enfermedad cardíaca, la diabetes tipo 2 y el cáncer, sino también para conferir diversas protecciones y riesgos a los descendientes de esa persona. Las ramificaciones inmediatas y prolongadas de la exposición ambiental temprana permiten comprender el impacto epidemiológico en los estados de enfermedad y una esperanza de prevención. Esta revisión destaca las contribuciones de varios estudios de población clave y explora brevemente las influencias ambientales específicas, incluidas las deficiencias nutricionales, la exposición a sustancias e infecciones y las experiencias adversas en la infancia. Se discuten los mecanismos de estas influencias (por ejemplo, estrés y epigenética), así como los posibles medios para mitigar sus consecuencias negativas.
Resumo
Influências ambientais na saúde e desenvolvimento: nutrição, exposição a substâncias, e experiências adversas na infância
Avanços científicos no ultimo século geraram evidência convincente de efeitos primários e secundários de condições gestacionais e da infância. Estas influências ambientais precoces tem potencial não apenas de impactar os resultados de saúde de um indivíduos, como doença cardíaca, diabetes tipo 2 e câncer, mas também conferem várias proteções e riscos para os descendentes deste indivíduo. As ramificações imediatas e extendidas da exposição ambiental precoce trazem uma compreensão do impacto epidemiológico nos estados de doença, e uma esperança de prevenção. Esta revisão destaca as contribuições de vários estudos populacionais importantes, e explora brevemente infuências ambientais específicas, incluindo deficiências nutricionais, exposição a substâncias e infecções, e experiências adversas na infância. Os mecanismos destas influências (ex: estresse e epigenética) são discutidos, assim como possíveis formas de mitigar suas consequências negativas.
What this paper adds
Substance exposures in utero are associated with epigenetic changes and negative outcomes.
Adverse childhood experiences in early childhood can induce HPA and epigenetic changes.
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Endogenous microRNA (miRNA) expression can be exploited for cell type-specific transgene expression as the addition of miRNA target sequences to transgenic cDNA allows for transgene downregulation ...specifically in cells expressing the respective miRNAs. Here, we have investigated the potential of miRNA-150 target sequences to specifically suppress gene expression in lymphocytes and thereby prevent transgene-induced lymphotoxicity. Abundance of miRNA-150 expression specifically in differentiated B and T cells was confirmed by quantitative reverse transcriptase PCR. Mono- and bicistronic lentiviral vectors were used to investigate the effect of miRNA-150 target sequences on transgene expression in the lymphohematopoietic system. After in vitro studies demonstrated effective downregulation of transgene expression in murine B220(+) B and CD3(+) T cells, the concept was further verified in a murine transplant model. Again, marked suppression of transgene activity was observed in B220(+) B and CD4(+) or CD8(+) T cells whereas expression in CD11b(+) myeloid cells, lin(-) and lin(-)/Sca1(+) progenitors, or lin(-)/Sca1(+)/c-kit(+) stem cells remained almost unaffected. No toxicity of miRNA-150 targeting in transduced lymphohematopoietic cells was noted. Thus, our results demonstrate the suitability of miRNA-150 targeting to specifically suppress transgene expression in lymphocytes and further support the concept of miRNA targeting for cell type-specific transgene expression in gene therapy approaches.
New neurons are continuously generated from neural stem cells with astrocyte properties, which reside in close proximity to the ventricle in the postnatal and adult brain. In this study we found that ...microRNA-124 (miR-124) dictates postnatal neurogenesis in the mouse subventricular zone. Using a transgenic reporter mouse we show that miR-124 expression is initiated in the rapid amplifying progenitors and remains expressed in the resulting neurons. When we stably inhibited miR-124 in vivo, neurogenesis was blocked, leading to the appearance of ectopic cells with astrocyte characteristics in the olfactory bulb. Conversely, when we overexpressed miR-124, neural stem cells were not maintained in the subventricular zone and neurogenesis was lost. In summary, our results demonstrate that miR-124 is a neuronal fate determinant in the subventricular zone.
Purpose: Across various health conditions and geographic regions, there remains a dearth of clinicians with the expertise and confidence to identify and manage children with disabilities. At the ...front line of this crisis are clinician-educators, who are tasked with caring for these unique patients and with training the future workforce. Balancing patient care and clinical instruction responsibilities is particularly challenging when trainees of varied educational levels and specialties report simultaneously. The lack of a standard curriculum further compounds the clinician-educator's teaching demands and threatens the consistency of trainees' learning. Recognizing these challenges in their work in a neonatal follow-up clinic, the authors sought a solution through an established curriculum development process.
Materials and methods: A needs assessment survey was conducted to gauge medical trainees' knowledge, skills, and experiences. Applying needs assessment findings, the authors developed a curriculum, which was administered online to several trainee cohorts just prior to rotations in the neonatal follow-up clinic.
Results: After completing the curriculum, trainees scored significantly higher on neonatal follow-up knowledge tests.
Conclusions: Providing advance exposure helped to ensure that trainees arrived with comparable basal knowledge, which served as a foundation for more advanced instruction. This curricular approach may be useful across teaching venues, especially those with multi-level or multi-discipline learners.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Bone marrow-derived macrophages account for substantial GBM tumor volume and contribute to the local inflammatory tumor microenvironment, disease progression and treatment ...response.
Material and Methods
We have developed a genetically modified, autologous hematopoietic stem cell-based platform designed to deliver Interferon-alpha (IFNa), thanks to a transcriptional and post-transcriptional control mechanism mediated by miRNA target sequences, specifically into the tumor microenvironment via Tie-2 expressing monocytes (Temferon).
Results
As of Feb 2022, 3 escalating doses of Temferon (from 0.5 to 2.0x106/kg) were tested across 15 patients with newly diagnosed, unmethylated MGMT glioblastoma (GBM) assigned to 5 cohorts. The duration of follow-up from surgery is 6 - 28 mo (2 - 25 mo after Temferon). To date, no dose limiting toxicities have been identified. As expected, one month after the administration of the highest tested dose, the hematopoietic system of Temferon-treated patients was composed of up to 30% of CD14+ genetically modified cells, as determined by the presence of vector genomes in the DNA in peripheral blood and bone marrow cells. Temferon-derived progeny persisted, albeit at lower levels, up to 18 months (longest time of analysis). Despite the substantial proportion of engineered cells, very low median concentrations of IFNα were detected in the plasma (D+30, 5.9; D+90, 8.8pg/mL) and in the CSF (D+30, 1.5; D+90, 2.4pg/mL), indicating tight regulation of transgene expression. SAEs were mostly attributed to conditioning chemotherapy (e.g. infections) or disease progression (e.g. seizures). 1 SUSAR (persistent GGT elevation) has occurred. Median OS is 15 mo from surgery (range 6.1-28.4 mo; 10.8 mo post Temferon). Of the 15 pts treated so far, 4 pts belonging to low dose cohorts underwent 2nd surgery. Homing of transduced cells from BM to the tumor site was demonstrated by the presence of gene-marked cells in the specimens collected from 3 of the 4 analyzed pts. Single-cell RNA seq performed on CD45+ cells purified from the TME of Temferon-treated pts compared to recurrent tumors belonging to GBM pts treated as per the current standard of care, highlighted a Temferon signature defined by the induction of markers of IFNa responses and macrophage repolarization. Potential long-term benefit with Temferon was identified in a patient from cohort 3, who had disease progression at D+120 with two distant enhancing lesions, and increased tumor necrosis. One year following Temferon, with no 2nd line therapy added, there was approximately 40% reduction in enhancing tumor volume compared to D+180 with a stable clinical and imaging picture thereafter.
Conclusion
The results provide initial evidence of Temferon’s potential to modulate the TME of GBM patients, and anecdotal evidence for long lasting effects of Temferon in prevention of disease progression.
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