Special education's future is threatened by anti-scientific sentiment and poor thinking about school reform. The devolution of special education has been caused by decades of illogical, destructive ...criticism and a focus on issues other than ensuring a free, appropriate public education (FAPE) for individuals with educational disabilities. Special education now needs a second revolution to reinstate its nature and purpose so that it can evolve as it should. "Revitalizing Special Education" presents neither a pessimistic nor a Pollyannish view of past or future, but rather is a careful assessment of some of the greatest threats to robust special education posed by distorted and misguided thinking about what special education is and does. Chapter authors propose logical and scientific analyses of problems and steps required to realize special education's promise, relying on empirical data and logical, linear thinking to confront educational issues, both philosophical and practical. A full range of alternative futures for special education must be considered. However, revolutionary thinking about possible futures is necessary for revitalization and meaningful evolution. The contributors to this book take up the details of thought and practice that are necessary for such revolution and evolution. Foreword written by Garry Hornby.
Microbial communities are shaped by viral predators. Yet, resolving which viruses (phages) and bacteria are interacting is a major challenge in the context of natural levels of microbial diversity. ...Thus, fundamental features of how phage-bacteria interactions are structured and evolve in the wild remain poorly resolved. Here we use large-scale isolation of environmental marine Vibrio bacteria and their phages to obtain estimates of strain-level phage predator loads, and use all-by-all host range assays to discover how phage and host genomic diversity shape interactions. We show that lytic interactions in environmental interaction networks (as observed in agar overlay) are sparse-with phage predator loads being low for most bacterial strains, and phages being host-strain-specific. Paradoxically, we also find that although overlap in killing is generally rare between tailed phages, recombination is common. Together, these results suggest that recombination during cryptic co-infections is an important mode of phage evolution in microbial communities. In the development of phages for bioengineering and therapeutics it is important to consider that nucleic acids of introduced phages may spread into local phage populations through recombination, and that the likelihood of transfer is not predictable based on lytic host range.
The rhetoric of the social model of disability is presented, and its basic claims are critiqued. Proponents of the social model use the distinction between impairment and disability to reduce ...disabilities to a single social dimension-social oppression. They downplay the role of biological and mental conditions in the lives of disabled people. Consequences of denying biological and mental realities involving disabilities are discussed. People will benefit most by recognizing both the biological and the social dimensions of disabilities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly ...expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic ...cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.
The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic ...leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.
Making public school accommodating of all learners such that the need for special education is obviated, or at least reduced, has long been a desideratum of educators. Various strategies for making ...general public education more accommodating of students with disabilities have been tried. The most recent efforts to improve the general education of students with disabilities involve various models of tiered education. Educational tiers can be logical and advantageous in some ways, holding promise for improving general education, but they do not address the core problems of special education. Special education is still needed as part of inclusive education.
Inclusive education has developed worldwide popularity in education for learners with various disabilities but is particularly controversial for students with intellectual disabilities because of ...their unique needs. The foremost of these are the development of the social, vocational and life skills needed to facilitate their transition to adulthood. This article presents a discussion that focuses on theory, practice and research relevant to inclusive education for students with intellectual disabilities. It points out that the movement for full inclusion started by focusing on students with intellectual disabilities and has encountered roadblocks to further progress because of its difficulties in addressing their special needs. This is explored by considering the theory underpinning the international drivers of the full inclusion movement, the reality of the implementation of inclusion policies worldwide, and research on the effects of inclusion of students with intellectual disabilities in mainstream schools.
The reasons are examined for the disparity between the inclusive vision espoused by Article 24 of the United Nations Convention on the Rights of Persons with Disabilities and the reality of the ...limited extent of inclusion in education systems worldwide. First, the leadership of key senior academics in the field of special education is considered to have been misguided in promoting a vision of full inclusion despite the lack of research evidence for the benefits of inclusive education over traditional special education provision. Second, attitudes toward and the treatment of people with disabilities have a long and complex history, and in this, many proponents of inclusion have been critical of 20th century special education. In particular, they claim that the sorting, labelling and categorizing required by special education have negative implications. Third, educators have been encouraged to imagine a system of education that is limitless, in the sense that all children with disabilities can be included in general education. This is because it is envisaged that general education classrooms will become so flexible that there will be no limits to the accommodation of students with disabilities, regardless of the nature or severity of their special educational needs. Fourth is the issue that deciding a student’s placement for education requires a judgment call and that, since human judgment is fallible, errors of judgment will always be made. Fifth, commitments to inclusion require that educators consider the practical, reality-based implications, whereas this has not been the case for many supporters of full inclusion. In conclusion, inclusion in the sense of students being physically present in general education classrooms is not considered as important as inclusion in the reality of being engaged in a program of instruction that is meaningful and challenging. Therefore, we consider that, rather than becoming extinct, special education needs to continue to be developed, disseminated and rigorously implemented in schools. Key special education strategies and approaches must co-exist with those from inclusive education, in order to provide effective education for all young people with special educational needs and disabilities.
General labels tend to obscure objective realities upon which disability rights are based and can deny individuals with disabilities their educational and civil rights. Undoubtedly, stigma can come ...from labels unnecessarily categorizing people into separate groups. However, stigma does not reside primarily in disability categories/terms but in what people think of words’ referents. The replacement of the old disability categories/terms with new ones is a case of what is called the “euphemism treadmill,” showing how concepts and mentally represented realities, not words, are the key issue. However, in the case of disabilities, scientific names are unavoidable for the purposes of research, education, advocacy, and social welfare. Some people try to avoid naming special education and its derivatives just as they do in the case of disability categories. We argue that scientifically validated disability and special education labels are necessary and legitimate classifications required for progress in disability research and practice. They provide the most direct route to legally protecting and serving individuals with educational disabilities.
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