Summary Use of proton beam therapy has expanded, with the number of proton centres rapidly increasing not only in the USA but also worldwide. The physical characteristics of the proton beam offer ...important advantages versus widely used photon techniques in terms of radiation precision. In head and neck cancer in particular, proton beam therapy is uniquely suited for the complex anatomy of tumours and sensitive surrounding organs. De-intensification and personalisation of treatment to limit toxicity are of renewed importance in the context of human papilloma virus-associated disease, in which young patients will be cured but bear the consequences of adverse effects for decades. Comparisons of radiation dose distributions between photon and proton techniques suggest considerable benefit in terms of toxicity sparing, but this has only recently been confirmed by substantial clinical data. In this Review, we attempt to define the role of this method in the contemporary multidisciplinary management of various types of head and neck cancer.
Two
longitudinal field experiments in a middle school examined how a brief
"values affirmation" affects students' psychological experience and
the relationship between psychological experience and ...environmental threat over
2 years. Together these studies suggest that values affirmations insulate
individuals' sense of belonging from environmental threat during a key
developmental transition. Study 1 provided an analysis of new data from a
previously reported study. African American students in the control condition
felt a decreasing sense of belonging during middle school, with low-performing
students dropping more in 7th grade and high-performing students dropping more
in 8th grade. The affirmation reduced this decline for both groups. Consistent
with the notion that affirmation insulates belonging from environmental threat,
affirmed African American students' sense of belonging in Study 1 fluctuated
less over 2 years and became less contingent on academic performance. Based on
the idea that developmentally sensitive interventions can have long-lasting
benefits, Study 2 showed that the affirmation intervention was more effective if
delivered before any drop in performance and subsequent psychological toll could
unfold. The role of identity threat and affirmation in affecting the encoding of
social experience, and the corresponding importance of timing treatments to
developmentally sensitive periods, are explored.
Variable levels of DNA methylation have been reported at tissue-specific differential methylation regions (DMRs) overlapping enhancers, including super-enhancers (SEs) associated with key cell ...identity genes, but the mechanisms responsible for this intriguing behavior are not well understood. We used allele-specific reporters at the endogenous Sox2 and Mir290 SEs in embryonic stem cells and found that the allelic DNA methylation state is dynamically switching, resulting in cell-to-cell heterogeneity. Dynamic DNA methylation is driven by the balance between DNA methyltransferases and transcription factor binding on one side and co-regulated with the Mediator complex recruitment and H3K27ac level changes at regulatory elements on the other side. DNA methylation at the Sox2 and the Mir290 SEs is independently regulated and has distinct consequences on the cellular differentiation state. Dynamic allele-specific DNA methylation at the two SEs was also seen at different stages in preimplantation embryos, revealing that methylation heterogeneity occurs in vivo.
Display omitted
•Allele-specific reporters revealed dynamic DNA methylation of Sox2 and miR290 SEs•DNMTs and transcription factor binding regulate methylation dynamics•SE DNA methylation directly regulates transcription in cis•Dynamic DNA methylation is co-regulated with MED1 recruitment and H3K27ac level
Song et al. used an allelic reporter approach to show super-enhancers allelic DNA methylation dynamics underlies locus-specific heterogeneity, which functionally impacts transcription and cellular states of mouse embryonic stem cells.
Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling ...these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.
Clostridium tetani and Clostridium botulinum produce two of the most potent neurotoxins known, tetanus neurotoxin and botulinum neurotoxin, respectively. Extensive biochemical and genetic ...investigation has been devoted to identifying and characterizing various C. botulinum strains. Less effort has been focused on studying C. tetani likely because recently sequenced strains of C. tetani show much less genetic diversity than C. botulinum strains and because widespread vaccination efforts have reduced the public health threat from tetanus. Our aim was to acquire genomic data on the U.S. vaccine strain of C. tetani to better understand its genetic relationship to previously published genomic data from European vaccine strains. We performed high throughput genomic sequence analysis on two wild-type and two vaccine C. tetani strains. Comparative genomic analysis was performed using these and previously published genomic data for seven other C. tetani strains. Our analysis focused on single nucleotide polymorphisms (SNP) and four distinct constituents of the mobile genome (mobilome): a hypervariable flagellar glycosylation island region, five conserved bacteriophage insertion regions, variations in three CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems, and a single plasmid. Intact type IA and IB CRISPR/Cas systems were within 10 of 11 strains. A type IIIA CRISPR/Cas system was present in two strains. Phage infection histories derived from CRISPR-Cas sequences indicate C. tetani encounters phages common among commensal gut bacteria and soil-borne organisms consistent with C. tetani distribution in nature. All vaccine strains form a clade distinct from currently sequenced wild type strains when considering variations in these mobile elements. SNP, flagellar glycosylation island, prophage content and CRISPR/Cas phylogenic histories provide tentative evidence suggesting vaccine and wild type strains share a common ancestor.
To advance understanding of doctoral student experiences and the high attrition rates among Science, Technology, Engineering, and Mathematics (STEM) doctoral students, we developed and examined the ...psychological profiles of different types of doctoral students. We used latent class analysis on self-reported psychological data relevant to psychological threat from 1,081 incoming doctoral students across three universities and found that the best-fitting model delineated four threat classes: Lowest Threat, Nonchalant, Engaged/Worried, and Highest Threat. These classes were associated with characteristics measured at the beginning of students' first semester of graduate school that may influence attrition risk, including differences in academic preparation (e.g., amount of research experience), self-evaluations and perceived fit (e.g., sense of belonging), attitudes towards graduate school and academia (e.g., strength of motivation), and interpersonal relations (e.g., perceived social support). Lowest Threat students tended to report the most positive characteristics and Highest Threat students the most negative characteristics, whereas the results for Nonchalant and Engaged/Worried students were more mixed. Ultimately, we suggest that Engaged/Worried and Highest Threat students are at relatively high risk of attrition. Moreover, the demographic distributions of profiles differed, with members of groups more likely to face social identity threat (e.g., women) being overrepresented in a higher threat profile (i.e., Engaged/Worried students) and underrepresented in lower threat profiles (i.e., Lowest Threat and Nonchalant students). We conclude that doctoral students meaningfully vary in their psychological threat at the beginning of graduate study and suggest that these differences may portend divergent outcomes.
A key question about achievement motivation is how to maintain it over time and in the face of stress and adversity. The present research examines how a motivational process triggered by a ...social-psychological intervention propagates benefits over a long period of time and creates an enduring shift in the way people interpret subsequent adversity. During their first or second year of college, 183 Latino and White students completed either a values affirmation intervention or control exercise as part of a laboratory study. In the affirmation intervention, students wrote about a core personal value, an exercise that has been found in previous research to buffer minority students against the stress of being negatively stereotyped in school. This single affirmation improved the college grade point average (GPA) of Latino students over 2 years. Students were re-recruited for a follow-up session near the end of those 2 years. Results indicated that GPA benefits occurred, in part, because the affirmation shifted the way Latino students spontaneously responded to subsequent stressors. In particular, in response to an academic stressor salience task about their end-of-semester requirements, affirmed Latino students spontaneously generated more self-affirming and less self-threatening thoughts and feelings as assessed by an open-ended writing prompt. They also reported having a greater sense of their adequacy as assessed by measures of self-integrity, self-esteem, and hope, as well as higher academic belonging. Discussion centers on how and why motivational processes can trigger effects that persist over surprisingly long periods of time.
Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a ...subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.
Demystifying Values-Affirmation Interventions Shnabel, Nurit; Purdie-Vaughns, Valerie; Cook, Jonathan E. ...
Personality & social psychology bulletin,
05/2013, Letnik:
39, Številka:
5
Journal Article
Recenzirano
Two experiments examined for the first time whether the specific content of participant-generated affirmation essays—in particular, writing about social belonging—facilitated an affirmation ...intervention’s ability to reduce identity threat among negatively stereotyped students. Study 1, a field experiment, revealed that seventh graders assigned to a values-affirmation condition wrote about social belonging more than those assigned to a control condition. Writing about belonging, in turn, improved the grade point average (GPA) of Black, but not White students. In Study 2, using a modified “belonging-affirmation” intervention, we directly manipulated writing about social belonging before a math test described as diagnostic of math ability. The more female participants wrote about belonging, the better they performed, while there was no effect of writing about belonging for males. Writing about social belonging improved performance only for members of negatively stereotyped groups. Implications for self-affirmation theory and practice are discussed.
PDF
