On the Equality of Sharp and Germ - Fields for Gaussian Processes and Fields

2000 Mathematics Subject Classification: 60G15, 60G60; secondary 31B15, 31B25, 60H15

NOTCH1 Gain of Function in Germ Cells Causes Failure of Spermatogenesis in Male Mice

NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icretransgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation.

Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU):A randomised, double-blind, placebo-controlled trial

Background: Delirium is frequently diagnosed in critically ill patients and is associated with poor clinical outcomes. Haloperidol is the most commonly used drug for delirium despite little evidence of its effectiveness. The aim of this study was to establish whether early treatment with haloperidol would decrease the time that survivors of critical illness spent in delirium or coma. Methods: We did this double-blind, placebo-controlled randomised trial in a general adult intensive care unit (ICU). Critically ill patients (≥18 years) needing mechanical ventilation within 72 h of admission were enrolled. Patients were randomised (by an independent nurse, in 1:1 ratio, with permuted block size of four and six, using a centralised, secure web-based randomisation service) to receive haloperidol 2·5 mg or 0·9% saline placebo intravenously every 8 h, irrespective of coma or delirium status. Study drug was discontinued on ICU discharge, once delirium-free and coma-free for 2 consecutive days, or after a maximum of 14 days of treatment, whichever came first. Delirium was assessed using the confusion assessment method for the ICU (CAM-ICU). The primary outcome was delirium-free and coma-free days, defined as the number of days in the first 14 days after randomisation during which the patient was alive without delirium and not in coma from any cause. Patients who died within the 14 day study period were recorded as having 0 days free of delirium and coma. ICU clinical and research staff and patients were masked to treatment throughout the study. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN83567338. Findings: 142 patients were randomised, 141 were included in the final analysis (71 haloperidol, 70 placebo). Patients in the haloperidol group spent about the same number of days alive, without delirium, and without coma as did patients in the placebo group (median 5 days [IQR 0-10] vs 6 days [0-11] days; p=0·53). The most common adverse events were oversedation (11 patients in the haloperidol group vs six in the placebo group) and QTc prolongation (seven patients in the haloperidol group vs six in the placebo group). No patient had a serious adverse event related to the study drug. Interpretation: These results do not support the hypothesis that haloperidol modifies duration of delirium in critically ill patients. Although haloperidol can be used safely in this population of patients, pending the results of trials in progress, the use of intravenous haloperidol should be reserved for short-term management of acute agitation. Funding: National Institute for Health Research. © 2013 Elsevier Ltd.

Beyond hope: Rhetorics of mobility, possibility, and literacy

When writing teachers enter the classroom, they often bring with them a deep faith in the power of literacy to rectify social inequalities and improve their students’ social and economic standing. It is this faith—this hope for change—that draws some writing teachers to locations of social and economic hardship. I am interested in how teachers and theorists construct their own narratives of social mobility, possibility, and literacy. My dissertation analyzes the production and expression of beliefs about literacy in the narratives of a diverse group of writing teachers and theorists, from those beginning their careers to those who are published and widely read. The central questions guiding this study are: How do teachers’ and theorists’ narratives of becoming literate intersect with literacy theories? and How do such literacy narratives intersect with beliefs in the power of literacy to improve individuals’ lives socially, economically, and personally? I contend that the professional literature needs to address more fully how teachers’ and theorists’ personal histories with literacy shape what they see as possible (and desirable) for students, especially those from marginalized communities. A central focus of the dissertation is on how teachers and theorists attempt to resolve a paradox they are likely to encounter in narratives about literacy. On one hand, they are immersed in a popular culture that cherishes narrative links between literacy and economic advancement (and, further, between such advancement and a “good life”). On the other hand, in professional discourse and in teacher preparation courses, they are likely to encounter narratives that complicate an assumed causal relationship between literacy and economic progress. Understanding, through literacy narratives, how teachers and theorists chart a practical path through or around this paradox can be beneficial to literacy education in three ways. First, it can offer direction in professional development and teacher education, addressing how teachers negotiate the boundaries between personal experience, theory, and pedagogy. Second, it can help teachers create spaces wherein students can explore the impact of paradoxical views about the role of literacy on their own lives. Finally, it can offer direction in public policy discourse, extending awareness of what we want—and need—from English language arts education in the twenty-first century. To explore these issues, I draw on case studies and ethnographic observation as well as narrative inquiry into teachers’ and theorists’ published literacy narratives. I situate my findings within three interrelated frames: 1) the narratives of new teachers, 2) the published works of literacy educators and theorists, and 3) my own literacy narrative. My first chapter, “Beyond Hope,” explores the tenuous connections between hope and critique in literacy studies and provides a methodological overview of the study. I argue that scholarship must move beyond a singular focus on either hope or critique in order to identify the transformative potential of literacy in particular circumstances. Analyzing literacy narratives provides a way of locating a critically informed sense of possibility. My second chapter, “Making Teachers, Making Literacy,” explores the intersection between teachers’ lives and the theories they study, based on qualitative analysis of a preservice course for secondary education English teachers. I examine how these preservice English teachers understood literacy, how their narratives of becoming literate and teaching English connected—and did not connect—with theoretical and pedagogical positions, and how these stories might inform their future work as practitioners. Centering primarily on preservice teachers who resisted Nancie Atwell’s pedagogy of possibility because they found it too good to be true, this research concentrates on moments of disjuncture, as expressed in class discussion and in one-on-one interviews, when literacy theories failed to align with aspiring teachers’ understandings of their own experiences and also with what they imagined as possible in disadvantaged educational settings. In my third and fourth chapters, I analyze the narratives of celebrated teachers and theorists who put forth an agenda that emphasizes possibilities through literacy, examining how they negotiate the relationship between their own literacy stories and literacy theories. Specifically, I investigate the narratives of three proponents of critical literacy: Mike Rose, Paulo Freire, and Myles Horton, all highly respected literacy teachers whose working-class backgrounds influenced their commitment to teaching in disenfranchised communities. In chapter 3, “Reading Lives on the Boundary,” I demonstrate how Mike Rose’s 1989 autobiographical text, Lives on the Boundary, juxtaposes rhetorics of mobility with critiques of such possibility. Through an analysis of work published in professional journals, I offer a reception history of Rose’s narrative, focusing specifically on how teachers have negotiated the tension between hope and critique. I follow this analysis with three case studies, drawn from a larger sampling, that inquire into the personal connections that writing teachers make with Lives on the Boundary. The teachers in this study, who provided written responses and participated in audio-recorded follow-up interviews, were asked to compare Rose’s story to their own stories, considering how their personal literacy histories influenced their teaching. My findings illustrate how a group of teachers and theorists have projected their own assessments of what literacy and higher education can and cannot accomplish onto this influential text. In my fourth chapter, “Horton and Freire’s Road as Literacy Narrative,” I concentrate on Myles Horton and Paulo Freire’s 1990 collaborative spoken book, We Make the Road by Walking. Central to my analysis are the educators’ stories about their formative years, including their own primary and secondary education experiences. I argue that We Make the Road by Walking demonstrates how theories of literacy cannot be divorced from personal histories. I begin by examining the spoken book as a literacy narrative that fuses personal and theoretical knowledge, focusing specifically on its authors’ ideas on theory. Drawing on Bakhtin’s notion of the chronotope—the intersection of time and space within narrative—I then explore the literacy narratives emerging from the production process of the book, in a video production about Horton and Freire’s meeting, and ultimately in the two men’s reflections on their childhood years (Dialogic). Interspersed with these accounts is archival material on the book’s editorial production that illustrates the value of increased dialogue between personal history and theories of literacy. My fifth chapter is both a reflective analysis and a qualitative study of my work at a men’s medium-high security prison in Illinois, where I conducted research and served as the instructor of an upper-level writing course, “Writing for a Change,” in the spring of 2009. Entitled “Doing Time with Literacy Narratives,” this chapter explores the complex ways in which literacy and incarceration are configured in students’ narratives as well as my own. With and against students’ stories, I juxtapose my own experiences with literacy, particularly in relation to being the son of an imprisoned father. In exploring the intersections between such stories, I demonstrate how literacy narratives can function as a heuristic for exploring beliefs about literacy between teachers and students both inside and outside of the prison-industrial complex. My conclusion pulls together the various themes that emerged in the three frames, from the making of new teachers to the published literacy narratives of teachers and theorists to my own literacy narrative. Writing teachers encounter considerable pressure to align their curricula with one or another theory of literacy, which has the effect of negating the authority of knowledge about literacy gleaned from experience as readers and writers. My dissertation contends that there is much to be gained by finding ways of articulating theories of literacy that encompass teachers’ knowledge of reading and writing as expressed in personal narratives of literacy. While powerful cultural rhetorics of upward social mobility often neutralize the critical potential of teachers’ own narratives of literacy—potential that has been documented by scholars in writing studies and allied disciplines—this is not always the case. The chapters in this dissertation offer evidence that hopeful and critical positions on the transformational possibilities of literacy are not mutually exclusive.

Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior

There is a growing recognition of the importance of the commensal intestinal microbiota in the development and later function of the central nervous system. Research using germ-free mice (mice raised without any exposure to microorganisms) has provided some of the most persuasive evidence for a role of these bacteria in gut-brain signalling. Key findings show that the microbiota is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition. Furthermore, the microbiota maintains central nervous system homeostasis by regulating immune function and blood brain barrier integrity. Studies have also found that the gut microbiota influences neurotransmitter, synaptic, and neurotrophic signalling systems and neurogenesis. The principle advantage of the germ-free mouse model is in proof-of-principle studies and that a complete microbiota or defined consortiums of bacteria can be introduced at various developmental time points. However, a germ-free upbringing can induce permanent neurodevelopmental deficits that may deem the model unsuitable for specific scientific queries that do not involve early-life microbial deficiency. As such, alternatives and complementary strategies to the germ-free model are warranted and include antibiotic treatment to create microbiota-deficient animals at distinct time points across the lifespan. Increasing our understanding of the impact of the gut microbiota on brain and behavior has the potential to inform novel management strategies for stress-related gastrointestinal and neuropsychiatric disorders.

[preservation Of The Fertility And The Ovaries In Women With Benign Adnexal Tumors].

To evaluate the sparing of fertility and ovaries in women submitted to surgical treatment for benign adnexal tumors. Between February 2010 and January 2014, 206 patients were included in this observational study as they were submitted to surgical treatment for benign ovarian tumors at CAISM, a tertiary hospital. Fertility sparing surgery was defined as tumorectomy or unilateral salpingoophorectomy without hysterectomy in premenopausal women. Preservation of the ovary occurred when at least one ovary or part of it was mantained. Of the 206 women with benign tumors, 120 (58%) were premenopausal and 86 (42%) were postmenopausal. There were 36 (30%) ovarian germ cell tumors, 31 (26%) epithelial neoplasms and 11 (9%) sex-cord stromal tumors among premenopausal women. In the group of postmenopausal women, 35 (41%) epithelial neoplasms, 27 (31%) sex-cord stromal tumors and 8 (9%) ovarian germ cell tumors were identified. Among 36 women with non-neoplastic ovarian tumors, 21 (58%) had endometriomas and 8 (22%) functional cysts. Among 22 women with extra-ovarian tumors, uterine leiomyomatosis was the most frequent finding (50%). In the group of women who were ≤ 35 years old, 26 (57%) were treated by tumorectomy and 18 (39%) were submitted to unilateral salpingoophorectomy with sparing of the uterus and the contralateral ovary. Women who were ≤ 35 years old were more frequently operated by laparoscopy which was associated with a higher number of fertility sparing procedures when compared to laparotomy (p<0.01). Twenty-six (28%) women submitted to hysterectomy with bilateral salpingoophorectomy were premenopausal. Although there is a trend to perform only tumorectomy in women who are ≤ 35 years old, a significant number of young women is still treated by salpingoophorectomy. Among 36- to 45-year-old women, only 70% had their fertility spared, while 20% had both ovaries removed. However, whenever possible, we must try to preserve the ovaries, mainly in premenopausal women.

The role of disulfide bridges in the 3-D structures of the antimicrobial peptides gomesin and protegrin-1: a molecular dynamics study

Some antimicrobial peptides have a broad spectrum of action against many different kinds of microorganisms. Gomesin and protegrin-1 are examples of such antimicrobial peptides, and they were studied by molecular dynamics in this research. Both have a beta-hairpin conformation stabilized by two disulfide bridges and are active against Gram-positive and Gram-negative bacteria, as well as fungi. In this study, the role of the disulfide bridge in the maintenance of the tertiary peptide structure of protegrin-1 and gomesin is analyzed by the structural characteristics of these peptides and two of their respective variants, gomy4 and proty4, in which the four cysteines are replaced by four tyrosine residues. The absence of disulfide bridges in gomy4 and proty4 is compensated by overall reinforcement of the original hydrogen bonds and extra attractive interactions between the aromatic rings of the tyrosine residues. The net effects on the variants with respect to the corresponding natural peptides are: i) maintenance of the original beta-hairpin conformation, with great structural similarities between the mutant and the corresponding natural peptide; ii) combination of positive F and. Ramachandran angles within the hairpin head region with a qualitative change to a combination of positive (F) and negative (.) angles, and iii) significant increase in structural flexibility. Experimental facts about the antimicrobial activity of the gomesin and protegrin-1 variants have also been established here, in the hope that the detailed data provided in the present study may be useful for understanding the mechanism of action of these peptides.

Endoscopic Ultrasound Facilitates Histological Diagnosis of Renal Cell Cancer

Over two-thirds of renal masses noted incidentally on abdominal CT scans performed for nonurological indications are most likely renal cell carcinoma (RCC). The prognosis in these instances is often quite favorable, as early diagnosis offers the best hope of a complete cure. We report the identification of a RCC incidentally at endoscopic ultrasound (EUS) while an earlier CT scan of abdomen was negative. The mass was biopsied resulting in a histological confirmation of RCC and successful surgical resection.

Ovariole structure and oogenesis in queens and workers of the stingless bee Melipona quadrifasciata (Hymenoptera: Apidae, Meliponini) kept under different social conditions

The high variability in the reproductive biology of stingless bees makes them very amenable for comparative studies with other eusocial bee taxa. We investigated the structural organization of the ovaries of Melipona quadrifasciata queens and workers kept under different social conditions by analyzing their general histology, mitotic activity, and microfilament organization. The overall dynamics of ovarian activity were similar in the two castes, and at emergence their ovarioles contained a previtellogenic follicle. Stingless bees and honey bees differ in the structural organization in the lower germarium, but they have in common synchronized mitotic activity and putative germ line stem cells in the terminal filament. Unlike honey bees, stingless bee workers lay trophic eggs in addition to reproductive eggs. The overall similarities in oogenesis between the two taxa suggest that the decision to form trophic eggs should only occur in the late stages of oogenesis.

Polymorphisms and DNA methylation of gene TP53 associated with extra-axial brain tumors

The p53 tumor suppressor gene is the most frequently mutated gene in human cancer; this gene is mutated in up to 50% of human tumors. It has a critical role in the cell cycle, apoptosis and cell senescence, and it participates in many crucial physiological and pathological processes. Polymorphisms of p53 have been suggested to be associated with genetically determined susceptibility in various types of cancer. Another process involved with the development and progression of tumors is DNA hypermethylation. Aberrant methylation of the promoter is an alternative epigenetic change in genetic mechanisms, leading to tumor suppressor gene inactivation. In the present study, we examined the TP53 Arg72Pro and Pro47Ser polymorphisms using PCR-RFLP and the pattern of methylation of the p53 gene by methylation-specific PCR in 90 extra-axial brain tumor samples. Patients who had the allele Pro of the TP53 Arg72Pro polymorphism had an increased risk of tumor development ( odds ratio, OR = 3.23; confidence interval at 95%, 95% CI = 1.71-6.08; P = 0.003), as did the allele Ser of TP53 Pro47Ser polymorphism (OR = 1.28; 95% CI = 0.03-2.10; P = 0.01). Comparison of overall survival of patients did not show significant differences. In the analysis of DNA methylation, we observed that 37.5% of meningiomas, 30% of schwannomas and 52.6% of metastases were hypermethylated, suggesting that methylation is important for tumor progression. We suggest that TP53 Pro47Ser and Arg72Pro polymorphisms and DNA hypermethylation are involved in susceptibility for developing extra-axial brain tumors.

The gene transformer-2 of Anastrepha fruit flies (Diptera, Tephritidae) and its evolution in insects

Background: In the tephritids Ceratitis, Bactrocera and Anastrepha, the gene transformer provides the memory device for sex determination via its auto-regulation; only in females is functional Tra protein produced. To date, the isolation and characterisation of the gene transformer-2 in the tephritids has only been undertaken in Ceratitis, and it has been shown that its function is required for the female-specific splicing of doublesex and transformer pre-mRNA. It therefore participates in transformer auto-regulatory function. In this work, the characterisation of this gene in eleven tephritid species belonging to the less extensively analysed genus Anastrepha was undertaken in order to throw light on the evolution of transformer-2. Results: The gene transformer-2 produces a protein of 249 amino acids in both sexes, which shows the features of the SR protein family. No significant partially spliced mRNA isoform specific to the male germ line was detected, unlike in Drosophila. It is transcribed in both sexes during development and in adult life, in both the soma and germ line. The injection of Anastrepha transformer-2 dsRNA into Anastrepha embryos caused a change in the splicing pattern of the endogenous transformer and doublesex pre-mRNA of XX females from the female to the male mode. Consequently, these XX females were transformed into pseudomales. The comparison of the eleven Anastrepha Transformer-2 proteins among themselves, and with the Transformer-2 proteins of other insects, suggests the existence of negative selection acting at the protein level to maintain Transformer-2 structural features. Conclusions: These results indicate that transformer-2 is required for sex determination in Anastrepha through its participation in the female-specific splicing of transformer and doublesex pre-mRNAs. It is therefore needed for the auto-regulation of the gene transformer. Thus, the transformer/transfomer-2 > doublesex elements at the bottom of the cascade, and their relationships, probably represent the ancestral state ( which still exists in the Tephritidae, Calliphoridae and Muscidae lineages) of the extant cascade found in the Drosophilidae lineage ( in which tra is just another component of the sex determination gene cascade regulated by Sex-lethal). In the phylogenetic lineage that gave rise to the drosophilids, evolution co-opted for Sex-lethal, modified it, and converted it into the key gene controlling sex determination.