Miracle-dz/UniFAR-FTUs huggingface dataset:
Experiences of first-time mentor teachers in New Zealand primary schools

Mentors hold the significant position of being able to influence the induction of beginning teachers into the profession. A mentor is usually the person who is closest to the beginning teacher in the professional context, who has the most direct contact with them, and has the responsibility of assisting them develop into the future of the teaching profession. The role the mentor plays in the induction programme has been acknowledged as one of the most important for beginning teachers and has been linked to important issues such as retention and professionalism. While there is considerable literature focusing on mentoring practices within New Zealand primary schools (children aged 5 to 12), there appears to be limited information regarding teachers who are new to mentoring (completing this role for the first time), and it is this gap in the literature that this thesis addresses. This research explores the experiences of a small group of first-time mentors within the New Zealand primary school environment. This study was undertaken in order to explore first-time mentors’ understanding of the roles and responsibilities inherent in being a mentor and additionally, to explore any challenges or tensions that exist between these roles and responsibilities, and lastly, to look at the implications of this in order to ascertain how better to assist novice mentors in the future. The study draws from social constructionism and interpretivism, whilst employing a qualitative approach. A case study method was used. The findings revealed some similarity to veteran mentors’ experiences, that mentoring is a complex and often challenging experience. Additionally the findings also identified that the needs of the first-time mentors mirrored those of a beginning teacher’s first year of teaching. Stark similarities of the peaks and troughs notably recognised in a beginning teacher’s first year, resonated with the novice mentors in this study and demonstrated the need for greater interpersonal, affective and cognitive support when fulfilling this role for the first time.
PNAS Plus Significance Statements

We have downscaled planetary boundaries and applied the “safe and just space for humanity” framework at the national scale, for the first time, creating a “barometer” for inclusive sustainable development for South Africa. The barometer presents the state and trajectory of a broad but manageable set of indicators for environmental and social priorities, and highlights the country’s proximity to environmental boundaries and the distance from eradication of social deprivation. This creates a monitoring and communication tool for national government for thinking in an integrated manner about environmental and social-development issues. Our case study (pp. E4399–E4408) provides insight into the challenges and complexities of developing indicators and targets for the proposed global Sustainable Development Goals that that are globally, regionally, and nationally relevant.
Mechanism of ganciclovir-induced chain termination revealed by resistant viral polymerase mutants with reduced exonuclease activity

Significance Nucleoside analogues include important drugs that target DNA polymerases and cause chain termination. However, how ganciclovir, the first line of treatment for human cytomegalovirus infections, does this is unknown. Ganciclovir resistance is a serious clinical problem. Many ganciclovir-resistant isolates contain substitutions in the 3′–5′ exonuclease domain of the catalytic subunit of viral DNA polymerase. How these mutations confer resistance is a long-standing question. This study shows that both wild-type and exonuclease mutant polymerases incorporate ganciclovir into DNA and continue synthesis, but whereas the wild-type enzyme excises nucleotides two positions downstream of incorporated ganciclovir, the mutant enzymes do not, permitting chain extension. These results show how a therapeutically important drug causes chain termination and explain an unusual mechanism of drug resistance. Many antiviral and anticancer drugs are nucleoside analogs that target polymerases and cause DNA chain termination. Interestingly, ganciclovir (GCV), the first line of therapy for human cytomegalovirus (HCMV) infections, induces chain termination despite containing the equivalent of a 3′-hydroxyl group. Certain HCMV GCV resistance (GCVr) mutations, including ones associated with treatment failures, result in substitutions in the 3′–5′ exonuclease (Exo) domain of the catalytic subunit of the viral DNA polymerase (Pol). To investigate how these mutations confer resistance, we overexpressed and purified wild-type (WT) HCMV Pol and three GCVr Exo mutants. Kinetic studies provided little support for resistance being due to effects on Pol binding or incorporation of GCV-triphosphate. The mutants were defective for Exo activity on all primer templates tested, including those with primers terminating with GCV, arguing against the mutations increasing excision of the incorporated drug. However, although the WT enzyme terminated DNA synthesis after incorporation of GCV-triphosphate and an additional nucleotide (N+1), the Exo mutants could efficiently synthesize DNA to the end of such primer templates. Notably, the Exo activity of WT Pol rapidly and efficiently degraded N+2 primer templates to N+1 products that were not further degraded. On N+1 primer templates, WT Pol, much more than the Exo mutants, converted the incoming deoxynucleoside triphosphate to its monophosphate, indicative of rapid addition and removal of incorporated nucleotides (“idling”). These results explain how GCV induces chain termination and elucidate a previously unidentified mechanism of antiviral drug resistance.
Domesticated transposase Kat1 and its fossil imprints induce sexual differentiation in yeast

Significance Transposable elements (TEs) are mobile genetic elements that colonize the nuclei of all organisms. Although TEs can be detrimental, they are considered important evolutionary forces. We discovered a domesticated TE in the mating-type locus of the yeast Kluyveromyces lactis. K. lactis hobo/Activator/Tam3 (hAT) transposase 1 (Kat1) mobilizes this TE from the genome by inducing DNA double-strand breaks followed by gene conversion, resulting in a switch of mating type. Hence, Kat1 triggers an adaptive genome rearrangement facilitating sexual differentiation. Surprisingly, the translation of Kat1 requires a programmed frameshift. The frameshift in the KAT1 gene dampens the activity of Kat1. In contrast, Kat1 is transcriptionally activated by nutrient limitation. Together our results reveal Kat1 as a highly regulated transposase that stimulates sexual reproduction. Transposable elements (TEs) have had a major influence on shaping both prokaryotic and eukaryotic genomes, largely through stochastic events following random or near-random insertions. In the mammalian immune system, the recombination activation genes1/2 (Rag1/2) recombinase has evolved from a transposase gene, demonstrating that TEs can be domesticated by the host. In this study, we uncovered a domesticated transposase, Kluyveromyces lactis hobo/Activator/Tam3 (hAT) transposase 1 (Kat1), operating at the fossil imprints of an ancient transposon, that catalyzes the differentiation of cell type. Kat1 induces mating-type switching from mating type a (MATa) to MATα in the yeast K. lactis. Kat1 activates switching by introducing two hairpin-capped DNA double-strand breaks (DSBs) in the MATa1–MATa2 intergenic region, as we demonstrate both in vivo and in vitro. The DSBs stimulate homologous recombination with the cryptic hidden MAT left alpha (HMLα) locus resulting in a switch of the cell type. The sites where Kat1 acts in the MATa locus most likely are ancient remnants of terminal inverted repeats from a long-lost TE. The KAT1 gene is annotated as a pseudogene because it contains two overlapping ORFs. We demonstrate that translation of full-length Kat1 requires a programmed −1 frameshift. The frameshift limited Kat1 activity, because restoring the zero frame causes switching to the MATα genotype. Kat1 also was transcriptionally activated by nutrient limitation via the transcription factor mating type switch 1 (Mts1). A phylogenetic analysis indicated that KAT1 was domesticated specifically in the Kluyveromyces clade of the budding yeasts. We conclude that Kat1 is a highly regulated transposase-derived endonuclease vital for sexual differentiation.
Variant alleles of cytokine genes influence risk and clinical course of Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare disease with heterogenous clinical presentation, ranging from a self-healing bone-lesion to multi-system life-threatening disease. The choice of appropriate therapy remains a significant challenge, with treatment options varying from watch-and-wait to intensive combination chemotherapy. In addition, the question whether of LCH represents a malignancy or is caused by an immune dysregulation remains unanswered to date. Although a clonality of LCH cells has been demonstrated in all studied cases of nonpulmonary LCH, recent data favour an immunological aberration as the origin of LCH (Abla et al, 2010). Multiple studies demonstrated that host genetic factors may modify the risk as well as the clinical course of various malignancies and immune-mediated diseases. To evaluate whether polymorphism of cytokines altering the function or expression of the molecule contribute to the pathogenesis and prognosis of LCH, we analysed five candidate genes regarding risk and clinical outcome in a large cohort of LCH patients. The study group consisted of patients with biopsy-proven LCH treated according to the clinical trials LCH-I (n = 33), LCH-II (n = 76), or LCH-III (n = 93) for whom samples were available. Patients were classified as having single-system or (B) (C)
Conservative Management of Atypical Hyperplasia and Grade I Endometrial Carcinoma: Review of the Literature and Presentation of a Series

Abstract Objective: The purpose of this study was to evaluate the safety of fertility-sparing treatment in young women with atypical hyperplasia (AH) or grade 1 endometrial cancer (EC). Design: This study was designed as a retrospective cohort study. Methods: All women ≤45 years of age with AH or grade 1 EC treated at Mayo Clinic between January 1, 1985 and December 31, 2005 were identified. Patient demographics, management, and follow-up data were retrospectively abstracted and analyzed. Results: Ninety-four women were treated for AH or grade 1 EC, 71 underwent immediate surgical treatment, and 23 elected to preserve fertility Among the latter, complete data were available for 21 patients (16 with AH and 5 with EC at initial diagnosis). During the first course, 11 received medroxyprogesterone acetate (MPA), 7 received megestrol acetate (MA), 1 received oral contraceptive pills, and 2 were observed. Response after the first course (median duration 6.1 months) was 71% overall; 81% in AH patients versus 40%.
THE RELATIONSHIP OF STUDENTS STUDY STRATEGIES WITH THEIR PERSONAL CHARACTERISTICS AND ACADEMIC BACKGROUND

Introduction. Learning and study strategies improve academic success through facilitating learning. Identifying the students’ learning and study strategies is essential for educational interventions. This research was conducted to determine students’ learning and study strategies and their relationship with their personal charactristics and academic background in Mashad University of Medical Sciences in 1999 and also, to compare these strategies with American students’ norms. Methods. In this descriptive analytical study 412 first to third year students from schools of medicine, dentistry and pharmacy were selected by a stratified random sampling. The Learning and Study Strategy Inventory (LASSI) prepared by Weinstein et al, which consists of 10 subscales was completed by the subjects. The profile of students’ learning and study strategies was compared with American students’ norms. Data was analyzed using Mannwhitney and Kruskal Wallis tests. Results. The median of students’ scores in test strategies, attitude, and anxiety control were 33, 32 and 31 out of 40, respectively which showed the most scores. The least score belonged to selecting main idea which was equal to 19. The median score for different areas of learning and study strategies had no significant difference according to discipline and study levels. Students’ mean score in test strategies, concentration and motivation was equal to 80, 75 and 15 percentile of American students’ norms, respectively. Conclusion. Students had good performances on test-strategies, anxiety control and concentration, but showed poor levels of motivation. The use of Weinstein learning and study strategies questionnaire in identifying students’ weaknesses and strengths in learning and studying is recommended.
G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Significance Angiogenin is a stress-activated ribonuclease that cleaves tRNA to produce bioactive small noncoding RNAs [tRNA-derived, stress-induced RNAs (tiRNAs)] that function in a cytoprotective stress response program. Point mutations that reduce its ribonuclease activity are found in a subset of patients with ALS, a fatal neurodegenerative disease. We have found that selected tiRNAs assume G-quadruplex (G4) structures that are necessary for cytoprotective and prosurvival functions. Moreover, stable DNA analogs of these G4-containing tiRNAs spontaneously enter motor neurons and confer cytoprotection against stress. Our results identify tiRNAs as leading compounds for the development of a new class of neuroprotective drugs and give insights into the molecular mechanisms underlying the pathobiology of expanded G4-forming hexanucleotide repeats in the C9ORF72 gene. Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5′- and 3′-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5′-tiRNAs (e.g., tiRNAAla, tiRNACys) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1–dependent manner. Remarkably, the ability of 5′-tiRNAAla to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.
Functional B-1 progenitor cells are present in the hematopoietic stem cell-deficient embryo and depend on Cbfβ for their development

Significance All lymphoid cells are considered to be products of hematopoietic stem cells (HSCs); however, it has been suggested, but not proven, that innate immune B-1 progenitor cells develop independently of HSCs in the fetal liver. B-1 cells, especially B-1a cells, are not replaced by adult bone marrow transplantation. Thus, it is critical to understand the origin and mechanisms required to sustain these cells in vivo because B-1 cells play important roles in the first line of defense against microbial infection and in preventing organ damage in autoimmune patients and infections in some patients after bone-marrow transplantation. We demonstrate that B-1 progenitor cells can develop independently of HSCs in the fetal liver and that their development relies critically on the expression of core-binding factor beta. The fetal liver is a major hematopoietic site containing progenitor cells that give rise to nearly all blood cells, including B-1 cells. Because the fetal liver is not a de novo site of hematopoietic stem cell (HSC) or progenitor-cell emergence, it must be seeded by yolk sac (YS)-derived erythromyeloid progenitors at embryonic day (E) 8.5–E10 and aorta-gonado-mesonephros (AGM)-derived HSCs at E10.5–E11.5. Although the B-1 progenitor cell pool in the fetal liver is considered to be of HSC origin, we have previously proposed that YS-derived B-1 progenitors may also contribute to this pool. Until now, it has been impossible to determine whether HSC-independent B-1 progenitor cells exist in the fetal liver. Here, we demonstrate the presence of transplantable fetal-liver B-1 and marginal zone B progenitor cells in genetically engineered HSC-deficient embryos. HSC-deficient YS and AGM tissues produce B-1 progenitors in vitro and thus may serve as sites of origin for the B-1 progenitors that seed the fetal liver. Furthermore, we have found that core-binding factor beta (Cbfβ) expression is required for fetal-liver B-1 progenitor cell maturation and expansion. Our data provide, to our knowledge, the first evidence for the presence of B-1 progenitor cells in the fetal liver that arise independently of HSCs and implicate Cbfβ as a critical molecule in the development of this lineage.
A spatially nonselective baseline signal in parietal cortex reflects the probability of a monkey’s success on the current trial

Significance Cortical neurons are often active when they are not participating in sensorimotor processes. Here we show that this baseline activity reflects a modulatory signal predicting the monkey’s success on a difficult task without specifying what the monkey perceives or will do. The activity correlates inversely with the monkey’s recent history of success, so that a period of failure is associated with an increase in the baseline and predicts an increase in the monkey’s likelihood of success. The activity is not related to the spatial locus of the monkey’s visual attention. We suggest that this activity is the cortical manifestation of an arousal or state process that controls the efficiency of an animal’s behavior without specifying the nature of that behavior. We recorded the activity of neurons in the lateral intraparietal area of two monkeys while they performed two similar visual search tasks, one difficult, one easy. Each task began with a period of fixation followed by an array consisting of a single capital T and a number of lowercase t’s. The monkey had to find the capital T and report its orientation, upright or inverted, with a hand movement. In the easy task the monkey could explore the array with saccades. In the difficult task the monkey had to continue fixating and find the capital T in the visual periphery. The baseline activity measured during the fixation period, at a time in which the monkey could not know if the impending task would be difficult or easy or where the target would appear, predicted the monkey’s probability of success or failure on the task. The baseline activity correlated inversely with the monkey's recent history of success and directly with the intensity of the response to the search array on the current trial. The baseline activity was unrelated to the monkey’s spatial locus of attention as determined by the location of the cue in a cued visual reaction time task. We suggest that rather than merely reflecting the noise in the system, the baseline signal reflects the cortical manifestation of modulatory state, motivational, or arousal pathways, which determine the efficiency of cortical sensorimotor processing and the quality of the monkey’s performance.
Primary refractory acute myeloid leukaemia – in search of better definitions and therapies

The definition of primary refractory acute myeloid leukaemia is the failure to achieve a response after one or two cycles of induction. Given that there are many different strategies involving different doses of cytarabine and anthracyclines, which may or may not be equivalent, and as this is an area of unmet need with the potential for the development of new agents and strategies, uniform criteria for response have been described that need to be adhered to. The outcome of patients with chemoresistant disease is poor with only a proportion of patients salvaged by allogeneic stem cell transplantation. Progress in supportive care strategies and donor identification has enabled more of these patients to undergo unrelated donor transplantation. Novel strategies and new agents directed at the biology of the disease and the mechanisms of resistance are needed.
A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients

The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti‐MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty‐five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m2 and PLD 5 mg/m2 were administered on days 1, 4, 8 and 11 of a 4‐week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar‐plantar erythrodysesthesia and myelosuppression compared to the standard dosing on a 3‐week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.
Secondary primary malignancies in patients with multiple myeloma treated with high‐dose chemotherapy and autologous blood stem cell transplantation

Secondary primary malignancies (SPM) are an emerging issue in patients with multiple myeloma (MM) since the lenalidomide arm of the French IFM 2005-02 trial has been closed as a consequence of a higher incidence of SPM in patients who had received lenalidomide as maintenance treatment compared to the patients in the placebo arm. To evaluate the incidence of SPM in the group of patients, who were treated with high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), we retrospectively looked at a homogeneous group of 313 consecutive patients, who were diagnosed with MM and had received HDT and autologous PBSCT at our hospital between December 1994 and January 2009. Induction treatment consisted of conventional chemotherapy without novel agents in 95% of patients and maintenance treatment was given with interferon or thalidomide in 37% und 35% of patients, respectively. Roland Fenk, Florian Neubauer, Ingmar Bruns, Christian Saure, Thomas Schroder, Ulrich Germing, Rainer Haas and Guido Kobbe