Where are G-quadruplexes located in the human transcriptome?

Abstract: It has been demonstrated that RNA G-quadruplexes (G4) are structural motifs present in transcriptomes and play important regulatory roles in several posttranscriptional mechanisms. However, the full picture of RNA G4 locations and the extent of their implication remain elusive. Solely computational prediction analysis of the whole transcriptome may reveal all potential G4, since experimental identifications are always limited to specific conditions or specific cell lines. The present study reports the first in-depth computational prediction of potential G4 region across the complete human transcriptome. Although using a relatively stringent approach based on three prediction scores that accounts for the composition of G4 sequences, the composition of their neighboring sequences, and the various forms of G4, over 1.1 million of potential G4 (pG4) were predicted. The abundance of G4 was computationally confirmed in both 5 and 3 UTR as well as splicing junction of mRNA, appreciate for the first time in the long ncRNA, while almost absent of most of the small ncRNA families. The present results constitute an important step toward a full understanding of the roles of G4 in posttranscriptional mechanisms

Allogeneic Hematopoietic Stem Cell Transplantation Following the Use of Hypomethylating Agents among Patients with Relapsed or Refractory AML: Findings from an International Retrospective Study

Abstract Patients with primary refractory or relapsed acute myeloid leukemia (RR-AML) have very poor prognosis. Due to limited treatment options, some patients are treated with hypomethylating agents (HMAs) due to their tolerability. Little is known about the role of allogeneic hematopoietic stem cell transplantation (HSCT) following HMA therapy in this setting. We retrospectively analyzed an international cohort of 655 RR-AML patients who received HMA therapy to study patterns and outcomes with HSCT. Only 37 patients (5.6%) patients underwent HSCT after HMA therapy. The conditioning regimen was myeloablative in 57% and nonmyeloablative in 43%. Patients received matched unrelated donor, matched sibling, haploidentical and mismatched unrelated HSCT in 56%, 24%, 16% and 4% of cases, respectively. Acute GvHD and chronic GvHD were observed in 40% and 17% of patients. While the median OS for the entire cohort of patients was 15.3 months (95% CI 9.5 – 21.7 months), OS reached 29.7 months (95% CI 7.01 – not-reached) for patients who achieved a complete remission (CR) to HMA and no intervening therapies between HMA therapy and HSCT. Our study suggests that HMA therapy can effectively bridge some patients with RR-AML to HSCT

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m$^{-}$$^{2}$ once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485

Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow–derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45+HLA-DR+ cells: CD1a+CD14− DC, CD1a−CD14+ DC, and CD1a−CD14+FXIIIa+ macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a+ and CD14+ DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4+ T cells, macrophages induce cytokine expression in memory CD4+ T cells and activation and proliferation of CD8+ T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells

Clinical outcomes and patient-matched molecular composition of relapsed medulloblastoma

© 2021 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. Methods: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. Results: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. Conclusion: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.info:eu-repo/semantics/publishedVersio

Dating the Origin of Language Using Phonemic Diversity

Language is a key adaptation of our species, yet we do not know when it evolved. Here, we use data on language phonemic diversity to estimate a minimum date for the origin of language. We take advantage of the fact that phonemic diversity evolves slowly and use it as a clock to calculate how long the oldest African languages would have to have been around in order to accumulate the number of phonemes they possess today. We use a natural experiment, the colonization of Southeast Asia and Andaman Islands, to estimate the rate at which phonemic diversity increases through time. Using this rate, we estimate that present-day languages date back to the Middle Stone Age in Africa. Our analysis is consistent with the archaeological evidence suggesting that complex human behavior evolved during the Middle Stone Age in Africa, and does not support the view that language is a recent adaptation that has sparked the dispersal of humans out of Africa. While some of our assumptions require testing and our results rely at present on a single case-study, our analysis constitutes the first estimate of when language evolved that is directly based on linguistic data

Standards in semen examination:publishing reproducible and reliable data based on high-quality methodology

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.Peer reviewe

Environmental Injustice in the Onondaga Lake Waterscape, New York State, USA

This paper examines two interrelated cases of environmental injustice and social mobilisation in the Onondaga lake watershed in Central New York State, USA: (1) the case of the Onondaga Nation, an indigenous people whose rights to, and uses of, water and other resources have been severely reduced through historical processes of Euro-American settlement and industrial development; and (2) the case of the city of Syracuse, New York’s Southside neighbourhood, a low-income community of colour, where a sewage treatment facility was constructed as part of a broader effort to remediate the effects of pollution in Onondaga lake. The Onondaga Nation and the Southside neighbourhood are connected by Onondaga creek, which flows through each before joining Onondaga lake. These communities are also linked by shared histories of marginalisation and environmental injustice. Taken together, the cases demonstrate the temporal and spatial continuities of social relations of power, and their embodiment in water resources. Conceptually, the paper brings together the literatures of environmental justice and the political ecology of water resources. In doing so, we employ the concept of waterscape as an analytical lens to examine processes of marginalisation and social exclusion in the Onondaga lake watershed. The waterscape concept, and the political ecology of water resources literature more generally, have much to contribute to the study of water-related environmental (in)justice

La conscience historique dans la région des Cantons de l'Est entre 1850 et 1960

À quoi sert l'histoire? Lasse d'entendre cette question que l'on m'adressait invariablement lorsque j'affirmais étudier en histoire, j'ai voulu approfondir ma réflexion sur le rôle de cette discipline dans la société québécoise. J'ai choisi de situer mon étude dans les Cantons de l'Est. Qu'est-ce qui constitue la conscience historique des communautés anglophone et francophone? Voilà ma question de recherche initiale. Mon objectif est d'établir les différents types de productions historiques et d'en analyser le contenu, cela dans le but de découvrir quelles étaient les manifestations d'appartenance sociale et les motivations des écrivains, tout en dressant une comparaison entre la production anglophone et francophone. J'ai établi un corpus de textes représentatif des deux communautés en tenant compte de la période de production puisque les deux groupes ne s'installèrent pas sur le territoire lors de la même période, ce qui explique la longue périodisation (1850-1960). J'ai sélectionné vingt-six ouvrages traitant de l'histoire des Cantons de l'Est, écrits, pour la plupart, par des auteurs de la région. Mon corpus de sources est constitué de quatorze sources anglophones et douze sources francophones."--Résumé abrégé par UMI