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Leukemia patients bearing the t(4;11)(q21;q23) translocations can be divided into two subgroups: those expressing both reciprocal fusion genes, and those that have only the MLL-AF4 fusion gene. Moreover, a recent study has demonstrated that patients expressing both fusion genes have a better outcome than patients that are expressing the MLL-AF4 fusion protein alone. All this may point to a clonal process where the reciprocal fusion gene AF4-MLL could be lost during disease progression, as this loss may select for a more aggressive type of leukemia. Therefore, we were interested in unraveling the decisive role of the AF4-MLL fusion protein at an early timepoint of disease development. We designed an experimental model system where the MLL-AF4 fusion protein was constitutively expressed, while an inducible AF4-MLL fusion gene was induced for only 48 h. Subsequently, we investigated genome-wide changes by RNA- and ATAC-Seq experiments at distinct timepoints. These analyses revealed that the expression of AF4-MLL for only 48 h was sufficient to significantly change the genomic landscape (transcription and chromatin) even on a longer time scale. Thus, we have to conclude that the AF4-MLL fusion protein works through a hit-and-run mechanism, probably necessary to set up pre-leukemic conditions, but being dispensable for later disease progression.
Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset. Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask. Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
To explore and describe attitudes and opinions towards suicidality in healthcare professionals (HCPs) working with oncological patients. Methods: A 48-item online questionnaire was developed and distributed to HCPs working with cancer patients. Three hundred fifty-four answered questionnaires were analyzed. Results: The majority of HCPs reported that they were able to understand why a cancer patient would commit suicide (87.8%) or would seek help from an assisted suicide organization (ASO; 83.9%). The understandable reasons were pain and physical impairments (51.4%), social isolation (19.8%), loss of control and autonomy (18.1%), terminal disease (17.2%), loss of meaning (15.3%), desperation (14.7%), and psychic distress (9.3%). Personal experiences with suicidality lead only 44.8% of HCPs to believe that thereby they would be better able to understand a patients’ wish for suicide. Religion was negatively associated with understanding of suicide and why a cancer patient would seek help from an ASO. Knowledge of suicidality was positively associated with why a cancer patient would seek help from an ASO. Conclusions: There is still little knowledge in oncology about the relation of HCPs’ attitudes toward suicidality in their patients and how those attitudes influence their behavior, especially care and treatment of patients. More research on this topic is needed. It stands to reason that more education about suicidality in cancer patients seems likely to improve understanding and attitudes and thereby influence care for cancer patients.
Objectives: Current treatments for chronic depression have focused on reducing interpersonal problems and negative affect, but paid little attention to promoting prosocial motivation and positive affect. Following this treatment focus, the objective of the present study was to examine whether the combination of metta (Loving Kindness) group meditation and subsequent tailored individual therapy focusing on kindness towards oneself and others (metta-based therapy, MBT) shows greater improvements in depressive symptoms than a wait list control group in patients with chronic depression. Methods: Forty-eight patients with DSM-5 persistent depressive disorder were randomly assigned to MBT or a wait list control condition. Outcome was assessed after group meditation, after subsequent individual therapy, and at 6-month follow-up. The primary outcome measure was an independent blind rating of depressive symptoms at post-test. Secondary outcome included changes in self-reported depression, behavioral activation, rumination, social functioning, mindfulness, compassion, and clinician-rated emotion regulation. Results: Mixed-design analyses showed significant differences between MBT and WLC in changes from pre- to post-test in clinician-rated and self-rated depression, behavioral activation, rumination, social functioning, mindfulness, and emotion regulation. Most of the changes occurred during group meditation and were associated with large effect sizes. Improvements were maintained at 6-month follow-up. Conclusions: The results provide preliminary support for the effectiveness of MBT in treating chronic depression. Trial Registration: ISRCTN, ISRCTN97264476.
When taking into consideration the demographic and socio-economic trends in most European countries, the demand for domestic services will be increasing in the next decades. This development could be used for creating formal employment opportunities in private households for unskilled and low-skilled labour. However, it is not an easy task since it entails devising a strategy for reducing the high share of informal labour in as well as overcoming the current fragmentation of the domestic services sector. Both on the national and EU level there is a need for policy advice on how to best integrate the diverse but yet interrelated needs and interests of the households, the employees and the firms as providers of domestic services into one coherent strategy. So far, such a comprehensive strategy can be found only in France where the BorlooPlan systematically integrated measures and tools from all relevant fields of politics. Thus it led to a significant growth of the domestic services sector and a substantial increase of formal employment. This brochure presents the Generalised Model, a tool for devising a similarly comprehensive and coherent strategy. It was constructed by drawing on the successful French strategy of creating more formal employment relationships through the systematic development of the domestic services sector. The brochure demonstrates how other countries can learn from the French experience by analysing their current situation and using the Generalised Model to create a strategy fitting their specific circumstances. By studying the situations in Germany, Austria, Italy and Poland and considering how to create strategies fitting the different national settings in these countries it is shown how the Generalised Model can put into practice. These case studies were conducted in the EU Project “Labour Market Instruments for Reducing Illegal Employment in Private Households of the Elderly”, supported by DG Employment, Social Affairs and Inclusion. The brochure intends to initiate and stimulate discourses on fostering the creation of formal employment in EU Member States. Therefore, it addresses different stakeholders such as policymakers on the national, regional and EU level, representatives of local administrations, providers of domestic services, domestic workers, trade unions or welfare associations, labour administration, placement services as well as providers of education and training.
Despite several decades of active research, there are still substantial gaps in the knowledge of parasitoid wasps in Australia, with many families and genera yet to be revised using modern approaches and only a fraction of the estimated fauna currently described. The genus Glyptapanteles Ashmead, 1904 is a member of the subfamily Microgastrinae (Hymenoptera: Braconidae) and all species in the subfamily are lepidopteran parasitoids. The genus previously contained only three species known from Australia: G. deliasa Austin & Dangerfield, 1992, G. drioplanetus Fagan-Jeffries & Austin, 2021 and G. mnesampela Austin, 2000. To undertake a revision of this morphologically-conserved group in Australia, we used a combination of molecular (cytochrome oxidase subunit one (COI) and wingless genes) and minimal morphological data to delimit and describe an additional 31 species: G. austini Fagan-Jeffries & Bird sp. nov. and the following 30 species all authored by Fagan-Jeffries, Bird & Austin: G. albigena sp. nov., G. andamookaensis sp. nov., G. arcanus sp. nov., G. aspersus sp. nov., G. austrinus sp. nov., G. baylessi sp. nov., G. bradfordae sp. nov., G. cooperi sp. nov., G. doreyi sp. nov., G. dowtoni sp. nov., G. eburneus sp. nov., G. erucadesolator sp. nov., G. ferrugineus sp. nov., G. foraminous sp. nov., G. goodwinnoakes sp. nov., G. guzikae sp. nov., G. harveyi sp. nov., G. kingae sp. nov., G. kittelae sp. nov., G. kurandaensis sp. nov., G. lambkinae sp. nov., G. lessardi sp. nov., G. mouldsi sp. nov., G. niveus sp. nov., G. rixi sp. nov., G. rodriguezae sp. nov., G. ruhri sp. nov., G. sanniopolus sp. nov., G. vergrandiacus sp. nov. and G. wrightae sp. nov. We provide a key to species groups and to the species able to be identified on morphological characters alone. Additionally, we provide a brief discussion of the difficulties in describing small, morphologically conserved wasps and the challenges associated with revising the taxonomy of hyperdiverse taxa in the context of the planned mission of Taxonomy Australia to accelerate the documentation of Australia’s biodiversity.
Five new and six known species belonging to the genus Basirotyleptus collected from the Western Ghats, India, are described and illustrated. Basirotyleptus conicaudatus sp. nov. is characterized by having 0.42–0.44 mm long body; odontostyle 9.5–10.0 μm, odontophore 11.5–12.0 μm; pharyngeal bulb pear-shaped, 14–15% of total neck length; female genital system mono-opisthodelphic; tail conoid with acute terminus. Basirotyleptus constrictus sp. nov. is characterized by having 0.38–0.49 mm long body; perioral disc distinct; odontostyle 9–10 μm, odontophore 14–15 μm; pharyngeal bulb pear-shaped, 15–17% of total neck length; female genital system mono-opisthodelphic; tail rounded to conoid. Basirotyleptus goaensis sp. nov. is characterized by having 0.73–0.87 mm long body; odontostyle 13.0–14.5 μm, odontophore 15.0–17.5 μm; pharyngeal bulb pyriform, 16–18% of total neck length; female genital system mono-opisthodelphic; tail rounded. Basirotyleptus neocaudatus sp. nov. is characterized by having 0.31–0.44 mm long body; odontostyle 7.5–9.5 μm, odontophore 10–13 μm; pharyngeal bulb pear-shaped, 14–19% of total neck length; female genital system mono-opisthodelphic; tail conoid with acute terminus. Basirotyleptus siddiqii sp. nov. is characterized by having 0.36 mm long body; odontostyle 7.5–8.0 μm, odontophore 10.0–10.5 μm; pharyngeal bulb pear-shaped, 15–16% of total neck length; female genital system mono-opisthodelphic; tail conoid. Six known species viz., B. basiri, B. pini, B. nindei, B. ethiopicus, B. acus, B. minutus are also described and illustrated. Along with light microscopic study, line drawings, compendium and key to species of Basirotyleptus are also provided.
We describe and illustrate eight new species of chewing lice in the genus Philopterus Nitzsch, 1818, parasitic on hosts in the bird families Cardinalidae, Chloropseidae, Hirundinidae, Icteridae, Motacillidae, Paridae, and Vangidae from China, Peru, South Africa, Thailand, and the USA. They are: Philopterus coriaceus sp. nov. from Molothrus oryzivorus oryzivorus (Gmelin, 1788); P. hebes sp. nov. from Chloropsis aurifrons inornata Kloss, 1918 and C. cochinchinensis kinneari Hall & Deignan, 1956; P. micropunctatus sp. nov. from Anthus hodgsoni Richmond, 1907; P. afropari sp. nov. from Melaniparus cinerascens cinerascens (Vieillot, 1818); P. pseudhirundo sp. nov. from Pseudhirundo griseopyga Sundevall, 1850; P. sinensis sp. nov. from Hemipus picatus capitalis (Horsfield, 1840); P. stansburyensis sp. nov. from Pheucticus melanocephalus melanocephalus (Swainson, 1827); and P. trepostephanus sp. nov. from Tephrodornis virgatus fretensis Robinson & Kloss, 1920 and T. v. mekongensis Meyer de Schauensee, 1946. Philopterus hebes sp. nov. constitutes the first record of the genus Philopterus from the Chloropseidae. We also provide some notes on the morphology and status of Cypseloecus Conci, 1941.