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Hydrofluorocarbons (HFCs) and so-called hydrofluoroolefins (HFOs) are used as refrigerants in air conditioning, refrigeration, chillers, heat pumps and devices for dehumidification and drying. However, many HFCs, including R-134a and R-125, have a high global warming potential and some of the HFCs and HFOs degrade atmospherically and form trifluoroacetic acid (TFA) as a persistent degradation product. Rising levels of TFA around the globe reveal an urgent need to replace fluorinated refrigerants with non-fluorinated working fluids to avoid direct emissions due to leakage, incorrect loading or removal. It is important, however, also to select refrigerants with high efficiencies to avoid increasing indirect CO 2 emissions due to higher energy consumption during the use phase. The present study investigates the available non-fluorinated alternatives to fluorinated refrigerants and shows that a transition to non-fluorinated refrigerants, in general, is possible and has happened in many sectors already. Technically, there are only slight barriers to overcome in order to replace fluorinated refrigerants in almost all newly developed systems conforming to existing standards. Additionally, we show that alternatives are available even for some use cases for which derogations have been proposed in the EU PFAS restriction proposal and suggest making these derogations more specific to support a speedy transition to non-fluorinated refrigerants in all sectors.

Abstract: Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between break point partners (motor neuron and pancreas homeobox 1 [MNX1] and ETS variant transcription factor 6 [ETV6]) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation break points on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) induced pluripotent stem cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer hijacking may be a more widespread consequence of translocations in which no oncofusion product was identified, including t(1;3) or t(4;12) AML., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Cone-beam computed tomography (CBCT)-based online adaptation is increasingly being introduced into many clinics. Upon implementation of a new treatment technique, a prospective risk analysis is required and enhances workflow safety. We conducted a risk analysis using Failure Mode and Effects Analysis (FMEA) upon the introduction of an online adaptive treatment programme (Wegener et al., Z Med Phys. 2022). A prospective risk analysis, lacking in-depth clinical experience with a treatment modality or treatment machine, relies on imagination and estimates of the occurrence of different failure modes. Therefore, we systematically documented all irregularities during the first year of online adaptation, namely all cases in which quality assurance detected undesired states potentially leading to negative consequences. Additionally, the quality of automatic contouring was evaluated. Based on those quantitative data, the risk analysis was updated by an interprofessional team. Furthermore, a hypothetical radiation therapist-only workflow during adaptive sessions was included in the prospective analysis, as opposed to the involvement of an interprofessional team performing each adaptive treatment. A total of 126 irregularities were recorded during the first year. During that time period, many of the previously anticipated failure modes (almost) occurred, indicating that the initial prospective risk analysis captured relevant failure modes. However, some scenarios were not anticipated, emphasizing the limits of a prospective risk analysis. This underscores the need for regular updates to the risk analysis. The most critical failure modes are presented together with possible mitigation strategies. It was further noted that almost half of the reported irregularities applied to the non-adaptive treatments on this treatment machine, primarily due to a manual plan import step implemented in the institution's workflow., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeard to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well., Methods: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2., Results: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants ( NR1H2 , GKAP1 ), four candidate genes with autosomal-recessive biallelic variants ( AKR1B10 , CLSTN3 , NDST4 , PLEKHB1 ) and one candidate gene with suggestive uniparental disomy ( SVEP1 ). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68)., Conclusions: According to previous studies, our study further implicates LZTR1 in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.

T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse cis-alterations, including SIL-TAL1 microdeletions, translocations with T-cell Receptor loci, and more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied by activating epigenetic marks. This observation laid the groundwork for an innovative paradigm concerning the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of T-ALL expressing TAL1 (TAL1+), the deregulation mechanism remains 'unresolved'. We took advantage of H3K27ac and H3K4me3 chromatin immunoprecipitation sequencing data of eight cases of T-ALL, including five TAL1+ cases. We identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an unresolved monoallelic TAL1+ case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor. Here we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks, and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.

Bats fly with highly articulated and heavy wings. To understand their power requirements, we develop a three-dimensional reduced-order model, and apply it to flights of Cynopterus brachyotis , the lesser dog-faced fruit bat. Using previously measured wing kinematics, the model computes aerodynamic forces using blade element momentum theory, and incorporates inertial forces of the flapping wing using the measured mass distribution of the membrane wing and body. The two are combined into a Lagrangian equation of motion, and we performed Monte Carlo simulations to address uncertainties in measurement errors and modelling assumptions. We find that the camber of the armwing decreases with flight speed whereas the handwing camber is more independent of speed. Wing camber disproportionately impacts energetics, mainly during the downstroke, and increases the power requirement from 8% to 22% over flight speed U = 3.2-7.4 m s -1 . We separate total power into aerodynamic and inertial components, and aerodynamic power into parasitic, profile and induced power, and find strong agreement with previous theoretical and experimental studies. We find that inertia of wings help to balance aerodynamic forces, alleviating the muscle power required for weight support and thrust generation. Furthermore, the model suggests aerodynamic forces assist in lifting the heavy wing during upstroke.

Objective: Large-scale genome sequencing efforts of human tumours identified epigenetic modifiers as one of the most frequently mutated gene class in human cancer. However, how these mutations drive tumour development and tumour progression are largely unknown. Here, we investigated the function of the histone demethylase KDM6A in gastrointestinal cancers, such as liver cancer and pancreatic cancer., Design: Genetic alterations as well as expression analyses of KDM6A were performed in patients with liver cancer. Genetic mouse models of liver and pancreatic cancer coupled with Kdm6a-deficiency were investigated, transcriptomic and epigenetic profiling was performed, and in vivo and in vitro drug treatments were conducted., Results: KDM6A expression was lost in 30% of patients with liver cancer. Kdm6a deletion significantly accelerated tumour development in murine liver and pancreatic cancer models. Kdm6a-deficient tumours showed hyperactivation of mTORC1 signalling, whereas endogenous Kdm6a re-expression by inducible RNA-interference in established Kdm6a-deficient tumours diminished mTORC1 activity resulting in attenuated tumour progression. Genome-wide transcriptional and epigenetic profiling revealed direct binding of Kdm6a to crucial negative regulators of mTORC1, such as Deptor, and subsequent transcriptional activation by epigenetic remodelling. Moreover, in vitro and in vivo genetic epistasis experiments illustrated a crucial function of Deptor and mTORC1 in Kdm6a-dependent tumour suppression. Importantly, KDM6A expression in human tumours correlates with mTORC1 activity and KDM6A-deficient tumours exhibit increased sensitivity to mTORC1 inhibition., Conclusion: KDM6A is an important tumour suppressor in gastrointestinal cancers and acts as an epigenetic toggle for mTORC1 signalling. Patients with KDM6A-deficient tumours could benefit of targeted therapy focusing on mTORC1 inhibition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The birth prevalence of laterality defects is about 1.1/10,000 comprising different phenotypes ranging from situs inversus totalis to heterotaxy, mostly associated with complex congenital heart defects (CHD) and situs abnormalities such as intestinal malrotation, biliary atresia, asplenia, or polysplenia. A proportion of laterality defects arise in the context of primary ciliary dyskinesia (PCD) accompanied by respiratory symptoms or infertility. In this study, exome sequencing (ES) was performed in 14 case-parent trios/quattros with clinical exclusion of PCD prior to analysis. Moreover, all cases and parents underwent detailed clinical phenotyping including physical examination, echocardiography by a skilled paediatric cardiologist and abdominal ultrasound examinations not to miss mildly affected individuals. Subsequent survey of the exome data comprised filtering for monoallelic de novo, rare biallelic, and X-linked recessive variants. In two families, rare variants of uncertain significance (VUS) in PKD1L1 and ZIC3 were identified. Both genes have been associated with laterality defects. In two of the remaining families, biallelic variants in LMBRD1 and DNAH17, respectively, were prioritized. In another family, an ultra-rare de novo variant in WDR47 was found. Extensive exome survey of 2,109 single exomes of individuals with situs inversus totalis, heterotaxy, or isolated CHD identified two individuals with novel monoallelic variants in WDR47, but no further individuals with biallelic variants in DNAH17 or LMBRD1. Overall, ES of 14 case-parent trios/quattros with cardiovascular laterality defects identified rare VUS in two families in known disease-associated genes PKD1L1 and ZIC3 and suggests DNAH17, LMBRD1, and WDR47 as potential genes involved in laterality defects., (© 2022. The Author(s).)

DNA methylation analysis by sequencing is becoming increasingly popular, yielding methylomes at single-base pair and single-molecule resolution. It has tremendous potential for cell-type heterogeneity analysis using intrinsic read-level information. Although diverse deconvolution methods were developed to infer cell-type composition based on bulk sequencing-based methylomes, systematic evaluation has not been performed yet. Here, we thoroughly benchmark six previously published methods: Bayesian epiallele detection, DXM, PRISM, csmFinder+coMethy, ClubCpG and MethylPurify, together with two array-based methods, MeDeCom and Houseman, as a comparison group. Sequencing-based deconvolution methods consist of two main steps, informative region selection and cell-type composition estimation, thus each was individually assessed. With this elaborate evaluation, we aimed to establish which method achieves the highest performance in different scenarios of synthetic bulk samples. We found that cell-type deconvolution performance is influenced by different factors depending on the number of cell types within the mixture. Finally, we propose a best-practice deconvolution strategy for sequencing data and point out limitations that need to be handled. Array-based methods-both reference-based and reference-free-generally outperformed sequencing-based methods, despite the absence of read-level information. This implies that the current sequencing-based methods still struggle with correctly identifying cell-type-specific signals and eliminating confounding methylation patterns, which needs to be handled in future studies., (© The Author(s) 2022. Published by Oxford University Press.)

Identifying the potential routes of airborne transmission during transportation is of critical importance to limit the spread of the SARS-CoV-2 virus. Here, we numerically solve the Reynolds-averaged Navier-Stokes equations along with the transport equation for a passive scalar in order to study aerosol transmission inside the passenger cabin of an automobile. Extending the previous work on this topic, we explore several driving scenarios including the effects of having the windows fully open, half-open, and one-quarter open, the effect of opening a moon roof, and the scaling of the aerosol transport as a function of vehicle speed. The flow in the passenger cabin is largely driven by the external surface pressure distribution on the vehicle, and the relative concentration of aerosols in the cabin scales inversely with vehicle speed. For the simplified geometry studied here, we find that the half-open windows configuration has almost the same ventilation effectively as the one with the windows fully open. The utility of the moonroof as an effective exit vent for removing the aerosols generated within the cabin space is discussed. Using our results, we propose a "speed-time" map, which gives guidance regarding the relative risk of transmission between driver and passenger as a function of trip duration and vehicle speed. A few strategies for the removal of airborne contaminants during low-speed driving, or in a situation where the vehicle is stuck in traffic, are suggested., (© 2022 Author(s).)