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Figure S1A. Correlation of patterns of DILD as per ATS/ERS classification and clinical severity. Figure S1B. A higher RMH DILD score predicts for increasing clinical severity of DILD as per CTCAE grading.

Table S1. Frequency of DILD as per category

Purpose:Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described.Patients and Methods:A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed.Results:Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01).Conclusions:DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.

Figure S1A. Correlation of patterns of DILD as per ATS/ERS classification and clinical severity. AIP correlated significantly with worse severity (P=0.002). NSIP, non-specific interstitial pneumonia; COP, cryptogenic organizing pneumonia; AIP, acute interstitial pneumonia; HP, hypersensitivity pneumonitis. Figure S1B. A higher RMH DILD score predicts for increasing clinical severity of DILD as per CTCAE grading. Shown are CTCAE grading and RMH DILD Score at the time of DILD detection. Box plot mapping RMH DILD Scores against CTCAE grading showing statistically significant worsening of CTCAE grading and symptoms with higher RMH DILD score (P=0.004); DILD was confirmed to be the cause of death in one patient who had an initial RMH DILD score of 5 and was asymptomatic with an excellent partial response to therapy and so was continued on therapy. This patient then developed symptomatic DILD with a worsening RMH DILD score of 8, deteriorated and died. RMH DILD score, Royal Marsden Hospital Score for drug induced interstitial lung disease; CTCAE, Common Terminology Criteria for Adverse Events Version 5.0. Figure S2. Continuation of IMP following radiological detection of asymptomatic DILD resulting in clinical deterioration. Images from a patient with breast cancer treated with an investigational drug-conjugate. Patient had no prior lung disease and no lung metastases at baseline. Cartoons (left) show RMH DILD scoring of matched sagittal radiographic images (right). The first row shows initial development of radiographic changes after 2 cycles of treatment when patient was asymptomatic (RMH DILD score of 5) and otherwise had a remarkable RECIST PR. With a further cycle of treatment, the changes had significantly worsened (RMH DILD score of 8), with development of rapidly progressive clinical symptoms which was ultimately fatal despite treatment with antibiotics, steroids, and respiratory support.

Leseprobe ----- Bibliographie: Bar-On, Dan: Moral und unterschwelliges Streben nach Macht. Interview mit einem KZ-Arzt und seinem Sohn [BIOS 1 (1988), Heft 2, 59-71], BIOS – Zeitschrift fur Biographieforschung, Oral History und Lebensverlaufsanalysen, 1+2-2019, S. 17-29. ----- Open-Access-Lizenz: Dieser Beitrag ist ab dem 16.11.2023 im Open Access unter der Creative-Commons-Lizenz CC BY 4.0 (Namensnennung 4.0 International) verfugbar. Weitere Informationen zur Lizenz und den Nutzungsbedingungen finden Sie hier .

Purpose: Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described. Patients and Methods: A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed. Results: Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01). Conclusions: DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.

Deleterious and intact mitochondrial DNA (mtDNA) mutations frequently co-exist (heteroplasmy). Such mutations likely survive and are inherited due to complementation via the intra-cellular mitochondrial network. Hence, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. To test this hypothesis, we assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin. Firstly, these animals displayed severe embryonic lethality and developmental delay. Strikingly, these phenotypes were relieved during subsequent generations in association with complete ΔmtDNA removal. Moreover, the rates of deletion loss negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. While introducing the ΔmtDNA into a fzo-1;pdr-1 (PARKIN ortholog) double mutant, we observed skew in the mendelian distribution of progeny, in contrast to normal distribution in the ΔmtDNA;fzo-1 mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. This underlines the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. Finally, while investigating heteroplasmy patterns in three Charcot-Marie-Tooth disease type 2A pedigrees, which carry a mutated mitofusin 2, we found a single potentially deleterious heteroplasmic mutation, whose levels were selectively reduced in the patient versus healthy maternal relatives. Taken together our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection, while inherited from generation to generation.

DNA harbors the blueprint for life. However, the instructions stored in the DNA could be altered at the RNA level before they are executed. One of these processes is RNA editing, which was shown to modify RNA sequences in many organisms. The most abundant modification is the deamination of adenosine (A) into inosine (I). In turn, inosine can be identified as a guanosine (G) by the ribosome and other cellular machineries such as reverse transcriptase. In multicellular organisms, enzymes from the ADAR (adenosine deaminase acting on RNA) family mediate RNA editing in mRNA, whereas enzymes from the ADAT family mediate A-to-I editing on tRNAs. In bacteria however, until recently, only one editing site was described, in tRNA(Arg), but never in mRNA. The tRNA site was shown to be modified by tadA (tRNA specific adenosine deaminase) which is believed to be the ancestral enzyme for the RNA editing family of enzymes. In our recent work, we have shown for the first time, editing on multiple sites in bacterial mRNAs and identified tadA as the enzyme responsible for this editing activity. Focusing on one of the identified targets – the self-killing toxin hokB, we found that editing is physiologically regulated and that it increases protein activity. Here we discuss possible modes of regulation on hokB editing, potential roles of RNA editing in bacteria, possible implications, and future research directions.

Flashlamp pumped Cth:YAG lasers are mainly used in medical applications (urology). The main laser transition is at 2.13μ and is called a quasi-three level having an emission cross-section of 7x10-21 cm2 and a ground state absorption of approximately 5%/cm. Because of the relatively low absorption, combined with a modest emission cross-section, the laser requires high reflectivity output coupling, and therefore high intra-cavity energy density which limits the output to approximately 4J/pulse for reliable operation. This paper will describe a method of efficiently generating high output energy at low intra-cavity energy density by using an alternative 2.097μ transition having an emission cross-section of 5x10-21 cm2 and a ground level absorption of approximately 14%/cm.

Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon. Furthermore, we identified the tRNA-specific adenosine deaminase (tadA) as the editing enzyme of all these editing sites, thus making it the first identified RNA editing enzyme that modifies both tRNAs and mRNAs. Interestingly, several of the editing targets are self-killing toxins that belong to evolutionarily conserved toxin-antitoxin pairs. We focused on hokB, a toxin that confers antibiotic tolerance by growth inhibition, as it demonstrated the highest level of such mRNA editing. We identified a correlated mutation pattern between the edited and a DNA hard-coded Cys residue positions in the toxin and demonstrated that RNA editing occurs in hokB in two additional bacterial species. Thus, not only the toxin is evolutionarily conserved but also the editing itself within the toxin is. Finally, we found that RNA editing in hokB increases as a function of cell density and enhances its toxicity. Our work thus demonstrates the occurrence, regulation, and functional consequences of RNA editing in bacteria.

[This corrects the article DOI: 10.1371/journal.pbio.1002557.].

Recently, we found dramatic mitochondrial DNA divergence of Israeli Chamaeleo chamaeleon populations into two geographically distinct groups. We aimed to examine whether the same pattern of divergence could be found in nuclear genes. However, no genomic resource is available for any chameleon species. Here we present the first chameleon transcriptome, obtained using deep sequencing (SOLiD). Our analysis identified 164,000 sequence contigs of which 19,000 yielded unique BlastX hits. To test the efficacy of our sequencing effort, we examined whether the chameleon and other available reptilian transcriptomes harbored complete sets of genes comprising known biochemical pathways, focusing on the nDNA-encoded oxidative phosphorylation (OXPHOS) genes as a model. As a reference for the screen, we used the human 86 (including isoforms) known structural nDNA-encoded OXPHOS subunits. Analysis of 34 publicly available vertebrate transcriptomes revealed orthologs for most human OXPHOS genes. However, OXPHOS subunit COX8 (Cytochrome C oxidase subunit 8), including all its known isoforms, was consistently absent in transcriptomes of iguanian lizards, implying loss of this subunit during the radiation of this suborder. The lack of COX8 in the suborder Iguania is intriguing, since it is important for cellular respiration and ATP production. Our sequencing effort added a new resource for comparative genomic studies, and shed new light on the evolutionary dynamics of the OXPHOS system.

The mitochondrial ribosome, which translates all mitochondrial DNA (mtDNA)-encoded proteins, should be tightly regulated pre- and post-transcriptionally. Recently, we found RNA-DNA differences (RDDs) at human mitochondrial 16S (large) rRNA position 947 that were indicative of post-transcriptional modification. Here, we show that these 16S rRNA RDDs result from a 1-methyladenosine (m1A) modification introduced by TRMT61B, thus being the first vertebrate methyltransferase that modifies both tRNA and rRNAs. m1A947 is conserved in humans and all vertebrates having adenine at the corresponding mtDNA position (90% of vertebrates). However, this mtDNA base is a thymine in 10% of the vertebrates and a guanine in the 23S rRNA of 95% of bacteria, suggesting alternative evolutionary solutions. m1A, uridine, or guanine may stabilize the local structure of mitochondrial and bacterial ribosomes. Experimental assessment of genome-edited Escherichia coli showed that unmodified adenine caused impaired protein synthesis and growth. Our findings revealed a conserved mechanism of rRNA modification that has been selected instead of DNA mutations to enable proper mitochondrial ribosome function., PLoS Biology, 14 (9), ISSN:1544-9173, ISSN:1545-7885

This article is based on a series of interviews with 73 individuals who participated in the 1948 war. Though the war had many physical as well as emotional casualties, surprisingly a relatively small portion of individuals were willing to admit the occurrence of combat stress reactions. This finding is quite puzzling in the face of the drastic course of the war. Hence, it is speculated that denial and suppressive processes underlie the interviewees' declarations. Moreover, it is assumed that this denial process is part of the construction of a monolithic social identity. The origins of this process and its implications for Israeli social identity are discussed.

Constructing physiologically relevant compartmental models of neurones is critical for understanding neuronal activity and function. We recently suggested that measurements from multiple locations along the soma, dendrites and axon are necessary as a data set when using a genetic optimization algorithm to constrain the parameters of a compartmental model of an entire neurone. However, recordings from L5 pyramidal neurones can routinely be performed simultaneously from only two locations. Now we show that a data set recorded from the soma and apical dendrite combined with a parameter peeling procedure is sufficient to constrain a compartmental model for the apical dendrite of L5 pyramidal neurones. The peeling procedure was tested on several compartmental models showing that it avoids local minima in parameter space. Based on the requirements of this analysis procedure, we designed and performed simultaneous whole-cell recordings from the soma and apical dendrite of rat L5 pyramidal neurones. The data set obtained from these recordings allowed constraining a simplified compartmental model for the apical dendrite of L5 pyramidal neurones containing four voltage-gated conductances. In agreement with experimental findings, the optimized model predicts that the conductance density gradients of voltage-gated K+ conductances taper rapidly proximal to the soma, while the density gradient of the voltage-gated Na+ conductance tapers slowly along the apical dendrite. The model reproduced the back-propagation of the action potential and the modulation of the resting membrane potential along the apical dendrite. Furthermore, the optimized model provided a mechanistic explanation for the back-propagation of the action potential into the apical dendrite and the generation of dendritic Na+ spikes.

In this essay, Shoshana Steinberg and Dan Bar-On present the work of a team of Israeli and Palestinian teachers who developed a history textbook that includes both groups' narratives of the same events side by side. These teachers then tested the effects of its use in both Israeli and Palestinian classrooms; for the first time, students on each side of the conflict were exposed to the other side's understanding of key historical events. The authors present the challenges that the team faced in developing the textbook and that teachers encountered in the classroom as well as the understanding and collaboration this project fostered. They argue that the process of creating the dual-narratives text, as well as the text itself, allows teachers to play a productive role in violent political conflicts.

While Holocaust related activities and educational programs around the world are growing in number, published reports on their impact are scarce, especially on the university level. The free responses of 94 Jewish‐Israeli university students who took the course “Psychology of the Holocaust” yielded eight themes. The results reflect a change of emphasis and movement from a mainly particularistic interpretation of the Holocaust to a more universalistic understanding of the Holocaust. This movement is explained by the occurrence of two reflective processes: situational and universal reflexivity of genocide and reflexivity regarding the personal and collective impact of genocide.

Eliezer Gruenbaum, the communist son of Yitzhak Gruenbaum, who was a prominent leader of Polish Jewry between the two world wars and Israel’s first interior minister, was a kapo in Auschwitz-Birkenau. Eliezer survived only to die fighting in the war for Israeli independence. His story is captivating not only for its biographical appeal but also for the unique “statement of defense” memoir he has left behind.This paper will expose the English-speaking reader to excerpts of this singular text for the first time. It will also offer a careful analysis and interpretation of Eliezer Gruenbaum’s psychological struggle to work through his controversial past. We will frame his narrative as wavering between two perhaps contradicting identifications—with his readers and with the victims—with neither of whom he can fully identify.The same activist stance that urged him to write, appealing to his reader’s acquittal, prevented him from truly understanding the total helplessness of the real victims. Eliezer Gruenbaum’s memoir constitutes an extraordinary piece of testimony. While there are numerous personal accounts of life in the camps written by Jews who had been inmates, Eliezer Gruenbaum’s text is unique for being the testimony of a Jew who served as a kapo in Birkenau, a precise recitation of his experience as the deputy chief of a barrack, and a vehement defense of the moral code he developed there in order to justify his situation. This was a perspective of events that had not yet been presented to the world, being published so soon after the war itself. Gruenbaum offers us a point of view that few others have chosen, doing so with a great measure of integrity.

Recent years have seen increased study of dendritic integration, mostly in acute brain slices. However, due to the low background activity in brain slices the integration of synaptic input in slice preparations may not truly reflect conditions in vivo. To investigate dendritic integration, back-propagation of the action potential (AP) and initiation of the dendritic Ca(2+) spike we simultaneously recorded membrane potential at the soma and apical dendrite of layer 5 (L5) pyramidal neurons in quiescent and excited acute brain slices. After excitation of the brain slice the somatic input resistance decreased and the apparent passive space constant shortened. However, the back-propagating AP and dendritic Ca(2+) spike were robust during increased synaptic activity. The dendritic Ca(2+) spike was suppressed by the ionic composition of the bath solution required for slice excitation, suggesting that Ca(2+) spikes may be smaller in vivo than in the acute slice preparation. The results presented here suggest that, under the conditions of slice excitation examined in this study, the increased membrane conductance induced by activation of voltage-gated channels during back-propagation of the AP and dendritic Ca(2+) spike initiation is sufficiently larger than the membrane conductance at subthreshold potentials to allow these two regenerative dendritic events to remain robust over several levels of synaptic activity in the apical dendrite of L5 pyramidal neurons.

Voltage-gated potassium channels effectively regulate dendritic excitability in neurones. It has been suggested that in the distal apical dendrite of layer 5B (L5B) neocortical pyramidal neurones, K+ conductances participate in active dendritic synaptic integration and control regenerative dendritic potentials. The ionic mechanism for triggering these regenerative potentials has yet to be elucidated. Here we used two-electrode voltage clamp (TEVC) to quantitatively record K+ conductance densities of a sustained K+ conductance in the soma and apical dendrite of L5B neurones of adult rats. We report that the somatic and proximal dendritic sustained voltage-gated K+ conductance density is more than 10-fold larger than previous estimates. The results obtained using TEVC were corroborated using current-clamp experiments in combination with compartmental modelling. Possible error sources, including inaccurate measurement of the passive membrane parameters and unknown axonal and basal dendritic conductance distributions, were shown not to distort the density estimation considerably. The sustained voltage-gated K+ conductance density was found to decrease steeply along the apical dendrite. The steep negative K+ conductance density gradient along the apical dendrite may help to define a distal, low-threshold region for amplification of distal synaptic input in L5B pyramidal neurones.

RNA-seq is becoming a preferred tool for genomics studies of model and non-model organisms. However, DNA-based analysis of organisms lacking sequenced genomes cannot rely on RNA-seq data alone to isolate most genes of interest, as DNA codes both exons and introns. With this in mind, we designed a novel tool, LEMONS, that exploits the evolutionary conservation of both exon/intron boundary positions and splice junction recognition signals to produce high throughput splice-junction predictions in the absence of a reference genome. When tested on multiple annotated vertebrate mRNA data, LEMONS accurately identified 87% (average) of the splice-junctions. LEMONS was then applied to our updated Mediterranean chameleon transcriptome, which lacks a reference genome, and predicted a total of 90,820 exon-exon junctions. We experimentally verified these splice-junction predictions by amplifying and sequencing twenty randomly selected genes from chameleon DNA templates. Exons and introns were detected in 19 of 20 of the positions predicted by LEMONS. To the best of our knowledge, LEMONS is currently the only experimentally verified tool that can accurately predict splice-junctions in organisms that lack a reference genome.

The current article presents an analysis of the life stories of three generations of women within a family headed by a Holocaust survivor. Its uniqueness lies in its double analysis of the stories told by these women, with an interval of 12 years between telling. The first series of interviews were conducted in the early 1990s within the framework of a pioneering study in which, for the first time, three generations in each of 20 families were interviewed and their narratives analyzed. The current analyses are based on the perspective that, through life narratives, it is possible to view the transformations of relationships over time and that these transformations in relationships are central to personal development. We will examine the relationships of the women in these three generations, both with significant others and with each other. We will trace processes of development and changes in these relationships over the 12 years. Finally, we will discuss the social and methodological implications of our study.

Cet article decrit les techniques du groupe TRT pour aider d’anciens ennemis a se rencontrer et perlaborer les traumatismes qui ont resulte de leur conflit.