Miracle-dz/UniFAR-FTUs huggingface dataset:
Small‐cell lung cancer from the peripheral lung is frequently accompanied by emphysema and interstitial lung disease in the background

It has long been thought that small‐cell lung cancer (SCLC) is a central type of tumor that is located in the proximal bronchi and the mediastinum. However, several studies reported that SCLC exhibited several types of spread pattern on computed tomography (CT). The aim of this study is to investigate the relationship between CT images and clinical characteristics in patients with SCLC.
Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection

Intraepithelial T cells (IETs) are in close contact with intestinal epithelial cells and the underlying basement membrane, and they detect invasive pathogens. How intestinal epithelial cells and basement membrane influence IET survival and function, at steady state or after infection, is unclear. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is constitutively expressed by intestinal epithelial cells and is important for protection from pathogenic bacteria. Here, we showed that at steady-state LIGHT, an HVEM ligand, binding to epithelial HVEM promoted the survival of small intestine IETs. RNA-seq and addition of HVEM ligands to epithelial organoids indicated that HVEM increased epithelial synthesis of basement membrane proteins, including collagen IV, which bound to β1 integrins expressed by IETs. Therefore, we proposed that IET survival depended on β1 integrin binding to collagen IV and showed that β1 integrin–collagen IV interactions supported IET survival in vitro. Moreover, the absence of β1 integrin expression by T lymphocytes decreased TCR αβ+ IETs in vivo. Intravital microscopy showed that the patrolling movement of IETs was reduced without epithelial HVEM. As likely consequences of decreased number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β1 integrins. Therefore, IETs, at steady state and after infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β1 integrins on IETs that were important for their maintenance and for their protective function in mucosal immunity. Description Epithelial HVEM maintains intraepithelial T cell survival and function and supports host defense. Intestinal epithelia maintain T cells Immune surveillance of the intestinal epithelium is crucial for intestinal homeostasis and protecting against infection. However, how the intestinal epithelium helps induce immune surveilling intraepithelial T cells (IET) is unclear. Here, Seo, Takahashi, and Wang et al. used mouse knockout models to demonstrate that herpes virus entry mediator (HVEM), a TNFR superfamily member, expression on intestinal epithelial cells was crucial for the survival and patrolling ability of intraepithelial CD8α T cells. LIGHT, a ligand for HVEM, was crucial for the HVEM-driven effects seen. Epithelial knockout of HVEM led to poorer protection against intestinal S. typimurium infection. Together, these data show that HVEM expression in intestinal epithelial cells is involved in IET-mediated immune surveillance of the small intestine.
Pressure‐dependent fouling behavior during sterile filtration of mRNA‐containing lipid nanoparticles

The COVID‐19 pandemic has generated growing interest in the development of mRNA‐based vaccines and therapeutics. However, the size and properties of the lipid nanoparticles (LNPs) used to deliver the nucleic acids can lead to unique phenomena during manufacturing that are not typical of other biologics. The objective of this study was to develop a more fundamental understanding of the factors controlling the performance of sterile filtration of mRNA‐LNPs. Experimental filtration studies were performed with a Moderna mRNA‐LNP solution using a commercially available dual‐layer polyethersulfone sterile filter, the Sartopore 2 XLG. Unexpectedly, increasing the transmembrane pressure (TMP) from 2 to 20 psi provided more than a twofold increase in filter capacity. Also surprisingly, the effective resistance of the fouled filter decreased with increasing TMP, in contrast to the pressure‐independent behavior expected for an incompressible media and the increase in resistance typically seen for a compressible fouling deposit. The mRNA‐LNPs appear to foul the dual‐layer filter by blocking the pores in the downstream sterilizing‐grade membrane layer, as demonstrated both by scanning electron microscopy and derivative analysis of filtration data collected for the two layers independently. These results provide important insights into the mechanisms governing the filtration of mRNA‐LNP vaccines and therapeutics.
Validation of thrombotic risk factors in 1381 patients with essential thrombocythaemia: A multicentre retrospective real‐life study

Thrombosis and haemorrhage are frequent in patients with essential thrombocythaemia (ET). The 2016 revised International Prognostic Score for Thrombosis in Essential Thrombocythaemia‐thrombosis (r‐IPSET‐t) score stratifies patients into very‐low‐ (VLR), low‐ (LR), intermediate‐ (IR) and high‐risk (HR) groups. We validated the r‐IPSET‐t in the biggest population of patients with ET (n = 1381) to date and found it to be a better fit than the earlier IPSET‐t score. With an average follow‐up of 87.7 months, there were 0.578 thrombotic events/person‐year and 0.286 bleeding events/person‐year after diagnosis. The 10‐year thrombosis‐free survival was 88% and 99% for the r‐IPSET‐t LR and VLR groups (p < 0.001). Cytoreduction was a thrombotic risk factor in younger patients (aged <60 years, hazard ratio 9.49, p = 0.026; aged ≥60 years, hazard ratio 1.04, p = 0.93). In multivariable Cox regression analysis, anti‐aggregation after diagnosis was protective for thrombosis (hazard ratio 0.31, p = 0.005) but a risk factor for major bleeding (hazard ratio 10.56, p = 0.021). Of the IPSET‐t HR and LR groups, 132/780 and 249/301 were re‐classified as LR and VLR respectively (p < 0.001). The European LeukemiaNET (ELN) does not recommend aspirin for VLR patients but in this real‐life analysis 83.1% of VLR patients received it. Our results validate the r‐IPSET‐t score as more predictive for thrombosis than the ELN‐recommended IPSET‐t and raise concerns about unnecessary cytoreductive and anti‐aggregative therapy.
Benchmarking bioinformatics approaches for tumour mutational burden evaluation from a large cancer panel against whole-exome sequencing

Tumour mutational burden (TMB) is used to predict response to immunotherapies. Although several groups have proposed calculation methods for TMB, a clear consensus has not yet emerged. In this study, we explored TMB calculation approaches with a 586-gene cancer panel (1.75 Mb) benchmarked to TMB measured by whole-exome sequencing (WES), using 30 samples across a range of tumour types. We explored variant allelic fraction (VAF) cut-offs of 5% and 10%, population database filtering at 0.001, 0.0001 and 0.000025, as well as different combinations of synonymous, insertion/deletion and intronic (splice site) variants, as well as exclusion of hotspot mutations, and examined the effect on TMB correlation. Good correlation (Spearman, range 0.66–0.78) between WES and panel TMB was seen across all methods evaluated. Each method of TMB calculation evaluated showed good positive per cent agreement and negative per cent agreement using 10 mutations/Mb as a cut-off, suggesting that multiple TMB calculation approaches may yield comparable results.
Data stream classification with ant colony optimisation

Data stream mining has recently emerged in response to the rapidly increasing continuous data generation. While the majority of Ant Colony Optimisation (ACO) rule induction algorithms have proved to be successful in producing both accurate and comprehensive classification models in nonstreaming (batch) settings, currently ACO‐based algorithms for classification problems are not suited to be applied to data stream mining. One of the main challenges is the iterative nature of ACO algorithms, where many procedures—for example, heuristic calculation, selection of continuous attributes, pruning—require multiple passes through the data to create a model. In this paper, we present a new ACO‐based algorithm for data stream classification. The proposed algorithm, called Stream Ant‐Miner (sAnt‐Miner), uses a novel hybrid pheromone model combining both a traditional construction graph and solution archives models to efficiently handle a large number of mixed‐type (nominal and continuous) attributes directly without the need for additional procedures, reducing the computational time required to complete an iteration of the algorithm. Our results show that sAnt‐Miner produces statistically significant concise models compared with state‐of‐the‐art rule induction data stream algorithms, without negative effects on their predictive accuracy.
Shorter average look durations to dynamic social stimuli are associated with higher levels of autism symptoms in young autistic children

Prior eye-tracking studies involving autistic individuals have focused on total looking time or proportion of looking time to key regions of interest. These studies have not examined another important feature, the ability to sustain attention to stimuli. In particular, the ability to sustain attention to a dynamic social stimulus might reflect more advanced self-regulatory skills that may enhance engagement with and comprehension of social information. In a sample of 155 autistic children (2–8 years of age), we examined children’s average look duration while they viewed a complex, dynamic stimulus containing both social and nonsocial elements. After accounting for children’s age and intelligence quotient, we found that shorter average look duration was associated with increased autism spectrum disorder severity across multiple clinical measures. To calculate average look duration, we divided the length of total looking time in seconds by the total number of uninterrupted looks to the video media. Thus, the ability to sustain attention while viewing complex dynamic information could be important for comprehending dynamic social information. Lay Abstract Many studies of autism look at the differences in how autistic research participants look at certain types of images. These studies often focus on where research participants are looking within the image, but that does not tell us everything about how much they are paying attention. It could be useful to know more about how well autistic research participants can focus on an image with people in it, because those who can look at images of people for longer duration without stopping may be able to easily learn other skills that help them to interact with people. We measured how long autistic research participants watched the video without breaking their attention. The video sometimes had a person speaking, and at other times had toys moving and making sounds. We measured the typical amount of time autistic research participants could look at the video before they looked away. We found that research participants with more severe autism tended to look at the video for shorter amounts of time. The ability to focus without stopping may be related to social skills in autistic people.
Kleene Algebra with Tests and Program Schematology

The theory of flowchart schemes has a rich history going back to Ianov (1960); see Manna (1974) for an elementary exposition. A central question in the theory of program schemes is scheme equivalence. Manna presents several examples of equivalence proofs that work by simplifying the schemes using various combinatorial transformation rules. In this paper we present a purely algebraic approach to this problem using Kleene algebra with tests (KAT). Instead of transforming schemes directly using combinatorial graph manipulation, we regard them as a certain kind of automaton on abstract traces. We prove a generalization of Kleene''s theorem and use it to construct equivalent expressions in the language of KAT. We can then give a purely equational proof of the equivalence of the resulting expressions. We prove soundness of the method and give a detailed example of its use.
Infection cycle and phylogeny of the Polinton-like virus Phaeocystis globosa virus virophage-14T

Virophages are small dsDNA viruses dependent on a nucleocytoplasmic large-DNA virus infection of a cellular host for replication. Putative virophages infecting algal hosts are classified together with polinton-like viruses, transposable elements widely found in algal genomes, yet the lack of isolated strains raises questions about their existence as independent entities. In this work we isolated and characterized a virophage (PgVV-14T) co-infecting Phaeocystis globosa with the Phaeocystis globosa virus-14T (PgV-14T). PgVV-14T decreases the fitness of its PgV-14T viral host, yet it does not salvage the cellular host population. We found viral-like elements resembling PgVV-14T in Phaeocystis genomes, suggesting that these virophages are capable of integrating to the cellular host genome, bridging the gap between Polinton-like viruses and virophages. This system, with a giant virus, a virophage and endogenous viral elements preying on an algal host, presents an opportunity to gain a better understanding on the evolution of eukaryotes and their viruses.
A clade of RHH proteins ubiquitous in Sulfolobales and their viruses regulates cell cycle progression

Coupling of cell growth, genome replication and segregation and cell division is crucial for all living organisms, yet cell progression control is largely underexplored in archaea. In this work, we characterize a ribbon-helix-helix transcriptional regulator (gp21) of rudivirus SIRV2, which infects the hyperthermophilic crenarchaeon S. islandicus LAL14/1. This protein belongs to a clade of highly conserved proteins of the Sulfolobales with homologs in several families of crenarchaeal viruses. Overexpression of gp21 and other members of the clade including the host homolog SiL_0190, results in impairment of cell division, evidenced by growth retardation, cell enlargement and an increase in DNA content. Additionally, gp21 can either repress or induce the transcription of several genes involved in cell division, DNA replication and cellular metabolism. Both gp21 and its cellular homolog SiL_0190 bind to the motif AGTATTA present in the promoter of their target genes, which correspond to the regulatory motif previously identified in a subset of cyclic genes in S. acidocaldarius ccr-2 (Cell Cycle Regulon 2) box. We therefore rename this clade of proteins Ccr-2 and their binding motif as ccr-2 box. Our results suggest that Ccr-2 is a master regulator of the cell cycle that silences genes involved in cell division and drives progression to the S-phase in Sulfolobales, a function exploited by all known viruses to facilitate viral propagation.
Engineering human Mucosal Associated Invariant T (MAIT) cells with chimeric antigen receptors for cancer immunotherapy1

Engineering immune cells with chimeric antigen receptors (CAR) is a promising technology in cancer immunotherapy. Besides classical cytotoxic CD8+ T cells, innate cell types such as NK cells have also been used to generate CAR-T or CAR-NK cells. Here we devised an approach to program a non-classical cytotoxic T cell subset called Mucosal Associated Invariant T (MAIT) cells into effective CAR-T cells against B cell lymphoma and breast cancer cells. Accordingly, we expressed anti-CD19 and anti-Her2 CARs in activated primary human MAIT cells and CD8+ T cells, expanded them in vitro and compared their cytotoxicity against tumor cell targets. We show upon activation through CARs, CAR-MAIT cells exhibit high levels of cytotoxicity towards target cells, comparable to CD8+ CAR-T cells, but interestingly expressed lower levels of IFN-γ than conventional CAR CD8+ T cells. Additionally, in the presence of vitamin B2 metabolite 5-ARU, which is a conserved compound that activates MAIT cells through MHC-I related (MR1) protein, MAIT cells killed MR1-expressing target breast cancer and B cell lymphoma cell lines in a dose dependent manner. Thus, MAIT cells can be genetically edited as CAR-T cells or mobilized and expanded by MR1 ligands as an off-the-shelf novel approach to cell-based cancer immunotherapy strategies while being comparable to conventional methods in effectivity. Key Points MAIT cells expressing CARs effectively kill CD19 and Her2 expressing targets CAR-MAITs display strong cytotoxicity with lower TNF-γ compared to CD8+ CAR-T cells
Higher mortality rates leave heated ecosystem with similar size- 2 structure despite larger, younger, and faster growing fish 3

23 Ectotherms are often predicted to “shrink” with global warming. This is in line with general 24 growth models and the temperature-size rule (TSR), both predicting smaller adult sizes with 25 warming. However, they also predict faster juvenile growth rates, leading to larger size-at-age 26 of young organisms. Hence, the result of warming on the size-structure of a population depends 27 on the interplay between how mortality rate, juvenile- and adult growth rates are affected by 28 warming. In this study, we use time series of biological samples spanning more than two 29 decades from a unique enclosed bay heated by cooling water from a nearby nuclear power plant 30 to become +8C warmer than its reference area. We used growth-increment biochronologies 31 (12658 reconstructed length-at-age estimates) to quantify how >20 years of warming has 32 affected body growth and size-at-age and catch data to quantify mortality rates and population 33 size-structure of Eurasian perch ( Perca fluviatilis ). In the heated area, growth rates were faster 34 for all sizes, and hence size-at-age was larger for all ages, compared to the reference area. 35 However, mortality rates were also higher, such that the difference in the size-spectrum 36 exponent (describing the proportion of fish by size) was relatively minor and statistically 37 uncertain. As such, our analysis reveals that mortality, in addition to plastic growth and size- 38 responses, is a key factor determining the size structure of populations exposed to warming. 39 Understanding the mechanisms by which warming affects the size-structure of populations is 40 critical for prediction the impacts of climate change on ecological functions, interactions, and 41 dynamics. 42 43 Ecosystem-scale warming experiments provide unique insight into potential impacts of climate change but are very rare. Our work utilizes an experimental set-up consisting of an enclosed bay heated by cooling water from a nuclear power plant for more than two decades, and a reference area. We analyze how changes in growth and mortality have affected the size- and age distribution in a common freshwater fish using time series of catch data and growth- increment biochronologies derived from their gill lids. Despite fish in the heated area being 51 ~10% larger at a given age, elevated mortality rates have resulted in similar size structures. Accounting for the interplay between mortality and growth is key for predicting climate impacts on the size-structure of populations.
Shared neurophysiological resources between exogenous and endogenous visuospatial attentional processes

Prevailing accounts of visuospatial attention differentiate exogenous (involuntary shifts) from endogenous (voluntary control) orienting of attention. While these two forms of attentional processes are functionally separable, their interactions have been at the center of ongoing debates for more than two decades. One hypothesis is that exogenous and endogenous attention interfere because they share processing resources. Here, we confirm that endogenous attention alters exogenous attention processing, and examine the role of alpha-band neurophysiological activity in such interference events. We contrast the effects of exogenous attention across two experimental conditions: a single-cueing condition where exogenous attention is engaged alone, and a double-cueing condition where exogenous attention is concurrently engaged with endogenous attention. Our results show that the engagement of endogenous attention alters the emergence of exogenous attention across cue-related and target-related brain processes. Importantly, we also report that classifiers trained to decode exogenous attention from the power and phase of alpha-band brain activity in the single-cueing condition fail to do so in the doublecueing condition, where endogenous attention is also engaged. Taken together, our observations challenge the idea that exogenous attention operates independently from top-down processes and demonstrate that both forms of attention orienting engage shared brain processes, which constrain their interactions. Significance Statement Visuospatial attention is often dichotomized into top-down and bottom-up components: Top-down attention reflects slow voluntary shifts of attention orienting, while bottom-up attention is recruited by emerging demands from the environment. A large body of previous findings support the view that these two forms of attention orienting are functionally separable, with some interactions. The current study examines such interactions between top-down and bottom-up attention. Using electroencephalography (EEG) and multivariate pattern classification techniques, the researchers show that top-down attention interferes with the brain activity patterns of bottom-up attention. Moreover, machine learning classifiers trained to detect bottom-up attention based on brain activity in the alpha band (8-12 Hz), a marker of visuospatial attention, fail systematically when top-down attention is also engaged. The authors therefore conclude that both forms of visuospatial orienting are supported by overlapping processes that share brain resources.
Structure of a LRRC8 chimera with physiologically relevant properties reveals heptameric assembly and pore-blocking lipids

Volume-regulated anion channels (VRACs) mediate Cl- and organic solute efflux from vertebrate cells and are essential for cell volume homeostasis. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A and LRRC8D channels have a hexameric structure. However, these channels are either non-functional or exhibit abnormal functional properties limiting their utility for structure-function analyses. We circumvented these limitations by developing novel homomeric LRRC8 chimeric channels with physiologically relevant functional properties. We demonstrate here that the LRRC8C-LRRC8A(IL125) chimera comprising LRRC8C and 25 amino acids unique to the first intracellular loop (IL1) of LRRC8A has a heptameric structure like that of homologous pannexin channels. Membrane lipids are a key structural element of the channel and are located between subunits and occluding the channel pore. Our results suggest that native VRAC/LRRC8 channels are heptamers and that associated lipids are likely essential for normal channel gating and regulation.