bluuebunny/crossref_metadata_2025 huggingface dataset:
Maptcha: An efficient parallel workflow for hybrid genome scaffolding
Authors: Bhowmik Oieswarya , Rahman Tazin , Kalyanaraman Ananth
Published: March 2024

Background: Genome assembly, which involves reconstructing a target genome, relies on scaffolding methods to organize and link partially assembled fragments. The rapid evolution of long read sequencing technologies toward more accurate long reads, coupled with the continued use of short read technologies, has created a unique need for hybrid assembly workflows. The construction of accurate genomic scaffolds in hybrid workflows is complicated due to scale, sequencing technology diversity (e.g., short vs. long reads, contigs or partial assemblies), and repetitive regions within a target genome. Results: In this paper, we present a new parallel workflow for hybrid genome scaffolding that would allow combining pre-constructed partial assemblies with newly sequenced long reads toward an improved assembly. More specifically, the workflow, called Maptcha, is aimed at generating long genome scaffolds of a target genome, from two sets of input sequences---an already constructed partial assembly of contigs, and a set of newly sequenced long reads. Our scaffolding approach internally uses an alignment-free mapping step to build a  graph using long reads as linking information. Subsequently, this graph is used to generate scaffolds. We present and evaluate a graph-theoretic ``wiring'' heuristic to perform this scaffolding step. To enable efficient workload management in a parallel setting, we use a batching technique that partitions the scaffolding tasks so that the more expensive alignment-based assembly step at the end can be efficiently parallelized. This step also allows the use of any standalone assembler of choice for generating the final scaffolds. Conclusions: Our experiments with Maptcha on a variety of input genomes, and comparison against a state-of-the-art hybrid scaffolder (LRScaf) demonstrate that Maptcha is able to generate longer and more accurate scaffolds in significantly faster runtimes. For instance, Maptcha produces scaffolds with an NG50 length of 4.8Mbp (compared to 171Kbp by LRScaf for T. crassiceps, and 81Mbp for Human chr 7 (compared to 4.5Mbp by LRScaf), while reducing the runtime from hours to minutes in several cases. We also performed a coverage experiment by varying the sequencing coverage depth for long reads, which demonstrated the potential of Maptcha to generate significantly longer scaffolds in low coverage settings (1x to 10x).
Identifying immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors
Authors: May Damon H. , Woodhouse Steven , Zahid H. Jabran , Elyanow Rebecca , Doroschak Kathryn , Noakes Matthew T. , Taniguchi Ruth , Yang Zheng , Grino John R. , Byron Rachel , Oaks Jamie , Sherwood Anna , Greissl Julia , Chen-Harris Haiyin , Howie Bryan , Robins Harlan S.
Published: March 2024

Memory T cells are records of clonal expansion from prior immune exposures, such as infections, vaccines and chronic diseases like cancer. A subset of the receptors of these expanded T cells in a typical immune repertoire are highly public, i.e., present in many individuals exposed to the same exposure. For the most part, the exposures associated with these public T cells are unknown.

To identify public T-cell receptor signatures of immune exposures, we mined the immunosequencing repertoires of tens of thousands of donors to define clusters of co-occurring T cells. We first built co-occurrence clusters of T cells responding to antigens presented by the same Human Leukocyte Antigen (HLA) and then combined those clusters across HLAs. Each cross-HLA cluster putatively represents the public T-cell signature of a single prevalent exposure.

Using repertoires from donors with known serological status for 7 prevalent exposures (HSV-1, HSV-2, EBV, Parvovirus,Toxoplasma gondii, Cytomegalovirus and SARS-CoV-2), we identified a single T-cell cluster strongly associated with each exposure and used it to construct a highly sensitive and specific diagnostic model for the exposure.

These T-cell clusters constitute the public immune responses to prevalent exposures, 7 known and many others unknown. By learning the exposure associations for more T-cell clusters, this approach could be used to derive a ledger of a person’s past and present immune exposures.
The white matter fiber tract deforms most in the perpendicular direction duringin vivovolunteer impacts
Authors: Zhou Zhou , Olsson Christoffer , Gasser T. Christian , Li Xiaogai , Kleiven Svein
Published: March 2024

White matter (WM) tract-related strains are increasingly used to quantify brain mechanical responses, but their dynamics in live human brains duringin vivoimpact conditions remain largely unknown. Existing research primarily looked into the normal strain along the WM fiber tracts (i.e., tract-oriented normal strain), but it is rarely the case that the fiber tract only endures tract-oriented normal strain during impacts. In this study, we aim to extend thein vivomeasurement of WM fiber deformation by quantifying the normal strain perpendicular to the fiber tract (i.e., tract-perpendicular normal strain) and the shear strain along and perpendicular to the fiber tract (i.e., tract-oriented shear strain and tract-perpendicular shear strain, respectively). To achieve this, we combine the three-dimensional strain tensor from the tagged magnetic resonance imaging (tMRI) with the diffusion tensor imaging (DTI) from an open-access dataset, including 44 volunteer impacts under two head loading modes, i.e., neck rotations (N = 30) and neck extensions (N = 14). The strain tensor is rotated to the coordinate system with one axis aligned with DTI-revealed fiber orientation and then four tract-related strain measures are calculated. The results show that tract-perpendicular normal strain peaks are the largest among the four strain types (p< 0.05, Friedman’s test). The distribution of tract-related strains is affected by the head loading mode, of which laterally symmetric patterns with respect to the midsagittal plane are noted under neck extensions, but not under neck rotations. Our study presents a comprehensivein vivostrain quantification towards a multifaceted understanding of WM dynamics. We find the WM fiber tract deforms most in the perpendicular direction, illuminating new fundamentals of brain mechanics. The reported strain images can be used to evaluate the fidelity of computational head models, especially those intended to predict fiber deformation under non-injurious conditions.
The respiratory cycle modulates distinct dynamics of affective and perceptual decision-making
Authors: Brændholt Malthe , Nikolova Niia , Vejlø Melina , Banellis Leah , Fardo Francesca , Kluger Daniel S. , Allen Micah
Published: March 2024

Respiratory rhythms play a critical role not only in homeostatic survival, but also in modulating other non-interoceptive perceptual and affective processes. Recent evidence from both human and rodent models indicates that neural and behavioural oscillations are influenced by respiratory state as breathing cycles from inspiration to expiration. To explore the mechanisms behind these effects, we carried out a psychophysical experiment where 41 participants categorised dot motion and facial emotion stimuli in a standardised discrimination task. When comparing behaviour across respiratory states, we found that inspiration accelerated responses in both domains. We applied a hierarchical evidence accumulation model to determine which aspects of the latent decision process best explained this acceleration. Computational modelling showed that inspiration reduced evidential decision boundaries, such that participants prioritised speed over accuracy in the motion task. In contrast, inspiration shifted the starting point of affective evidence accumulation, inducing a bias towards categorising facial expressions as more positive. These findings provide a novel computational account of how respiratory rhythms modulate distinct aspects of perceptual and affective decision-dynamics.
Variations of autonomic arousal mediate the reportability of mind-blanking occurrences
Authors: Alexandros Boulakis Paradeisios , John Simos Nicholas , Stefania Zoi , Sepehr Mortaheb , Christina Schmidt , Federico Raimondo , Athena Demertzi
Published: March 2024

Mind-blanking (MB) is the inability to report mental events during unconstraint thinking. Previous work shows that MB is linked to decreased levels of cortical arousal, indicating dominance of cerebral mechanisms when reporting mental states. What remains inconclusive is whether MB can also ensue from autonomic arousal manipulations, pointing to the implication of peripheral physiology to mental events. Using experience-sampling, neural, and physiological measurements in 26 participants, we first show that MB was reported more frequently in low arousal conditions, elicited by sleep deprivation. Also, there was partial evidence for a higher number of MB reports in high arousal conditions, elicited by intense physical exercise. Transition probabilities revealed that, after sleep deprivation, mind-wandering was more likely to be followed by MB and less likely to be followed by more mind-wandering reports. Using classification schemes, we show higher performance of a balanced random forest classifier trained on both neural and physiological markers in comparison to performance when solely neural or physiological were used. Collectively, we show that both cortical and autonomic arousal affect MB report occurrences. Our results establish that MB is supported by combined brain-body configurations, and, by linking mental and physiological states they pave the way for novel, embodied accounts of spontaneous thinking.
TheDrosophilaRNA binding protein Hrp48 binds a specific RNA sequence of themsl-2mRNA 3’ UTR to regulate translation
Authors: Lomoschitz Andrea , Meyer Julia , Guitart Tanit , Krepl Miroslav , Lapouge Karine , Hayn Clara , Schweimer Kristian , Simon Bernd , Šponer Jiří , Gebauer Fátima , Hennig Janosch
Published: March 2024

Repression ofmsl-2mRNA translation is essential for viability ofDrosophila melanogasterfemales to prevent hypertranscription of both X chromosomes. This translational control event is coordinated by the female-specific protein Sex-lethal (Sxl) which recruits the RNA binding proteins Unr and Hrp48 to the 3’ untranslated region (UTR) of themsl-2transcript and represses translation initiation. The mechanism exerted by Hrp48 during translation repression and its interaction withmsl-2are not well understood. Here we investigate the RNA binding specificity and affinity of the tandem RNA recognition motifs of Hrp48. Using NMR spectroscopy, molecular dynamics simulations and isothermal titration calorimetry, we identified the exact region ofmsl-23’ UTR recognized by Hrp48. Additional biophysical experiments and translation assays give further insights into complex formation of Hrp48, Unr, Sxl and RNA. Our results show that Hrp48 binds independent of Sxl and Unr downstream of the E and F binding sites of Sxl and Unr tomsl-2.
Unravelling the architecture of Major Histocompatibility Complex class II haplotypes in rhesus macaques
Authors: de Groot Nanine , van der Wiel Marit , Le Ngoc Giang , de Groot Natasja G. , Bruijnesteijn Jesse , Bontrop Ronald E.
Published: March 2024

The regions in the genome that encode components of the immune system are often featured by polymorphism, copy number variation and segmental duplications. There is a need to thoroughly characterize these complex regions to gain insight into the impact of genomic diversity on health and disease. Here we resolve the organization of complete major histocompatibility complex (MHC) class II regions in rhesus macaques by using a long-read sequencing strategy (Oxford Nanopore Technologies) in concert with adaptive sampling. In particular, the expansion and contraction of the primateDRB-region appears to be a dynamic process that involves the rearrangement of different cassettes of paralogous genes. These chromosomal recombination events are propagated by a conserved pseudogene,DRB6, which features the integration of two retroviral elements. In contrast, theDRAlocus appears to be protected from rearrangements, which may be due to the presence of an adjacently located truncated gene segment,DRB9. With our sequencing strategy, the annotation, evolutionary conservation, and potential function of pseudogenes can be reassessed, an aspect that was neglected by most genome studies in primates. Furthermore, our approach facilitates the characterization and refinement of an animal model essential to study human biology and disease.
Virological characteristics of SARS-CoV-2 Omicron BA.5.2.48
Authors: Wang Wenqi , Jin Qiushi , Liu Ruixue , Zeng Wentao , Zhu Pengfei , Li Tingting , Wang Tiecheng , Xiang Haiyang , Zhang Hang , Chen Qin , Gao Yun , Lai Yana , Yan Fang , Xia Xianzhu , Li Jianmin , Wang Xuefeng , Gao Yuwei
Published: March 2024

With the prevalence of sequentially-emerged sublineages including BA.1, BA.2 and BA.5, SARS-CoV-2 Omicron infection has transformed into a regional epidemic disease. As a sublineage of BA.5, the BA.5.2.48 outbreak and evolved into multi-subvariants in China without clearly established virological characteristics, especially the pathogenicity. Though reduced airborne transmission and pathogenicity of former Omicron sublineages have been revealed in animal models, the virological characteristics of BA.5.2.48 was unidentified. Here, we evaluated the in vitro and in vivo virological characteristics of two isolates of the prevalent BA.5.2.48 subvariant, DY.2 and DY.1.1 (a subvariant of DY.1). DY.2 replicates more efficiently than DY.1.1 in HelahACE2+cells and Calu-3 cells. The A570S mutation (of DY.1) in a normal BA.5 spike protein (DY.2) leads to a 20% improvement in the hACE2 binding affinity, which is slightly reduced by a further K147E mutation (of DY.1.1). Compared to the normal BA.5 spike, the double-mutated protein demonstrates efficient cleavage and reduced fusogenicity. BA.5.2.48 demonstrated enhanced airborne transmission capacity in hamsters than BA.2. The pathogenicity of BA.5.2.48 is greater than BA.2, as revealed in K18-hACE2 rodents. Under immune selection pressure, DY.1.1 shows stronger fitness than DY.2 in hamster turbinates. Thus the outbreaking prevalent BA.5.2.48 multisubvariants exhibites divergent virological features.

Importance

Omicron continues to circulate and evolves novel sublineages with indistinguishable pathogenicity and transmission. Therefore humanized Omicron-sensitive animal models must be applied to evaluate the virological characteritics and antiviral therapeutics. By using multiple models including the Omicron-lethal H11-K18-hACE2 rodents, BA.5.2.48 revealed higher pathogenicity in the novel H11-K18-hACE2 rodent models than the previously epidemic BA.2, and thus the models are more adapted to Omicron studies. Moreover, the regional outbreaking of BA.5.2.48 promotes the multidirectional evolution of its subvariants, gaining either enhanced pathogenicity or a fitness in upper airways which is associated with higher transmission, highlighting the importance of surveillance and virological studies on regionally endemic sublineages which represents the short-run evolutionary direction of Omicron.
Chitin synthase targeting antifungal agents for Mucormycosis (Black fungus disease) caused byRhizopus delemar- Anin-silicostudy
Authors: George Abhilash J , Nair Achuthsankar S , Vijayalakshmio B
Published: March 2024

Mucormycosis, a severe fungal infection caused byMucoralesfungi, particularlyRhizopus delemar, has prompted the development of new and more potent antifungal drugs due to the emergence of drug-resistant strains. Currently used drugs are known to be toxic to human cells also, which is a major drawback in their administration. Antifungal drugs commercially under use and their structurally modified analogues along with 30 plants reported with antifungal activity from IMPPAT database, totalling 229 compounds, were screened against the best modelled structure of Chitin Synthase, a key target enzyme ofRhizopus delemarbyin-silicomolecular docking studies. Computerized methods to assess absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was employed to further filter key lead drug candidates from among the docked ligands that could act as potential antifungal medications. Modified structures of Posaconazole, Nikkomycin and Isavuconazole were found to give better docking results than compared to the original drugs, though they failed to comply with ADMET parameters. Among the phytochemicals, 1-nonacosanol displayed binding affinity (highest LibDock score) greater than the synthetic drugs and their derivatives, though it too failed to comply with ADMET parameters. The phytochemical Dihydrocapsaicin was found to be the best compound that satisfied all the parameters such as ADMET, TOPKAT, Lipinski’s and Veber’s rule along with good binding affinity. All in all, this novel study paves a way to investigate the interaction of Chitin Synthase inhibitors at molecular level to achieve an alternative solution with less toxic effects to treat Mucormycosis.
Anthropometric-related percentile curves for muscle size and strength of lower limb muscles of typically developing children
Authors: Vandekerckhove Ines , Hanssen Britta , Peeters Nicky , Dewit Tijl , Beukelaer Nathalie De , Van den Hauwe Marleen , Waele Liesbeth De , Campenhout Anja Van , Groote Friedl De , Desloovere Kaat
Published: March 2024

Aims

To establish anthropometric-related percentile curves for muscle size and strength in a cohort of typically developing (TD) children and to demonstrate their use through applications in children with cerebral palsy (CP) and Duchenne muscular dystrophy (DMD).

Methods

Lower limb muscle size and strength were assessed in a large cross-sectional cohort of TD children with 3D freehand ultrasound (four muscles, n=154, male/female=82/72, age range: 0y7mo-17y10mo) and fixed dynamometry (seven muscle groups, n=153, male/female=108/45, age range: 4y6mo-16y1mo), respectively. Generalized additive models for location, scale and shape were used to estimate anthropometric-related, i.e. body mass and height, TD percentile curves and to convert outcomes of individual patients with CP and DMD into z-scores.

Results

Muscle size and strength, as well as their inter-subject variation, increased with increasing anthropometric values. Individual patients exhibited negative z-scores, indicating muscle size and strength deficits in reference to TD peers.

Interpretation

The established anthropometric-related percentile curves for muscle size and strength in a cohort of TD children can successfully be used to express patient outcomes in reference to TD. This facilitates the interpretation of muscle size and weakness in children with a motor disability and allows for the evaluation of the disease progression and treatment impact during growth.
Is artificial intelligence for medical professionals serving the patients? Protocol for a mixed method systematic review on patient-relevant benefits and harms of algorithmic decision-making.
Authors: Wilhelm Christoph , Steckelberg Anke , Rebitschek Felix G.
Published: March 2024

Background Algorithmic decision making (ADM) utilizes algorithms to collect and process data and develop models to make or support decisions. Advances in artificial intelligence (AI) have led to the development of support systems that can be superior to medical professionals without AI support in certain tasks. However, whether patients can benefit from this remains unclear. The aim of this systematic review is to assess the current evidence on patient-relevant benefits and harms when healthcare professionals use ADM systems (developed using or working with AI) compared to healthcare professionals without AI-related ADM (standard care) - regardless of the clinical issues. Furthermore, for interpreting collected evidence and analysing preconditions for the implementation of AI-related ADM in healthcare, experts from research, practice, and regulation will be interviewed. Methods Following the PRISMA statement and the MECIR standards for reporting systematic reviews, MEDLINE and PubMed (via PubMed), EMBASE (via Elsevier), IEEE Xplore, CENTRAL will be searched using English free text terms in title/abstract, Medical Subject Headings (MeSH) terms and Embase Subject Headings (Emtree) fields. Additional studies will be identified by contacting authors of included studies and through reference lists of included studies. Grey literature searches will be conducted in Google Scholar. Risk of bias will be assessed by using Cochranes RoB 2 for randomised trials and ROBINS-I for non-randomised trials. Transparent reporting of the included studies will be assessed using the CONSORT-AI extension statement. Following the SRQR statement, semi-structured interviews will be conducted and analysed with the help of a qualitative content analysis according to Mayring. Based on the research questions and the findings of the systematic review, the study and interview guide will be developed a priori. Discussion It is expected that there will be a substantial shortage of suitable studies that compare healthcare professionals with and without ADM systems concerning patient-relevant endpoints. This can be attributed to the prioritization of technical quality criteria and, in some cases, clinical parameters over patient-relevant endpoints in the development of study designs. Furthermore, it is anticipated that a significant portion of the identified studies will exhibit relatively poor methodological quality and provide only limited generalizable results.
Optimised Nanobody-based Quenchbodies for Enhanced Protein Detection
Authors: Cater Jordan Harry , Elsalamouny Nehad , Mansour Ghada H , Hutchinson Sebastian , Mc Guinness Conall , Mueller Stefan H. , Spinks Richard Raymond , Shanmugam Nirukshan , Pichard-Kostuch Adeline , Zahoransky Viktor , Ghodke Harshad , Ribezzi-Crivellari Marco , Yu Haibo , van Oijen Antoine M , Griffiths Andrew D. , Spenkelink Lisanne M.
Published: March 2024

Quenchbodies, antibodies labelled with fluorophores that increase in intensity upon antigen binding, offer great promise for biosensor development. Nanobody-based quenchbodies are particularly attractive due to their small size, ease of expression, high stability, rapid evolvability, and amenability to protein engineering. However, existing designs for protein detection show limited dynamic range, with fluorescence increases of only 1.1-1.7 fold. Here we identify the tryptophan residues in the nanobody complementarity-determining regions (CDRs) that are critical to quenchbody performance. Using a combination of rational design and molecular dynamics simulations, we developed an optimised nanobody scaffold with tryptophans introduced at key positions. We used this scaffold in an in vitro directed-evolution screen against human inflammatory cytokine interleukin-6 (IL-6). This yielded quenchbodies with 1.5-2.4-fold fluorescence increases, enabling IL-6 detection down to 2 nM. Our scaffold provides a valuable platform for developing biosensors for diverse protein targets, with applications in research, diagnostics, and environmental monitoring.
A high-resolution haplotype pangenome uncovers somatic hybridization, recombination and intercontinental migration in oat crown rust
Authors: Henningsen Eva C. , Lewis David , Nazareno Eric , Huang Yung-Fen , Steffenson Brian J. , Boesen Brendan , Kianian Shahryar F. , Stone Eric , Dodds Peter N. , Sperschneider Jana , Figueroa Melania
Published: March 2024

Basidiomycetes like rust fungi have complex reproductive cycles and dikaryotic life stages which influence their population structure and evolution.Puccinia coronataf. sp.avenae(Pca), the causal agent of oat crown rust, is a pathogen of global economic importance. To investigate the genetic diversity of the species, as well as the role of mating type system and nuclear exchange (somatic hybridization) in host adaptation ofPcawe acquired whole genome sequencing data of Taiwanese and Australian isolates, adding to existing data for USA and South African populations. An atlas of 30 chromosome-level, fully-phased nuclear haplotypes from six USA isolates and nine Australian isolates was generated to capture the genomic composition of key oat crown rust lineages. This study provides evidence of nuclear exchange and recombination of haplotypes in both the USA and AustralianPcapopulations as mechanisms for the introduction of genetic diversity. The limitations of assuming clonal evolutionary history from virulence phenotyping is demonstrated by the detection of either sexual or cryptic genetic recombination in thePcaAustralian population. Overall, the characterization of intercontinental migration ofPcaat the haplotype level provides further impetus for molecular monitoring of rust pathogen populations on a global scale.
What We (Don’t) Know about Parrot Welfare: A Systematic Literature Review
Authors: Piseddu Andrea , van Zeeland Yvonne R. A. , Rault Jean-Loup
Published: March 2024

Parrots are popular companion animals but show prevalent and at times severe welfare issues. Nonetheless, there are no scientific tools available to assess parrot welfare. The aim of this systematic review was to identify valid and feasible outcome measures that could be used as welfare indicators for companion parrots. From 1848 peer-reviewed studies retrieved, 98 met our inclusion and exclusion criteria (e.g. experimental studies, captive parrots). For each outcome collected, validity was assessed based on the statistical significance reported by the authors, as other validity parameters were rarely available for evaluation. Feasibility was assigned by considering the need for specific instruments, veterinary-level expertise or handling the parrot. A total of 1512 outcomes were evaluated, of which 572 had a significant p-value and were considered feasible. These included changes in behaviour (e.g. activity level, social interactions, exploration), body measurements (e.g. body weight, plumage condition) and abnormal behaviours, amongst others. However, a high risk of bias undermined the internal validity of these outcomes. Moreover, a strong taxonomic bias, a predominance of studies on parrots in laboratories, and an underrepresentation of companion parrots jeopardized their external validity. These results provide a promising starting point for validating a set of welfare indicators in parrots.
Intrinsically disordered RNA-binding motifs cooperate to catalyze RNA folding and drive phase separation
Authors: Niedner-Boblenz Annika , Monecke Thomas , Hennig Janosch , Klostermann Melina , Hofweber Mario , Davydova Elena , Gerber André P. , Anosova Irina , Mayer Wieland , Müller Marisa , Heym Roland Gerhard , Janowski Robert , Paillart Jean-Christophe , Dormann Dorothee , Zarnack Kathi , Sattler Michael , Niessing Dierk
Published: March 2024

RNA-binding proteins are essential for gene regulation and the spatial organization of cells. Here, we report that the yeast ribosome biogenesis factor Loc1p is an intrinsically disordered RNA-binding protein with eight repeatingpositively charged,unstructurednucleic acid binding (PUN) motifs. While a single of these previously undefined motifs stabilizes folded RNAs, multiple copies strongly cooperate to catalyze RNA folding. In the presence of RNA, these multivalent PUN motifs drive phase separation. Proteome-wide searches in pro-and eukaryotes for proteins with similar arrays of PUN motifs reveal a strong enrichment in RNA-mediated processes and DNA remodeling. Thus, PUN motifs are potentially involved in a large variety of RNA-and DNA-related processes by concentrating them in membrane-less organelles. The general function and wide distribution of PUN motifs across species suggests that in an ancient “RNA world” PUN-like motifs may have supported the correct folding of early ribozymes.
Identification of stress specific autophagy regulators from tandem CRISPR screens
Authors: Losier Truc T. , Rousseaux Maxime W.C. , Russell Ryan C.
Published: March 2024

Autophagy is a conserved degradative process that promotes cellular homeostasis under stress conditions. Under nutrient starvation autophagy is largely non-selective, promoting the indiscriminate breakdown of cytosolic components. Conversely, selective autophagy is responsible for the specific turnover of damaged organelles including endoplasmic reticula, lysosomes, mitochondria, and peroxisomes. The mechanisms of selective autophagy are best understood through the activity of cargo-specific receptors called autophagy receptors, which facilitate the engulfment of the targeted cargo within autophagosomes, leading to subsequent degradation. We hypothesized that selective autophagy may be regulated by distinct upstream signaling from starvation induced autophagy, providing an additional layer of regulatory control to targeted autophagic degradation. To comprehensively address this question we conducted kinome-wide CRISPR screens to identify distinct signaling pathways responsible for the regulation of basal autophagy, starvation-induced autophagy, and two types of selective autophagy, ER-phagy and pexophagy. These parallel screens identified established and novel autophagy shared regulators under these conditions, as well as kinases specifically required for ER-phagy or pexophagy. More specifically, CDK11A and NME3 were further characterized to be selective ER-phagy regulators. Meanwhile, PAN3 and CDC42BPG were identified as activator or inhibitor of pexophagy, respectively. Collectively, these datasets provide the first comparative description of the kinase signaling specificity, separating regulation of selective autophagy and bulk autophagy.

Highlights

Parallel pooled kinome genetic knockout screens reveal known and novel regulators of autophagy under basal conditions, nutrient starvation, ER stress, and peroxisomal stress

Selective ER and peroxisomal autophagy both have unique activators and inhibitors that distinguish them from bulk autophagy

CDK11A and NME3 specifically induce and inhibit ER-phagy, respectively

PAN3 and CDC42BPG specifically induce and inhibit pexophagy, respectively
Tangled genetic relationships within theFusobacteriumgenus
Authors: Molteni Cristian , Forni Diego , Cagliani Rachele , Sironi Manuela
Published: March 2024

Fusobacteria have been associated to different diseases, including colorectal cancer (CRC), but knowledge of which taxonomic groups contribute to specific conditions is incomplete. We analyzed the genetic diversity and relationships within theFusobacteriumgenus. We report recent and ancestral recombination in core genes, indicating that fusobacteria have mosaic genomes and emphasizing that taxonomic demarcation should not rely on single genes/gene regions. Across databases, we found ample evidence of species miss-classification and of undescribed species, which are both expected to complicate disease association. By focusing on a lineage that includesF. periodonticum/pseudoperiodonticumandF. nucleatum, we show that genomes belong to four modern populations, but most known species/subspecies emerged from individual ancestral populations. Of these, theF. periodonticum/pseudoperiodonticumpopulation experienced the lowest drift and displays the highest genetic diversity, in line with the less specialized distribution of these bacteria in oral sites. A highly drifted ancestral population instead contributed genetic ancestry to a new species, which includes genomes classified within theF. nucleatum animalisdiversity in a recent CRC study. Thus, evidence herein calls for a re-analysis ofF. nucleatum animalisfeatures associated to CRC. More generally, our data inform future molecular profiling approaches to investigate the epidemiology ofFusobacterium-associated diseases.
The structure of the R2T complex reveals a different architecture of the related HSP90 co-chaperones R2T and R2TP
Authors: Palacios-Abella Alberto , López-Perrote Andrés , Boskovic Jasminka , Fonseca Sandra , Úrbez Cristina , Rubio Vicente , Llorca Oscar , Alabadí David
Published: March 2024

Heat shock protein 90 (HSP90) is a molecular chaperone that contributes to the maturation and activation of substrates in multiple cellular pathways. Its activity is supported by various co-chaperones. One of these is R2TP, a complex of RuvBL1-RuvBL2-RPAP3-PIH1D1 in humans, which is involved in the assembly of various multiprotein complexes, including mTORC1 and Box C/D and Box H/ACA snoRNPs. Structural analyses have shown that the complex is organized around a heterohexameric ring of the ATPases RuvBL1-RuvBL2 in both yeast and humans. In addition, several R2TP-like co-chaperones have been identified in humans, such as R2T, which lacks PIH1D1, but these are less well characterized. In seed plants, there are no PIH1D1 orthologs. Here, we have identified the R2T complex ofArabidopsisand determined its cryoEM structure. R2T associates with the prefoldin-like complexin vivoand is located in the cytosolic and nuclear compartments. R2T is organized as a dodecamer of AtRuvBL1-AtRuvBL2a that forms two rings, with one AtRPAP3 anchored to each ring. AtRPAP3 has no effect on the ATPase activity of AtRuvBL1-AtRuvBL2a and binds with a different stoichiometry than that described for human R2TP. We show the interaction of AtRPAP3 with AtRuvBL2a and AtHSP90in vivoand describe the residues involved. Taken together, our results show that AtRPAP3 recruits AtRuvBL1-AtRuvBL2a and AtHSP90 via a mechanism that is also conserved in other eukaryotes, but that R2T and R2TP co-chaperone complexes have distinct structures that also suggest differences in their functions and mechanisms.
STORMM: Structure and TOpology Replica Molecular Mechanics for chemical simulations
Authors: Cerutti David Shawkey , Boothroyd Simon , Wiewiora Rafal , Sherman Woody
Published: March 2024

The Structure and TOpology Replica Molecular Mechanics (STORMM) code is a next-generation molecular simulation engine and associated libraries optimized for performance on fast, multicore central processor units (CPUs) and graphics processing units (GPUs) with independent memory and tens of thousands of threads. STORMM is built to run thousands of independent molecular mechanical calculations on a single GPU with novel implementations that optimize numerical precision, mathematical operations, throughput, and resource management. The libraries are built around accessible classes with detailed documentation, supporting fine-grained parallelism and algorithm development as well as macroscopic manipulations of groups of systems on and off of the GPU. A primary intention of the STORMM libraries is to provide developers of atomic simulation methods with access to a high-performance molecular mechanics engine with extensive facilities to prototype and develop bespoke tools aimed toward drug discovery applications. In its present state, STORMM delivers molecular dynamics simulations of small molecules and small proteins in implicit solvent with tens to hundreds of times the throughput of conventional codes. The engineering paradigm also transforms two of the most memory bandwidth-intensive aspects of condensed-phase dynamics, particle-mesh mapping and valence interactions, into compute-bound problems for several times the scalability of existing programs. Numerical methods for getting the most out of each bit of information present in stored coordinates and lookup tables are also presented, delivering improved accuracy over methods implemented in other molecular dynamics engines. The open-source code is released under the MIT license.
Unlocking Precision Gene Therapy: Harnessing AAV Tropism with Nanobody Swapping at Capsid Hotspots
Authors: Hoffmann Mareike D. , Gallant Joseph P. , LeBeau Aaron M. , Schmidt Daniel
Published: March 2024

Adeno-associated virus has been remarkably successful in the clinic, but its broad tropism is a practical limitation of precision gene therapy. A promising path to engineer AAV tropism is the addition of binding domains to the AAV capsid that recognize cell surface markers present on a targeted cell type. We have recently identified two previously unexplored capsid regions near the 2-fold valley and 5-fold pore of the AAV capsid that are amenable to insertion of larger protein domains including nanobodies. Here, we demonstrate that these hotspots facilitate AAV tropism switching through simple nanobody replacement without extensive optimization in both VP1 and VP2. We demonstrate highly specific targeting of human cancer cells expressing fibroblast activating protein (FAP). Our data suggest that engineering VP2 is the preferred path for maintaining both virus production yield and infectivity. Our study shows that nanobody swapping at multiple capsid location is a viable strategy for nanobody-directed cell-specific AAV targeting.
Donor side effects experienced under minimal controlled ovarian stimulation (COS) with in vitro maturation (IVM) versus conventional COS forin vitrofertilization (IVF) treatment
Authors: Marchante Maria , Barrachina Ferran , Piechota Sabrina , Fernandez-González Marta , Giovannini Alexa , Smith Trozalla , Kats Simone , Paulsen Bruna , González Eva , Calvente Virginia , Silvan Ana , Abittan Baruch , Klein Joshua , Klatsky Peter , Ordonez Daniel , Kramme Christian C.
Published: March 2024

Objective

To evaluate how minimal controlled ovarian stimulation (COS) for in vitro maturation (IVM) affects subjects’ oocyte retrieval experiences compared to conventional COS, considering side effects

Design

Retrospective Survey Study

Setting

Clinical in vitro fertilization (IVF) treatment centers in Spain and the United States.

Subjects

Data were collected from subjects undergoing minimal COS (n=110; 600-800 IU FSH) for IVM and conventional COS for egg donation (n=48; 2000-3000 IU FSH) from April 2022 to November 2023. In the same period, a pairwise comparison of subjects (n=13) undergoing both minimal COS for IVM and conventional COS for oocyte cryopreservation was conducted.

Intervention/Exposure

Minimal and conventional controlled ovarian stimulation.

Main Outcome Measures

The most common side effects suffered during ovarian stimulation and after OPU, satisfaction level, and the likelihood of recommending or repeating minimal or conventional COS. Statistical analysis included Mann Whitney, Wilcoxon, Chi-square, and McNemar tests, with a significance level set at p<0.05.

Results

During minimal COS, most subjects did not experience breast swelling (86%), pelvic or abdominal pain (76%), nausea or vomiting (96%), and bleeding (96%). After oocyte pick-up, the majority (75%) reported no pelvic or abdominal pain. The most common side effect was abdominal swelling (52%). Compared to conventional COS cycles, minimal COS subjects reported significantly less post-retrieval pain, with 33% experiencing no pain (vs. 6%; p=0.0011) and with a reduced severe level of pain (5% vs.19%; p=0.0097), leading to fewer subjects requiring pain medication (25% vs. 54%; p=0.0003). Additionally, 85% of women were very satisfied with minimal stimulation and would recommend or repeat the treatment. In the comparison in which each donor underwent both minimal and conventional COS treatments, women indicated more side effects with the conventional stimulation, presenting a significantly overall higher level of pain (p=0.0078).

Conclusion

Reducing the hormonal dose for ovarian stimulation has a beneficial effect on subjects, suggesting the combination of minimal COS with IVM techniques is a well-tolerated alternative for women who cannot or do not wish to undergo conventional controlled ovarian hyperstimulation.
Nonlocal effects on the shock-augmented ignition scheme of laser inertial fusion
Authors: Yuan W. Q. , Zhao Z. H. , Zhu S. P. , He X. T. , Qiao B.
Published: March 2024

Shock-augmented ignition (SAI) has recently been proposed as a viable approach to optimize the shock ignition scheme of laser fusion, which may substantially reduce laser power and intensity requirements and, as a result, greatly inhibit the growth of laser-plasma instabilities. However, the nonlocal thermal transport effect, which is believed to play a significant role in shock ignition, has not been considered in evaluation of the SAI scheme yet. Here, by self-consistently including modeling of the space-time-dependent nonlocal thermal transport into the radiation hydrodynamic simulations, we revisit the whole implosion and ignition dynamics of SAI numerically and theoretically. We find that, due to the nonlocal effect, on the one hand, the time-delay window between the igniter spike and the compression pulse in the drive laser for achieving high-gain fusion is much broadened from about 0.45 to 0.7 ns, relaxing the difficulty of laser pulse shaping; on the other hand, both the coast time and the fusion burn duration are significantly reduced by, respectively, 0.22 ns and 47 ps, in favor of increasing the hot-spot pressure around the stagnation stage.

Published by the American Physical Society
2024
Synthesis, crystal structure and in-silico evaluation of arylsulfonamide Schiff bases for potential activity against colon cancer
Authors: Kolade Sherif O. , Aina Oluwafemi S. , Gordon Allen T. , Hosten Eric C. , Olasupo Idris A. , Ogunlaja Adeniyi S. , Asekun Olayinka T. , Familoni Oluwole B.
Published: March 2024

This report presents a comprehensive investigation into the synthesis and characterization of Schiff base compounds derived from benzenesulfonamide. The synthesis process, involved the reaction between N-cycloamino-2-sulfanilamide and various substituted o-salicylaldehydes, resulted in a set of compounds that were subjected to rigorous characterization using advanced spectral techniques, including 1H NMR, 13C NMR and FT–IR spectroscopy, and single-crystal X-ray diffraction. Furthermore, an in-depth assessment of the synthesized compounds was conducted through Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) analysis, in conjunction with docking studies, to elucidate their pharmacokinetic profiles and potential. Impressively, the ADMET analysis showcased encouraging drug-likeness properties of the newly synthesized Schiff bases. These computational findings were substantiated by molecular properties derived from density functional theory (DFT) calculations using the B3LYP/6-31G* method within the Jaguar Module of Schrödinger 2023-2 from Maestro (Schrodinger LLC, New York, USA). The exploration of frontier molecular orbitals (HOMO and LUMO) enabled the computation of global reactivity descriptors (GRDs), encompassing charge separation (E
gap) and global softness (S). Notably, within this analysis, one Schiff base, namely, 4-bromo-2-{N-[2-(pyrrolidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 20, emerged with the smallest charge separation (ΔE
gap = 3.5780 eV), signifying heightened potential for biological properties. Conversely, 4-bromo-2-{N-[2-(piperidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 17, exhibited the largest charge separation (ΔE
gap = 4.9242 eV), implying a relatively lower propensity for biological activity. Moreover, the synthesized Schiff bases displayed remarkeable inhibition of tankyrase poly(ADP-ribose) polymerase enzymes, integral in colon cancer, surpassing the efficacy of a standard drug used for the same purpose. Additionally, their bioavailability scores aligned closely with established medications such as trifluridine and 5-fluorouracil. The exploration of molecular electrostatic potential through colour mapping delved into the electronic behaviour and reactivity tendencies intrinsic to this diverse range of molecules.
A new winding homogenization method based on thermal resistance concept
Authors: Hashemi Ali , Yazdanpanah Qaraei Parsa , Shabanian-Poodeh Mostafa
Published: March 2024

Purpose

The aim of this paper is to provide a simple yet accurate and efficient geometric method for thermal homogenization of impregnated and non-impregnated coil winding technologies based on the concept of thermal resistance.

Design/methodology/approach

For regular windings, the periodic microscopic cell in the winding space is identified. Also, for irregular windings, the average microscopic cell of the winding is determined. An approximation is used to calculate the thermal resistance of the winding cell. Based on this approximation, the winding insulation is considered as a circular ring around the wire. Mathematical equations are obtained to calculate the equivalent thermal resistance of the cell. The equivalent thermal conductivity of the winding is calculated using equivalent thermal resistance of the cell. Winding thermal homogenization is completed by determining the equivalent thermal properties of the cell.

Findings

The thermal pattern of different windings is simulated and compared with the results of different homogenization methods. The results show that the proposed method is applicable for a wide range of windings in terms of winding scheme, packing factor and winding insulation. Also, the results show that the proposed method is more accurate than other winding homogenization methods in calculating the equivalent thermal conductivity of the winding.

Research limitations/implications

In this paper, the change of electrical resistance of the winding with temperature and thermal contact between the sub-components are ignored. Also, liquid insulators, such as oils, and rectangular wires were not investigated. Research in these topics is considered as future work.

Originality/value

Unlike other homogenization methods, the proposed method can be applied to non-impregnated and irregular windings. Also, compared to other homogenization methods, the proposed method has a simpler formulation that makes it easier to program and implement. All of these indicate the efficiency of the proposed method in the thermal analysis of the winding.
Extractivism and the engendering of disasters: disaster risk creation in the era of the Anthropocene
Authors: Bradshaw Sarah
Published: March 2024

Purpose

This paper argues that extractivist logic creates the environmental conditions that produce “natural” hazards and also the human conditions that produce vulnerability, which combined create disasters. Disaster Risk Creation is then built into the current global socio-economic system, as an integral component not accidental by-product.

Design/methodology/approach

As part of the movement to liberate disasters as discipline, practice and field of enquiry, this paper does not talk disasters per se, but rather its focus is on “extractivism” as a fundamental explanator for the anthropogenic disaster landscape that now confronts us.

Findings

Applying a gender lens to extractivism as it relates to disaster, further highlights that Disaster Risk Management rather than alleviating, creates the problems it seeks to solve, suggesting the need to liberate gender from Disaster Risk Management, and the need to liberate us all from the notion of managing disasters. Since to ‘manage’ disaster risk is to accept uncritically the structures and systems that create that risk, then if we truly want to address disasters, our focus needs to be on the extractive practices, not the disastrous outcomes.

Originality/value

The fundamental argument is that through privileging the notion of “disaster” we create it, bring it into existence, as something that exists in and of itself, apart from wider socio-economic structures and systems of extraction and exploitation, rather than recognising it for what it is, an outcome/end product of those wider structures and systems. Our focus on disaster is then misplaced, and perhaps what disaster studies needs to be liberated from, is itself.