julilili42/papers huggingface dataset:
Hidden functional complexity in the flora of an early land ecosystem
2023-08-29

Summary The first land ecosystems were composed of organisms considered simple in nature, yet the morphological diversity of their flora was extraordinary. The biological significance of this diversity remains a mystery largely due to the absence of feasible study approaches. To study the functional biology of Early Devonian flora, we have reconstructed extinct plants from fossilised remains in silico . We explored the morphological diversity of sporangia in relation to their mechanical properties using finite element method. Our approach highlights the impact of sporangia morphology on spore dispersal and adaptation. We discovered previously unidentified innovations among early land plants, discussing how different species might have opted for different spore dispersal strategies. We present examples of convergent evolution for turgor pressure resistance, achieved by homogenisation of stress in spherical sporangia and by torquing force in Tortilicaulis‐like specimens. In addition, we show a potential mechanism for stress‐assisted sporangium rupture. Our study reveals the deceptive complexity of this seemingly simple group of organisms. We leveraged the quantitative nature of our approach and constructed a fitness landscape to understand the different ecological niches present in the Early Devonian Welsh Borderland flora. By connecting morphology to functional biology, these findings facilitate a deeper understanding of the diversity of early land plants and their place within their ecosystem.
The redox-sensitive R-loop of the carbon control protein SbtB contributes to the regulation of the cyanobacterial CCM
2023-08-29

Abstract SbtB is a PII-like protein that regulates the carbon-concentrating mechanism (CCM) in cyanobacteria. SbtB proteins can bind many adenyl nucleotides and possess a characteristic C-terminal redox sensitive loop (R-loop) that forms a disulfide bridge in response to the diurnal state of the cell. SbtBs also possess an ATPase/ADPase activity that is modulated by the redox-state of the R-loop. To investigate the R-loop in the cyanobacterium Synechocystis sp. PCC 6803, site-specific mutants, unable to form the hairpin and permanently in the reduced state, and a R-loop truncation mutant, were characterized under different inorganic carbon (C i ) and light regimes. Growth under diurnal rhythm showed a role of the R-loop as sensor for acclimation to changing light conditions. The redox-state of the R-loop was found to impact the binding of the adenyl-nucleotides to SbtB, its membrane association and thereby the CCM regulation, while these phenotypes disappeared after truncation of the R-loop. Collectively, our data imply that the redox-sensitive R-loop provides an additional regulatory layer to SbtB, linking the CO 2 -related signaling activity of SbtB with the redox state of cells, mainly reporting the actual light conditions. This regulation not only coordinates CCM activity in the diurnal rhythm but also affects the primary carbon metabolism.
Are metacognition interventions in young children effective? Evidence from a series of meta-analyses
2023-08-29

*This paper is not yet published.* A metacognitive learner acts in a planful way, monitors their progress, flexibly adapts their strategies, and reflects on their learning. Unsurprisingly, a metacognitive approach to learning is an important predictor of children’s academic performance and many attempts have been made to promote metacognition in young children. The current meta-analytic study evaluates the impact of such metacognition interventions on outcomes related to self-regulated learning and academic achievement in typically developing pre- and elementary school children. Structural, content-related, and methodological moderators were tested in this study including 349 effect sizes from 67 studies. An overall effectiveness of metacognition interventions was evidenced at immediate post-test g = 0.48 (95% CI [0.35, 0.61]), and at follow-up g = 0.29 (95% CI [0.17, 0.40]). Interestingly, metacognition interventions effectively enhanced children’s self-efficacy only at follow-up, suggesting that the positive impact of these interventions can unfold over a protracted period. For the first time, children’s executive functions were considered as outcome variables and results indicated a positive impact of metacognition interventions on these variables. One notable finding was that interventions that were delivered by teachers or task materials were more effective than interventions that were delivered by researchers for two outcomes related to self-regulated learning. This finding may reflect recent improvements in how teachers and researchers collaborate to develop intervention programs. The study supports and extends existing evidence that young learners benefit from metacognition interventions in myriad ways and provides novel insights relevant for pedagogical practice and theories of self-regulated learning.
Diagnostic Approaches for Neuroendocrine Neoplasms of Unknown Primary (NEN-UPs) and Their Prognostic Relevance—A Retrospective, Long-Term Single-Center Experience
2023-08-29

Neuroendocrine neoplasms (NENs) represent a rare and heterogenous group of tumors with predominantly gastroenteropancreatic or pulmonary origin. Despite numerous diagnostic efforts, the primary tumor site remains unknown in up to 20% of the patients diagnosed with NEN. In this subgroup of NEN patients, a standard diagnostic algorithm has not yet been integrated into clinical routine. Of note, an undetermined primary tumor site in NENs is associated with an impaired clinical outcome by at least “formally” limiting treatment options exclusively approved for NENs of a certain histological origin. In this retrospective study, a patient cohort of 113 patients initially diagnosed with NEN of unknown primary (NEN-UP) was analyzed. In 13 patients (11.5%) a primary tumor site could be identified subsequently, amongst others, by performing somatostatin receptor (SSTR)-PET-based imaging, which was irrespective of the initial clinical or demographic features. Diagnostic work-up and therapeutic regimens did not differ significantly between patients with an identified or unidentified primary tumor site; only a detailed immunohistochemical assessment providing additional information on the tumor origin proved to be significantly associated with the detection of a primary tumor site. Our study revealed that a profound diagnostic work-up, particularly including SSTR-PET-based imaging, leads to additional treatment options, finally resulting in significantly improved clinical outcomes for patients with NEN-UPs.
Broad time‐dependent transcriptional activity of metabolic genes of E. coli O104:H4 strain C227/11Φcu in a soil microenvironment at low temperature
2023-08-29

Abstract In the current study, metabolic genes and networks that influence the persistence of pathogenic Escherichia coli O104:H4 strain C227/11Φcu in agricultural soil microenvironments at low temperature were investigated. The strain was incubated in alluvial loam (AL) and total RNA was prepared from samples at time point 0, and after 1 and 4 weeks. Differential transcriptomic analysis was performed by RNA sequencing analysis and values obtained at weeks 1 and 4 were compared to those of time point 0. We found differential expression of more than 1500 genes for either time point comparison. The two lists of differentially expressed genes were then subjected to gene set enrichment of Gene Ontology terms. In total, 17 GO gene sets and 3 Pfam domains were found to be enriched after 1 week. After 4 weeks, 17 GO gene sets and 7 Pfam domains were statistically enriched. Especially stress response genes and genes of the primary metabolism were particularly affected at both time points. Genes and gene sets for uptake of carbohydrates, amino acids were strongly upregulated, indicating adjustment to a low nutrient environment. The results of this transcriptome analysis show that persistence of C227/11Φcu in soils is associated with a complex interplay of metabolic networks.
The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development
2023-08-29

Abstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na -coupled citrate co-transporter that mediates the entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a therapeutic target for reducing progression of kidney disease via its effects on citrate metabolism. However, evidence of its efficacy in humans is limited. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts. Methods The primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large scale genetic consortia and biobanks, with sample sizes ranging from 5,023 to 1,320,016 individuals. Results We found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p=0.002), cystatin C-eGFR (p=0.005), and lower BUN (p=3×10 -3 ). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses also identified evidence of associations with higher plasma calcium levels (p=6×10 -13 ) and lower fasting glucose (p=0.02). PheWAS did not identify any safety concerns. Conclusion This Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function. Further study in the form of early-stage clinical trials may now be warranted to help translate these findings towards improving patient care.
Chandra X-ray spectroscopy of the focused wind in the Cygnus X-1 system
2023-08-29

We present an analysis of three Chandra High Energy Transmission Gratings observations of the black hole binary Cyg X-1/HDE 226868 at different orbital phases. The stellar wind that is powering the accretion in this system is characterized by temperature and density inhomogeneities including structures, or “clumps”, of colder, more dense material embedded in the photoionized gas. As these clumps pass our line of sight, absorption dips appear in the light curve. We characterize the properties of the clumps through spectral changes during various dip stages. Comparing the silicon and sulfur absorption line regions (1.6–2.7 keV ≡ 7.7–4.6 Å) in four levels of varying column depth reveals the presence of lower ionization stages, i.e., colder or denser material, in the deeper dip phases. The Doppler velocities of the lines are roughly consistent within each observation, varying with the respective orbital phase. This is consistent with the picture of a structure that consists of differently ionized material, in which shells of material facing the black hole shield the inner and back shells from the ionizing radiation. The variation of the Doppler velocities compared to a toy model of the stellar wind, however, does not allow us to pin down an exact location of the clump region in the system. This result, as well as the asymmetric shape of the observed lines, point at a picture of a complex wind structure.
The X-ray polarization of the Seyfert 1 galaxy IC 4329A
2023-08-30

ABSTRACT We present an X-ray spectro-polarimetric analysis of the bright Seyfert galaxy IC 4329A. The Imaging X-ray Polarimetry Explorer (IXPE) observed the source for ∼500 ks, supported by XMM–Newton (∼60 ks) and NuSTAR (∼80 ks) exposures. We detect polarization in the 2–8 keV band with 2.97σ confidence. We report a polarization degree of 3.3 ± 1.1 per cent and a polarization angle of 78° ± 10° (errors are 1σ confidence). The X-ray polarization is consistent with being aligned with the radio jet, albeit partially due to large uncertainties on the radio position angle. We jointly fit the spectra from the three observatories to constrain the presence of a relativistic reflection component. From this, we obtain constraints on the inclination angle to the inner disc (&amp;lt;39° at 99 per cent confidence) and the disc inner radius (&amp;lt;11 gravitational radii at 99 per cent confidence), although we note that modelling systematics in practice add to the quoted statistical error. Our spectropolarimetric modelling indicates that the 2–8 keV polarization is consistent with being dominated by emission directly observed from the X-ray corona, but the polarization of the reflection component is completely unconstrained. Our constraints on viewer inclination and polarization degree tentatively favour more asymmetric, possibly out-flowing, coronal geometries that produce more highly polarized emission, but the coronal geometry is unconstrained at the 3σ level.
Therapeutic targeting of the complement system in ocular disease
2023-08-30

The complement system is involved in the pathogenesis of several ocular diseases, providing a rationale for the investigation of complement-targeting therapeutics for these conditions. Dry age-related macular degeneration, as characterised by geographic atrophy (GA), is currently the most active area of research for complement-targeting therapeutics, with a complement C3 inhibitor approved in the United States earlier this year marking the first approved therapy for GA. This review discusses the role of complement in ocular disease, provides an overview of the complement-targeting agents currently under development for ocular conditions, and reflects on the lessons that can be learned from the preclinical investigations and clinical trials conducted in this field to date.
Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases: emerging concepts, recent advances, and the putative role of clonal hematopoiesis. A report of the 2022 EA4HP/SH lymphoma workshop
2023-08-30

Abstract Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases were discussed at the 2022 European Association for Haematopathology/Society for Hematopathology lymphoma workshop held in Florence, Italy. This session focused on (i) primary nodal EBV-positive T and NK-cell lymphomas (primary nodal-EBV-TNKL), (ii) extranodal EBV-positive T/NK lymphoproliferative diseases (LPD) in children and adults, (iii) cytotoxic peripheral T-cell lymphomas, NOS (cPTCL-NOS), EBV-negative, and (iv) miscellaneous cases. Primary nodal-EBV-TNKL is a newly recognized entity which is rare, aggressive, and associated with underlying immune deficiency/immune dysregulation. All cases presented with lymphadenopathy but some demonstrated involvement of tonsil/Waldeyer’s ring and extranodal sites. The majority of tumors are of T-cell lineage, and the most frequent mutations involve the epigenetic modifier genes, such as TET2 and DNMT3A , and JAK-STAT genes. A spectrum of EBV-positive T/NK LPD involving extranodal sites were discussed and highlight the diagnostic challenge with primary nodal-EBV-TNKL when these extranodal EBV-positive T/NK LPD cases demonstrate predominant nodal disease either at presentation or during disease progression from chronic active EBV disease. The majority of cPTCL-NOS demonstrated the TBX21 phenotype. Some cases had a background of immunosuppression or immune dysregulation. Interestingly, an unexpected association of cPTCL-NOS, EBV-positive and negative, with TFH lymphomas/LPDs was observed in the workshop cases. Similar to a published literature, the genetic landscape of cPTCL-NOS from the workshop showed frequent mutations in epigenetic modifiers, including TET2 and DNMT3A , suggesting a role of clonal hematopoiesis in the disease pathogenesis.
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
2023-08-30

Abstract Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1 +/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1 +/ − mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/ − brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.
Exhumation and incision of the eastern Central Andes, southern Peru: Low-temperature thermochronology observations
2023-08-30

Quantifying the impacts of past changes in tectonics or climate on mountain topography has proven challenging. The incision of the eastern Central Andean Plateau has been interpreted as both a result of deformation-related uplift and erosion and climate-driven erosion. Here, we contribute &amp;gt;100 new apatite and zircon (U-Th)/He and fission-track dates from 51 new and eight previous bedrock samples. These samples were combined with previous thermochronometer data from three ∼190-km-long and ∼200-km-apart across-strike transects along the eastern margin of the Andean Plateau in southern Peru. We discuss age-distance, age-elevation, and inverse thermal history model results along these transects to constrain the timing and extent of recent canyon incision compared to the region's long-term (∼40 Myrs) exhumation history. Results indicate that, along the plateau flank, long-term, deformation-related exhumation is superimposed by a regional, synchronous canyon incision-related signal since ∼4–3 Ma. This incision is traceable from at least the Abancay Deflection in southern Peru to southern Bolivia along the eastern Central Andes. Based on the regional and synchronous character of canyon incision across areas with different deformation histories and exhumation magnitude, we suggest that paleoclimate change was a significant contributor to incision. However, structural processes resulting in surface uplift, erosion, and exhumation continued post-mid Miocene and contributed to the observed exhumation magnitude.
With or Without You: Programming with Effect Exclusion
2023-08-30

Type and effect systems have been successfully used to statically reason about effects in many different domains, including region-based memory management, exceptions, and algebraic effects and handlers. Such systems’ soundness is often stated in terms of the absence of effects. Yet, existing systems only admit indirect reasoning about the absence of effects. This is further complicated by effect polymorphism which allows function signatures to abstract over arbitrary, unknown sets of effects. We present a new type and effect system with effect polymorphism as well as union, intersection, and complement effects. The effect system allows us to express effect exclusion as a new class of effect polymorphic functions: those that permit any effects except those in a specific set. This way, we equip programmers with the means to directly reason about the absence of effects. Our type and effect system builds on the Hindley-Milner type system, supports effect polymorphism, and preserves principal types modulo Boolean equivalence. In addition, a suitable extension of Algorithm W with Boolean unification on the algebra of sets enables complete type and effect inference. We formalize these notions in the λ ∁ calculus. We prove the standard progress and preservation theorems as well as a non-standard effect safety theorem: no excluded effect is ever performed. We implement the type and effect system as an extension of the Flix programming language. We conduct a case study of open source projects identifying 59 program fragments that require effect exclusion for correctness. To demonstrate the usefulness of the proposed type and effect system, we recast these program fragments into our extension of Flix.
Hybrid zone analysis confirms cryptic species of banded newt and does not support competitive displacement since secondary contact
2023-08-30

Abstract When two putatively cryptic species meet in nature, hybrid zone analysis can be used to estimate the extent of gene flow between them. Two recently recognized cryptic species of banded newt (genus Ommatotriton ) are suspected to meet in parapatry in Anatolia, but a formal hybrid zone analysis has never been conducted. We sample populations throughout the range, with a focus on the supposed contact zone, and genotype them for 31 nuclear DNA SNP markers and mtDNA. We determine the degree of genetic admixture, introgression, and niche overlap. We reveal an extremely narrow hybrid zone, suggesting strong selection against hybrids, in line with species status. The hybrid zone does not appear to be positioned at an ecological barrier, and there is significant niche overlap. Therefore, the hybrid zone is best classified as a tension zone, maintained by intrinsic selection against hybrids. While the two banded newt species can evidently backcross, we see negligible introgression and the pattern is symmetric, which we interpret as supporting the fact that the hybrid zone has been practically stationary since its origin (while extensive hybrid zone movement has been suggested in other newt genera in the region). Our study illustrates the use of hybrid zone analysis to test cryptic species status.