julilili42/papers huggingface dataset:
Altered desensitization and internalization patterns of rodent versus human glucose‐dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge
2024-07-01

Abstract Background and Purpose The gut hormone glucose‐dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose‐stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR‐targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C‐terminus. Experimental Approach The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta‐arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C‐terminal tails were studied in parallel. Key Results The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for G αs activation, especially, the mouse GIPR shows reduced receptor desensitization, internalization and beta‐arrestin recruitment. Using an enzyme‐stabilized, long‐acting GIP analogue, the species differences were even more pronounced. ‘Tail‐swapped’ human, rat and mouse GIPRs were all fully functional in their G αs coupling, and the mouse GIPR regained internalization and beta‐arrestin 2 recruitment properties with the human tail. The human GIPR lost the ability to recruit beta‐arrestin 2 when its own C‐terminus was replaced by the rat or mouse tail. Conclusions and Implications Desensitization of the human GIPR is dependent on the C‐terminal tail. The species‐dependent functionality of the C‐terminal tail and the different species‐dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR‐targeting therapeutic compounds. LINKED ARTICLES This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc
An IXPE-led X-Ray Spectropolarimetric Campaign on the Soft State of Cygnus X-1: X-Ray Polarimetric Evidence for Strong Gravitational Lensing
2024-07-01

Abstract We present the first X-ray spectropolarimetric results for Cygnus X-1 in its soft state from a campaign of five IXPE observations conducted during 2023 May–June. Companion multiwavelength data during the campaign are likewise shown. The 2–8 keV X-rays exhibit a net polarization degree PD = 1.99% ± 0.13% (68% confidence). The polarization signal is found to increase with energy across the Imaging X-ray Polarimetry Explorer’s (IXPE) 2–8 keV bandpass. The polarized X-rays exhibit an energy-independent polarization angle of PA = −25.°7 ± 1.°8 east of north (68% confidence). This is consistent with being aligned to Cyg X-1’s au-scale compact radio jet and its parsec-scale radio lobes. In comparison to earlier hard-state observations, the soft state exhibits a factor of 2 lower polarization degree but a similar trend with energy and a similar (also energy-independent) position angle. When scaling by the natural unit of the disk temperature, we find the appearance of a consistent trend line in the polarization degree between the soft and hard states. Our favored polarimetric model indicates that Cyg X-1’s spin is likely high ( a * ≳ 0.96). The substantial X-ray polarization in Cyg X-1's soft state is most readily explained as resulting from a large portion of X-rays emitted from the disk returning and reflecting off the disk surface, generating a high polarization degree and a polarization direction parallel to the black hole spin axis and radio jet. In IXPE’s bandpass, the polarization signal is dominated by the returning reflection emission. This constitutes polarimetric evidence for strong gravitational lensing of X-rays close to the black hole.
Mid- and late-life lifestyle activities as main drivers of general and domain-specific cognitive reserve in individuals with Parkinson’s disease: cross-sectional and longitudinal evidence from the LANDSCAPE study
2024-07-01

Abstract Background Cognitive reserve (CR) is considered a protective factor for cognitive function and may explain interindividual differences of cognitive performance given similar levels of neurodegeneration, e.g., in Alzheimer ́s disease. Recent evidence suggests that CR is also relevant in Parkinson’s disease (PD). Objective We aimed to explore the role of life-stage specific CR for overall cognition and specific cognitive domains cross-sectionally and longitudinally in PD. Methods The cross-sectional analysis with data from the DEMPARK/LANDSCAPE study included 81 individuals without cognitive impairment (PD-N) and 87 individuals with mild cognitive impairment (PD-MCI). Longitudinal data covered 4 years with over 500 observations. CR was operationalized with the Lifetime of Experiences Questionnaire (LEQ), capturing the complexity of lifestyle activities across distinct life-stages. Cognition was assessed using a comprehensive neuropsychological test battery. Results Higher LEQ scores, particularly from mid- and late-life, were observed in PD-N compared to PD-MCI [ F (1,153) = 4.609, p = .033, η p 2 = 0.029]. They were significantly associated with better cognitive performance (0.200 ≤ β ≤ 0.292). Longitudinally, linear mixed effect models (0.236 ≤ marginal R 2 ≤ 0.441) revealed that LEQ scores were positively related to cognitive performance independent of time. However, the decline in overall cognition and memory over time was slightly more pronounced with higher LEQ scores. Conclusions This study emphasizes the association between complex lifestyle activities and cognition in PD. Data indicate that while CR might be related to a delay of cognitive decline, individuals with high CR may experience a more pronounced drop in overall cognition and memory. Future studies will have to replicate these findings, particularly regarding domain-specific effects and considering reverse causal mechanisms.
Streamlined spatial and environmental expression signatures characterize the minimalist duckweedWolffia australiana
2024-07-01

Single-cell genomics permits a new resolution in the examination of molecular and cellular dynamics, allowing global, parallel assessments of cell types and cellular behaviors through development and in response to environmental circumstances, such as interaction with water and the light–dark cycle of the Earth. Here, we leverage the smallest, and possibly most structurally reduced, plant, the semiaquatic Wolffia australiana , to understand dynamics of cell expression in these contexts at the whole-plant level. We examined single-cell-resolution RNA-sequencing data and found Wolffia cells divide into four principal clusters representing the above- and below-water-situated parenchyma and epidermis. Although these tissues share transcriptomic similarity with model plants, they display distinct adaptations that Wolffia has made for the aquatic environment. Within this broad classification, discrete subspecializations are evident, with select cells showing unique transcriptomic signatures associated with developmental maturation and specialized physiologies. Assessing this simplified biological system temporally at two key time-of-day (TOD) transitions, we identify additional TOD-responsive genes previously overlooked in whole-plant transcriptomic approaches and demonstrate that the core circadian clock machinery and its downstream responses can vary in cell-specific manners, even in this simplified system. Distinctions between cell types and their responses to submergence and/or TOD are driven by expression changes of unexpectedly few genes, characterizing Wolffia as a highly streamlined organism with the majority of genes dedicated to fundamental cellular processes. Wolffia provides a unique opportunity to apply reductionist biology to elucidate signaling functions at the organismal level, for which this work provides a powerful resource.
Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences
2024-07-01

ABSTRACT Pontocerebellar hypoplasia type 2a (PCH2a) is an ultra-rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. A homozygous founder variant in TSEN54, which encodes a tRNA splicing endonuclease (TSEN) complex subunit, is causal. The pathological mechanism of PCH2a remains unknown due to the lack of a model system. Therefore, we developed human models of PCH2a using regionalized neural organoids. We generated induced pluripotent stem cell (iPSC) lines from three males with genetically confirmed PCH2a and subsequently differentiated cerebellar and neocortical organoids. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. Neocortical PCH2a organoids demonstrated milder growth deficits. Although PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we generated a human model of PCH2a, providing the foundation for deciphering brain region-specific disease mechanisms. Our first analyses suggest a neurodevelopmental aspect of PCH2a.
Minimal important difference of the Migraine Disability Assessment (MIDAS): Longitudinal data from the DMKG Headache Registry
2024-07-01

Background The Migraine Disability Assessment (MIDAS) is widely used. However, there are limited data on how much a reduction in the MIDAS score indicates a change that matters to the patient. Methods Data from the DMKG (i.e. German Migraine and Headache Society) Headache Registry were used to determine the minimal important difference (MID) of the MIDAS, using the Patient Global Impression of Change (PGIC) as anchor and applying average change and receiver operating characteristic curve methods. Results In total, 1218 adult migraine patients (85.6% female, 40.2 ± 12.8 years, baseline MIDAS 44.2 ± 47.4, follow-up MIDAS 36.5 ± 45.3) were included. For patients with baseline MIDAS &gt;20 (MIDAS grade IV, n = 757), different methods using PGIC “somewhat improved” as anchor yielded percent change MIDs of the MIDAS between −29.4% and −33.2%. For baseline MIDAS between 6 and 20 (grades II and III, n = 334), using PGIC “much improved” as anchor, difference change MIDs were between −3.5 and −4.5 points. Conclusions Based on the above results, we estimated the MID of the MIDAS at −30% for patients with a baseline MIDAS &gt;20, and at −4 points for those with a baseline MIDAS of 6–20, for a tertiary headache care population. Trial Registration The DMKG Headache Registry is registered with the German Clinical Trials Register (DRKS 00021081).
Metabolic syndrome-associated murine aortic wall stiffening is associated with premature elastic fibers aging
2024-07-01

Aortic elastic fibers of young (6-mo old) individuals with diabetes degrade prematurely and exhibit an appearance like that found in aged (20-mo old) nondiabetic mice. Exacerbated elastolysis and elastin-derived peptide production are characteristic elements, contributing to early aortic wall rigidity and hypertension development. Therefore, limiting this early aging could be a judicious therapeutic approach to reduce cardiovascular complications and premature death in patients with diabetes.
Pangenome graph layout by Path-Guided Stochastic Gradient Descent
2024-07-01

Abstract Motivation The increasing availability of complete genomes demands for models to study genomic variability within entire populations. Pangenome graphs capture the full genomic similarity and diversity between multiple genomes. In order to understand them, we need to see them. For visualization, we need a human-readable graph layout: a graph embedding in low (e.g. two) dimensional depictions. Due to a pangenome graph’s potential excessive size, this is a significant challenge. Results In response, we introduce a novel graph layout algorithm: the Path-Guided Stochastic Gradient Descent (PG-SGD). PG-SGD uses the genomes, represented in the pangenome graph as paths, as an embedded positional system to sample genomic distances between pairs of nodes. This avoids the quadratic cost seen in previous versions of graph drawing by SGD. We show that our implementation efficiently computes the low-dimensional layouts of gigabase-scale pangenome graphs, unveiling their biological features. Availability and implementation We integrated PG-SGD in ODGI which is released as free software under the MIT open source license. Source code is available at https://github.com/pangenome/odgi.
Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals
2024-07-01

Abstract Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross‐sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug–indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.
The evolutionary consequences of interactions between the epigenome, the genome and the environment
2024-07-01

Abstract The epigenome is the suite of interacting chemical marks and molecules that helps to shape patterns of development, phenotypic plasticity and gene regulation, in part due to its responsiveness to environmental stimuli. There is increasing interest in understanding the functional and evolutionary importance of this sensitivity under ecologically realistic conditions. Observations that epigenetic variation abounds in natural populations have prompted speculation that it may facilitate evolutionary responses to rapid environmental perturbations, such as those occurring under climate change. A frequent point of contention is whether epigenetic variants reflect genetic variation or are independent of it. The genome and epigenome often appear tightly linked and interdependent. While many epigenetic changes are genetically determined, the converse is also true, with DNA sequence changes influenced by the presence of epigenetic marks. Understanding how the epigenome, genome and environment interact with one another is therefore an essential step in explaining the broader evolutionary consequences of epigenomic variation. Drawing on results from experimental and comparative studies carried out in diverse plant and animal species, we synthesize our current understanding of how these factors interact to shape phenotypic variation in natural populations, with a focus on identifying similarities and differences between taxonomic groups. We describe the main components of the epigenome and how they vary within and between taxa. We review how variation in the epigenome interacts with genetic features and environmental determinants, with a focus on the role of transposable elements (TEs) in integrating the epigenome, genome and environment. And we look at recent studies investigating the functional and evolutionary consequences of these interactions. Although epigenetic differentiation in nature is likely often a result of drift or selection on stochastic epimutations, there is growing evidence that a significant fraction of it can be stably inherited and could therefore contribute to evolution independently of genetic change.
The convex relationship between plant cover and biomass: Implications for assessing species and community properties
2024-07-01

Abstract Questions Cover and biomass serve as common measures of species abundance in plant ecology. However, the underlying relationship between these two measures and its implications remain poorly understood. This makes results based on cover and biomass difficult to compare. Locations Wet meadow, southeast of České Budějovice, Czech Republic (48°57′ N, 14°36′ E). Method We developed theoretical expectations for systematic differences in characterizing vegetation using cover and biomass for species and community characteristics, including species diversity, temporal dynamics, and responses to experimental manipulations. We then tested these expectations using cover and biomass data from an experimental study of fertilization and dominant removal spanning 14 years (2001–2014). Results Consistent with our expectations, on average, species biomass corresponded to the power of species cover, with a power coefficient slightly below 3/2. Community diversity indices calculated using cover and biomass were tightly correlated but were higher for cover. Temporal variabilities based on cover and biomass for individual species were also correlated, but higher for biomass than cover. Though strongly correlated, cover data show much stronger asynchrony, suggesting higher importance of compensatory dynamics. However, using the sum of individual species' cover values as a measure of total community abundance or productivity is problematic. Such a measure is nearly independent of total biomass and leads to contradictory results when used to characterize temporal variability. Species‐ and community‐level responses to treatments were congruent between the measures. Conclusions Our study provides theoretical background for a convex relationship between plant cover and biomass. The data analysis confirms the relationship and its consequences for describing species‐ and community‐level properties. Most characteristics are well correlated between cover and biomass, but with one metric systematically shifted higher in many cases. Total abundance is the most sensitive measure and is well characterized by sum of biomass, but not by sum of cover. Understanding these systematic differences allows meaningful comparison of studies based on biomass and cover.
Autologous haematopoiesis stem cell transplantation (AHSCT) for treatment-refractory autoimmune diseases in children
2024-07-01

Objectives To evaluate the long-term effectiveness and safety of autologous haematopoiesis stem cell transplantation (AHSCT) for severe, refractory autoimmune diseases in paediatric patients. Methods A single-centre study of consecutive children and adolescents with refractory autoimmune diseases undergoing AHSCT was performed. Demographics, clinical, laboratory features, pre-AHSCT medications, disease activity and functional status were captured. The primary outcome was progression-free survival, secondary outcomes included overall survival, disease-specific treatment responses, disease activity at the last follow-up and AHSCT safety. Results The study included seven patients: two systemic sclerosis, one pansclerotic morphoea, one eosinophilic fasciitis, one juvenile dermatomyositis and two patients with systemic juvenile idiopathic arthritis; four women, three men median age at AHSCT of 10 years (7–19), median follow-up post-AHSCT of 17 years. Median progression-free survival and overall survival was 4.2 years (95% CI: 0.98 to 8.3) and 17 years (95% CI: 11.8 to 22.1), respectively. Progression-free survival rates at 1 and 2 years post-AHSCT were 100% and 77%, respectively. All children survived. All patients are in clinical remission, only four require ongoing immunotherapy. Safety: Three experienced infections, including HHV6, Candida and Ralstonia sepsis; one developed a systemic inflammatory response syndrome; two new onset secondary autoimmune diseases including autoimmune haemolytic anaemia, Graves’ disease and one was found to have a breast fibroadenoma. Treatment toxicity: one cyclophosphamide-associated transient renal failure and pericardial effusion, one patient with amenorrhoea/infertility. Conclusions AHSCT was an effective and safe approach for children and adolescents with treatment-refractory autoimmune diseases. The indication and timing of transplantation requires a careful consideration and a multidisciplinary approach.
From 3D to 5D tracking: SMX ASIC-based double-sided micro-strip detectors for comprehensive space, time, and energy measurements
2024-07-01

Abstract We present the recent development of a lightweight detector capable of accurate spatial, timing, and amplitude resolution of charged particles. The technology is based on double-sided double-metal p+ – n – n+ micro-strip silicon sensors, ultra-light long aluminum-polyimide micro-cables for the analogue signal transfer, and a custom-developed SMX read-out ASIC capable of measurement of the time (Δ t ≲ 5 ns) and amplitude. Dense detector integration enables a material budget &gt; 0.3 % X 0 . A sophisticated powering and grounding scheme keeps the noise under control. In addition to its primary application in Silicon Tracking System of the future CBM experiment in Darmstadt, our detector will be utilized in other research applications.