julilili42/papers huggingface dataset:
The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development
2023-12-18

Abstract Background Solute carrier family 13 member 5 (SLC13A5) is a Na + -coupled citrate co-transporter that mediates entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a target for reducing progression of kidney disease. 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 5023 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 −4 ). 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 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. Conclusions 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.
Modelling individual aesthetic judgements over time
2023-12-18

Listening to music, watching a sunset—many sensory experiences are valuable to us, to a degree that differs significantly between individuals, and within an individual over time. We have theorized (Brielmann &amp; Dayan 2022 Psychol. Rev . 129 , 1319–1337 ( doi:10.1037/rev0000337 ))) that these idiosyncratic values derive from the task of using experiences to tune the sensory-cognitive system to current and likely future input. We tested the theory using participants’ ( n = 59) ratings of a set of dog images ( n = 55) created using the NeuralCrossbreed morphing algorithm. A full realization of our model that uses feature representations extracted from image-recognizing deep neural nets (e.g. VGG-16) is able to capture liking judgements on a trial-by-trial basis (median r = 0.65), outperforming predictions based on population averages (median r = 0.01). Furthermore, the model’s learning component allows it to explain image sequence dependent rating changes, capturing on average 17% more variance in the ratings for the true trial order than for simulated random trial orders. This validation of our theory is the first step towards a comprehensive treatment of individual differences in evaluation. This article is part of the theme issue ‘Art, aesthetics and predictive processing: theoretical and empirical perspectives’.
Validation of Constant Work Rate Cycling Endurance Time for Use in Chronic Obstructive Pulmonary Disease Clinical Trials
2023-12-18

<b>Rationale:</b> A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life among patients with chronic obstructive pulmonary disease (COPD) that is not fully accepted in regulatory decision making, hampering drug development. <b>Objectives:</b> To demonstrate, as we previously asserted (Casaburi <i>COPD</i> 2022;9:252), that constant work rate cycling endurance time is an appropriate exercise endurance measure in patients with COPD. <b>Methods:</b> To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2,166 subjects) and 15 exercise training (3,488 subjects) studies (Casaburi <i>COPD</i> 2022;9:520). <b>Results:</b> Construct validity was demonstrated: <i>1</i>) peak physiologic and perceptual responses were similar for constant work rate and incremental cycling; <i>2</i>) after bronchodilator therapy, there were greater increases in endurance time in patients with more severe airflow limitation; <i>3</i>) after exercise training, endurance time increases were similar across airflow limitation severities; and <i>4</i>) there were correlations between changes in endurance time and changes in mechanistically related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points after the intervention. Responsiveness was confirmed, with significant increases in endurance time after active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation and after exercise training. On the basis of regression analysis using multiple anchor variables, the minimum important difference for endurance time increase is estimated to be approximately 1 minute. <b>Conclusions:</b> Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to the evaluation of treatment benefit supporting regulatory decision making and evidence-based therapeutic recommendations.
Anopheles gambiae s.s. resistance to pyrethroids and DDT in semi-urban and rural areas of the Moyen-Ogooué Province, Gabon
2023-12-18

Abstract Background Pyrethroids are the main insecticides used in vector control for malaria. However, their extensive use in the impregnation of long-lasting insecticidal nets (LLINs) and indoor residual spraying has led to the development of resistance, threatening its success as a tool for malaria control. Baseline data prior to large scale distribution of LLINs are important for the implementation of efficient strategies. However, no data on the susceptibility of malaria vectors is available in the Moyen-Ogooué Province in Gabon. The aim of this study was to assess the susceptibility to pyrethroids and organochlorides of malaria vectors from a semi-urban and rural areas of the province and to determine the frequency of insecticide resistance genes. Methods Larvae were collected from breeding sites in Lambaréné and Zilé and reared to adults. Three to five-day old female Anopheles gambiae sensu lato mosquitoes were used in cone tube assays following the WHO susceptibility tests protocol for adult mosquitoes. A subsample was molecularly identified using the SINE200 protocol and the frequency of Vgsc-1014 F and − 1014 S mutations were determined. Results Anopheles gambiae sensu stricto ( s.s .) was the sole species present in both Lambaréné and Zilé. Mosquito populations from the two areas were resistant to pyrethroids and organochlorides. Resistance was more pronounced for permethrin and DDT with mortality lower than 7% for both insecticides in the two study areas. Mosquitoes were statistically more resistant ( P &lt; 0.0001) to deltamethrin in Lambaréné (51%) compared to Zilé (76%). All the mosquitoes tested were heterozygous or homozygous for the knockdown resistance ( Kdr ) mutations Vgsc-L1014F and Vgsc-L1014S with a higher proportion of Vgsc-L1014F homozygous in Lambaréné (76.7%) compared to Zilé (57.1%). Conclusion This study provides evidence of widespread resistance to pyrethroids in An. gambiae s.s. , the main malaria vector in the Moyen-Ogooué Province. Further investigation of the mechanisms underlining the resistance of An. gambiae s.s. to pyrethroids is needed to implement appropriate insecticide resistance management strategies.
Diversity and taxonomy of the Late Triassic sauropodomorphs (Saurischia, Sauropodomorpha) stored in the Palaeontological Collection of Tübingen, Germany, historically referred to Plateosaurus
2023-12-18

The genus Plateosaurus is one of the most challenging aspects of early-diverging sauropodomorph taxonomy, with a total of 29 names and a century of revisions. As a result, nomina dubia have been treated as synonyms of Plateosaurus trossingensis, adding to the confusion about the extent of morphological variability. Here, we provide a thorough revision of the taxonomy proposed by von Huene as well as the subsequent taxonomic interpretations of Plateosaurus through a complete inventory of the specimens stored in the Palaeontological Collection of Tübingen. We reassess the status of the specimens in the collection and propose that the sauropodomorph-bearing layers are not necessarily monospecific. Most of the original fieldwork documentation has been lost, but we use the taxonomy established by von Huene as a historical reference point to reconstruct what was known at the time. This revised taxonomy of Plateosaurus narrows the genus to three species: Pl. trossingensis, Pl. longiceps, and Pl. gracilis (as a metataxon), and restricts the genera Gresslyosaurus and Pachysaurus to large and robust individuals, as pragmatic decisions aimed to test their affinities to other Late Triassic sauropodomorphs. Future studies should consider not only morphological variability, but also stratigraphy, palaeogeography, and environmental data when delineating species within and outside the Plateosaurus plexus.
Ghrelin is associated with an elevated mood after an overnight fast in depression
2023-12-18

Abstract Background Major depressive disorder (MDD) comprises subtypes with distinct symptom profiles. For example, patients with melancholic and atypical MDD differ in the direction of appetite and body weight changes as well as mood reactivity. Despite reported links to altered energy metabolism, the role of circulating neuropeptides from the gut in modulating such symptoms remains largely elusive. Methods We collected data from 103 participants, including 51 patients with MDD and 52 healthy control participants (HCP). After an overnight fast, we measured blood levels of (acyl and des-acyl) ghrelin and participants reported their current metabolic and mood states using visual analog scales (VAS). Furthermore, they completed symptom-related questionnaires (i.e., STAI-T). Results Patients with atypical versus melancholic MDD reported less negative affect ( p = .025). Higher levels of acyl ghrelin (corrected for BMI) were associated with improved mood ( p = .012), specifically in patients with MDD. These associations of ghrelin were not mood-item specific and exceeded correlations with trait markers of negative affectivity. In contrast to associations with mood state, higher levels of ghrelin were not associated with increased hunger per se or changes in appetite in patients with MDD. Limitations The study is limited by the cross-sectional design without an intervention. Conclusions Our results reveal potentially mood-enhancing effects of ghrelin in fasting individuals that exceed associations with metabolic state ratings. These associations with circulating neuropeptides might help explain anti-depressive effects of fasting interventions and could complement conventional treatments in patients with melancholic MDD. Graphical abstract
Logan Medallist 8. Trace Elements in Iron Formation as a Window into Biogeochemical Evolution Accompanying the Oxygenation of Earth’s Atmosphere
2023-12-18

Iron formations exemplify a type of sedimentary rock found in numerous Archean and Proterozoic supracrustal successions. They serve as a valuable chemical record of Precambrian seawater chemistry and post-depositional iron cycling. These formations accumulated on the seafloor for over two billion years during the early history of our planet, offering a unique opportunity to study environmental changes that occurred during Earth's evolution. Among these changes, one of the most significant events was the shift from an anoxic planet to one where oxygen (O2) became consistently present in both the marine water column and atmosphere. This progression towards global oxygenation was closely linked to the emergence of aerobic microbial metabolisms, which profoundly impacted continental weathering processes, nutrient supply to the oceans, and ultimately, the diversification of the biosphere and complex life forms. In this review, we synthesize two decades of research into the temporal fluctuations of trace element concentrations in iron formations. Our aim is to shed light on the complex mechanisms that contributed to the oxygenation of Earth's surface environments.
Differentiation of bladder cancer with water flow elastography (WaFE)
2023-12-18

Cancer affects the mechanical properties of tissue. Therefore, elastography techniques can be used to differentiate cancerous from healthy tissue. Due to probe size and restricted handling, most elastography techniques are not applicable in minimally invasive surgery (MIS). Established techniques such as endoscopic ultrasound elastography measure under undefined boundary conditions, making the determination of quantitative mechanical properties challenging. Water flow elastography (WaFE) has recently been introduced for application in MIS. Here, we present an improved WaFE measurement method in which the probe attaches itself to the sample with a small suction pressure. This leads to defined boundary conditions, allowing for a quantitative determination of the Young's modulus of tissue. To facilitate fast measurements, we developed a correction model for the hydrodynamic resistance and the fluid inertia of the tubing. We used WaFE for ex vivo measurements on human bladders and found a significantly larger Young's modulus for cancerous vs. healthy tissue. We determined the optimal classification threshold for the Young's modulus to be 8 kPa and found that WaFE can differentiate between cancerous and healthy tissue with a sensitivity of 0.96 and a specificity of 1. Our results underline that WaFE can be a helpful differentiating tool in MIS.
Concurrent gliomas in patients with multiple sclerosis
2023-12-18

Abstract Background Concurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives. Methods A multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients. Results MS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation. Conclusions Concurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.
Author Correction: Accurate long-read sequencing identified GBA1 as major risk factor in the Luxembourgish Parkinson’s study
2023-12-18

npj Parkinson’s Disease, published online 23 November 2023 In this article the wrong Table appeared as Table 3.; the Table should have appeared as shown below. The original article has been corrected. The following text that describes data from the previous version of Table 3 has also been removed: “Compared to severe (6.4 ± 4.7) and risk (4.4 ± 4.9) variant carriers, the mild (1.7 ± 1.4) variant carriers show a significantly shorter disease duration (Table 3).” (Table presented.) Features All pathogenic variants (n = 67) Severe (n = 21) Mild (n = 7) Risk (n = 39) Non carriers (n = 554) AAA, mean (SD) 66.5 (±10.2) [OR = 0.31; p = 0.3977] 65.1 (±10.2) [OR = 0.08; p = 0.292] 67.1 (±15.6) [OR = 0.59; p = 0.8959] 67.1 (±9.2) [OR = 0.57; p = 0.7512] 67.6 (±10.7) Sex, Male n (%) 40 (59.7%) [OR = 0.71; p = 0.1912] 13 (61.9%) [OR = 0.78; p = 0.5795] 5 (71.4%) [OR = 1.19; p = 0.8336] 22 (56.4%) [OR = 0.62; p = 0.151] 375 (67.7%) AAO, mean (SD) 61.6 (±11.5) [OR = 0.35; p = 0.484] 58.6 (±13.1) [OR = 0.02; p = 0.1158] 65.4 (±17.0) [OR = 16.16; p = 0.5308] 62.5 (±9.3) [OR = 0.9; p = 0.9548] 62.6 (±11.6) AAO &lt; 45, N (%) 8 (11.9%) [OR = 1.74; p = 0.1767] 2 (28.6%) [OR = 5.14; p = 0.0549] 1 (2.6%) [OR = 0.34; p = 0.2907] 40 (7.2%) Disease Duration, mean (SD) 4.7 (±4.8) [OR = 0.79; p = 0.7303] 6.4 (±4.7) [OR = 4.07; p = 0.2238] 1.7 (±1.4) [OR = 0.04; p =0.0981] 4.4 (±4.9) [OR = 0.57; p = 0.5103] 5.0 (±5.2) Family History, N (%) 8 (38.1%) [OR = 1.8; p = 0.2001] 2 (28.6% [OR = 1.17; p = 0.8508] 15 (38.5%) [OR = 1.83; p = 0.0782] 141 (25.5%).
Nanobodies as novel tools to monitor the mitochondrial fission factor Drp1
2023-12-18

Abstract In cells, mitochondria undergo constant fusion and fission. An essential factor for fission is the mammalian dynamin-related protein 1 (Drp1). Dysregulation of Drp1 has been linked to neurodegenerative diseases including Parkinson’s as well as cardiovascular diseases and cancer. Here, we developed nanobodies (Nbs) for proteomics, advanced microscopy and live cell imaging of Drp1. To specifically enrich endogenous Drp1 with interacting proteins for proteomics, we functionalized high-affinity Nbs as capture matrices. Furthermore, we detected Drp1 by bivalent Nbs combined with site-directed fluorophore labelling in super-resolution STORM microscopy. For real-time imaging of Drp1, we intracellularly expressed fluorescently labelled Nbs, so-called chromobodies (Cbs). To improve the signal-to-noise ratio, we further converted Cbs into a “turnover-accelerated” format. With these imaging probes, we visualized the dynamics of endogenous Drp1 upon compound-induced mitochondrial fission in living cells. Considering the wide range of research applications, the presented Nb toolset will open up new possibilities for advanced functional studies of Drp1 in disease-relevant models.
Practical Theology
2023-12-18

Abstract In this chapter, Friedrich Schleiermacher’s definition of practical theology is first developed on the basis of his Brief Outline. In addition, his definition of theology as a theory of church leadership is expounded. Historical, philosophical, and practical theology form the context of reference in Schleiermacher’s work. Theology’s reference to the historical-empirical form of Christianity, which precedes theology as a positive science, is essential. The second part presents the structure of Schleiermacher’s lecture notes on practical theology as well as essential points of the “rules of art” (Kunstregeln) on practical theology. This includes the distinction between church service and church government, as well as central insights into worship, preaching, and pastoral care. Finally, Schleiermacher’s concept of practical theology as a theory of practice is highlighted against the background of contemporary university reform and the foundation of church seminars as an institutional supplement for practical theology.
EACTS/STS Guidelines for diagnosing and treating acute and chronic syndromes of the aortic organ
2023-12-19

A clinical guideline aims to apply to all patients with a specific condition.However, there will inevitably be situations where its recommendations aren't suitable for a particular patient.While healthcare professionals and others are encouraged to consider these guidelines in their professional judgement, they don't override the responsibility of healthcare professionals to make decisions tailored to each patient's unique circumstances.Such decisions should be aligned with the latest official recommendations, guidelines from relevant public health authorities, and applicable rules and regulations.It is important that these decisions are made in collaboration with, and agreed upon by, the patient and/or their guardian or carer.
Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis
2023-12-19

Abstract Objective Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state‐of‐the‐art clinical settings and trials applying combined outcome parameters. Methods Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed‐25‐foot walk test (T25FW), and nine‐hole‐peg‐test (9HPT)). Results 243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7–61.2], 135 female, median follow‐up: 29.3 months [17.9–40.9]) were included. NfL (age‐) and GFAP (age‐ and sex‐) adjusted Z scores were higher in pwPMS compared to HC ( p &lt; 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits ( n = 169). GFAP Z score &gt;3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12–5.08], p = 0.025). In PPMS, GFAP Z score &gt;3 was associated with higher risk for CDP (HR: 2.88 [1.21–6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53–12.13], p = 0.006). Interpretation Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non‐active pwPMS with particularly high progression risk.