julilili42/papers huggingface dataset:
Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans
2024-04-07

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.
Microclimate, an important part of ecology and biogeography
2024-04-08

Abstract Brief introduction: What are microclimates and why are they important? Microclimate science has developed into a global discipline. Microclimate science is increasingly used to understand and mitigate climate and biodiversity shifts. Here, we provide an overview of the current status of microclimate ecology and biogeography in terrestrial ecosystems, and where this field is heading next. Microclimate investigations in ecology and biogeography We highlight the latest research on interactions between microclimates and organisms, including how microclimates influence individuals, and through them populations, communities and entire ecosystems and their processes. We also briefly discuss recent research on how organisms shape microclimates from the tropics to the poles. Microclimate applications in ecosystem management Microclimates are also important in ecosystem management under climate change. We showcase new research in microclimate management with examples from biodiversity conservation, forestry and urban ecology. We discuss the importance of microrefugia in conservation and how to promote microclimate heterogeneity. Methods for microclimate science We showcase the recent advances in data acquisition, such as novel field sensors and remote sensing methods. We discuss microclimate modelling, mapping and data processing, including accessibility of modelling tools, advantages of mechanistic and statistical modelling and solutions for computational challenges that have pushed the state‐of‐the‐art of the field. What's next? We identify major knowledge gaps that need to be filled for further advancing microclimate investigations, applications and methods. These gaps include spatiotemporal scaling of microclimate data, mismatches between macroclimate and microclimate in predicting responses of organisms to climate change, and the need for more evidence on the outcomes of microclimate management.
Multifeature quantitative motor assessment of upper limb ataxia including drawing and reaching
2024-04-08

Abstract Objective Voluntary upper limb movements are an ecologically important yet insufficiently explored digital‐motor outcome domain for trials in degenerative ataxia. We extended and validated the trial‐ready quantitative motor assessment battery “Q‐Motor” for upper limb movements with clinician‐reported, patient‐focused, and performance outcomes of ataxia. Methods Exploratory single‐center cross‐sectional assessment in 94 subjects (46 cross‐genotype ataxia patients; 48 matched controls), comprising five tasks measured by force transducer and/or position field: Finger Tapping, diadochokinesia, grip‐lift, and—as novel implementations—Spiral Drawing, and Target Reaching. Digital‐motor measures were selected if they discriminated from controls (AUC &gt;0.7) and correlated—with at least one strong correlation (rho ≥0.6)—to the Scale for the Assessment and Rating of Ataxia (SARA), activities of daily living (FARS‐ADL), and the Nine‐Hole Peg Test (9HPT). Results Six movement features with 69 measures met selection criteria, including speed and variability in all tasks, stability in grip‐lift, and efficiency in Target Reaching. The novel drawing/reaching tasks best captured impairment in dexterity (|rho 9HPT | ≤0.81) and FARS‐ADL upper limb items (|rho ADLul | ≤0.64), particularly by kinematic analysis of smoothness (SPARC). Target hit rate , a composite of speed and endpoint precision , almost perfectly discriminated ataxia and controls (AUC: 0.97). Selected measures in all tasks discriminated between mild, moderate, and severe impairment (SARA upper limb composite: 0–2/&gt;2–4/&gt;4–6) and correlated with severity in the trial‐relevant mild ataxia stage (SARA ≤10, n = 20). Interpretation Q‐Motor assessment captures multiple features of impaired upper limb movements in degenerative ataxia. Validation with key clinical outcome domains provides the basis for evaluation in longitudinal studies and clinical trial settings.
De novovariants in the non-coding spliceosomal snRNA geneRNU4-2are a frequent cause of syndromic neurodevelopmental disorders
2024-04-08

Abstract Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 ’s role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
Dynamic brain communication underwriting face pareidolia
2024-04-08

Face pareidolia is a tendency to seeing faces in nonface images that reflects high tuning to a face scheme. Yet, studies of the brain networks underwriting face pareidolia are scarce. Here, we examined the time course and dynamic topography of gamma oscillatory neuromagnetic activity while administering a task with nonface images resembling a face. Images were presented either with canonical orientation or with display inversion that heavily impedes face pareidolia. At early processing stages, the peaks in gamma activity (40 to 45 Hz) to images either triggering or not face pareidolia originate mainly from the right medioventral and lateral occipital cortices, rostral and caudal cuneus gyri, and medial superior occipital gyrus. Yet, the difference occurred at later processing stages in the high-frequency range of 80 to 85 Hz over a set of the areas constituting the social brain. The findings speak rather for a relatively late neural network playing a key role in face pareidolia. Strikingly, a cutting-edge analysis of brain connectivity unfolding over time reveals mutual feedforward and feedback intra- and interhemispheric communication not only within the social brain but also within the extended large-scale network of down- and upstream regions. In particular, the superior temporal sulcus and insula strongly engage in communication with other brain regions either as signal transmitters or recipients throughout the whole processing of face-pareidolia images.
Towards spatio-temporal comparison of simulated and reconstructed sea surface temperatures for the last deglaciation
2024-04-08

Abstract. An increasing number of climate model simulations is becoming available for the transition from the Last Glacial Maximum to the Holocene. Assessing the simulations' reliability requires benchmarking against environmental proxy records. To date, no established method exists to compare these two data sources in space and time over a period with changing background conditions. Here, we develop a new algorithm to rank simulations according to their deviation from reconstructed magnitudes and temporal patterns of orbital and millennial-scale temperature variations. The use of proxy forward modeling allows for accounting for non-climatic processes that affect the temperature reconstructions. It further avoids the need to reconstruct gridded fields or regional mean temperature time series from sparse and uncertain proxy data. First, we test the reliability and robustness of our algorithm in idealized experiments with prescribed deglacial temperature histories. We quantify the influence of limited temporal resolution, chronological uncertainties, and non-climatic processes by constructing noisy pseudo-proxies. While model–data comparison results become less reliable with increasing uncertainties, we find that the algorithm discriminates well between simulations under realistic non-climatic noise levels. To obtain reliable and robust rankings, we advise spatial averaging of the results for individual proxy records. Second, we demonstrate our method by quantifying the deviations between an ensemble of transient deglacial simulations and a global compilation of sea surface temperature reconstructions. The ranking of the simulations differs substantially between the considered regions and timescales, which suggests that optimizing for agreement with the temporal patterns of a small set of proxies might be insufficient for capturing the spatial structure of the deglacial temperature variability. We attribute the diversity in the rankings to more regionally confined temperature variations in reconstructions than in simulations, which could be the result of uncertainties in boundary conditions, shortcomings in models, or regionally varying characteristics of reconstructions such as recording seasons and depths. Future work towards disentangling these potential reasons can leverage the flexible design of our algorithm and its demonstrated ability to identify varying levels of model–data agreement. Additionally, the algorithm can be applied to variables like oxygen isotopes and climate transitions such as the penultimate deglaciation and the last glacial inception.
Soluble NKG2DLs Are Elevated in Breast Cancer Patients and Associate with Disease Outcome
2024-04-08

Ligands of the natural killer group 2D (NKG2DL) family are expressed on malignant cells and are usually absent from healthy tissues. Recognition of NKG2DLs such as MICA/B and ULBP1-3 by the activating immunoreceptor NKG2D, expressed by NK and cytotoxic T cells, stimulates anti-tumor immunity in breast cancer. Upregulation of membrane-bound NKG2DLs in breast cancer has been demonstrated by immunohistochemistry. Tumor cells release NKG2DLs via proteolytic cleavage as soluble (s)NKG2DLs, which allows for effective immune escape and is associated with poor prognosis. In this study, we collected serum from 140 breast cancer (BC) and 20 ductal carcinoma in situ (DCIS) patients at the time of initial diagnosis and 20 healthy volunteers (HVs). Serum levels of sNKG2DLs were quantified through the use of ELISA and correlated with clinical data. The analyzed sNKG2DLs were low to absent in HVs and significantly higher in BC patients. For some of the ligands analyzed, higher sNKG2DLs serum levels were associated with the classification of malignant tumor (TNM) stage and grading. Low sMICA serum levels were associated with significantly longer progression-free (PFS) and overall survival (OS). In conclusion, we provide the first insights into sNKG2DLs in BC patients and suggest their potential role in tumor immune escape in breast cancer. Furthermore, our observations suggest that serum sMICA levels may serve as a prognostic parameter in the patients analyzed in this study.
Severity Identification of Graves Orbitopathy via Random Forest Algorithm
2024-04-08

Abstract This study aims to establish a random forest model for detecting the severity of Graves Orbitopathy (GO) and identify significant classification factors. This is a hospital-based study of 199 patients with GO that were collected between December 2019 and February 2022. Clinical information was collected from medical records. The severity of GO can be categorized as mild, moderate-to-severe, and sight-threatening GO based on guidelines of the European Group on Graves’ orbitopathy. A random forest model was constructed according to the risk factors of GO and the main ocular symptoms of patients to differentiate mild GO from severe GO and finally was compared with logistic regression analysis, Support Vector Machine (SVM), and Naive Bayes. A random forest model with 15 variables was constructed. Blurred vision, disease course, thyroid-stimulating hormone receptor antibodies, and age ranked high both in mini-decreased gini and mini decrease accuracy. The accuracy, positive predictive value, negative predictive value, and the F1 Score of the random forest model are 0.83, 0.82, 0.86, and 0.82, respectively. Compared to the three other models, our random forest model showed a more reliable performance based on AUC (0.85 vs. 0.83 vs. 0.80 vs. 0.76) and accuracy (0.83 vs. 0.78 vs. 0.77 vs. 0.70). In conclusion, this study shows the potential for applying a random forest model as a complementary tool to differentiate GO severity.
The time course of spontaneous closure of idiopathic full-thickness macular holes
2024-04-08

Abstract Purpose Spontaneous closure of idiopathic full-thickness macular holes (iFTMH) has been reported regularly. However, little is known about its probability and timeline. Methods In this retrospective study all consecutive patients who presented between August 2008 and August 2019 were screened for the presence of a macular hole and only iFTMHs were included. The primary outcome measure was the spontaneous closure of the iFTMH. Results Of 1256 eyes with macular holes, 338 fulfilled the inclusion criteria. Spontaneous closure of the iFTMH was detected in 31 eyes (9.2%) with a median time of 44 days after diagnosis. Eyes exhibiting spontaneous closure demonstrated a higher baseline best-corrected visual-acuity (BCVA) and smaller iFTMH diameter ( p &lt; 0.0001 and p &lt; 0.0001, respectively). The mean BCVA improved from 0.4 logMAR (SD ± 0.21) to 0.29 logMAR (SD ± 0.20) after spontaneous closure ( p = 0.031). The iFTMH diameter was positively correlated with the time to spontaneous closure (Pearson-r = 0.37, p = 0.0377). Spontaneously closed iFTMHs reopened in 16% ( n = 5) of cases, with a median of 136 days after closure. A logistic regression model showed the hole diameter was associated with spontaneous closure (odds-Ratio 0.97, 95%CI [0.96, 0.98]). The Kaplan–Meier-Curve revealed that approximately 25% of small-iFTMH ( n = 124) and 55% of iFTMH with a diameter &lt; 150μm ( n = 48) closed spontaneously within two months. Conclusion The established gold-standard for the treatment of iFTMHs is macular surgery. However, the potential for spontaneous closure of small iFTMHs must be acknowledged. Therefore, if surgical treatment is delayed in individual cases, close observation is recommended.
Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle
2024-04-08

Abstract The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilized 1H-NMR spectroscopy-based metabolomics, in situenzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs-cycle, fueled by glutamine and branched-chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill-cycle; 3) the lactate-releasing Cori-cycle. Moreover, the metabolomic data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.
Physical Activity, Sedentary Behavior, and Their Predictors Among Nursing Home Residents—Cross-Sectional Results of the BaSAlt Study
2024-04-08

Little is known about physical activity (PA) and sedentary behavior (SB) among nursing home residents although PA is known as a health promoter. This study examined PA, SB, and their predictors among nursing home residents ( n = 63). Dependent variables were accelerometry-based PA and SB. Predictor variables included in a path analysis were age, sex, body mass index, Barthel Index, cognitive status (Mini-Mental State Examination), physical performance (hand grip strength and habitual walking speed), and well-being (World Health Organization-5 well-being index). PA was very low ( M steps per day = 2,433) and SB was high ( M percentage of sedentary time = 89.4%). PA was significantly predicted by age (β = −0.27, p = .008), body mass index (β = −0.29, p = .002), Barthel Index (β = 0.24, p = .040), and hand grip strength (β = 0.30, p = .048). SB was significantly predicted by body mass index (β = 0.27, p = .008) and Barthel Index (β = −0.30, p = .012). Results might be helpful for everyday practice to identify individuals at high risk for low PA and high SB.
A Novel PINK1 p.F385S Loss‐of‐Function Mutation in an Indian Family with Parkinson's Disease
2024-04-08

Abstract Background Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. Objective The aim of this study was to characterize a novel phosphatase tensin homolog‐induced serine/threonine kinase 1 ( PINK1 ) mutation causing PD in an Indian family. Methods Exome sequencing of a well‐characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. Results We identified a homozygous chr1:20648535–20648535 T&gt;C on GRCh38 (p.F385S) mutation in exon 6 of PINK1 , which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved DFG motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. Conclusions We characterized a novel nonconservative mutation in the DFG motif of PINK1 , which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Sustained effect of prasinezumab on Parkinson’s disease motor progression in the open-label extension of the PASADENA trial
2024-04-08

Abstract The PASADENA study is an ongoing Phase II, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of intravenous prasinezumab, administered every 4 weeks, in early-stage Parkinson’s disease (PD). During the double-blind study period, prasinezumab-treated individuals showed less progression of motor signs (Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III). We evaluated here whether the effect of prasinezumab on motor progression, assessed as change in MDS-UPDRS Part III in OFF- and ON-state, and MDS-UPDRS Part II scores was sustained over 4 years from the start of the trial. We compared participants enrolled in the PASADENA open-label extension (OLE) to an external comparator arm derived from the Parkinson's Progression Markers Initiative (PPMI) observational study. Both PASADENA delayed- (n = 94) and early-start (n = 177) groups showed a slower decline (less increase in score) on MDS-UPDRS Part III in OFF- (-51% for the delayed-start group and − 65% for the early-start group) and ON-state (-94% for the delayed-start group and − 118% for the early-start group), and on MDS-UPDRS Part II (-48% for the delayed-start group and − 40% for the early-start group), compared with the PPMI external comparator (n = 303). This exploratory analysis, which requires confirmation in future studies, suggests that the effect of prasinezumab in slowing motor progression in PD may be sustained long-term.
Metabolic fingerprinting by nuclear magnetic resonance of hepatocellular carcinoma cells during p53 reactivation‐induced senescence
2024-04-08

Abstract Cellular senescence is characterized by stable cell cycle arrest. Senescent cells exhibit a senescence‐associated secretory phenotype that can promote tumor progression. The aim of our study was to identify specific nuclear magnetic resonance (NMR) spectroscopy‐based markers of cancer cell senescence. For metabolic studies, we employed murine liver carcinoma Harvey Rat Sarcoma Virus (H‐Ras) cells, in which reactivation of p53 expression induces senescence. Senescent and nonsenescent cell extracts were subjected to high‐resolution proton ( 1 H)‐NMR spectroscopy‐based metabolomics, and dynamic metabolic changes during senescence were analyzed using a magnetic resonance spectroscopy (MRS)‐compatible cell perfusion system. Additionally, the ability of intact senescent cells to degrade the extracellular matrix (ECM) was quantified in the cell perfusion system. Analysis of senescent H‐Ras cell extracts revealed elevated sn‐glycero‐3‐phosphocholine, myoinositol, taurine, and creatine levels, with decreases in glycine, o‐phosphocholine, threonine, and valine. These metabolic findings were accompanied by a greater degradation index of the ECM in senescent H‐Ras cells than in control H‐Ras cells. MRS studies with the cell perfusion system revealed elevated creatine levels in senescent cells on Day 4, confirming the 1 H‐NMR results. These senescence‐associated changes in metabolism and ECM degradation strongly impact growth and redox metabolism and reveal potential MRS signals for detecting senescent cancer cells in vivo.