julilili42/papers huggingface dataset:
Surgical Management of Pre-Chiasmatic Intraorbital Optic Nerve Gliomas in Children after Loss of Visual Function—Resection from Bulbus to Chiasm
2022-03-24

Optic pathway gliomas in children carry significant morbidity and therapeutic challenges. For the subgroup of pre-chiasmatic gliomas, intraorbital and intradural resection is a curative option after blindness. We present a two-center cohort using different surgical approaches. A retrospective analysis was performed, including 10 children. Mean age at surgery was 6.8 years. Interval between diagnosis and surgery was 1–74 (mean 24 ± 5.5, median 10) months. Indications for surgery were exophthalmos, pain, tumor progression, or a combination. Eight patients underwent an extradural trans-orbital-roof approach to resect the intra-orbital tumor, including the optic canal part plus intradural pre-chiasmatic resection. Gross total resection was achieved in 7/8, and none had a recurrence. One residual behind the bulbus showed progression, treated by chemotherapy. In two patients, a combined supra-orbital mini-craniotomy plus orbital frame osteotomy was used for intraorbital tumor resection + intradural pre-chiasmatic dissection. In these two patients, remnants of the optic nerve within the optic canal remained stable. No patient had a chiasmatic functional affection nor permanent oculomotor deficits. In selected patients, a surgical resection from bulb to chiasm ± removal of optic canal tumor was safe without long-term sequela and with an excellent cosmetic result. Surgery normalizes exophthalmos and provides an effective tumor control.
Impact of Whole-Body Perfusion in Postoperative Outcomes After Aortic Arch Reconstruction Surgery in Neonates and Infants
2022-03-24

Introduction: The aim of this study was to determine whether whole-body perfusion (WBP) consisting of a combined antegrade cerebral perfusion (ACP) and lower body perfusion (LBP) improves the outcome after aortic arch reconstruction surgery in neonates compared with ACP. Methods: Sixty-five consecutive patients under one year of age who underwent aortic arch reconstruction as the main procedure or as part of a more complex surgery from 2014-2020 in our center were included. The patients were separated into two groups, according to the perfusion strategy, either ACP (34 patients) as the control group or WBP (31 patients) as the intervention group. LBP was achieved through an arterial sheath in the femoral artery. Outcome parameters were postoperative renal, gastrointestinal, and neurological complications and 30-day mortality. Results: The patients in the WBP group showed lower intraoperative lactate levels and close to normal early postoperative renal and hepatic enzymes and LDH at PICU admission compared with the patients in the ACP group. The number of patients suffering from postoperative neurological complications and multiorgan failure was lower in the WBP group. Conclusion: In our experience, the combined use of ACP and LBP through the femoral artery showed an improvement, regarding postoperative neurologic complications in neonates and infants undergoing aortic arch surgery.
Calibration of Near-Infrared Spectra for Phosphorus Fractions in Grassland Soils on the Tibetan Plateau
2022-03-24

Soil phosphorus (P) is essential for plant growth and influences biological processes. Determining the amounts of available P to plants has been challenging, and many different approaches exist. The traditional Hedley sequential extraction method and its subsequent modification are applied to determine different soil P forms, which is critical for understanding its dynamics and availability. However, quantifying organic and inorganic P (Po &amp; Pi) in different extracts is labor-intensive and rarely used with large sample numbers. As an alternative, near-infrared spectroscopy (NIRS) has been employed to determine different P fractions at reasonable costs in a short time. This study aimed to test whether the analysis of P fractions with NIRS is an appropriate method to disentangle the effects of P limitation on high-altitude grassland ecosystems, particularly with fertilizer amendments. We explored NIRS in soils from the grassland soil samples on the northern Tibetan Plateau. First, we extracted the P fractions of 191 samples from the Haibei Alpine Meadow Ecosystem Research Station at four depth increments (0–10 cm, 10–20 cm, 20–40 cm, and 40–70 cm), including nutrient additions of nitrogen (N) and P. We compared the results of the Hedley extraction with the laboratory-based NIRS model. The fractionation data were correlated with the corresponding NIRS soil spectra; the coefficient of determination (R2) of the NIRS calibrations to predict P in P fractions ranged between 0.12 and 0.90; the ratio of (standard error of) prediction to the standard deviation (RPD) ranged between 1.07 and 3.21; the ratio of performance to inter-quartile distance (RPIQ) ranged from 0.3 to 4.3; and the model prediction quality was higher for Po than Pi fractions, and decreased with fertilizer amendment. However, the external-validation results were not precise enough for the labile P fractions (RPD &lt; 1.4) due to the limited number of samples. The results indicate that using NIRS to predict the more stable P pools, combined with Hedley fractionation focusing on the labile P pool, can be a promising approach for soils in alpine grasslands on the Tibetan Plateau.
Physically Constrained Generative Adversarial Networks for Improving Earth System Model Precipitation Output
2022-03-24

Abstract Precipitation results from complex processes across many scales, making its accurate simulation in Earth system models (ESMs) challenging. Existing post-processing methods can improve ESM simulations locally, but cannot correct errors in modelled spatial patterns. Here we propose a framework based on physically constrained generative adversarial networks (GANs) to improve local distributions and spatial structure simultaneously. We apply our approach to the computationally efficient ESM CM2Mc-LPJmL. Our method outperforms existing ones in correcting local distributions, and leads to strongly improved spatial patterns especially regarding the intermittency of daily precipitation. Notably, a double-peaked Intertropical Convergence Zone, a common problem in ESMs, is removed. Enforcing a physical constraint to preserve global precipitation sums, the GAN can generalize to future climate scenarios unseen during training. Feature attribution shows that the GAN identifies regions where the ESM exhibits strong biases. Our method constitutes a general framework for correcting ESM variables and enables realistic simulations at a fraction of the computational costs.
Intratumoral in vivo staging of breast cancer by multi-tracer PET and advanced analysis
2022-03-24

Abstract The staging and local management of breast cancer involves the evaluation of the extent and completeness of excision of both the invasive carcinoma component and also the intraductal component or ductal carcinoma in situ. When both invasive ductal carcinoma and coincident ductal carcinoma in situ are present, assessment of the extent and localization of both components is required for optimal therapeutic planning. We have used a mouse model of breast cancer to evaluate the feasibility of applying molecular imaging to assess the local status of cancers in vivo. Multi-tracer positron emission tomography (PET) and magnetic resonance imaging (MRI) characterize the transition from premalignancy to invasive carcinoma. PET tracers for glucose consumption, membrane synthesis, and neoangiogenesis in combination with a Gaussian mixture model-based analysis reveal image-derived thresholds to separate the different stages within the whole-lesion. Autoradiography, histology, and quantitative image analysis of immunohistochemistry further corroborate our in vivo findings. Finally, clinical data further support our conclusions and demonstrate translational potential. In summary, this preclinical model provides a platform for characterizing multistep tumor progression and provides proof of concept that supports the utilization of advanced protocols for PET/MRI in clinical breast cancer imaging.
Arabidopsis AGO4 loses its Cajal body localization when heterologously expressed in Nicotiana benthamiana
2022-03-24

In plants, the RNA-directed DNA methylation (RdDM) pathway plays a major role in establishing DNA methylation. At least some components of the RdDM machinery, including the central component AGO4, are known to concentrate in a subnuclear compartment called the Cajal body in the model plant <i>Arabidopsis thaliana</i>. The molecular underpinnings of Cajal body localization, however, have remained elusive so far. Here, we found that Arabidopsis AGO4 (AtAGO4) fused to GFP does not present its typical Cajal body localization, when transiently expressed in <i>Nicotiana benthamiana</i>. Nevertheless, the endogenous AGO4 protein from <i>N. benthamiana</i> shows a clear accumulation in the Cajal body. Thus, our results suggest that the Cajal body localization of AtAGO4 requires specific molecular machinery that cannot be replaced by orthologues in <i>N. benthamiana</i>. This study presents an experimental system that could lead to mechanistic insights into the targeting of proteins to and localization in the Cajal body in plants.
High-Spin (S = 1) Blatter-Based Diradical with Robust Stability and Electrical Conductivity
2022-03-25

Triplet ground-state organic molecules are of interest with respect to several emerging technologies but usually show limited stability, especially as thin films. We report an organic diradical, consisting of two Blatter radicals, that possesses a triplet ground state with a singlet-triplet energy gap, Δ<i>E</i><sub>ST</sub> ≈ 0.4-0.5 kcal mol<sup>-1</sup> (2<i>J</i>/<i>k</i> ≈ 220-275 K). The diradical possesses robust thermal stability, with an onset of decomposition above 264 °C (TGA). In toluene/chloroform, glassy matrix, and fluid solution, an equilibrium between two conformations with Δ<i>E</i><sub>ST</sub> ≈ 0.4 kcal mol<sup>-1</sup> and Δ<i>E</i><sub>ST</sub> ≈ -0.7 kcal mol<sup>-1</sup> is observed, favoring the triplet ground state over the singlet ground-state conformation in the 110-330 K temperature range. The diradical with the triplet ground-state conformation is found exclusively in crystals and in a polystyrene matrix. The crystalline neutral diradical is a good electrical conductor with conductivity comparable to the thoroughly optimized bis(thiazolyl)-related monoradicals. This is surprising because the triplet ground state implies that the underlying π-system is cross-conjugated and thus is not compatible with either good conductance or electron delocalization. The diradical is evaporated under ultra-high vacuum to form thin films, which are stable in air for at least 18 h, as demonstrated by X-ray photoelectron and electron paramagnetic resonance (EPR) spectroscopies.
A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies
2022-03-25

Abstract Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P &amp;lt; 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (&amp;gt;90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
Novel Blood Vascular Endothelial Subtype-Specific Markers in Human Skin Unearthed by Single-Cell Transcriptomic Profiling
2022-03-25

Ample evidence pinpoints the phenotypic diversity of blood vessels (BVs) and site-specific functions of their lining endothelial cells (ECs). We harnessed single-cell RNA sequencing (scRNA-seq) to dissect the molecular heterogeneity of blood vascular endothelial cells (BECs) in healthy adult human skin and identified six different subpopulations, signifying arterioles, post-arterial capillaries, pre-venular capillaries, post-capillary venules, venules and collecting venules. Individual BEC subtypes exhibited distinctive transcriptomic landscapes associated with diverse biological pathways. These functionally distinct dermal BV segments were characterized by their unique compositions of conventional and novel markers (e.g., arteriole marker GJA5; arteriole capillary markers ASS1 and S100A4; pre-venular capillary markers SOX17 and PLAUR; venular markers EGR2 and LRG1), many of which have been implicated in vascular remodeling upon inflammatory responses. Immunofluorescence staining of human skin sections and whole-mount skin blocks confirmed the discrete expression of these markers along the blood vascular tree in situ, further corroborating BEC heterogeneity in human skin. Overall, our study molecularly refines individual BV compartments, whilst the identification of novel subtype-specific signatures provides more insights for future studies dissecting the responses of distinct vessel segments under pathological conditions.
Comprehensive variant spectrum of the CNGA3 gene in patients affected by achromatopsia
2022-03-25

Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
Ethnomedicinal Plants in Herbal Remedies Used for Treatment of Skin Diseases by Traditional Healers in Songkhla Province, Thailand
2022-03-25

Skin disorders are a worldwide health problem that normally affect human life. A traditional healer is an important expert in researching notable medicinal plants for skin disease treatment. This study aimed to determine the traditional knowledge and the use of medicinal plants for the treatment of skin diseases among traditional healers in the Songkhla province, Thailand. The ethnobotanical information was collected from experienced traditional healers by semi-structured interviews and participant observations. Plant specimens were also collected and identified using the standard taxonomic method. The data were analyzed by interpretation and descriptive statistics. Twenty-five polyherbal formulations for the treatment of skin diseases were obtained from traditional healers with at least 10 years of experience. A total of 66 plant species in 38 families were documented. Leaves and trees were the most commonly employed plant parts and plant habits included in the herbal remedies, respectively. Fabaceae, Rubiaceae, and Zingiberaceae were the majority of the cited families. Oryza sativa L. and Zingiber montanum (J. Koenig) Link ex A.Dietr. were the most preferred plants combined in the prescriptions, which had the highest use value (UV = 0.83). The highest relative frequency of citation was represented by Curcuma longa L., Eurycoma longifolia Jack, Knema globularia (Lamk.) Warb, and Senna siamea (Lam.) Irwin &amp; Barneby. (0.55 each). This research suggests the importance of traditional healers in the healing of skin diseases with herbal remedies. A variety of medicinal plants are used in the prescriptions for the treatment of skin disorders in the Songkhla province, in the south of Thailand. Pharmacological and toxicological activities as well as phytochemical constituents of polyherbal remedies should be further investigated to scientifically verify further applications of widely practiced herbal medicines.
The TLR‐chaperone CNPY3 is a critical regulator of NLRP3‐inflammasome activation
2022-03-25

Abstract TLRs mediate the recognition of microbial and endogenous insults to orchestrate the inflammatory response. TLRs localize to the plasma membrane or endomembranes, depending on the member, and rely critically on ER‐resident chaperones to mature and reach their subcellular destinations. The chaperone canopy FGF signaling regulator 3 (CNPY3) is necessary for the proper trafficking of multiple TLRs including TLR1/2/4/5/9 but not TLR3. However, the exact role of CNPY3 in inflammatory signalling downstream of TLRs has not been studied in detail. Consistent with the reported client specificity, we report here that functional loss of CNPY3 in engineered macrophages impairs downstream signalling by TLR2 but not TLR3. Unexpectedly, CNPY3‐deficient macrophages show reduced IL‐1ß and IL‐18 processing and production independent of the challenged upstream TLR species, demonstrating a separate, specific role for CNPY3 in inflammasome activation. Mechanistically, we document that CNPY3 regulates caspase‐1 localization to the apoptosis speck and autoactivation of caspase‐1. Importantly, we were able to recapitulate these findings in macrophages from an early infantile epileptic encephalopathy (EIEE) patient with a novel CNPY3 loss‐of‐function variant. Summarizing, our findings reveal a hitherto unknown, TLR‐independent role of CNPY3 in inflammasome activation, highlighting a more complex and dedicated role of CNPY3 to the inflammatory response than anticipated.
A Genome-Wide Gene-Based Gene–Environment Interaction Study of Breast Cancer in More than 90,000 Women
2022-03-25

Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P &amp;lt; 0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE = 4.44 × 10−6). In this transcriptome-informed genome-wide gene–environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Our study suggests a limited role of gene–environment interactions in breast cancer risk.
The genetic interaction of REVOLUTA and WRKY53 links plant development, senescence, and immune responses
2022-03-25

In annual plants, tight coordination of successive developmental events is of primary importance to optimize performance under fluctuating environmental conditions. The recent finding of the genetic interaction of WRKY53 , a key senescence-related gene with REVOLUTA , a master regulator of early leaf patterning, raises the question of how early and late developmental events are connected. Here, we investigated the developmental and metabolic consequences of an alteration of the REVOLUTA and WRKY53 gene expression, from seedling to fruiting. Our results show that REVOLUTA critically controls late developmental phases and reproduction while inversely WRKY53 determines vegetative growth at early developmental stages. We further show that these regulators of distinct developmental phases frequently, but not continuously, interact throughout ontogeny and demonstrated that their genetic interaction is mediated by the salicylic acid (SA). Moreover, we showed that REVOLUTA and WRKY53 are keys regulatory nodes of development and plant immunity thought their role in SA metabolic pathways, which also highlights the role of REV in pathogen defence. Together, our findings demonstrate how late and early developmental events are tightly intertwined by molecular hubs. These hubs interact with each other throughout ontogeny, and participate in the interplay between plant development and immunity.