Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular testing in indeterminate thyroid nodules: an additional tool for clinical decision-making

Summary Thyroid nodules are commonly encountered in clinical practice, affecting up to 50% of the population. The large majority of thyroid lumps are benign incidental findings detected by imaging, while approximately 5-15% harbor malignancy. For a target patient’s care, it is of paramount importance to identify and treat thyroid malignancy, while preventing unnecessary invasive surgery in patients with benign lesions. Although fine needle aspiration (FNA) associated with cytological examination provides malignant risk information, 20-30% of diagnoses fall into the “indeterminate thyroid nodule” (ITN) category. ITN clinical management remains a challenging issue for physicians since the ITN risk of malignancy varies from 5% to 40% and most thyroid nodules undergo overtreatment with surgery procedures. ITN molecular testing may better define malignant risk in the single nodule and is able to discriminate with accuracy benign from malignant nodules. Nowadays there are different technologies and different molecular panels, each with its own specificity, sensitivity and predictive values. In view of widespread introduction of molecular testing, some outstanding questions remain and are addressed in the present review such as the presence of molecular panels acting as “rule in” or “rule out” tools, the effective impact of testing results in the clinical decision-making process, and the prohibitive cost of commercial assays associated with the lack of test reimbursement in national health systems.
Eﬃcient solution of the SVD recommendation model with implicit feedback

Collaborative ﬁltering, an important part of the recommendation system, has become a mainstream recommendation method. In collaborative ﬁltering methods based on potential factors, SVD recommendation models are often used to analyze user preferences. With the recent research of SVD recommendation models, some SVD recommendation models with implicit feedback, such as SVD++ and TrustSVD, have been successively proposed. These types of models can more eﬀectively mine useful information from limited data sources and achieve better results than traditional SVD recommendation model, thereby garnering widespread attention. However, most existing papers focus on model design and the lack of eﬃcient algorithms for SVD recommendation models with implicit feedback. Therefore, this paper ﬁrst studies the general gradient solution framework of the SVD recommendation model. Then, it considers the SVD++ recommendation model as a breakthrough and designs an eﬃcient solution algorithm, namely, BCDSVD++, based on the block coordinate descent method. Furthermore, we solve the two key problems of capacity matrix inversion and sparse data optimization processing. Experiments show that the proposed BCDSVD++ algorithm yields better solution eﬃciency and convergence ability than the traditional parallel gradient descent method.
A SIMPLE METHOD FOR

A simple method for outlining or contouring any area defined by a change in film density or fluoroscopic screen intensity is described. The entire process, except for the positioning of an electronic window, is accomplished using a small computer having appropriate software. The electronic window is operator positioned over the area to be processed. The only requirement is that the window be large enough to encompass
University of Birmingham Them and us

This research examined the role that group dynamics played in the 2016 US Presidential election. Just prior to the election, participants were assessed on perceived self-similarity to group members’ views, perception of own leader’s prototypicality, perceptions of social values, and strength of support (attitudes). Results indicated that Democrats were more inclusive, seeing more similarity between themselves and members from the outgroup political party, while Republicans displayed more ingroup solidarity and negative attitudes toward outgroup members. Trump was viewed as a more prototypical leader by Republicans than Clinton was by Democrats. These results may help to explain the perhaps surprising fragility of Democrat voters’ support for Clinton.
AliNA – a deep learning program for RNA secondary structure prediction

Nowadays there are numerous discovered natural RNA variations participating in different cellular processes and artificial RNA, e. g. , aptamers, riboswitches. One of the required tasks in the investigation of their functions and mechanism of influence on cells and interaction with targets is the prediction of RNA secondary structures. The classic thermodynamic‐based prediction algorithms do not consider the specificity of biological folding and deep learning methods that were designed to resolve this issue suffer from homology‐based methods problems. Herein, we present a method for RNA secondary structure prediction based on deep learning – AliNA (ALIgned Nucleic Acids). Our method successfully predicts secondary structures for non‐homologous to train‐data RNA families thanks to usage of the data augmentation techniques. Augmentation extends existing datasets with easily‐accessible simulated data. The proposed method shows a high quality of prediction across different benchmarks including pseudoknots. The method is available on GitHub for free (https://github.com/Arty40m/AliNA).
In vivo CRISPR screen identifies LTN1 as a novel tumor suppressor ubiquitinating insulin–like growth factor 2 mRNA–binding protein 1 in hepatocellular carcinoma

Background and Aims: Hepatocellular carcinoma (HCC) is a frequent and aggressive kind of cancer. Although E3 ligases play important roles in HCC development, several E3 ligases remain unknown. Approach and Results: Through in vivo CRISPR knockout (KO) screens targeting related E3 ligase genes in HCC nude mice models, we discovered LTN1 as a novel tumor suppressor in HCC. Co-IP paired with 2D-LC-MS/MS and subsequent western blotting in HCC cells were used to identify the interactome of LTN1. Compared to matched normal tissues, the expression of LTN1 was decreased in human HCC tissues (ANT) (157/209). Clinically, patients with HCC who expressed low levels of LTN1 had a poor prognosis. Forced expression of LTN1 decreased cell growth in vitro and in vivo, whereas knockdown of LTN1 increased cell growth. Mechanistically, elevated LTN1 expression inhibited HCC cell growth by ubiquitinating and destabilizing the IGF2BP1 protein, which inhibited the c-Myc and IGF-1R signaling pathways. There was a negative correlation between the LTN1 protein expression and the IGF2BP1 protein expression in HCC tissues (R2=0.2799, P=0.0165). Conclusions: LTN1 may be a crucial tumor suppressor for determining the prognosis and a possible therapeutic target since it inhibits the proliferation of HCC cells by ubiquitinating IGF2BP1.
Social problems in young children: the interplay of ADHD symptoms and facial emotion recognition

ABSTRACT Facial emotion recognition (FER) deficits interfere with interpretation of social situations and selection of appropriate responses. Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms are independently associated with social difficulties and might exacerbate the influence of deficient FER, because children with ADHD symptoms have fewer compensatory resources in social situations when they misinterpret emotions. Very few studies have tested this hypothesis in a community context, where child ADHD symptoms vary on a continuum. The current study extended this work by utilising a community sample (N = 87) of boys and girls in middle childhood (M = 7.83 years) and testing for moderation of FER effects separately by ADHD symptom type (ADHD-I = inattentive, H = hyperactive/impulsive, C = combined) using linear regression. While lower FER was associated with more social problems, this relationship was qualified by the presence of ADHD symptoms. Specifically, only children with relatively high ADHD symptoms in our community sample showed this inverse relationship, which was clearest among children with elevated ADHD-C or ADHD-I symptoms. No gender differences were observed. These results support our primary hypothesis, extend prior findings to boys and girls in the community, and have implications for understanding how ADHD symptoms and FER influence youth social deficits.
Exploration of Serum lipid levels during twin pregnancy

Abstract Objective: This study aims to characterize changes in serum lipid levels throughout twin pregnancies and explore the relationship between lipid levels and gestational diabetes mellitus (GDM) and hypertensive disorders complicating pregnancy (HDCP). Methods: We retrospectively studied 297 twin pregnancies of women who received regular prenatal care and delivered at the Beijing Obstetrics and Gynecology Hospital over a period of two years. Demographic and medical data of the participants were collected by questionnaires and medical records review. Serum lipid levels were measured in the first trimester (6–13 weeks), second trimester (24–28 weeks), and third trimester (34–37 weeks). A multivariate regression model was constructed to examine the association between lipid levels and pregnancy complications. A decision tree was used to explore the relationship between early serum lipid glucose levels and GDM and HDCP in twin pregnancies. Results: Triglyceride (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels increased significantly from the first trimester to the third trimester, with the exception of high-density lipoprotein cholesterol (HDL-C), which decreased in the third trimester in twin pregnancies (p < 0.001). The levels of TC in the GDM and HDCP group were significantly elevated compared to those in the normal group in early pregnancies (p < 0.05, p < 0.05). In the second trimester, TG in the HDCP group was substantially higher than that in the normal group (p = 0.01). In the third trimester, LDL-C and HDL-C levels in the GDM group are significantly lower than that in the normal group (p < 0.05, p < 0.05). After adjusting for confounders, body mass index (BMI) is independently associated with GDM (odds ratio [OR] = 1.129, 95% confidence interval [CI]: 1.007–1.266) and HDCP(odds ratio [OR] = 1.170, 95% confidence interval [CI]: 1.031–1.329). The variation amplitude of HDL-C in the third trimester is related to the occurrence of GDM and HDCP(GDM:OR = 0.271, 95%CI: 0.095–0.778; HDCP: OR =0.249, 95% CI: 0.075–0.823). TG and TC levels in DCDA twins were significantly higher than that in MCDA twins in the first trimester(TG: p < 0.05, TC: p < 0.05). In the decision tree model for GDM, fasting blood glucose in the first trimester (FBG), TC, and pre-pregnancy BMI were identified as important nodes, while in the HDCP model, pre-pregnancy BMI, TC, and TG were key nodes. Conclusion: Serum lipid levels in twin pregnancies increase gradually during pregnancy. BMI is independently associated with the occurrence of GDM and HDCP. HDL-C may serve as a protective factor for GDM and HDCP. The predictive effect of early blood lipid on GDM and HDCP in twin pregnancy needs further study.
Cost–effectiveness of weekly gastro-resistant risedronate 35 mg, compared with weekly alendronate 70 mg tablets, in the treatment of postmenopausal osteoporosis in Spain

Aim: To estimate the cost–effectiveness of treating postmenopausal osteoporosis (PMO) with weekly gastro-resistant risedronate 35 mg gastro-resistant tablets (RIS-GR), compared with weekly alendronate 70 mg tablets (ALN) in Spain. Methods: A probabilistic analysis (second-order Monte Carlo simulation) was performed with a time horizon of 5 years, from the perspective of the Spanish National Health System. The bone fracture probabilities were obtained from a cohort study of 3614 women from USA with PMO treated with RIS-GR (1807) or ALN (1807) (Thomasius, 2022). The pharmacological cost and the cost of fractures were obtained from Spanish sources (€ 2022). The utilities of patients with and without fracture (quality-adjusted life years [QALYs]) were obtained from the medical literature. Results: Compared with ALN, treatment with RIS-GR can avoid 79 fractures (between 75 and 82) every 1000 patients treated, and 0.0119 QALYs would be gained (between 0.0098 and 0.0140) per patient. Additionally, GR-RIS would generate a cost saving per patient of €1994 (€1437–2904) with a probability of 99.7%. The scenario analyses confirmed the stability of the base case results. Conclusion: According to this study, RIS-GR would be the dominant treatment (lower costs with QALY gain) compared with ALN.
Deep learning in MRI‐guided radiation therapy: A systematic review

Abstract Recent advances in MRI‐guided radiation therapy (MRgRT) and deep learning techniques encourage fully adaptive radiation therapy (ART), real‐time MRI monitoring, and the MRI‐only treatment planning workflow. Given the rapid growth and emergence of new state‐of‐the‐art methods in these fields, we systematically review 197 studies written on or before December 31, 2022, and categorize the studies into the areas of image segmentation, image synthesis, radiomics, and real time MRI. Building from the underlying deep learning methods, we discuss their clinical importance and current challenges in facilitating small tumor segmentation, accurate x‐ray attenuation information from MRI, tumor characterization and prognosis, and tumor motion tracking. In particular, we highlight the recent trends in deep learning such as the emergence of multi‐modal, visual transformer, and diffusion models.
Diversity and Evolution of Highly Repetitive DNA Sequences Constituting Chromosome Site-Specific Heterochromatin in Two Gerbillinae Species

Constitutive heterochromatin, consisting of repetitive sequences, diverges very rapidly; therefore, its nucleotide sequences and chromosomal distributions are often largely different, even between closely related species. The chromosome C-banding patterns of two Gerbillinae species, Meriones unguiculatus and Gerbillus perpallidus, vary greatly, even though they belong to the same subfamily. To understand the evolution of C-positive heterochromatin in these species, we isolated highly repetitive sequences, determined their nucleotide sequences, and characterized them using chromosomal and filter hybridization. We obtained a centromeric repeat (MUN-HaeIII) and a chromosome 13-specific repeat (MUN-EcoRI) from M. unguiculatus. We also isolated a centromeric/pericentromeric repeat (GPE-MBD) and an interspersed-type repeat that was predominantly amplified in the X and Y chromosomes (GPE-EcoRI) from G. perpallidus. GPE-MBD was found to contain a 17-bp motif that is essential for binding to the centromere-associated protein CENP-B. This indicates that it may play a role in the formation of a specified structure and/or function of centromeres. The nucleotide sequences of the three sequence families, except GPE-EcoRI, were conserved only in Gerbillinae. GPE-EcoRI was derived from the long interspersed nuclear elements 1 retrotransposon and showed sequence homology throughout Muridae and Cricetidae species, indicating that the repeat sequence occurred at least in the common ancestor of Muridae and Cricetidae. Due to a lack of assembly data of highly repetitive sequences constituting heterochromatin in whole-genome sequences of vertebrate species published to date, the knowledge obtained in this study provides useful information for a deep understanding of the evolution of repetitive sequences in not only rodents but also in mammals.
A differentiated look at emotions: association between gaze behaviour during the processing of affective videos and emotional granularity

ABSTRACT The ability to distinguish between subtle differences among emotions of similar valence is labelled emotion differentiation (ED). Previous research has demonstrated that people high in ED are less likely to use disengagement regulation strategies (i.e. avoidance/distraction) during negative affective states. The present eye-tracking study examined associations between ED and visual attention/avoidance of affective stimuli. A total of 160 participants viewed emotional video clips (positive/ negative), which were concurrently presented with a non-affective distractor image. After each video, participants verbally described their experienced emotions with adjectives in an open-response format. Moreover, they completed an ED questionnaire. The computed ED specificity index for the negative videos (the number of specific adjectives divided by all adjectives used) was positively associated with the scores on the ED questionnaire and visual revisits for the negative videos (how many times the participants gazed back and forth between video and distractor). This viewing style might reflect more active exploratory behaviour directed toward acquiring information about the negative stimulus and its context. The ED measures were not associated with the gaze behaviour for positive videos.
Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice

BACKGROUND: Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) serves as a central driver of multiple cardiac disorders. METHODS: To develop a comprehensive therapy for heart failure, we used CRISPR-Cas9 adenine base editing to ablate the autophosphorylation site of CaMKIIδ. We generated mice harboring a phospho-resistant CaMKIIδ mutation in the germline and subjected these mice to severe transverse aortic constriction, a model for heart failure. Cardiac function, transcriptional changes, apoptosis, and fibrosis were assessed by echocardiography, RNA sequencing, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and standard histology, respectively. Specificity toward CaMKIIδ gene editing was assessed using deep amplicon sequencing. Cellular Ca2+ homeostasis was analyzed using epifluorescence microscopy in Fura-2–loaded cardiomyocytes. RESULTS: Within 2 weeks after severe transverse aortic constriction surgery, 65% of all wild-type mice died, and the surviving mice showed dramatically impaired cardiac function. In contrast to wild-type mice, CaMKIIδ phospho-resistant gene-edited mice showed a mortality rate of only 11% and exhibited substantially improved cardiac function after severe transverse aortic constriction. Moreover, CaMKIIδ phospho-resistant mice were protected from heart failure–related aberrant changes in cardiac gene expression, myocardial apoptosis, and subsequent fibrosis, which were observed in wild-type mice after severe transverse aortic constriction. On the basis of identical mouse and human genome sequences encoding the autophosphorylation site of CaMKIIδ, we deployed the same editing strategy to modify this pathogenic site in human induced pluripotent stem cells. It is notable that we detected a >2000-fold increased specificity for editing of CaMKIIδ compared with other CaMKII isoforms, which is an important safety feature. While wild-type cardiomyocytes showed impaired Ca2+ transients and an increased frequency of arrhythmias after chronic β-adrenergic stress, CaMKIIδ-edited cardiomyocytes were protected from these adverse responses. CONCLUSIONS: Ablation of CaMKIIδ autophosphorylation by adenine base editing may offer a potential broad-based therapeutic concept for human cardiac disease.
ANGPTL3 Deficiency and Risk of Hepatic Steatosis

BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.
Itaconate-producing neutrophils regulate local and systemic inflammation following trauma

Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury — potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate — and demonstrate a therapeutic potential for exogenous itaconate following tendon injury