Miracle-dz/UniFAR-FTUs huggingface dataset:
Microstructural Alterations in Hippocampal Subfields Mediate Age-Related Memory Decline in Humans

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20–38 years old) and older (ages 59–84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.
Preoperative Prediction of Extramural Venous Invasion in Rectal Cancer: Comparison of the Diagnostic Efficacy of Radiomics Models and Quantitative Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Background: To compare the diagnostic performance of radiomics models with that of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion parameters for the preoperative prediction of extramural venous invasion (EMVI) in rectal cancer patients and to develop a preoperative nomogram for predicting the EMVI status. Methods: In total, 106 rectal cancer patients were enrolled in our study. All patients under went preoperative rectal high-resolution MRI and DCE-MRI. We built five models based on the perfusion parameters of DCE-MRI (quantitative model), the radiomics of T2-weighted (T2W) CUBE imaging (R1 model), DCE-MRI (R2 model), clinical features (clinical model), and clinical-radiomics features. The predictive efficacy of the radiomics signature was assessed and internally verified. The area under the receiver operating curve (AUC) was used to compare the diagnostic performance of different radiomics models and DCE-MRI quantitative parameters. The radiomics score and clinical-pathologic risk factors were incorporated into an easy-to-use nomogram. Results: The quantitative parameters Ktrans and Ve were significantly higher in the EMVI-positive group than in the EMVI-negative group (both P =0.02). Ktrans combined with Ve showed a fair degree of accuracy (AUC 0.680 in the training cohort and AUC 0.715 in the validation cohort) compared with Ktrans or Ve alone. The AUCs of the R1 and R2 models were 0.826, 0.715 and 0.872, 0.812 in the training and validation cohorts, respectively. In addition, the R2-C model yielded an AUC of 0.904 in the training cohort and 0.812 in the validation cohort. The nomogram was presented based on the clinical-radiomics model. The calibration curves showed good agreement. Conclusion: The radiomics nomogram that incorporates the radiomics score, histopathological grade and T stage demonstrated better diagnostic accuracy than the DCE-MRI quantitative parameters and may have significant clinical implications for the preoperative individualized prediction of EMVI in rectal cancer patients.
WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.
CD4+ T Cells in the Blood of MS Patients Respond to Predicted Epitopes From B cell Receptors Found in Spinal Fluid

B cells are important pathogenic players in multiple sclerosis (MS), but their exact role is not known. We have previously demonstrated that B cells from cerebrospinal fluid (CSF) of MS patients can activate T cells that specifically recognize antigenic determinants (idiotopes) from their B cell receptors (BCRs). The aim of this study was to evaluate whether in silico prediction models could identify antigenic idiotopes of immunoglobulin heavy-chain variable (IGHV) transcriptomes in MS patients. We utilized a previously assembled dataset of CSF IGHV repertoires from MS patients. To guide selection of potential antigenic idiotopes, we used in silico predicted HLA-DR affinity, endosomal processing, as well as transcript frequency from nine MS patients. Idiotopes with predicted low affinity and low likelihood of cathepsins cleavage were inert controls. Peripheral blood mononuclear cells from these patients were stimulated with the selected idiotope peptides in presence of anti-CD40 for 12 h. T cells were then labeled for activation status with anti-CD154 antibodies and CD3+CD4+ T cells phenotyped as memory (CD45RO+) or naïve (CD45RO−), with potential for brain migration (CXCR3 and/or CCR6 expression). Anti-CD14 and -CD8 were utilized to exclude monocytes and CD8+ T cells. Unstimulated cells or insulin peptides were negative controls, and EBNA-1 peptides or CD3/CD28 beads were positive controls. The mean proportion of responding memory CD4+ T cells from all nine MS patients was significantly higher for idiotope peptides with predicted high HLA-DR affinity and high likelihood of cathepsin cleavage, than toward predicted inert peptides. Responses were mainly observed toward peptides affiliated with the CDR3 region. Activated memory CD4+ T cells expressed the chemokine receptor CCR6, affiliated with a Th17 phenotype and allowing passage into the central nervous system (CNS). This in vitro study suggests that that antigenic properties of BCR idiotopes can be identified in silico using HLA affinity and endosomal processing predictions. It further indicates that MS patients have a memory T cell repertoire capable of recognizing frequent BCR idiotopes found in endogenous CSF, and that these T cells express chemokine receptors allowing them to reach the CSF B cells expressing these idiotopes.
Ill-Defined Problem Solving Does Not Benefit From Daytime Napping

The main goal of the present study was to explore the role of sleep in the process of ill-defined problem solving. The results of previous studies indicate that various cognitive processes are largely dependent on the quality and quantity of sleep. However, while sleep-related memory consolidation seems to be well-grounded, with regard to the impact of sleep on problem solving, existing research yields mixed and rather inconclusive results. Moreover, this effect has been mainly tested using simple and well-defined, common laboratory problems, such as the remote associate test (RAT), crossword and anagram puzzles, numeric and logic problems, etc. What is lacking is research on the effect of sleep on solving more complex and more real-life oriented ill-defined problems. In the present study, we hypothesized that sleep can improve performance in solving this kind of problems. The study involved 40 participants, randomly assigned to two experimental conditions: sleep group and waking group. The experimental protocol comprised three stages: problem presentation, retention interval, and testing stage. The problem was presented to the participants in the form of an interactive computer game concerning a complex, elaborate crime story. During the retention interval, the participants—depending on the condition—took a nap or stayed awake; sleeping participants underwent polysomnography recording, while waking participants performed activities not related to the experimental problem. In the testing stage, participants tried to solve the presented problem. The solutions generated were assessed both for quality (reasonableness, consistency, and story recall) and creativity (fluency, flexibility, originality, and elaboration). Contrary to expectations, we found no effect of sleep on ill-defined problem solving. Neither quality nor creativity of the solutions generated by the participants was higher in the nap group than in the waking group. There were also no performance improvements with regard to any sleep stage or incidence of dreams. Our study adds to a growing body of evidence that sleep probably might provide an incubation gap, but not a facilitating environment serving the purpose of problem solving, at least with regard to ill-defined problems.
Drug Targeting of Genomic Instability in Multiple Myeloma

Genomic instability can be observed at both chromosomal and chromatin levels. Instability at the macro level includes centrosome abnormalities (CA) resulting in numerical as well as structural chromosomal changes, whereas instability at the micro level is characterized by defects in DNA repair pathways resulting in microsatellite instability (MIN) or mutations. Genomic instability occurs during carcinogenesis without impairing survival and growth, though the precise mechanisms remain unclear. Solid tumors arising from most cells of epithelial origin are characterized by genomic instability which renders them resistant to chemotherapy and radiotherapy. This instability is also observed in 25% of myeloma patients and has been shown to be highly prognostic, independently of the international staging system (ISS). However, a biomarker of aberrant DNA repair and loss of heterozygosity (LOH), was only observed at a frequency of 5% in newly diagnosed patients. Several new molecules targeting the pathways involved in genomic instability are under development and some have already entered clinical trials. Poly(ADP-ribose) polymerase-1 (PARP) inhibitors have been FDA-approved for the treatment of breast cancer type 1 susceptibility protein (BRCA1)-mutated metastatic breast cancer, as well as ovarian and lung cancer. Topoisomerase inhibitors and epigenetic histone modification-targeting inhibitors, such as HDAC (Histone Deacetylase) inhibitors which are novel agents that can target genomic instability. Several of the small molecule inhibitors targeting chromosomal level instability such as PARP, Akt, Aurora kinase, cyclin dependent kinase or spindle kinase inhibitors have been tested in mouse models and early phase I/II trials. ATM, ATR kinase inhibitors and DNA helicase inhibitors are also promising novel agents. However, most of these drugs are not effective as single agents but appear to act synergistically with DNA damaging agents such as radiotherapy, platinum derivatives, immunomodulators, and proteasome inhibitors. In this review, new drugs targeting genomic instability and their mechanisms of action will be discussed.
Gibbs Free Energy Calculation of Mutation in PncA and RpsA Associated With Pyrazinamide Resistance

A central approach for better understanding the forces involved in maintaining protein structures is to investigate the protein folding and thermodynamic properties. The effect of the folding process is often disturbed in mutated states. To explore the dynamic properties behind mutations, molecular dynamic (MD) simulations have been widely performed, especially in unveiling the mechanism of drug failure behind mutation. When comparing wild type (WT) and mutants (MTs), the structural changes along with solvation free energy (SFE), and Gibbs free energy (GFE) are calculated after the MD simulation, to measure the effect of mutations on protein structure. Pyrazinamide (PZA) is one of the first-line drugs, effective against latent Mycobacterium tuberculosis isolates, affecting the global TB control program 2030. Resistance to this drug emerges due to mutations in pncA and rpsA genes, encoding pyrazinamidase (PZase) and ribosomal protein S1 (RpsA) respectively. The question of how the GFE may be a measure of PZase and RpsA stabilities, has been addressed in the current review. The GFE and SFE of MTs have been compared with WT, which were already found to be PZA-resistant. WT structures attained a more stable state in comparison with MTs. The physiological effect of a mutation in PZase and RpsA may be due to the difference in energies. This difference between WT and MTs, depicted through GFE plots, might be useful in predicting the stability and PZA-resistance behind mutation. This study provides useful information for better management of drug resistance, to control the global TB problem. Graphical Abstract Most of the functions are performed by DNA, RNA, and proteins molecules. Mutations in these molecules may affect the dynamic properties and free energies, results in weak or loss of interactions.
Behavioral Model of Middle-Aged and Seniors for Bicycle Tourism

This research centers on the behavioral tendency of the middle-aged and seniors in bicycle tourism at environmentally protected scenic areas and its relevant influence factors. The theory of planned behavior (TPB) is adopted as the basis of this study. The middle-aged and seniors are the subjects of this research. A questionnaire survey is conducted at environmentally protected national scenic areas in Taiwan. A total of 230 samples are drawn with a random sampling method, and 210 are valid. The findings indicate two things. First, when applying the TPB to different fields of the study, the level of predictability may vary. Another finding is that subjective norm shows a higher level of susceptibility to sport habit and predictability to behavioral intention than the other two constructs. With an empirical analysis, the study is able to provide middle-aged and senior participants and sport administration authorities with relevant suggestions for reference at the end of this paper.
Antibiotic resistance among citrobacter species from different clinical specimens

ABSTRACT: A total of 222 isolates of Citrobacter species were recovered from 3147 clinical specimens, during a two-year period from January 1996 to December 1997. Majority were urinary isolates (40.5 percent). Antibiogram of the isolates revealed that 42.3 percent were totally resistant to all the antibiotics tested, while 57.66 percent isolates were susceptible to aminoglycosides and cephalosporins. One hundred and thirty two of the isolates were C. diversus of which 34 percent were totally resistant to all tested antibiotics. 54.4 percent of the C. freundii isolates were totally resistant. The isolates that exhibited high level of resistance were mainly from surgical wards indicating nosocomially -acquired infection.
The Two Sides of Linguistic Context: Eye-Tracking as a Measure of Semantic Competition in Spoken Word Recognition Among Younger and Older Adults

Studies of spoken word recognition have reliably shown that both younger and older adults’ recognition of acoustically degraded words is facilitated by the presence of a linguistic context. Against this benefit, older adults’ word recognition can be differentially hampered by interference from other words that could also fit the context. These prior studies have primarily used off-line response measures such as the signal-to-noise ratio needed for a target word to be correctly identified. Less clear is the locus of these effects; whether facilitation and interference have their influence primarily during response selection, or whether their effects begin to operate even before a sentence-final target word has been uttered. This question was addressed by tracking 20 younger and 20 older adults’ eye fixations on a visually presented target word that corresponded to the final word of a contextually constraining or neutral sentence, accompanied by a second word on the computer screen that in some cases could also fit the sentence context. Growth curve analysis of the time-course of eye-gaze on a target word showed facilitation and inhibition effects begin to appear even as a spoken sentence is unfolding in time. Consistent with an age-related inhibition deficit, older adults’ word recognition was slowed by the presence of a semantic competitor to a degree not observed for younger adults, with this effect operating early in the recognition process.
SET and MYND domain-containing protein 3 inhibits tumor cell sensitivity to cisplatin

Cisplatin resistance has been a major factor limiting its clinical use as a chemotherapy drug. The present study aimed to investigate whether SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase closely associated with tumors can affect the sensitivity of tumors to cisplatin chemotherapy. Real time-qPCR, western blotting, the luciferase reporter, MTT and clonogenic assays were performed to detect the effects of SMYD3 on the chemotherapy capacity of cisplatin. In the present study, SMYD3 exhibited different expression patterns in MCF-7 and T47D breast cancer cells. In addition, this differential expression was associated with tumor cell resistance to cisplatin. Furthermore, SMYD3 knockdown following small interfering RNA transfection increased cisplatin sensitivity, whereas SMYD3 overexpression decreased cisplatin sensitivity. In addition, SMYD3 knockdown synergistically enhanced cisplatin-induced cell apoptosis. SMYD3 expression was downregulated during cisplatin treatment. In addition, transcriptional regulatory activities of SMYD3 3′-untranslated region were also downregulated. These results suggested that SMYD3 may affect cell sensitivity to cisplatin and participate in the development of cisplatin resistance, which is a process that may involve microRNA-124-mediated regulation.
IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection

IL-27 signaling activates the production of antiviral proteins in the skin and inhibits Zika virus infection. In the skin, antiviral proteins and other immune molecules serve as the first line of innate antiviral defense. Here, we identify and characterize the induction of cutaneous innate antiviral proteins in response to IL-27 and its functional role during cutaneous defense against Zika virus infection. Transcriptional and phenotypic profiling of epidermal keratinocytes treated with IL-27 demonstrated activation of antiviral proteins OAS1, OAS2, OASL, and MX1 in the skin of both mice and humans. IL-27–mediated antiviral protein induction was found to occur in a STAT1- and IRF3-dependent but STAT2-independent manner. Moreover, using IL27ra mice, we demonstrate a significant role for IL-27 in inhibiting Zika virus morbidity and mortality following cutaneous, but not intravenous, inoculation. Together, our results demonstrate a critical and previously unrecognized role for IL-27 in cutaneous innate antiviral immunity against Zika virus.
Upregulated miR-665 expression independently predicts poor prognosis of lung cancer and facilitates tumor cell proliferation, migration and invasion

Non-small cell lung cancer (NSCLC) is one of the leading causes of global cancer-associated mortality. Aberrant microRNAs (miRs) have been reported to be involved in the pathogenesis of various cancer types. The present study aimed to investigate the expression profile and prognostic value of miR-665 in patients with NSCLC, and to analyze its functional role in tumor progression using NSCLC cells. Reverse transcription-quantitative PCR was used to estimate the expression levels of miR-665. Kaplan-Meier survival curves and Cox regression analysis were performed to evaluate the prognostic value of miR-665. The effects of miR-665 on NSCLC cell proliferation, migration and invasion were examined by cell transfection, and the target gene of miR-665 was explored. miR-665 expression was elevated in the tissue and cell samples of NSCLC. This increased miR-665 expression was associated with lymph node metastasis and TNM stage. An independent association between miR-665 and overall survival was identified in patients with NSCLC. When regulating the expression levels of miR-665 in vitro, NSCLC cell proliferation, migration and invasion were enhanced by overexpression of miR-665, but were inhibited by knockdown of miR-665. The luciferase activity results indicated that the protein tyrosine phosphatase receptor type B (PTPRB) was a direct target of miR-665 in NSCLC cells. The present study provided evidence for the clinical significance of a decreased expression of miR-665 in the prognosis of NSCLC. Upregulation of miR-665 contributed to tumor cell proliferation, migration and invasion by targeting PTPRB, suggesting the potential of miR-665 as a candidate therapeutic target for NSCLC treatment.