Miracle-dz/UniFAR-FTUs huggingface dataset:
Disruption of nNOS–NOS1AP protein–protein interactions suppresses neuropathic pain in mice

Abstract Elevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. Here, we evaluated the involvement of interactions between neuronal nitric oxide synthase (nNOS) and the nitric oxide synthase 1 adaptor protein (NOS1AP) in pronociceptive signaling and neuropathic pain. TAT-GESV, a peptide inhibitor of the nNOS–NOS1AP complex, disrupted the in vitro binding between nNOS and its downstream protein partner NOS1AP but not its upstream protein partner postsynaptic density 95 kDa (PSD95). Putative inactive peptides (TAT-cp4GESV and TAT-GESV&Dgr;1) failed to do so. Only the active peptide protected primary cortical neurons from glutamate/glycine-induced excitotoxicity. TAT-GESV, administered intrathecally (i.t.), suppressed mechanical and cold allodynia induced by either the chemotherapeutic agent paclitaxel or a traumatic nerve injury induced by partial sciatic nerve ligation. TAT-GESV also blocked the paclitaxel-induced phosphorylation at Ser15 of p53, a substrate of p38 MAPK. Finally, TAT-GESV (i.t.) did not induce NMDAR-mediated motor ataxia in the rotarod test and did not alter basal nociceptive thresholds in the radiant heat tail-flick test. These observations support the hypothesis that antiallodynic efficacy of an nNOS–NOS1AP disruptor may result, at least in part, from blockade of p38 MAPK-mediated downstream effects. Our studies demonstrate, for the first time, that disrupting nNOS–NOS1AP protein–protein interactions attenuates mechanistically distinct forms of neuropathic pain without unwanted motor ataxic effects of NMDAR antagonists.
Contribution of macrophages in the contrast loss in iron oxide-based MRI cancer cell tracking studies

Magnetic resonance imaging (MRI) cell tracking of cancer cells labeled with superparamagnetic iron oxides (SPIO) allows visualizing metastatic cells in preclinical models. However, previous works showed that the signal void induced by SPIO on T2(*)-weighted images decreased over time. Here, we aim at characterizing the fate of iron oxide nanoparticles used in cell tracking studies and the role of macrophages in SPIO metabolism. In vivo MRI cell tracking of SPIO positive 4T1 breast cancer cells revealed a quick loss of T2* contrast after injection. We next took advantage of electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICP-MS) for characterizing the evolution of superparamagnetic and non-superparamagnetic iron pools in 4T1 breast cancer cells and J774 macrophages after SPIO labeling. These in vitro experiments and histology studies performed on 4T1 tumors highlighted the quick degradation of iron oxides by macrophages in SPIO-based cell tracking experiments. In conclusion, the release of SPIO by dying cancer cells and the subsequent uptake of iron oxides by tumor macrophages are limiting factors in MRI cell tracking experiments that plead for the use of (MR) reporter-gene based imaging methods for the long-term tracking of metastatic cells.
Semi-Supervised Dimension Reduction Using Trace Ratio Criterion

In this brief, we address the trace ratio (TR) problem for semi-supervised dimension reduction. We first reformulate the objective function of the recent work semi-supervised discriminant analysis (SDA) in a TR form. We also observe that in SDA the low-dimensional data representation F is constrained to be in the linear subspace spanned by the training data matrix X (i.e., F = XT W). In order to relax this hard constraint, we introduce a flexible regularizer ||F - XT W||2 which models the regression residual into the reformulated objective function. With such relaxation, our method referred to as TR based flexible SDA (TR-FSDA) can better cope with data sampled from a certain type of nonlinear manifold that is somewhat close to a linear subspace. In order to address the non-trivial optimization problem in TR-FSDA, we further develop an iterative algorithm to simultaneously solve for the low-dimensional data representation F and the projection matrix W. Moreover, we theoretically prove that our iterative algorithm converges to the optimum based on the Newton-Raphson method. The experiments on two face databases, one shape image database and one webpage database demonstrate that TR-FSDA outperforms the existing semi-supervised dimension reduction methods.
The modeled cost‐effectiveness of family‐based and adolescent‐focused treatment for anorexia nervosa

BACKGROUND Anorexia nervosa (AN) is a prevalent, serious mental disorder. We aimed to evaluate the cost-effectiveness of family-based treatment (FBT) compared to adolescent-focused individual therapy (AFT) or no intervention within the Australian healthcare system. METHOD A Markov model was developed to estimate the cost and disability-adjusted life-year (DALY) averted of FBT relative to comparators over 6 years from the health system perspective. The target population was 11-18 year olds with AN of relatively short duration. Uncertainty and sensitivity analyses were conducted to test model assumptions. Results are reported as incremental cost-effectiveness ratios (ICER) in 2013 Australian dollars per DALY averted. RESULTS FBT was less costly than AFT. Relative to no intervention, the mean ICER of FBT and AFT was $5,089 (95% uncertainty interval (UI): dominant to $16,659) and $51,897 ($21,591 to $1,712,491) per DALY averted. FBT and AFT are 100% and 45% likely to be cost-effective, respectively, at a threshold of AUD$50,000 per DALY averted. Sensitivity analyses indicated that excluding hospital costs led to increases in the ICERs but the conclusion of the study did not change. CONCLUSION FBT is the most cost-effective among treatment arms, whereas AFT was not cost-effective compared to no intervention. Further research is required to verify this result.
CTCF Binding Sites in the Herpes Simplex Virus 1 Genome Display Site-Specific CTCF Occupation, Protein Recruitment, and Insulator Function

ABSTRACT There are seven conserved CTCF binding domains in the herpes simplex virus 1 (HSV-1) genome. These binding sites individually flank the latency-associated transcript (LAT) and the immediate early (IE) gene regions, suggesting that CTCF insulators differentially control transcriptional domains in HSV-1 latency. In this work, we show that two CTCF binding motifs in HSV-1 display enhancer blocking in a cell-type-specific manner. We found that CTCF binding to the latent HSV-1 genome was LAT dependent and that the quantity of bound CTCF was site specific. Following reactivation, CTCF eviction was dynamic, suggesting that each CTCF site was independently regulated. We explored whether CTCF sites recruit the polycomb-repressive complex 2 (PRC2) to establish repressive domains through a CTCF-Suz12 interaction and found that Suz12 colocalized to the CTCF insulators flanking the ICP0 and ICP4 regions and, conversely, was removed at early times postreactivation. Collectively, these data support the idea that CTCF sites in HSV-1 are independently regulated and may contribute to lytic-latent HSV-1 control in a site-specific manner. IMPORTANCE The role of chromatin insulators in DNA viruses is an area of interest. It has been shown in several beta- and gammaherpesviruses that insulators likely control the lytic transcriptional profile through protein recruitment and through the formation of three-dimensional (3D) chromatin loops. The ability of insulators to regulate alphaherpesviruses has been understudied to date. The alphaherpesvirus HSV-1 has seven conserved insulator binding motifs that flank regions of the genome known to contribute to the establishment of latency. Our work presented here contributes to the understanding of how insulators control transcription of HSV-1.
Antibacterial and Antibiofilm Activities of a Novel Synthetic Cyclic Lipopeptide against Cariogenic Streptococcus mutans UA159

ABSTRACT Despite continuous efforts to control cariogenic dental biofilms, very few effective antimicrobial treatments exist. In this study, we characterized the activity of the novel synthetic cyclic lipopeptide 4 (CLP-4), derived from fusaricidin, against the cariogenic pathogen Streptococcus mutans UA159. We determined CLP-4's MIC, minimum bactericidal concentration (MBC), and spontaneous resistance frequency, and we performed time-kill assays. Additionally, we assessed CLP-4's potential to inhibit biofilm formation and eradicate preformed biofilms. Our results demonstrate that CLP-4 has strong antibacterial activity in vitro and is a potent bactericidal agent with low spontaneous resistance frequency. At a low concentration of 5 μg/ml, CLP-4 completely inhibited S. mutans UA159 biofilm formation, and at 50 μg/ml, it reduced the viability of established biofilms by >99.99%. We also assessed CLP-4's cytotoxicity and stability against proteolytic digestion. CLP-4 withstood trypsin or chymotrypsin digestion even after treatment for 24 h, and our toxicity studies showed that CLP-4 effective concentrations had negligible effects on hemolysis and the viability of human oral fibroblasts. In summary, our findings showed that CLP-4 is a potent antibacterial and antibiofilm agent with remarkable stability and low nonspecific cytotoxicity. Hence, CLP-4 is a promising novel antimicrobial peptide with potential for clinical application in the prevention and treatment of dental caries.
Adeno-Associated Viral Vector (Serotype 2)–Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial

Importance Nerve growth factor (NGF) is an endogenous neurotrophic factor that prevents the death and augments the functional state of cholinergic neurons of the basal forebrain, a cell population that undergoes extensive degeneration in Alzheimer disease (AD). Objective To determine whether stereotactically guided intracerebral injections of adeno-associated viral vector (serotype 2)–nerve growth factor (AAV2-NGF) are well tolerated and exhibit preliminary evidence of impact on cognitive decline in mild to moderate AD-associated dementia. Design, Setting, and Participants In a multicenter phase 2 trial, 49 participants with mild to moderate AD were randomly assigned in a 1:1 ratio to receive stereotactically guided intracerebral injections of AAV2-NGF or sham surgery. Participants were enrolled between November 2009 and December 2012. Analyses began in February 2015. The study was conducted at 10 US academic medical centers. Eligibility required a diagnosis of mild to moderate dementia due to AD and individuals aged 55 to 80 years. A total of 39 participants did not pass screening; the most common reason was Mini-Mental State Examination scores below cutoff. Analyses were intention-to-treat. Interventions Stereotactically guided intracerebral injections of AAV2-NGF into the nucleus basalis of Meynert of each hemisphere or sham surgery. Main Outcomes and Measures Change from baseline on the Alzheimer’s Disease Assessment Scale–cognitive subscale at month 24. Results Among 49 participants, 21 (43%) were women, 42 (86%) self-identified as white, and the mean (SD) age was 68 (6.4) years. AAV2-NGF was safe and well-tolerated through 24 months. No significant difference was noted between the treatment group and placebo on the primary outcome measure, the Alzheimer’s Disease Assessment Scale–cognitive subscale (mean [SD] score, 14.52 [4.66] vs 9.11 [4.65], P = .17). Conclusions and Relevance This multicenter randomized clinical trial demonstrated the feasibility of sham-surgery–controlled stereotactic gene delivery studies in patients with AD. AAV2-NGF delivery was well-tolerated but did not affect clinical outcomes or selected AD biomarkers. Pathological confirmation of accurate gene targeting is needed. Trial Registration clinicaltrials.gov Identifier NCT00876863
Modeling and numerical solution of inverse optimal control problems for the analysis of human motions

In this thesis, inverse optimal control problems are modeled, solution strategies are analyzed and numerical results are discussed. The human motions considered in the examples are assumed to be (approximately) optimal with respect to an unknown cost function. The goal of the inversion is to find this cost function using a suitable setting. The solution method combines a collocation approach and a reformulation of the resulting bilevel-problem using optimality conditions.
The Impact of Key HIV Intervention Components as Predictors of Sexual Barrier Use

Behavioral interventions have utilized a variety of strategies and components to reduce HIV risk. This article describes the partner intervention, a couple-based group HIV risk reduction intervention implemented in 6 urban community health clinics in Lusaka, Zambia, and examines the components of the intervention and their relationship with condom use. Couple members completed assessments on condom use, acceptability, willingness to use condoms, communication, intimate partner violence (IPV), self-efficacy, and HIV information at baseline and 6 months’ follow-up. This study examined the relative impact of elements of the intervention as predictors of condom use. Changes in acceptability had the greatest overall influence on condom use, followed by social support, relationship consensus, and willingness to use condoms. Changes in self-efficacy, IPV, negotiation, and information had no influence. Results support the use of multidimensional approaches in behavioral interventions and highlight the importance of identifying critical elements of interventions to maximize risk reduction outcomes.
Rationalizing Rac1 and RhoA GTPase signaling: A mathematical approach

ABSTRACT Precise spatiotemporal dynamics of Rho GTPases are essential for efficient cell migration. Manipulating Rac1 and RhoA signaling is thus a potential intervention strategy to abrogate harmful cell invasion and subsequent metastasis; however GTPase signaling can be extremely complicated due to crosstalk and the multitude of upstream regulators and downstream effectors. Studying Rho GTPase networks in a formal mathematical setting can therefore be of great use. We recently built a predictive model based on Boolean logic which identified a negative feedback loop critical for RhoA and Rac1 activity. Here, we discuss the value and potential pitfalls of different mathematical approaches which have been used to study Rho GTPase dynamics, and highlight the importance of choosing the correct approach given the data available and outputs desired. Overall, a mathematical approach, particularly when combined iteratively with in vitro experiments, can be of great use in deriving new biological insight to further harness the activity of Rho GTPases.
Exercise capacity following a percutaneous endoscopic gastrostomy in a young female with cystic fibrosis: a case report

Cystic fibrosis (CF) is a genetic condition affecting the respiratory and gastrointestinal systems, with patients experiencing problems maintaining weight, especially during rapid growth periods such as puberty. The aim of this case report was to monitor the effect of gastrostomy insertion and implementation of overnight supplemental feeding upon clinical outcomes, including body mass index (BMI), lung function (FEV1), and exercise‐related variables (maximal oxygen uptake [VO2max] and ventilatory efficiency [VE/VO2]) in an 11‐year‐old female with CF. Combined incremental and supramaximal exercise testing to exhaustion was performed at four time points: 3 months prior to the procedure (T1), 2 days prior to (T2), 4 months (T3), and 1 year following the procedure (T4). Improvements following gastrostomy insertion were observed at the 1 year follow‐up with regards to BMI (+20%); whereas absolute VO2max remained stable and lung function fluctuated throughout the period of observation. Declines in function with regards to body weight relative VO2max (−16.3%) and oxygen uptake efficiency (+7.5%) were observed during this period. This case report is the first to consider exercise‐related clinical outcomes in assessing the effect of implementing gastrostomy feeding in CF. The varied direction and magnitude of the associations between variables shows that further investigations are required.
Magnetic resonance imaging, microscopy, and spectroscopy of the central nervous system in experimental animals

SummaryOver the last two decades, microscopic resolutionin vivo magnetic resonance imaging (MRI) techniques have been developed and extensively used in the study of animal models of human diseases. Standard MRI methods are frequently used in clinical studies and in the general clinical practice of human neurological diseases. This generates a need for similar studies in experimental animal research. Because small rodents are the most commonly used species as animal models of neurological diseases, the MRI techniques need to be able to provide microscopic resolution and high signal-to-noise ratio images in relatively short time. Small animal MRI systems use very high field-strength magnets, which results in higher signal to noise ratio; however, the contrast characteristics of live tissue are different at these field strengths. In addition to standard MRI techniques, several new applications have been implemented in experimental animals, including diffusion and perfusion studies, MR angiography, functional MRI studies, MRI tractography, proton and phosphorous spectroscopy, cellular and molecular imaging using novel contrast methods. Here we give an overview of how to establish a small animal imaging facility with the goal of CNS imaging. We describe the basic physical processes leading to MR signal generation, highlighting the differences between standard clinical MRI and small animal MRI. Finally, typical findings in the most common neurological disease categories and novel MRI/magnetic resonance spectroscopy methods used in their study are also described.
Two Separate Defects Affecting True Naive or Virtual Memory T Cell Precursors Combine To Reduce Naive T Cell Responses with Aging

Naive T cell responses are eroded with aging. We and others have recently shown that unimmunized old mice lose ≥70% of Ag-specific CD8 T cell precursors and that many of the remaining precursors acquire a virtual (central) memory (VM; CD44hiCD62Lhi) phenotype. In this study, we demonstrate that unimmunized TCR transgenic (TCRTg) mice also undergo massive VM conversion with age, exhibiting rapid effector function upon both TCR and cytokine triggering. Age-related VM conversion in TCRTg mice directly depended on replacement of the original TCRTg specificity by endogenous TCRα rearrangements, indicating that TCR signals must be critical in VM conversion. Importantly, we found that VM conversion had adverse functional effects in both old wild-type and old TCRTg mice; that is, old VM, but not old true naive, T cells exhibited blunted TCR-mediated, but not IL-15–mediated, proliferation. This selective proliferative senescence correlated with increased apoptosis in old VM cells in response to peptide, but decreased apoptosis in response to homeostatic cytokines IL-7 and IL-15. Our results identify TCR as the key factor in differential maintenance and function of Ag-specific precursors in unimmunized mice with aging, and they demonstrate that two separate age-related defects—drastic reduction in true naive T cell precursors and impaired proliferative capacity of their VM cousins—combine to reduce naive T cell responses with aging.
Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study

Renal impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiologic changes, in addition to a decrease in glomerular filtration rate, that impact the pharmacokinetics (PK) and, specifically, the renal clearance (CLR) of compounds, including alterations of drug transporter (DT)/drug-metabolizing enzyme expression and activity, as well as protein binding. The objectives of this study were to use a physiologically based pharmacokinetic modeling platform to 1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs), and free fraction (fu) on PK predictions for the organic cation transporter 2/multidrug and toxin extrusion protein 1 substrate metformin in RI populations; and 2) use available in vitro data to improve predictions of CLR for two actively secreted substrates, metformin and ranitidine. The goal was to identify changes in parameters other than glomerular filtration rate—namely, fu and DT expression/activity—that are consistent with in vitro and clinical data in RI, and predict the importance of these parameters in the PK of metformin and ranitidine in RI patients. Our results demonstrated that including alterations in DT expression and fu, and including TDIs affecting DT activity, as indicated by in vitro data, improved the simulated predictions of CLR and other PK parameters for both metformin and ranitidine in RI. Our simulations suggest that modifications of DT expression/activity and fu are necessary for improved predictions of CLR in RI for compounds that are actively secreted, and that improvement of PK predictions in RI populations for metformin and ranitidine can be obtained by incorporating in vitro data.
IL‐6 up‐regulates Mcl‐1 in human myeloma cells through JAK / STAT rather than Ras / MAP kinase pathway

Mcl‐1 is an anti‐apoptotic member of the Bcl‐2 family which is tightly regulated during myeloid and B cell differentiation. We have recently reported that Mcl‐1 is expressed in human myeloma cells and that Mcl‐1 and Bcl‐xL expression are correlated. In the current study, we demonstrate that IL‐6, a survival factor for the human myeloma cell line MDN, rapidly up‐regulates Mcl‐1 whereas it has no effect on Bcl‐2 protein level. In MDN cells, IL‐6 induces both extracellular signal‐regulated protein kinase (ERK)1,2 and STAT3 activation whereas STAT1 and STAT5 activation remains undetectable. Furthermore, while investigating the IL‐6 signaling pathway leading to Mcl‐1 up‐regulation, we show that a janus kinase (JAK)‐2 inhibitor is able to inhibit both STAT3 activation and Mcl‐1 up‐regulation whereas an MAP/ERK kinase (MEK) inhibitor has no effect. In conclusion, our data suggest the involvement of the JAK / STAT pathway but not of the Ras / mitogen‐activated protein (MAP) kinase pathway in IL‐6‐induced Mcl‐1 up‐regulation.
The fuzzy mapping aggregation operator based on rimer and its application

AbstractA fuzzy mapping aggregation operator based on RIMER and its application in Chinese word semantic proofing system for special domain are discussed deeply in this paper. Firstly, the fuzzy mapping aggregation operator based on RIMER are introduced and followed by the corresponding fuzzy inference method. Secondly, the collection of the sensitive words and their substitutions and the soft inference are discussed mainly based on our previous achievements. Then the new flowchart of the semantic analysis and the bases and the modules in the Chinese word proofing system are illustrated subsequently. The experiment shows that it is more feasible and practical method for semantic analysis.