Miracle-dz/UniFAR-FTUs huggingface dataset:
Detection of cell death in tumors by using MR imaging and a gadolinium-based targeted contrast agent.

PURPOSE To prospectively determine in an animal model whether an ionic gadolinium (Gd(3+)) chelate conjugate of the C2A domain of synaptotagmin I can be used with magnetic resonance (MR) imaging to detect tumor cell death noninvasively in vivo. MATERIALS AND METHODS Animal experiments were approved by a local ethics review committee. Gd(3+) chelates and fluorescent probes were attached to the lysine epsilon-amino groups of a glutathione-S-transferase-C2A fusion protein. Binding to phosphatidylserine (PS) was characterized by using surface plasmon resonance, and binding to dying cells in vitro was characterized by using flow cytometry and MR imaging. Binding to dying tumor cells in vivo was detected with T1 mapping and T1-weighted MR imaging and compared in drug-treated animals (n = 10); in animals injected with a site-directed mutant, which was inactive in PS binding (PS inactive) and which showed lesser binding to dying cells (n = 6); and in untreated animals injected with PS-active (n = 6) and PS-inactive (n = 6) contrast agents. Among groups, differences that were significant were analyzed by using analysis of variance and Dunnett post hoc analysis. RESULTS The contrast agent had a relatively high affinity for PS (dissociation constant = 333 nmol/L +/- 85 [mean +/- standard error of the mean]; n = 3) and bound to apoptotic and necrotic, but not viable, cells in vitro. There was a greater tumor accumulation of the PS-active contrast agent compared with the PS-inactive contrast agent in drug-treated animals (P < .05) and compared with untreated animals injected with the PS-active and PS-inactive contrast agents (P < .01 for both). CONCLUSION A relatively small (approximately 100 kDa) Gd(3+)-based contrast agent, which gives positive contrast on MR images, can be used to detect tumor cell death in vivo, and future derivatives of it may be used to assess early tumor responses to treatment.
Inhibition of pyruvate dehydrogenase kinase enhances the antitumor efficacy of oncolytic reovirus.

Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here we investigated whether cancer cell metabolism defines its susceptibility to OV, and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus. In particular, reovirus infection accentuated Warburg-like metabolic perturbations in cell lines relatively resistant to oncolysis. These metabolic changes were facilitated by oxidative stress-induced inhibitory phosphorylation of pyruvate dehydrogenase (PDH) that impaired the routing of pyruvate into the TCA cycle and established a metabolic state unsupportive of OV replication. From the therapeutic perspective, reactivation of PDH in cancer cells that were weakly sensitive for reovirus, either through PDH kinase (PDK) inhibitors dichloroacetate and AZD7545 or shRNA-specific depletion of PDK1, enhanced the efficacy of reovirus-induced oncolysis in vitro and in vivo. These findings identify targeted metabolic reprogramming as a possible combination strategy to enhance the antitumour effects of OV in clinics.
LOW-COMPLEXITY PERCEPTUAL JPEG 2000 ENCODER FOR AERIAL IMAGES Graduate Students :

A highly compressed image inevitably has visible compression artifacts. To minimize these artifacts, many compression algorithms exploit the varying sensitivity of the human visual system (HVS) to different frequencies. However, this sensitivity has typically been measured at the near-threshold level where distortion is just noticeable. Thus, it is unclear that the same sensitivity applies at the supra-threshold level where distortion is highly visible. In this paper, we measure the sensitivity of the HVS for several supra-threshold distortion levels based on our JPEG2000 distortion model. Then, a low-complexity JPEG2000 encoder using the measured sensitivity is described. For aerial images, the proposed encoder significantly reduces encoding time while maintaining superior visual quality compared with a conventional JPEG2000 encoder.
Follicle-stimulating hormone and luteinizing hormone increase Ca2+ in the granulosa cells of mouse ovarian follicles†

Abstract In mammalian ovarian follicles, follicle stimulating hormone (FSH) and luteinizing hormone (LH) signal primarily through the G-protein Gs to elevate cAMP, but both of these hormones can also elevate Ca2+ under some conditions. Here, we investigate FSH- and LH-induced Ca2+ signaling in intact follicles of mice expressing genetically encoded Ca2+ sensors, Twitch-2B and GCaMP6s. At a physiological concentration (1 nM), FSH elevates Ca2+ within the granulosa cells of preantral and antral follicles. The Ca2+ rise begins several minutes after FSH application, peaks at ∼10 min, remains above baseline for another ∼10 min, and depends on extracellular Ca2+. However, suppression of the FSH-induced Ca2+ increase by reducing extracellular Ca2+ does not inhibit FSH-induced phosphorylation of MAP kinase, estradiol production, or the acquisition of LH responsiveness. Like FSH, LH also increases Ca2+, when applied to preovulatory follicles. At a physiological concentration (10 nM), LH elicits Ca2+ oscillations in a subset of cells in the outer mural granulosa layer. These oscillations continue for at least 6 h and depend on the activity of Gq family G-proteins. Suppression of the oscillations by Gq inhibition does not inhibit meiotic resumption, but does delay the time to 50% ovulation by about 3 h. In summary, both FSH and LH increase Ca2+ in the granulosa cells of intact follicles, but the functions of these Ca2+ rises are only starting to be identified. Summary Sentence Both FSH and LH increase Ca2+ in the granulosa cells of intact ovarian follicles from mice expressing genetically encoded sensors.
Rosiglitazone has a neutral effect on the risk of dementia in type 2 diabetes patients

This study investigated whether rosiglitazone might increase or reduce dementia risk. Taiwan’s National Health Insurance database was used to enroll a cohort of 1:1 matched-pairs of ever and never users of rosiglitazone based on propensity score from patients with new-onset type 2 diabetes during 1999-2006. The patients were alive on January 1, 2007 and were followed up for dementia until December 31, 2011. A total of 5,048 pairs of never users and ever users were identified. The incident case numbers were 127 and 121, respectively. The adjusted hazard ratio for ever versus never users was 0.895 (95% confidence interval: 0.696-1.151). The adjusted hazard ratios for the first (<12.1 months), second (12.1-25.1 months) and third (>25.1 months) tertiles of cumulative duration of rosiglitazone therapy were 0.756 (0.509-1.123), 0.964 (0.685-1.357) and 0.949 (0.671-1.341), respectively. When cumulative duration was treated as a continuous variable, the adjusted hazard ratio was 1.000 (0.992-1.008). Subgroup analyses conducted in ever users and never users of metformin and in patients diagnosed with diabetes during three different periods of time, i.e., 1999-2000, 2001-2003 and 2004-2006, all supported a neutral effect of rosiglitazone. In conclusion, rosiglitazone does not increase or redcue the risk of dementia.
Physiologically‐Based Pharmacokinetic Modeling of Fluconazole Using Plasma and Cerebrospinal Fluid Samples From Preterm and Term Infants

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically‐based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration‐time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.
Causes of mortality in backyard poultry in eight states in the United States

A comprehensive understanding of common diseases of backyard poultry flocks is important to providing poultry health information to flock owners, veterinarians, and animal health officials. We collected autopsy reports over a 3-y period (2015–2017) from diagnostic laboratories in 8 states in the United States; 2,509 reports were collected, involving autopsies of 2,687 birds. The primary cause of mortality was categorized as infectious, noninfectious, neoplasia or lymphoproliferative disease, or undetermined. Neoplasia or lymphoproliferative disease was the most common primary diagnosis and involved 42% of the total birds autopsied; 63% of these cases were diagnosed as Marek’s disease or leukosis/sarcoma. Bacterial, parasitic, and viral organisms were commonly detected, involving 42%, 28%, and 7% of the birds autopsied, respectively, with 2 or more organisms detected in 69% of birds. Our findings demonstrate the importance of educating flock owners about disease prevention and biosecurity practices. The detection of zoonotic bacteria including paratyphoid salmonellae, Campylobacter spp. , Listeria monocytogenes, and Mycobacterium avium, and the detection of lead and other heavy metals, indicate public health risks to flock owners and consumers of backyard flock egg and meat products.
In situ evaluation of the microbial adhesion on a hard acrylic resin and a soft liner used in removable prostheses.

PURPOSE The purpose of this study was to evaluate, in situ, the initial adhesion of microorganisms to as well as the surface roughness and chemical composition of ProBase Hot (Ivoclar Vivadent), a hard acrylic resin, and Vertex Soft (Vertex-Dental), an acrylic-based soft liner, used in removable dental prostheses. MATERIALS AND METHODS Equal sized disks of ProBase Hot and Vertex Soft were prepared and polished according to the recommended procedures for clinical use. Two disks of each material were mounted in individual oral splints and exposed for 4 hours to the oral cavities of 15 participants. The microbial adhesion to each material's surface was measured with the pour plate technique using rich and selective growth media. Statistical analysis was performed using the Student t test. Scanning electron microscopy and chemical composition analyses obtained through electron probe radiographic microanalysis of sample disks also were performed. RESULTS In comparison to ProBase Hot, Vertex Soft presented higher microbial adhesion, namely regarding total aerobes, anaerobes, streptococci, and mutans streptococci (P < .05). Also, Vertex Soft presented higher surface roughness. Differences in the chemical composition of the two materials also were found. CONCLUSIONS The Vertex Soft liner has been found to be more susceptible to microbial adhesion than the acrylic resin ProBase Hot, probably due to its greater surface roughness. The application of Vertex Soft liner to a hard denture base may lead to a higher risk of oral and systemic infections for patients, highlighting a greater need for plaque control, especially for more susceptible individuals.
Real‐life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program

Eribulin mesylate (EM) was recently approved for metastatic breast cancer (MBC) chemotherapy (CT) in late lines by the FDA, with debated results in second line. We evaluated outcomes in breast cancer patients receiving EM as second, third and fourth line in a national real‐life cohort of 16,703 consecutive MBC patients initiating their first metastatic therapeutic line between 2008 and 2014. Primary and secondary objectives were overall survival (OS) and progression‐free survival (PFS). An imbalance was seen for HER2+ tumors and concomitant anti‐HER2 targeted therapies use, we thus performed a subanalysis in HER2− patients. PFS and OS were significantly better in EM patients in third and fourth lines, compared to “Other chemotherapies” patients (PFS: 4.14 vs. 3.02 months, p = 0.0010; 3.61 vs. 2.53 months, p = 0.0102, third and fourth‐line; OS: 11.27 vs. 7.65 months, p = 0.0001; 10.91 vs. 5.95 months, p < 0.0001, third and fourth‐line). No significant difference was reported in second‐line (PFS: 5.06 vs. 4.14 months, p = 0.1171; OS: 13.99 vs. 11.66 months, p = 0.151). Among HER2− patients, a significant difference was seen for all lines, including 2nd‐line (PFS: 4.57 vs. 3.91 months, p = 0.0379; OS: 14.98 vs. 10.51 months, p = 0.0113). In this large real‐world database, HER2‐negative MBC patients receiving EM in second or later CT line presented significantly better PFS and OS. This difference disappeared in second line in the overall population, probably because of the imbalance in HER2‐targeted treatments use. Our results mirror those of the published randomized trials. The effect of anti‐HER2 therapies addition in this setting still needs to be defined.
Emerging strategies for the identification of protein–metabolite interactions

Abstract Interactions between biological molecules enable life. The significance of a cell-wide understanding of molecular complexes is thus obvious. In comparison to protein–protein interactions, protein–metabolite interactions remain under-studied. However, this has been gradually changing due to technological progress. Here, we focus on the interactions between ligands and receptors, the triggers of signalling events. While the number of small molecules with proven or proposed signalling roles is rapidly growing, most of their protein receptors remain unknown. Conversely, there are numerous signalling proteins with predicted ligand-binding domains for which the identities of the metabolite counterparts remain elusive. Here, we discuss the current biochemical strategies for identifying protein–metabolite interactions and how they can be used to characterize known metabolite regulators and identify novel ones.
A cluster analysis of serious adverse event reports after human papillomavirus (HPV) vaccination in Danish girls and young women, September 2009 to August 2017

Background Suspected adverse events (AE) after human papillomavirus (HPV) vaccines include postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS), complex regional pain syndrome (CRPS) and symptoms including headache and orthostatic intolerance. Aim We aimed to identify phenotypes of AEs after HPV vaccination, defined as patterns of AE terms (signs, symptoms, diagnoses), and to evaluate if identified phenotypes reflected previously suspected symptomatology or heightened public concerns over HPV vaccine safety since 1 January 2015. Methods We conducted a retrospective observational study using latent class cluster analysis of all serious AE reports (n = 963) reported by females residing in Denmark between September 2009 and August 2017. Resulting clusters were characterised according to AE terms associated with POTS, CFS and CRPS before (September 2009–December 2014) and during (January 2015–August 2017) a time of heightened media activity regarding HPV vaccines. Results Four clusters of AE reports were distinguished. The most common symptoms were fatigue, dizziness and headache but their frequency varied among clusters. The majority of reports in one cluster were submitted during a period of heightened media activity, including an anomalous spike in submissions in December 2015; a high proportion of these reports included the symptoms cognitive disorder (78%), abdominal pain (77%), dysuria (60%) and sleep disorder (60%). Conclusions Non-specific symptoms including headache, fatigue and dizziness feature prominently in serious AE reports from females in Denmark. Our analysis identified a cluster of reports, likely media stimulated, with a focus on symptoms of CFS and POTS.
Semi-Parametric Model-Based Clustering for DNA Microarray Data

Various clustering methods have been proposed for the analysis of gene expression data, but conventional clustering algorithms have several critical limitations; how to set parameters such as number of clusters, initial cluster centers, and so on. In this paper, we propose a semi-parametric model-based clustering algorithm in which the underlying model is a mixture of Gaussian. Each gene expression data builds a Gaussian kernel, and the uncertainty of microarray data is naturally integrated in the data representation. Our algorithm provides a principled method to automatically determine parameters - number of components in the mixture, mean, covariance, and weight of each Gaussian - by mean-shift procedure (Comaniciu and Meer, 1999) and curvature fitting. After the initialization, expectation maximization (EM) algorithm is employed for clustering to achieve maximum likelihood (ML). The performance of our algorithm is compared with standard EM algorithm using real data as well as synthetic data
A Systematic Review and Meta-Analysis on the Association Between Driving Ability and Neuropsychological Test Performances after Moderate to Severe Traumatic Brain Injury

Abstract Objectives: Guidelines on return-to-driving after traumatic brain injury (TBI) are scarce. Since driving requires the coordination of multiple cognitive, perceptual, and psychomotor functions, neuropsychological testing may offer an estimate of driving ability. To examine this, a meta-analysis of the relationship between neuropsychological testing and driving ability after TBI was performed. Methods: Hedge’s g and 95% confidence intervals were calculated using a random effects model. Analyses were performed on cognitive domains and individual tests. Meta-regressions examined the influence of study design, demographic, and clinical factors on effect sizes. Results: Eleven studies were included in the meta-analysis. Executive functions had the largest effect size (g = 0.60 [0.39–0.80]), followed by verbal memory (g = 0.49 [0.27–0.71]), processing speed/attention (g = 0.48 [0.29–0.67]), and visual memory (g = 0.43 [0.14–0.71]). Of the individual tests, Useful Field of Vision (UFOV) divided attention (g = 1.12 [0.52–1.72]), Trail Making Test B (g = 0.75 [0.42–1.08]), and UFOV selective attention (g = 0.67 [0.22–1.12]) had the largest effects. The effect sizes for Choice Reaction Time test and Trail Making Test A were g = 0.63 (0.09–1.16) and g = 0.58 (0.10–1.06), respectively. Years post injury (β = 0.11 [0.02–0.21] and age (β = 0.05 [0.009–0.09]) emerged as significant predictors of effect sizes (both p < .05). Conclusions: These results provide preliminary evidence of associations between neuropsychological test performance and driving ability after moderate to severe TBI and highlight moderating effects of demographic and clinical factors.
Correlations and stratification analysis between premature ejaculation and psychological disorders

We studied the associations and correlations between premature ejaculation (PE) and psychological disorders, such as anxiety and depression, in new perspectives with an aim of improving PE patients' treatment outcomes. Between December 2017 and December 2018, we selected 1,010 men aged over 18 years old. Self‐estimated IELT, the premature ejaculation diagnostic tool, the International Index of Erectile Function‐5, the General Anxiety Disorder‐7 and the Patients Health Questionnaire‐9 were used to measure latency time, premature ejaculation, erectile dysfunction, anxiety and depression respectively. Premature ejaculation patients were categorised into two types: lifelong PE (LPE) and acquired PE (APE). Among the 958 men evaluated, the prevalence of anxiety and depression in PE group was 82.07% (444/541) and 74.68% (404/541) respectively. Premature ejaculation patients after adjustment for age, negative association of IIEF‐5 and positive relation of PEDT score with GAD‐7/PHQ‐9 were observed (p < 0.01 for all). These associations in men with LPE were stronger than APE. Stratification of the duration of PE showed that the longer the duration is, the more the prevalence of anxiety and depression will be. Age stratification showed that under the impact of PE, young men tend to have severe psychological problems.
Compartments for Synthetic Cells: Osmotically Assisted Separation of Oil from Double Emulsions in a Microfluidic Chip

Liposomes are used in synthetic biology as cell‐like compartments and their microfluidic production through double emulsions allows for efficient encapsulation of various components. However, residual oil in the membrane remains a critical bottleneck for creating pristine phospholipid bilayers. It has been discovered that osmotically driven shrinking leads to detachment of the oil drop. Separation inside a microfluidic chip has been realized to automate the procedure, which allows for controlled continuous production of monodisperse liposomes.
Altitude and risk of depression and anxiety: findings from the intern health study

Abstract Multiple studies suggest that the risks of depression and suicide increase with increasing altitude of residence, but no studies have assessed whether changing altitude changes these risks. To address this gap, this study used data from the Intern Health Study, which follows students from the end of medical school through the first year of residency, recording depression via the 9-item Patient Health Questionnaire (PHQ-9), anxiety via the 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), and multiple risk factors for these symptoms. Data from 3764 medical students representing 46 schools and 282 residencies were available. Odds ratios (OR) representing the effects of altitude on psychiatric symptoms were estimated using generalized linear models. After excluding participants with missing altitude data, 3731 medical students were analyzed. High altitude residence (> 900 m) was significantly associated with PHQ-9 total score (OR = 1.32, 95% CI = 1.001–1.75, p < 0.05), and PHQ-9 suicidal ideation (OR = 1.79, 95% CI = 1.08–0.02, p = 0.02). Moving from low to high altitude was significantly associated with PHQ-9 total score (OR = 1.47, 95% CI = 1.087–1.98, p = 0.01), GAD-7 total score (OR = 1.40, 95% CI = 1.0040–1.95, p < 0.05), and PHQ-9 suicidal ideation (OR = 1.10, 95% CI = 1.01–1.19, p = 0.02). The data suggest that moving from low to high altitude is associated with increasing symptoms of depression, anxiety, and suicidal ideation.