Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Multivesicular Bodies as Prevacuolar Compartments in Nicotiana tabacum BY-2 Cells Online version contains Web-only data.

Little is known about the dynamics and molecular components of plant prevacuolar compartments (PVCs). We have demonstrated recently that vacuolar sorting receptor (VSR) proteins are concentrated on PVCs. In this study, we generated transgenic Nicotiana tabacum (tobacco) BY-2 cell lines expressing two yellow fluorescent protein (YFP)-fusion reporters that mark PVC and Golgi organelles. Both transgenic cell lines exhibited typical punctate YFP signals corresponding to distinct PVC and Golgi organelles because the PVC reporter colocalized with VSR proteins, whereas the Golgi marker colocalized with mannosidase I in confocal immunofluorescence. Brefeldin A induced the YFP-labeled Golgi stacks but not the YFP-marked PVCs to form typical enlarged structures. By contrast, wortmannin caused YFP-labeled PVCs but not YFP-labeled Golgi stacks to vacuolate. VSR antibodies labeled multivesicular bodies (MVBs) on thin sections prepared from high-pressure frozen/freeze substituted samples, and the enlarged PVCs also were indentified as MVBs. MVBs were further purified from BY-2 cells and found to contain VSR proteins via immunogold negative staining. Similar to YFP-labeled Golgi stacks, YFP-labeled PVCs are mobile organelles in BY-2 cells. Thus, we have unequivocally identified MVBs as PVCs in N. tabacum BY-2 cells. Uptake studies with the styryl dye FM4-64 strongly indicate that PVCs also lie on the endocytic pathway of BY-2 cells.
Chronic, multisite, multielectrode recordings in macaque monkeys

A paradigm is described for recording the activity of single cortical neurons from awake, behaving macaque monkeys. Its unique features include high-density microwire arrays and multichannel instrumentation. Three adult rhesus monkeys received microwire array implants, totaling 96–704 microwires per subject, in up to five cortical areas, sometimes bilaterally. Recordings 3–4 weeks after implantation yielded 421 single neurons with a mean peak-to-peak voltage of 115 ± 3 μV and a signal-to-noise ratio of better than 5:1. As many as 247 cortical neurons were recorded in one session, and at least 58 neurons were isolated from one subject 18 months after implantation. This method should benefit neurophysiological investigation of learning, perception, and sensorimotor integration in primates and the development of neuroprosthetic devices.
A New Potential Predictor of Coronary Artery Disease: The Ratio of Mitral Peak Filling Velocity to Mitral Annular Velocity in Early Diastole

Background The aim of this study was to explore the value of the ratio of mitral peak filling velocity (E) to mitral annular velocity (e’) in early diastole as a predictor of coronary artery disease (CAD). Material/Methods The study population consisted of 83 consecutive patients (aged 38–77 years, 22 women and 61 men) who received coronary angiography. The E/e’ ratio was estimated by echocardiographic examination. Statistical significance was determined by receiver operating characteristic (ROC) curve and multiple logistic regression analyses. Results ROC curve analysis showed that the optimal E/e’ ratio cut-off for predicting CAD was 8.153 with a specificity of 72.4% and sensitivity of 57.4%. The area under the ROC curve was 0.635 with a 95% confidence interval (CI) for normal distribution of 0.515–0.755 (p=0.043). Multivariate logistic regression analysis demonstrated that the E/e’ ratio was closely associated with CAD (odds ratio [OR], 1.350; 95% CI, 1.087–1.676, p=0.007). Conclusions The E/e’ ratio is a simple and practical predictor of CAD and may be an independent risk factor for CAD. Large-cohort and multi-center studies are required to confirm these observations.
Current Trends in Multidrug Optimization: An Alley of Future Successful Treatment of Complex Disorders

The identification of effective and long-lasting cancer therapies still remains elusive, partially due to patient and tumor heterogeneity, acquired drug resistance, and single-drug dose-limiting toxicities. The use of drug combinations may help to overcome some limitations of current cancer therapies by challenging the robustness and redundancy of biological processes. However, effective drug combination optimization requires the careful consideration of numerous parameters. The complexity of this optimization problem is clearly nontrivial and likely requires the assistance of advanced heuristic optimization techniques. In the current review, we discuss the application of optimization techniques for the identification of optimal drug combinations. More specifically, we focus on the application of phenotype-based screening approaches in the field of cancer therapy. These methods are divided into three categories: (1) modeling methods, (2) model-free approaches based on biological search algorithms, and (3) merged approaches, particularly phenotypically driven network biology methods and computation network models relying on phenotypic data. In addition to a brief description of each approach, we include a critical discussion of the advantages and disadvantages of each method, with a strong focus on the limitations and considerations needed to successfully apply such methods in biological research.
Nf1-deficient mouse Schwann cells are angiogenic and invasive and can be induced to hyperproliferate: reversion of some phenotypes by an inhibitor of farnesyl protein transferase

We have developed a potential model of Schwann cell tumor formation in neurofibromatosis type 1 (NF1). We show that mouse Schwann cells heterozygous or null at Nf1 display angiogenic and invasive properties, mimicking the behavior of Schwann cells from human neurofibromas. Mutations at Nf1 are insufficient to promote Schwann cell hyperplasia. Here we show that Schwann cell hyperplasia can be induced by protein kinase A activation in mutant cells. Removal of serum from the culture medium also stimulates hyperplasia, but only in some mutant cells. After serum removal, clones of hyperproliferating Schwann cells lose contact with axons in vitro, develop growth factor-independent proliferation, and exhibit decreased expression of the cell differentiation marker P0 protein; hyperproliferating cells develop after a 1-week lag in Schwann cells heterozygous at Nf1. The experiments suggest that events subsequent to Nf1 mutations are required for development of Schwann cell hyperplasia. Finally, an anti-Ras farnesyl protein transferase inhibitor greatly diminished both clone formation and hyperproliferation of null mutant cells, but not invasion; farnesyl transferase inhibitors could be useful in treating benign manifestations of NF1.
Market Timing Ability of Indian Firms in Open Market Repurchases

The paper examines the market timing ability of Indian fi rms engaged in open market repur- chases. The study is primarily motivated by the unique disclosure feature of repurchases in India, where the disclosures are far more frequent than in any other market. We find that the repurchasing firms in India are able accumulate shares at favorable prices similar to the US market. However, the cost savings do not translate into signifi cant wealth creation for the insiders as indicated by the short-run and long-run abnormal returns. This is contrary to the evidence from markets like the US. Further, the cross-sectional variations in the cost savings from repurchase execution in India are explained by the overall market returns and not by firm characteristics. These fi ndings contrast with that of US, where the firm characteristics signi ficantly explain the cross-sectional variation in the savings measure. It appears that the more frequent disclosure of repurchase activity in India cripples the market timing ability by reducing the information asymmetry between the firm and the outsiders. This conclusion is further supported by the irrelevance of the past or concurrent stock returns in explaining the time variation in the repurchase activity of fi rms.
Chapter 4 Lazy Kernel-density-based Classification Using P-trees 4.1. Introduction

Kernel functions can be seen as the unifying concept behind many techniques in classification and clustering. This chapter introduces kernel functions and describes a simple implementation based on the concept, which is related to a technique that is known in machine learning as Parzen Window classification [1] and extends previous work using P-trees [2]. Chapters 5 and 6 present two different, related algorithms that can be explained in the kernel-based framework. Section 4.4 compares the results of the classification algorithms of Chapters 5 and 6 with the straightforward kernel-based algorithm of this chapter. In Chapter 5, a very simple kernel function, a step function, is used and combined with an entropy-based attribute selection scheme that is similar to decision tree induction. It is described in the decision tree/rule-based framework that is well established independently of kernel functions [3,4]. It does, however, differ from those other methods in its treatment of continuous data. Comparable methods take the attitude that continuous data must be discretized before classification starts. Our kernel-based derivation leads to a fundamentally different strategy, in which neighborhoods are determined on the fly. This strategy can be followed efficiently using the HOBBit distance [5] which is designed to suit P-trees well. A second kernel-based algorithm is the subject of Chapter 6. It assumes attribute independence improves the validity of this assumption by joining attributes, which makes it
DeltaPath: Precise and Scalable Calling Context Encoding

Calling context provides important information for a large range of applications, such as event logging, profiling, debugging, anomaly detection, and performance optimization. While some techniques have been proposed to track calling context efficiently, they lack a reliable and precise decoding capability; or they work only under restricted conditions, that is, small programs without object-oriented programming or dynamic component loading. These shortcomings have limited the application of calling context tracking in practice. We propose an encoding technique without those limitations: it provides precise and reliable decoding, supports large-sized programs, both procedural and objected-oriented ones, and can cope with dynamic class/library loading. The technique thus enables calling context tracking in a wide variety of scenarios. The evaluation on SPECjvm shows that its efficiency is comparable with that of the state-of-the-art approach while our technique provides precise decoding and demonstrates scalability and flexibility.
Identifying patterns in informal sources of security information

Computer users have access to computer security information from many different sources, but few people receive explicit computer security training. Despite this lack of formal education, users regularly make many important security decisions, such as “Should I click on this potentially shady link? ” or “Should I enter my password into this form? ” For these decisions, much knowledge comes from incidental and informal learning. To better understand differences in the security-related information available to users for such learning, we compared three informal sources of computer security information: news articles, web pages containing computer security advice, and stories about the experiences of friends and family. Using a Latent Dirichlet Allocation topic model, we found that security information from peers usually focuses on who conducts attacks, information containing expertise focuses instead on how attacks are conducted, and information from the news focuses on the consequences of attacks. These differences may prevent users from understanding the persistence and frequency of seemingly mundane threats (viruses, phishing), or from associating protective measures with the generalized threats the users are concerned about (hackers). Our findings highlight the potential for sources of informal security education to create patterns in user knowledge that affect their ability to make good security decisions.
Living Without Creatine: Unchanged Exercise Capacity and Response to Chronic Myocardial Infarction in Creatine-Deficient Mice

Rationale: Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective: We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results: Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase [GAMT]) voluntarily ran just as fast and as far as controls (>10 km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent left ventricular (LV) remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT−/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT−/− hearts accumulated the creatine precursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions: Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle.
Pulmonary Mycobacterium sherrisii Infection in a Human Immunodeficiency Virus Type 1-Infected Patient

ABSTRACT We report the first case of a pulmonary infection with Mycobacterium sherrisii in a patient with advanced human immunodeficiency virus infection. Mycobacterium sherrisii is a newly described nontuberculous mycobacterium related to Mycobacterium simiae. Sequencing of the 16S rRNA gene was used for species identification. Treatment and antibiotic susceptibilities are described.
Staggered Consistent Checkpointing

A consistent checkpointing algorithm saves a consistent view of a distributed application's state on stable storage. The traditional consistent checkpointing algorithms require different processes to save their state at about the same time. This causes contention for the stable storage, potentially resulting in large overheads. Staggering the checkpoints taken by various processes can reduce checkpoint overhead. This paper presents a simple approach to arbitrarily stagger the checkpoints. Our approach requires that the processes take consistent logical checkpoints, as compared to consistent physical checkpoints enforced by existing algorithms. Experimental results on nCube-2 are presented.
The Development of Professionalism: Curriculum Matters

The authors propose that professionalism, rather than being left to the chance that students will model themselves on ideal physicians or somehow be permeable to other elements of professionalism, is fostered by students' engagement with significant, integrated experiences with certain kinds of content. Like clinical reasoning, which cannot occur in a vacuum but must be built on particular knowledge, methods, and the development of skills, professionalism cannot flourish without its necessary basis of knowledge, methods, and skills. The authors present the need for an intellectual widening of the medical curriculum, so that students acquire not only the necessary tools of scientific and clinical knowledge, methods, and skills but also other relevant tools for professional development that can be provided only by particular knowledge, methods, and skills outside bioscience domains. Medical students have little opportunity to engage any body of knowledge not gained through bioscientific/empirical methods. Yet other bodies of knowledge—philosophy, sociology, literature, spirituality, and aesthetics—are often the ones where compassion, communication, and social responsibility are addressed, illuminated, practiced, and learned. To educate broadly educated physicians who develop professionalism throughout their education and their careers requires a full-spectrum curriculum and the processes to support it. The authors sketch the ways in which admission, the curriculum (particularly promoting a sociologic consciousness, interdisciplinary thinking, and understanding of the economic/political dimensions of health care), and assessment and licensure would function.
Antenatal Depression in Anuradhapura, Sri Lanka and the Factor Structure of the Sinhalese Version of Edinburgh Post Partum Depression Scale among Pregnant Women

Background Mental health problems among women of reproductive age group contribute to 7% of Global Burden of Diseases of women of all ages. Purpose of this study was to determine the prevalence and correlates of antenatal depression among pregnant women in Anuradhapura, Sri Lanka, and to explore the factor structure of EPDS. Methods Pregnant women with gestational age of 24–36 weeks and residing in Anuradhapura district, Sri Lanka were recruited to the study using a two stage cluster sampling procedure. Sinhalese version of Edinburgh Post Partum Depression Scale (EPDS) and an interviewer administered questionnaire was use to collect data. A cut off value of 9 was used for the Sinhalese version of EPDS. Results A total of 376 pregnant women were studied. Median EPDS score among pregnant women was 5 (IQR 2–8). Prevalence of antenatal depression in this study sample was 16.2% (n = 61). Thought of self harming (item number 10) was reported by 26 pregnant women (6.9%). None of the socio-demographic factors were associated with depression in this study sample. Having heart burn was significantly associated with depressive symptoms (p = 0.041). Sri Lankan version of EPDS showed a two factor solution. Anxiety was not emerged as a separate factor in this analysis. Conclusions Prevalence of antenatal depression in Anuradhapura, Sri Lanka was relatively low. Anxiety was not emerged as a separate factor in the Sinhalese version of the EPDS.
Development of a new Sindbis virus transducing system and its characterization in three Culicine mosquitoes and two Lepidopteran species

Alphavirus transducing systems (ATSs) are alphavirus‐based tools for expressing genes in insects. Here we describe an ATS (5′dsMRE16ic) based entirely on Sindbis MRE16 virus. GFP expression was used to characterize alimentary tract infections and dissemination in three Culicine and two Lepidopteran species. Following per os infection, 5′dsMRE16ic‐EGFP efficiently infected Aedes aegypti and Culex tritaeniorhynchus, but not Culex pipiens pipiens. Ae. aegypti clearly showed accumulation of green fluorescent protein (GFP) in the posterior midgut and foregut/midgut junction within 2–3 days postinfection. Following parenteral infection of larvae, Bombyx mori had extensive GFP expression in larvae and adults, but Manduca sexta larvae were mostly resistant. 5′dsMRE16ic should be a valuable tool for gene expression in several important insect species that are otherwise difficult to manipulate genetically.
Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB1 receptor (CB1R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB1Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB1R/β1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.
Presynaptic Localization and Possible Function of Calcium-Activated Chloride Channel Anoctamin 1 in the Mammalian Retina

Calcium (Ca2+)-activated chloride (Cl−) channels (CaCCs) play a role in the modulation of action potentials and synaptic responses in the somatodendritic regions of central neurons. In the vertebrate retina, large Ca2+-activated Cl− currents (ICl(Ca)) regulate synaptic transmission at photoreceptor terminals; however, the molecular identity of CaCCs that mediate ICl(Ca) remains unclear. The transmembrane protein, TMEM16A, also called anoctamin 1 (ANO1), has been recently validated as a CaCC and is widely expressed in various secretory epithelia and nervous tissues. Despite the fact that tmem16a was first cloned in the retina, there is little information on its cellular localization and function in the mammalian retina. In this study, we found that ANO1 was abundantly expressed as puncta in 2 synaptic layers. More specifically, ANO1 immunoreactivity was observed in the presynaptic terminals of various retinal neurons, including photoreceptors. ICl(Ca) was first detected in dissociated rod bipolar cells expressing ANO1. ICl(Ca) was abolished by treatment with the Ca2+ channel blocker Co2+, the L-type Ca2+ channel blocker nifedipine, and the Cl− channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and niflumic acid (NFA). More specifically, a recently discovered ANO1-selective inhibitor, T16Ainh-A01, and a neutralizing antibody against ANO1 inhibited ICl(Ca) in rod bipolar cells. Under a current-clamping mode, the suppression of ICl(Ca) by using NPPB and T16Ainh-A01 caused a prolonged Ca2+ spike-like depolarization evoked by current injection in dissociated rod bipolar cells. These results suggest that ANO1 confers ICl(Ca) in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission.