Miracle-dz/UniFAR-FTUs huggingface dataset:
Botulinum toxin and spasticity

The clinical effects of botulinum toxin have been recognised since the end of the 19th century. It is the most potent neurotoxin known and it is produced by the gram negative anaerobic bacterium Clostridium botulinum. The paralytic effect of the toxin is due to blockade of neuromuscular transmission.1 Injection into a muscle causes chemodenervation and local paralysis and this effect has led to the development of the toxin as a therapeutic tool. It is now used clinically for a wide range of conditions,2particularly focal dystonias, and increasingly for spasticity. This paper reviews the mode of action of botulinum and focuses on its use in the management of spasticity. There are seven immunologically distinct serotypes of botulinum toxin (labelled A-G). This review concentrates on the only type in routine clinical use—type A (BTX-A). Currently, type B,3 4type C,5 and type F6-8are being investigated for clinical use and type B may be available in the near future. Botulinum toxin acts at the neuromuscular junction by inhibiting the release of acetylcholine. It acts selectively on peripheral cholinergic nerve endings causing chemical denervation after the binding, internalisation, and activation of the toxin at the neuromuscular junction. The toxin is synthesised as a relatively inactive single polypeptide chain. Selective high affinity binding of BTX-A occurs at the neuromuscular junction. After internalisation, it is activated when its structure is modified by cleavage of the disulfide bond linking the light and heavy chain. The N terminal of the heavy chain then promotes penetration and translocation of the light chain across the endosomal membrane into the cytosol. This then interacts with, and cleaves the fusion protein SNAP 25 (synaptosomal associated protein) inhibiting the calcium mediated release of acetylcholine from the presynaptic nerve terminal.9 10 Nerve sprouting and muscle re-innervation …
High-throughput single-cell gene-expression profiling with multiplexed error-robust fluorescence in situ hybridization

Significance Image-based approaches to single-cell transcriptomics offer the ability to quantify not only the copy number of RNAs within cells but also the intracellular RNA location and the spatial organization of cells within cultures or tissues. Here we report advances in multiplexed error-robust fluorescence in situ hybridization (MERFISH) that increase the measurement throughput by two orders of magnitude and allow gene expression profiling of ∼40,000 human cells in a single 18-h measurement. This drastic increase in throughput should facilitate the identification and study of rare populations of cells as well as the characterization of transcriptionally distinct cell types within large tissue regions. Image-based approaches to single-cell transcriptomics, in which RNA species are identified and counted in situ via imaging, have emerged as a powerful complement to single-cell methods based on RNA sequencing of dissociated cells. These image-based approaches naturally preserve the native spatial context of RNAs within a cell and the organization of cells within tissue, which are important for addressing many biological questions. However, the throughput of these image-based approaches is relatively low. Here we report advances that lead to a drastic increase in the measurement throughput of multiplexed error-robust fluorescence in situ hybridization (MERFISH), an image-based approach to single-cell transcriptomics. In MERFISH, RNAs are identified via a combinatorial labeling approach that encodes RNA species with error-robust barcodes followed by sequential rounds of single-molecule fluorescence in situ hybridization (smFISH) to read out these barcodes. Here we increase the throughput of MERFISH by two orders of magnitude through a combination of improvements, including using chemical cleavage instead of photobleaching to remove fluorescent signals between consecutive rounds of smFISH imaging, increasing the imaging field of view, and using multicolor imaging. With these improvements, we performed RNA profiling in more than 100,000 human cells, with as many as 40,000 cells measured in a single 18-h measurement. This throughput should substantially extend the range of biological questions that can be addressed by MERFISH.
A STUDY OF HEAVY METAL POLLUTION IN LAKE VICTORIA SEDIMENTS BY ENERGY DISPERSIVE X-RAY FLUORESCENCE

Sources of heavy metal pollution of Lake Victoria is of interest due to its economic and domestic implication in East Africa. Sediments from the shore of Lake Victoria and from some streams flowing into the lake have been analyzed for their heavy metal content using Energy Dispersive X-Ray Fluorescence (EDXRF) analysis. The samples were collected from seventeen different locations around the Municipality of Mwanza divided into three zones according to their activities. The results show that sediments from Mwanza North, which is least in anthropogenic activities, contains Cr and Co in addition to metals of terrestrial origin (K, Ca, Ti, Mn, Fe, Rb, Sr, Y, and Zr), samples from Mwanza Central, which is the town center, contains high concentrations of V, Cu, Zn and Pb, and samples collected from Mwanza South, which is the industrial area, contains the highest concentrations of V, Cu, Zn, As and Pb. It is concluded that the industrial and sewage wastes discharged into the lake are the main sources of the heavy metal contamination of Lake Victoria. Further studies will be required to assess detriments of these pollutants to human and aquatic life before policy for the factories responsible is put in place.
What predicts depression in cardiac patients: Sociodemographic factors, disease severity or theoretical vulnerabilities?

Depression is associated with increased cardiovascular risk in acute coronary syndrome (ACS) patients, but some argue that elevated depression is actually a marker of cardiovascular disease severity. Therefore, disease indices should better predict depression than established theoretical causes of depression (interpersonal life events, reinforcing events, cognitive distortions, type D personality). However, little theory-based research has been conducted in this area. In a cross-sectional design, ACS patients (n = 336) completed questionnaires assessing depression and psychosocial vulnerabilities. Nested logistic regression assessed the relative contribution of demographic or vulnerability factors, or disease indices or vulnerabilities to depression. In multivariate analysis, all vulnerabilities were independent significant predictors of depression (scoring above threshold on any scale, 48%). Demographic variables accounted for <1% of the variance of depression status, with vulnerabilities accounting for significantly more (pseudo R 2 = 0.16, χ 2(change) = 150.9, df = 4, p < 0.001). Disease indices accounted for 7% of the variance in depression (pseudo R 2 = 0.07, χ 2 = 137.9, p < 0.001). However, adding the vulnerabilities increased the overall variance explained to 22% (pseudo R 2 = 0.22, χ 2 = 58.6, df = 4, p < 0.001). Theoretical vulnerabilities predicted depression status better than did either demographic or disease indices. The presence of these proximal causes of depression suggests that depression in ACS patients is not simply a result of cardiovascular disease severity.
Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges

Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all.
Novel gain control in a multichannel semiconductor optical amplifier with equivalent circuit using nonlinear state-space methods

We develop the first state-space model of a semiconductor optical amplifier that contains nonlinear gain compression and electronic parasitics. The new model adds an equivalent circuit to account for parasitics encountered during electronic SOA control, and polynomial nonlinear gain compression to account for spectral hole burning and carrier heating. Using the model we design a controller that regulates SOA output power by first relating the SOA’s source voltage to its gain, and then driving an optical control channel that keeps the input power constant.
GALAXY HALO FORMATION IN THE ABSENCE OF VIOLENT RELAXATION AND A UNIVERSAL DENSITY PROFILE OF THE HALO CENTER

While N-body simulations testify to a cuspy profile of the central region of dark matter halos, observations favor a shallow, cored density profile of the central region of at least some spiral galaxies and dwarf spheroidals. We show that a central profile, very close to the observed one, inevitably forms in the center of dark matter halos if we make a supposition about a moderate energy relaxation of the system during the halo formation. If we assume the energy exchange between dark matter particles during the halo collapse is not too intensive, the profile is universal: it depends almost not at all on the properties of the initial perturbation and is very akin, but not identical, to the Einasto profile with a small Einasto index n ∼ 0.5. We estimate the size of the “central core” of the distribution, i.e., the extent of the very central region with a respectively gentle profile, and show that the cusp formation is unlikely, even if the dark matter is cold. The obtained profile is in good agreement with observational data for at least some types of galaxies but clearly disagrees with N-body simulations.
Stages of Meningococcal Sepsis Simulated In Vitro, with Emphasis on Complement and Toll-Like Receptor Activation

ABSTRACT The clinical presentation of meningococcal disease is closely related to the number of meningococci in the circulation. This study aimed to examine the activation of the innate immune system after being exposed to increasing and clinically relevant concentrations of meningococci. We incubated representative Neisseria meningitidis serogroup B (ST-32) and serogroup C (ST-11) strains and a lipopolysaccharide (LPS)-deficient mutant (the 44/76 lpxA mutant) in human serum and whole blood and measured complement activation and cytokine secretion and the effect of blocking these systems. HEK293 cells transfected with Toll-like receptors (TLRs) were examined for activation of NF-κB. The threshold for cytokine secretion and activation of NF-κB was 103 to 104 meningococci/ml. LPS was the sole inflammation-inducing molecule at concentrations up to 105 to 106 meningococci/ml. The activation was dependent on TLR4-MD2-CD14. Complement contributed to the inflammatory response at ≥105 to 106 meningococci/ml, and complement activation increased exponentially at ≥107 bacteria/ml. Non-LPS components initiated TLR2-mediated activation at ≥107 bacteria/ml. As the bacterial concentration exceeded 107/ml, TLR4 and TLR2 were increasingly activated, independent of CD14. In this model mimicking human disease, the inflammatory response to N. meningitidis was closely associated with the bacterial concentration. Therapeutically, CD14 inhibition alone was most efficient at a low bacterial concentration, whereas addition of a complement inhibitor may be beneficial when the bacterial load increases.
Cardiac resynchronization therapy: relevance of right ventricular function evaluation.

Heart failure constitutes one of the major public health problems with an incidence that approaches 10 per 1000 population after 65 years of age.1 The majority of clinical trials have focused mostly on left ventricular (LV) failure and have led to established therapeutic approaches that are included in the current guidelines.2,3 In contrast, right ventricular (RV) failure is poorly understood and its therapeutic management is largely empirical. Chronic LV failure is the most frequent cause of RV dysfunction.4 Importantly, the presence of RV dysfunction is a strong and independent predictor of mortality in patients with chronic LV heart failure.5,6 Therefore, routine evaluation of RV performance in patients with LV heart failure is mandatory in order to refine the therapeutic management of these patients. Cardiac resynchronization therapy (CRT) is an established treatment for patients with chronic LV heart failure. By restoring the atrio-, inter-, and intra-ventricular synchronicity, CRT improves LV diastolic filling, increases LV stroke volume, decreases mitral regurgitation, and induces favourable LV reverse remodelling.7,8 In addition, several studies have shown a significant improvement in RV dimensions and function after CRT.9,10 Finally, this improvement in both LV and RV performance leads to improved survival of heart failure patients treated with CRT.8,11 The mid- and long-term response to CRT is influenced by several pathophysiological factors. Left ventricular dyssynchrony, extent … *Corresponding author. Tel: +31 71 526 2020; fax: +31 71 526 6809, Email: j.j.bax{at}lumc.nl
The basic rules and methods of mosquito rearing (Aedes aegypti)

The rearing of Aedes mosquitoes is complex and demanding for several reasons. Aedes larvae are affected by temperature, density and available nutrition, mating is not necessarily accomplished naturally and females need a blood meal to develop eggs. The climate chambers where the mosquitoes are kept are warm and sweaty. Due to these tropical conditions the larvae develop fast and need to be cared for daily. The Laboratory of Entomology in National Institute of Malaria Research Bangalore has cultured different colonies of different vectors successfully. In this paper, we discuss different aspects off the rearing process which affect mosquito fitness and are of importance for the quality of fundamental and applied research.
Pazopanib in the management of advanced soft tissue sarcomas

Therapy of soft tissue sarcomas represents an area of significant unmet need in oncology. Angiogenesis has been explored as a potential target both preclinically and clinically, with suggestions of activity. Pazopanib is a multitargeted tyrosine kinase inhibitor with prominent antiangiogenic effects. In a Phase II study, pazopanib demonstrated activity in strata enrolling patients with leiomyosarcomas, synovial sarcomas, or other sarcomas but not those enrolling adipocytic sarcomas. PALETTE, the pivotal Phase III trial, demonstrated improved progression-free survival versus placebo in pazopanib-treated patients previously treated for advanced soft tissue sarcomas. No survival benefit was observed, and adipocytic sarcomas were excluded. Health-related quality-of-life assessments indicated significant decrements in several areas affected by pazopanib toxicities, but no global deterioration. Cost-effectiveness analyses indicate that pazopanib therapy may or may not be cost-effective in different geographic settings. Pazopanib provides important proof-of-concept for antiangiogenic therapy in soft tissue sarcomas. Its use can be improved by further biological studies of its activity profile in sarcomas, studies of biological rational combinations, and clinicopathologic/biological correlative studies of activity to allow better drug targeting.
Probing the mechanism of incorporation of fluorescently labeled actin into stress fibers

The mechanism of actin incorporation into and association with stress fibers of 3T3 and WI38 fibroblasts was examined by fluorescent analog cytochemistry, fluorescence recovery after photobleaching (FRAP), image analysis, and immunoelectron microscopy. Microinjected, fluorescein- labeled actin (AF-actin) became associated with stress fibers as early as 5 min post-injection. There was no detectable cellular polarity in the association of AF-actin with pre-existing stress fibers relative to perinuclear or peripheral regions. The rate of incorporation was quantified by image analysis of images generated with a two-dimensional photon counting microchannel plate camera. After equilibration of up to 2 h post-injection, FRAP demonstrated that actin subunits exchanged rapidly between filaments in stress fibers and the surrounding cytoplasm. When co-injected with rhodamine-labeled bovine serum albumin as a control, only actin was detected in the phase-dense stress fibers. The control protein was excluded from fibers and any linear fluorescence of the control was demonstrated as a pathlength artifact. The incorporation of AF-actin into stress fibers was studied by immunoelectron microscopy using anti-fluorescein as the primary antibody and goat anti-rabbit IgG coupled to peroxidase as the secondary antibody. At 5 min post-injection, reaction product was localized periodically in some fibers with a periodicity of approximately 0.75 microns. In large diameter fibers at 5 min post- injection, the analog was seen first on the surface of fibers, with individual filaments resolvable within the core. In the same cell, thinner diameter fibers were labeled uniformly throughout the diameter. By 20 min post-injection, most fibers were uniformly labeled. We conclude that the rate of actin subunit exchange in vivo is extremely rapid with molecular incorporation into actin filaments of stress fibers occurring as early as a few minutes post-injection. Exchange appears to first occur in filaments along the surface of stress fibers and then into more central regions in a periodic manner. We suggest that the periodic localization of actin at very early time points is due to a local microheterogeneity in which microdomains of fast vs. slower incorporation result from the periodic localization of actin- binding protein, such as alpha-actinin, along the length of the fiber.
Attitudes and confidence towards computers and books as learning tools: a cross-sectional study of student cohorts

Students today comprise a very diverse group, and this will be reflected in their attitudes towards learning. This study set out to examine four different cohorts of UK students during the same time period. Contrary to expectations, it was found that attitudes towards books and computers, as measured by separate but matched scales, were equal, even though experience of the two media varied considerably. A key predictor for computer attitude was found to be confidence for learning from computers rather than general computer confidence. Further, attitudes and confidence towards books and computers as learning tools varied significantly across the four cohorts.
Targeted Antiepidermal Growth Factor Receptor (Cetuximab) Immunoliposomes Enhance Cellular Uptake In Vitro and Exhibit Increased Accumulation in an Intracranial Model of Glioblastoma Multiforme

Therapeutic advances do not circumvent the devastating fact that the survival rate in glioblastoma multiforme (GBM) is less than 5%. Nanoparticles consisting of liposome-based therapeutics are provided against a variety of cancer types including GBM, but available liposomal formulations are provided without targeting moieties, which increases the dosing demands to reach therapeutic concentrations with risks of side effects. We prepared PEGylated immunoliposomes (ILs) conjugated with anti-human epidermal growth factor receptor (EGFR) antibodies Cetuximab (α-hEGFR-ILs). The affinity of the α-hEGFR-ILs for the EGF receptor was evaluated in vitro using U87 mg and U251 mg cells and in vivo using an intracranial U87 mg xenograft model. The xenograft model was additionally analyzed with respect to permeability to endogenous albumin, tumor size, and vascularization. The in vitro studies revealed significantly higher binding of α-hEGFR-ILs when compared with liposomes conjugated with isotypic nonimmune immunoglobulin. The uptake and internalization of the α-hEGFR-ILs by U87 mg cells were further confirmed by 3D deconvolution analyses. In vivo, the α-hEGFR-ILs accumulated to a higher extent inside the tumor when compared to nonimmune liposomes. The data show that α-hEGFR-ILs significantly enhance the uptake and accumulation of liposomes in this experimental model of GBM suggestive of improved specific nanoparticle-based delivery.
Tensor Products of Weakly Smooth Codes are Robust

We continue the study of robusttensor codes and expand the class of base codes that can be used as a starting point for the construction of locally testable codes via robust two-wise tensor products. In particular, we show that all unique-neighbor expander codes and all locally correctable codes, when tensored with any other good-distance code, are robust and hence can be used to construct locally testable codes. Previous works by [2] required stronger expansion properties to obtain locally testable codes. Our proofs follow by defining the notion of weakly smoothcodes that generalize the smoothcodes of [2]. We show that weakly smooth codes are sufficient for constructing robust tensor codes. Using the weaker definition, we are able to expand the family of base codes to include the aforementioned ones.
Data-Driven Design of HMM Topology for Online Handwriting Recognition

Although HMM is widely used for online handwriting recognition, there is no simple and well-established method of designing the HMM topology. We propose a data-driven systematic method to design HMM topology. Data samples in a single pattern class are structurally simplified into a sequence of straight-line segments. Then the resulting multiple models of the class are combined to form an architecture of a multiple parallel-path HMM, which behaves as single HMM. To avoid excessive growing of the number of the states, parameter trying is applied such that structural similarity among patterns is reflected. Experiments on online Hangul recognition showed about 19% of error reductions, compared to the intuitive deisgn method.
Up-regulation of cytochrome P450 and phase II enzymes by xenobiotics in precision-cut tissue slices

Induction of the drug-metabolising enzyme systems is a major cause of clinically relevant drug interactions. The potential of a drug to engage in such interactions may be assessed in in vitro systems such as precision-cut tissue slices. Precision-cut tissue slices have a number of important advantages compared with the use of cells in culture, especially when tissues with a heterogeneous cellular population are concerned. Extensive studies concerned with the induction of cytochrome P450 and Phase II enzymes in precision-cut tissue slices from various animal and human tissues, such as liver, lung and intestine, using established inducing agents have revealed that slices mimic the in vivo situation. Precision-cut tissue slices is a reliable, informative and cost-effective technique for assessing the potential of chemicals to up-regulate drug-metabolising enzyme systems.