Role of taurine in the central nervous system

Taurine demonstrates multiple cellular functions including a central role as a neurotransmitter, as a trophic factor in CNS development, in maintaining the structural integrity of the membrane, in regulating calcium transport and homeostasis, as an osmolyte, as a neuromodulator and as a neuroprotectant. The neurotransmitter properties of taurine are illustrated by its ability to elicit neuronal hyperpolarization, the presence of specific taurine synthesizing enzyme and receptors in the CNS and the presence of a taurine transporter system. Taurine exerts its neuroprotective functions against the glutamate induced excitotoxicity by reducing the glutamate-induced increase of intracellular calcium level, by shifting the ratio of Bcl-2 and Bad ratio in favor of cell survival and by reducing the ER stress. The presence of metabotropic taurine receptors which are negatively coupled to phospholipase C (PLC) signaling pathway through inhibitory G proteins is proposed, and the evidence supporting this notion is also presented

Asymptotics of Reaction-Diffusion Fronts with One Static and One Diffusing Reactant

The long-time behavior of a reaction-diffusion front between one static (e.g. porous solid) reactant A and one initially separated diffusing reactant B is analyzed for the mean-field reaction-rate density R(\rho_A,\rho_B) = k\rho_A^m\rho_B^n. A uniformly valid asymptotic approximation is constructed from matched self-similar solutions in a reaction front (of width w \sim t^\alpha where R \sim t^\beta enters the dominant balance) and a diffusion layer (of width W \sim t^{1/2} where R is negligible). The limiting solution exists if and only if m, n \geq 1, in which case the scaling exponents are uniquely given by \alpha = (m-1)/2(m+1) and \beta = m/(m+1). In the diffusion layer, the common ad hoc approximation of neglecting reactions is given mathematical justification, and the exact transient decay of the reaction rate is derived. The physical effects of higher-order kinetics (m, n > 1), such as the broadening of the reaction front and the slowing of transients, are also discussed.Comment: final version, new title & combustion reference

Enabling Large Language Models to Generate Text with Citations

Large language models (LLMs) have emerged as a widely-used tool for information seeking, but their generated outputs are prone to hallucination. In this work, our aim is to allow LLMs to generate text with citations, improving their factual correctness and verifiability. Existing work mainly relies on commercial search engines and human evaluation, making it challenging to reproduce and compare different modeling approaches. We propose ALCE, the first benchmark for Automatic LLMs' Citation Evaluation. ALCE collects a diverse set of questions and retrieval corpora and requires building end-to-end systems to retrieve supporting evidence and generate answers with citations. We develop automatic metrics along three dimensions -- fluency, correctness, and citation quality -- and demonstrate their strong correlation with human judgements. Our experiments with state-of-the-art LLMs and novel prompting strategies show that current systems have considerable room for improvement -- For example, on the ELI5 dataset, even the best models lack complete citation support 50% of the time. Our analyses further highlight promising future directions, including developing better retrievers, advancing long-context LLMs, and improving the ability to synthesize information from multiple sources.Comment: Accepted by EMNLP 2023. Code and data are available at https://github.com/princeton-nlp/ALC

Taurine protection of PC12 cells against endoplasmic reticulum stress induced by oxidative stress

<p>Abstract</p> <p>Background</p> <p>Taurine is a free amino acid present in high concentrations in a variety of organs of mammalians. As an antioxidant, taurine has been found to protect cells against oxidative stress, but the underlying mechanism is still unclear.</p> <p>Methods</p> <p>In this report, we present evidence to support the conclusion that taurine exerts a protective function against endoplasmic reticulum (ER) stress induced by H₂O₂ in PC 12 cells. Oxidative stress was introduced by exposure of PC 12 cells to 250 uM H₂O₂ for 4 hours.</p> <p>Results</p> <p>It was found that the cell viability of PC 12 cells decreased with an increase of H₂O₂ concentration ranging from approximately 76% cell viability at 100 uM H₂O₂ down to 18% at 500 uM H₂O₂. At 250 uM H₂O₂, cell viability was restored to 80% by taurine at 25 mM. Furthermore, H₂O₂ treatment also caused a marked reduction in the expression of Bcl-2 while no significant change of Bax was observed. Treatment with taurine restored the reduced expression of Bcl-2 close to the control level without any obvious effect on Bax. Furthermore, taurine was also found to suppress up-regulation of GRP78, GADD153/CHOP and Bim induced by H₂O₂, suggesting that taurine may also exert a protective function against oxidative stress by reducing the ER stress.</p> <p>Conclusion</p> <p>In summary, taurine was shown to protect PC12 cells against oxidative stress induced by H₂O₂. ER stress was induced by oxidative stress and can be suppressed by taurine.</p

Investigation into New Ground Based Communications Service Offerings in Response to SmallSat Trends

The number of NASA sponsored Small Satellite (SmallSat) missions is expected to continue to grow rapidly in the next decade and beyond. There is a growing trend towards more ambitious SmallSat missions, including formation flying (Constellation, Cluster, Trailing) SmallSats and SmallSats destined for lunar orbit and beyond. This paper will present an overview of new service offerings the NASA Near Earth Network (NEN) is currently investigating and demonstrating. It will describe the benefits that new service offerings such as Multiple Spacecraft Per Aperture (MSPA), Ground-based Phased Array (GBPA) antennas, Ground Based Electronically Steered Array (GBESA), and Ground-based Antenna Arraying (GBAA) could provide to individual or formation flying SmallSats anywhere from low-earth orbit to the Sun-Earth Lagrange point orbits. It will also present potential implementation options for future demonstrations at the NASA Goddard Space Flight Center (GSFC) Wallops Flight Facility (WFF) as well as goals and objectives of such demonstrations

Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases

In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders

Urothelial Inverted Papilloma of the Lower Urinary Tract—A Benign Lesion or a Precursor of Malignancy?

ObjectiveWe investigated the clinical characteristics and follow-up results of patients with a lower urinary tract inverted papilloma (IP) in our hospital, with the intention of clarifying whether certain groups require more aggressive surveillance.Materials and MethodsWe conducted a retrospective study of lower urinary tract IP, using the pathology database of Taipei Veterans General Hospital, from September 1992 to February 2008. In total, 67 patients were enrolled. Patients' clinical characteristics, symptoms, tumor locations, and follow-up data were analyzed.ResultsAmong the 67 patients diagnosed with IP, 59 were male and eight were female, with a mean age of 67.9 ± 12.4 years. Gross hematuria and lower-urinary-tract symptoms were the most common symptoms. All of the patients received transurethral resection as initial treatment. Thirty-eight of these patients were monitored for a median of 21 months (range: 3–168 months). Seven patients had synchronous urothelial malignancies, and one had recurrent IP during follow-up. No patient had subsequent urothelial carcinoma or IP recurrence without a synchronous or previous urothelial malignancy during follow-up.ConclusionThere is a low incidence of developing a subsequent malignancy with a simple IP lesion during follow-up. Rigorous surveillance may be unnecessary in IP patients without a synchronous or previous urothelial malignancy

Race does not explain genetic heterogeneity in pharmacogenomic pathways

Polymorphic alleles in the human genome have been identified as affecting numerous drug responses. Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in different racial groups, we investigated whether a patient's race could predict presence of drug-relevant genetic variants well enough to be used as a substitute for individual genotyping

Comprehensive quality control utilizing the prehybridization third-dye image leads to accurate gene expression measurements by cDNA microarrays

BACKGROUND: Gene expression profiling using microarrays has become an important genetic tool. Spotted arrays prepared in academic labs have the advantage of low cost and high design and content flexibility, but are often limited by their susceptibility to quality control (QC) issues. Previously, we have reported a novel 3-color microarray technology that enabled array fabrication QC. In this report we further investigated its advantage in spot-level data QC. RESULTS: We found that inadequate amount of bound probes available for hybridization led to significant, gene-specific compression in ratio measurements, increased data variability, and printing pin dependent heterogeneities. The impact of such problems can be captured through the definition of quality scores, and efficiently controlled through quality-dependent filtering and normalization. We compared gene expression measurements derived using our data processing pipeline with the known input ratios of spiked in control clones, and with the measurements by quantitative real time RT-PCR. In each case, highly linear relationships (R(2)>0.94) were observed, with modest compression in the microarray measurements (correction factor<1.17). CONCLUSION: Our microarray analytical and technical advancements enabled a better dissection of the sources of data variability and hence a more efficient QC. With that highly accurate gene expression measurements can be achieved using the cDNA microarray technology