Determining CaMKII Variant Activities and Their Roles in Human Disease

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is involved in Ca2+signaling throughout the body. CaMKII is enriched in the hippocampus and required for learning and memory formation. Four highly conserved genes encode CaMKII in vertebrates: A, B, G, and D. All CaMKII variants are constituted of a kinase domain, regulatory segment, variable linker, and hub domain. These domains comprise an individual subunit which oligomerize together via the hub domain to form multimeric holoenzymes. These four genes are most variable in the linker domain due to extensive alternative splicing. The variable linker significantly impacts the activation of CaMKIIA. Herein, I attempt to develop an in vitro assay which resembles physiological activation of CaMKII via Ca2+ oscillations. I provide preliminary data which indicate that alternative splicing of the variable linker in CaMKIIA modulates the Ca2+ frequency dependent autonomy of these variants. Additionally, neuronal CaMKII variants of CaMKIIA and CaMKIIB decode Ca2+ oscillations into different levels of autonomous activity. Lastly, I assess the impacts of three de novo mutations (Q274P, R275H, and F294S) on Ca2+/CaM sensitivity in CaMKIID by providing data that these 3 mutants increase the sensitivity of CaMKIId to Ca2+/CaM and that Q274P and F294S mutants display Ca2+/CaM independent activity

Miller v. Commissioner: Deductibility of Casualty Losses After Voluntary Election Not to File an Insurance Claim

Taxpayers who suffer casualty losses may decide, for a variety of reasons, not to file an insurance claim for recovery of those losses. Section 165 of the Internal Revenue Code of 1954 allows a deduction for “any loss sustained during the taxable year and not compensated for by insurance or otherwise.”\u27 Consequently, the question arises whether a taxpayer may claim a casualty loss deduction even though the taxpayer did not seek insurance reimbursement for the loss. In Miller v. Commissioner, the United States Court of Appeals for the Sixth Circuit, in a 6-5 en banc decision, expressly overruled its previous decision in Kentucky Utilities Co. v. Glenn and held that a taxpayer who voluntarily chooses not to file an insurance claim for recovery of a loss could still claim a section 165 deduction. Part I of this comment examines the Miller holding and its underlying rationale. Part II addresses the impact of Miller on federal income tax law and suggests that by overruling Kentucky Utilities, Miller changes the law regarding the deductibility of losses under section 165 after a voluntary election not to file an insurance claim. Part III concludes that the Sixth Circuit\u27s literal interpretation of section 165(a)\u27s language “not compensated for by insurance or otherwise”\u27 is a significant defeat for the Internal Revenue Service

Laser microsculpting for the generation of robust diffractive security markings on the surface of metals

AbstractWe report the development of a laser-based process for the direct writing (‘microsculpting’) of unique security markings (reflective phase holograms) on the surface of metals. In contrast to the common approaches used for unique marking of the metal products and components, e.g., polymer holographic stickers which are attached to metals as an adhesive tape, our process enables the generation of the security markings directly onto the metal surface and thus overcomes the problems with tampering and biocompatibility which are typical drawbacks of holographic stickers. The process uses 35ns laser pulses of wavelength 355nm to generate optically-smooth deformations on the metal surface using a localised laser melting process. Security markings (holographic structures) on 304-grade stainless steel surface are fabricated, and their resulted optical performance is tested using a He–Ne laser beam of 632.8nm wavelength

Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal-regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease

Lights In - A Business Plan (Confidential)

Lights In is a radically efficient lighting services enterprise for businesses. Our primary function will be to convert SMEs to more energy efficient light bulbs and/or fittings prior to the phasing out of halogen bulbs in 2018 or before they need to replace them due to expiry of their lifespan. Cost savings will be immediately apparent, and all customer investment will be recouped within two years. Not only will our service substantially reduce business energy consumption, it will enable our customers to qualify for efficiency-based funding, loans and tax relief. Our consultancy will manage the whole process for them, from a lighting design service to maximising the effects of artificial lighting, to installation, to the development of Energy Management Systems and to the application for and accessing of financial incentives and tax breaks. Our business is scalable. We will outsource installation until sufficient sales are apparent and then employ trainees until they qualify and can manage on their own. Our costs correlate to the amount of custom we develop, and we can pause or grow swiftly according to demand. We are the only consultancy that offers such a holistic package at such a competitive rate. We are open to partnerships, alliances and publicity in order to promote the value of energy efficiency. Our experience of running a start-up limited company for the last 9 years and our contacts within the service sector and the East Midlands will enable us to make a significant impact with this new venture. Our target market is primarily service sector related businesses, of which there are 12,000 in the East Midlands alone that meet our criteria. We have tailored our offer for the target market based on our extensive primary and secondary research. Our findings have also confirmed that there is strong interest in our consultancy and services. We have purposefully created a lean business so that we can maintain low costs and pass these on to our customers. We have identified a business model that will encourage businesses to make the change to energy efficient lighting and to do this we must operate on a low cost and low charge basis. We forecast that we will break-even by the end of the first quarter and stabilise before 18 months. By the end of the third year we anticipate employing a further five staff and having profit before tax of over £120,000. To achieve these goals we will need to source £15,000 in funds by our second month in business for lighting inventory and our minimal running costs. This will be added to the £5,000 we will personally invest

cantnlp@LT-EDI@RANLP-2023: Homophobia/Transphobia Detection in Social Media Comments using Spatio-Temporally Retrained Language Models

This paper describes our multiclass classification system developed as part of the LTEDI@RANLP-2023 shared task. We used a BERT-based language model to detect homophobic and transphobic content in social media comments across five language conditions: English, Spanish, Hindi, Malayalam, and Tamil. We retrained a transformer-based crosslanguage pretrained language model, XLMRoBERTa, with spatially and temporally relevant social media language data. We also retrained a subset of models with simulated script-mixed social media language data with varied performance. We developed the best performing seven-label classification system for Malayalam based on weighted macro averaged F1 score (ranked first out of six) with variable performance for other language and class-label conditions. We found the inclusion of this spatio-temporal data improved the classification performance for all language and task conditions when compared with the baseline. The results suggests that transformer-based language classification systems are sensitive to register-specific and language-specific retraining

Integration techniques of pHEMTs and planar Gunn diodes on GaAs substrates

This work presents two different approaches for the implementation of pseudomorphic high electron mobility transistors (pHEMTs) and planar Gunn diodes on the same gallium arsenide substrate. In the first approach, a combined wafer is used where a buffer layer separates the active layers of the two devices. A second approach was also examined using a single wafer where the AlGaAs/InGaAs/GaAs heterostructures were designed for the realisation of pHEMTs. The comparison between the two techniques showed that the devices fabricated on the single pHEMT wafer presented superior performance over the combined wafer technique. The DC and small-signal characteristics of the pHEMTs on the single wafer were enhanced after the use of T-gates with 70 nm length. The maximum transconductance of the transistors was equal to 780 mS/mm with 200 GHz maximum frequency of oscillation (fmax). Planar Gunn diodes fabricated in the pHEMT wafer, with 1.3 μm anode-to-cathode separation (LAC) presented oscillations at 87.6 GHz with maximum power of oscillation equal to -40 dBm

Mapping gene-by-gene single-nucleotide variation in 8,535 <i>Mycobacterium tuberculosis</i> genomes:a resource to support potential vaccine and drug development

Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosisMycobacterium bovi

Decoupling the Spread of Grasslands from the Evolution of Grazer-type Herbivores in South America

The evolution of high-crowned cheek teeth (hypsodonty) in herbivorous mammals during the late Cenozoic is classically regarded as an adaptive response to the near-global spread of grass-dominated habitats. Precocious hypsodonty in middle Eocene (~38 million years (Myr) ago) faunas from Patagonia, South America, is therefore thought to signal Earth’s first grasslands, 20 million years earlier than elsewhere. Here, using a high-resolution, 43–18 million-year record of plant silica (phytoliths) from Patagonia, we show that although open-habitat grasses existed in southern South America since the middle Eocene (~40 Myr ago), they were minor floral components in overall forested habitats between 40 and 18 Myr ago. Thus, distinctly different, continent-specific environmental conditions (arid grasslands versus ash-laden forests) triggered convergent cheek–tooth evolution in Cenozoic herbivores. Hypsodonty evolution is an important example where the present is an insufficient key to the past, and contextual information from fossils is vital for understanding processes of adaptation