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OSCA/TMEM63s form mechanically activated (MA) ion channels in plants and animals, respectively. OSCAs and related TMEM16s and transmembrane channel-like (TMC) proteins form homodimers with two pores. Here, we uncover an unanticipated monomeric configuration of TMEM63 proteins. Structures of TMEM63A and TMEM63B (referred to as TMEM63s) revealed a single highly restricted pore. Functional analyses demonstrated that TMEM63s are bona fide mechanosensitive ion channels, characterized by small conductance and high thresholds. TMEM63s possess evolutionary variations in the intracellular linker IL2, which mediates dimerization in OSCAs. Replacement of OSCA1.2 IL2 with TMEM63A IL2 or mutations to key variable residues resulted in monomeric OSCA1.2 and MA currents with significantly higher thresholds. Structural analyses revealed substantial conformational differences in the mechano-sensing domain IL2 and gating helix TM6 between TMEM63s and OSCA1.2. Our studies reveal that mechanosensitivity in OSCA/TMEM63 channels is affected by oligomerization and suggest gating mechanisms that may be shared by OSCA/TMEM63, TMEM16, and TMC channels.

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Metaplastic Breast Cancer (MBC) is a rare group of tumors often presenting as triple-negative. MBC accounts for less than 1% of all breast cancers with the spindle cell variant comprising less than 0.5%. While rare, spindle cell carcinoma is the commonest subtype in the western world. It has a more aggressive biological behavior with increased risk of recurrence and death due to disease compared to triple negative breast cancers. There is no treatment guideline for management of MBC due to the rarity of the disease. Instead, treatment is theorized based off success with other types of aggressive breast and metaplastic cancers of different tissue. We present the first known case report of male spindle cell carcinoma of the breast treated with KEYNOTE-522 regimen. Therapy included a first phase with pembrolizumab (dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin and second phase, with four cycles of pembrolizumab with doxorubicin-cyclophosphamide.

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Papillary breast carcinomas comprise <1% of all breast cancers. They are notorious among surgical pathologists for posing diagnostic difficulty, especially with small sample sizes, such as a core-needle biopsy and carry potential for overtreatment. Solid-papillary carcinoma is a subtype of papillary breast carcinomas that affects elderly females and generally has a favorable diagnosis in its in-situ form. This report focuses on the unique and clinically aggressive presentation and treatment of invasive solid-papillary carcinoma that was discovered along the axillary chest wall after an ipsilateral mastectomy for multifocal ductal carcinoma in situ.

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Optical materials engineered to dynamically and selectively manipulate electromagnetic waves are essential to the future of modern optical systems. In this paper, we simulate various metasurface configurations consisting of periodic 1D bars or 2D pillars made of the ternary phase change material Ge2Sb2Te5 (GST). Dynamic switching behavior in reflectance is exploited due to a drastic refractive index change between the crystalline and amorphous states of GST. Selectivity in the reflection and transmission spectra is manipulated by tailoring the geometrical parameters of the metasurface. Due to the immense number of possible metasurface configurations, we train deep neural networks capable of exploring all possible designs within the working parameter space. The data requirements, predictive accuracy, and robustness of these neural networks are benchmarked against a ground truth by varying quality and quantity of training data. After ensuring trustworthy neural network advisory, we identify and validate optimal GST metasurface configurations best suited as dynamic switchable mirrors depending on selected light and manufacturing constraints.

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BACKGROUND: International professional bodies have been quick to disseminate initial guidance documents during the COVID-19 pandemic. In the absence of firm evidence, these have been developed by expert committees, limited in participant number. This study aimed to validate international COVID-19 surgical guidance using a rapid Delphi consensus exercise. METHODS: Delphi statements were directly mapped to guidance from surgical professional bodies in the US and Europe (SAGES/EAES), the UK (Joint RCS), and Australasia (RACS), to validate content against international consensus. Agreement from ≥70% participants was determined as consensus agreement. RESULTS: The Delphi exercise was completed by 339 individuals from 41 countries and 52 statements were mapped to the guidance, 47 (90.4%) reaching consensus agreement. Of these, 27 statements were mapped to SAGES/EAES guidance, 21 to the Joint RCS document, and 33 to the RACS document. Within the SAGES/EAES document, 92.9% of items reached consensus agreement (median 89.0%, range 60.5-99.2%), 90.4% within the Joint RCS document (87.6%, 63.4-97.9%), and 90.9% within the RACS document (85.5%, 18.7-98.8%). Statements lacking consensus related to the surgical approach (open vs. laparoscopic), dual consultant operating, separate instrument decontamination, and stoma formation rather than anastomosis. CONCLUSION: Initial surgical COVID-19 guidance from the US, Europe and Australasia was widely supported by an international expert community, although a small number of contentious areas emerged. These findings should be addressed in future guidance iterations, and should stimulate urgent investigation of non-consensus areas.

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A minority of radiotherapy patients experience adverse reactions as a result of the inevitable irradiation of the surrounding healthy tissue. These reactions range in severity and affect the patient's quality of life, as well as being dose-limiting. If the patients most at risk of toxicity could be identified before radiotherapy, the treatment pathway, radiation dose or fractionation could be altered to reduce toxicity while maintaining efficacy. Previous research is described on how chemotherapy treatments could be improved through the delivery of drugs at specific times of the day ('chronomodulation') based on the circadian rhythm. More recently time-of-day effects have been investigated for radiotherapy, yielding complex results, but with some promise for genetic prediction of the optimal time for treatment. This would allow an almost cost-free modification to treatment that would reduce toxicity. Despite the increasing evidence for 'chronotherapy' for treating cancer, little work has looked into the potential mechanisms underlying the time-of-day effect, which potentially include differences in inflammation, cell cycle or hormones. This overview discusses the main findings from chronotherapy so far and comments on why elucidating the biological mechanisms relating radiotherapy toxicity to the circadian cycle warrants further investigation.

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Mitogenomic trees for Bivalvia have proved problematic in the past, but several highly divergent lineages were missing from these analyses and increased representation of these groups may yet improve resolution. Here, we add seven new sequences from the Anomalodesmata and one unidentified semelid species (Bryopa lata, Euciroa cf. queenslandica, Laternula elliptica, Laternula truncata, Lyonsia norwegica, Myadora brevis, Tropidomya abbreviata, "Abra" sp.). We show that relationships in a mitogenomic tree for the Class are improved by the addition of seven anomalodesmatans from this highly divergent clade, but are still not completely consistent with relationships recovered in studies of nuclear genes. We suggest that some anomalous relationships (for instance the non-monophyly of Bivalvia) may be partially explained by compositional heterogeneity in the mitogenome and suggest that the addition of more taxa may help resolve both this effect and possible instances of long branch attraction. We also identify several curious features about anomalodesmatan mitogenomes. For example, many protein-coding gene boundaries are poorly defined in marine bivalves, but particularly so in anomalodesmatans, primarily due to non-conserved boundary sequences. The use of transcriptomic and genomic data together enabled better definition of gene boundaries, the identification of possible pseudogenes and suggests that most genes are translated monocistronically, which contrasts with many other studies. We also identified a possible case of gene duplication of ND5 in Myadora brevis (Myochamidae). Mitogenome size in the Anomalodesmata ranges from very small compact molecules, with the smallest for Laternula elliptica (Laternulidae) only 14,622bp, to Bryopa lata (Clavagellidae) which is at least 31,969bp long and may be >40,000bp. Finally, sampled species show a high degree of sequence divergence and variable gene order, although intraspecific variation in Laternula elliptica is very low.

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In the metals industry, recycling is commonly included among the most viable options for climate change mitigation, because using secondary (recycled) instead of primary sources in metal production carries both the potential for significant energy savings and for greenhouse gas emissions reduction. Secondary metal production is, however, limited by the relative quantity of scrap available at end-of-life for two reasons: long product lifespans during use delay the availability of the material for reuse and recycling; and end-of-life recycling rates are low, a result of inefficient collection, separation, and processing. For a few metals, additional losses exist in the form of in-use dissipation. The sum of these lost material flows forms the theoretical maximum potential for future efficiency improvements. Based on a dynamic material flow analysis, we have evaluated these factors from an energy perspective for 50 metals and calculated the corresponding greenhouse gas emissions associated with the supply of lost material from primary sources that would otherwise be used to satisfy demand. A use-by-use examination demonstrates the potential emission gains associated with major application sectors. The results show that minimizing in-use dissipation and constraints to metal recycling have the potential to reduce greenhouse gas emissions from the metal industry by about 13-23%, corresponding to 1% of global anthropogenic greenhouse gas emissions.

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The growth in technological innovation that has occurred over the past decades has, in part, been possible because an increasing number of metals of the periodic table are used to perform specialized functions. However, there have been increasing concerns regarding the reliability of supply of some of these metals. A main contributor to these concerns is the fact that many of these metals are recovered only as by-products from a limited number of geopolitically concentrated ore deposits, rendering their supplies unable to respond to rapid changes in demand. Companionality is the degree to which a metal is obtained largely or entirely as a by-product of one or more host metals from geologic ores. The dependence of companion metal availability on the production of the host metals introduces a new facet of supply risk to modern technology. We evaluated companionality for 62 different metals and metalloids, and show that 61% (38 of 62) have companionality greater than 50%. Eighteen of the 38-including such technologically essential elements as germanium, terbium, and dysprosium-are further characterized as having geopolitically concentrated production and extremely low rates of end-of-life recycling. It is this subset of companion metals-vital in current technologies such as electronics, solar energy, medical imaging, energy-efficient lighting, and other state-of-the-art products-that may be at the greatest risk of supply constraints in the coming decades.

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Imbalances between metal supply and demand, real or anticipated, have inspired the concept of metal criticality. We here characterize the criticality of 62 metals and metalloids in a 3D "criticality space" consisting of supply risk, environmental implications, and vulnerability to supply restriction. Contributing factors that lead to extreme values include high geopolitical concentration of primary production, lack of available suitable substitutes, and political instability. The results show that the limitations for many metals important in emerging electronics (e.g., gallium and selenium) are largely those related to supply risk; those of platinum group metals, gold, and mercury, to environmental implications; and steel alloying elements (e.g., chromium and niobium) as well as elements used in high-temperature alloys (e.g., tungsten and molybdenum), to vulnerability to supply restriction. The metals of most concern tend to be those available largely or entirely as byproducts, used in small quantities for highly specialized applications, and possessing no effective substitutes.

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It is indisputable that modern life is enabled by the use of materials in its technologies. Those technologies do many things very well, largely because each material is used for purposes to which it is exquisitely fitted. The result over time has been a steady increase in product performance. We show that this materials complexity has markedly increased in the past half-century and that elemental life cycle analyses characterize rates of recycling and loss. A further concern is that of possible scarcity of some of the elements as their use increases. Should materials availability constraints occur, the use of substitute materials comes to mind. We studied substitution potential by generating a comprehensive summary of potential substitutes for 62 different metals in all their major uses and of the performance of the substitutes in those applications. As we show herein, for a dozen different metals, the potential substitutes for their major uses are either inadequate or appear not to exist at all. Further, for not 1 of the 62 metals are exemplary substitutes available for all major uses. This situation largely decouples materials substitution from price, thereby forcing material design changes to be primarily transformative rather than incremental. As wealth and population increase worldwide in the next few decades, scientists will be increasingly challenged to maintain and improve product utility by designing new and better materials, but doing so under potential constraints in resource availability.

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Because modern technology depends on reliable supplies of a wide variety of materials and because of increasing concern about those supplies, a comprehensive methodology was created to quantify the degree of criticality of the metals of the periodic table. In this paper, we apply this methodology to iron and several of its main alloying elements (i.e., vanadium, chromium, manganese, and niobium). These elements represent the basic metals of any industrial society and are vital for national security and economic well-being. Assessments relating to the dimensions of criticality - supply risk, vulnerability to supply restriction, and environmental implications - for 2008 are made on the global level and for the United States. Evaluations of each of the multiple indicators are presented, with aggregate results plotted in "criticality space", together with Monte Carlo simulation-derived "uncertainty cloud" estimates. Iron has the lowest supply risk, primarily because of its widespread geological occurrence. Vanadium displays the highest cradle-to-gate environmental implications, followed by niobium, chromium, manganese, and iron. Chromium and manganese, both essential in steel making, display the highest vulnerability to supply restriction, largely because substitution or substitution at equal performance is not possible for all end-uses. From a comprehensive perspective, we regard the overall criticality as low for iron and modest for the alloying elements we evaluated.

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Metals are used in a variety of ways, many of which lead to dissipative releases to the environment. Such releases are relevant from both a resource use and an environmental impact perspective. We present a historical analysis of copper dissipative releases in the United States from 1975 to 2000. We situate all dissipative releases in copper's life cycle and introduce a conceptual framework by which copper dissipative releases may be categorized in terms of intentionality of use and release. We interpret our results in the context of larger trends in production and consumption and government policies that have served as drivers of intentional copper releases from the relevant sources. Intentional copper releases are found to be both significant in quantity and highly variable. In 1975, for example, the largest source of intentional releases was from the application of copper-based pesticides, and this decreased more than 50% over the next 25 years; all other sources of intentional releases increased during that period. Overall, intentional copper releases decreased by approximately 15% from 1975 to 2000. Intentional uses that are unintentionally released such as copper from roofing, increased by the same percentage. Trace contaminant sources such as fossil fuel combustion, i.e., sources where both the use and the release are unintended, increased by nearly 50%. Intentional dissipative uses are equivalent to 60% of unintentional copper dissipative releases and more than five times that from trace sources. Dissipative copper releases are revealed to be modest when compared to bulk copper flows in the economy, and we introduce a metric, the dissipation index, which may be considered an economy-wide measure of resource efficiency for a particular substance. We assess the importance of dissipative releases in the calculation of recycling rates, concluding that the inclusion of dissipation in recycling rate calculations has a small, but discernible, influence, and should be included in such calculations.

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Because modern technology depends on reliable supplies of a wide variety of materials, and because of increasing concern about those supplies, a comprehensive methodology has been created to quantify the degree of criticality of the metals of the periodic table. In this paper, we apply this methodology to the elements of the geological copper family: Cu, As, Se, Ag, Te, and Au. These elements are technologically important, but show a substantial variation in different factors relating to their supply risk, vulnerability to supply restriction, and environmental implications. Assessments are made on corporate, national, and global levels for year 2008. Evaluations of each of the multiple indicators are presented and the results plotted in "criticality space", together with Monte Carlo simulation-derived "uncertainty cloud" estimates for each of the aggregated evaluations. For supply risk over both the medium term and long term, As is the highest risk of the six metals, with Se and Ag nearly as high. Gold has the most severe environmental implications ranking. Vulnerability to supply restriction (VSR) at the corporate level for an invented solar cell manufacturing firm shows Se, Te, and Cu as approximately equal, Cu has the highest VSR at the national level, and Cu and Au have the highest VSRs at the global level. Criticality vector magnitudes are greatest at the global level for As (and then Au and Ag) and at the national level for As and Au; at the corporate level, Se is highest with Te and Cu lower. An extension of this work, now in progress, will provide criticality estimates for several different development scenarios for the period 2010-2050.

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Cobalt is a vital element in many technological applications, which, together with its increasing end-use in batteries, makes it important to quantify its cycle of use. We have done so for the planet as a whole and for the three principal cobalt-using countries - China, Japan, and the United States - for 2005. Together, China, Japan, and the United States accounted for approximately 65% of the cobalt fabricated and manufactured into end-use products (a total of 37 Gg Co). A time residence model allowed calculations of in-use stock accumulation and recycled and landfilled flows. China had the largest accumulation of in-use stock at some 4.3 Gg Co, over half of which was comprised of consumer battery stock. More than half of the stock accumulation in the United States was estimated to be in aircraft, rocket, and gas turbine engines, with a total in-use stock accumulation of approximately 3 Gg Co. The largest amounts of cobalt landfilled in China, the United States, and the planet were from the "chemical and other uses" category, and Japan's largest landfilled flow was in consumer batteries.

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Peliosis is a rare condition of multiple blood-filled cysts within the parenchyma of a solid organ. Splenic peliosis is an extremely rare entity, although there is often a risk of spontaneous rupture. We present a case where our otherwise fairly healthy patient presented us with a diagnosis dilemma and was then found to have splenic peliosis histologically post-splenectomy. We discuss the current available literature and emphasise the importance of awareness of such a condition.

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Tungsten's unique properties, such as its high density and melting point, are manifest in a variety of technological applications, and attention has recently centered upon the health and environmental effects of tungsten. Utilizing material flow analysis, the amounts of tungsten produced, fabricated and manufactured, entering use, and entering waste management in the United States from 1975-2000 were determined, with the inclusion of net trade, and with attention paid to the way that tungsten partitions into in-use reservoirs and the quantities of tungsten that enter the environment as a result of anthropogenic processes. The results from two approaches are presented: the first and typical, approach for historical material flow analysis studies, whereby tungsten use in products over time was approximated using end-use sectors used by the United States Bureau of Mines and the United States Geological Survey (the "end-use sector model") and a second, more detailed approach whereby the historical pattern of end-use products was determined (the "finished product model"). These models represent the first life cycle of tungsten that takes into account both finished product trade and varying residence times for products entering use. For the cumulative time period of 1975-2000, approximately 60% of the supply to fabrication and manufacturing processes in the United States consisted of imports. The tungsten embodied in products used in applications other than transportation is discarded (i.e., enters the waste stream, which encompasses both material that is eventually landfilled and that is eventually recycled) in the same year it enters service. Of its items entering end-of-life for the cumulative time period, 50-70% of tungsten is estimated to be landfilled. In both models, the largest flows of tungsten to the environment were estimated to originate from post-consumer discards. Approximately 8-17 times as much tungsten entered landfills than was estimated to be generated as waste from fabrication and manufacturing processes; for tailings, these ratios are even greater. Tungsten is an example of a critical mineral resource where the majority of the United States' supply comes from imports, it has vital uses in manufacturing, and it has a high rate of loss at end-of-life.

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BACKGROUND AND PURPOSE: Several studies using radioligand binding assays, have shown that measurement of thermodynamic parameters can allow discrimination of agonists and antagonists (Weiland et al., 1979; Borea et al., 1996a). Here we investigate whether agonists and antagonists can be thermodynamically discriminated at CCK(2) receptors in rat cerebral cortex. EXPERIMENTAL APPROACH: The pK(L) of [(3)H]-JB93182 in rat cerebral cortex membranes was determined at 4, 12, 21 and 37 degrees C in 50 mM Tris-HCl buffer (buffer B pH 6.96; containing 0.089 mM bacitracin). pK(I) values of ligands of diverse chemical structure and with differing intrinsic activity (alpha), as defined by the lumen-perfused rat and mouse stomach bioassays, were determined in buffer B at 4, 12, 21 and 37 degrees C. KEY RESULTS: [(3)H]-JB93182 labelled a homogeneous population of receptors in rat cerebral cortex at 4, 12, 21 and 37 degrees C and the pK(L) and B(max) were not altered by incubation temperature. [(3)H]-JB93182 binding reached equilibrium after 10, 50, 90 and 220 min at 37, 21, 12 and 4 degrees C, respectively. pK(I) values for R-L-365,260, R-L-740,093, YM220, PD134,308 and JB95008 were higher at 4 degrees C than at 37 degrees C. There was no effect of temperature on pK(I) values for pentagastrin, CCK-8S, S-L-365,260, YM022, PD140,376 and JB93242. CONCLUSIONS AND IMPLICATIONS: CCK(2) receptor agonists and antagonists at rat CCK(2) receptors cannot be discriminated by thermodynamic analysis using [(3)H]-JB93182 as the radioligand.

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