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Proline is an anomalous amino acid. Its nitrogen atom is covalently locked within a ring, thus it is the only proteinogenic amino acid with a constrained phi angle. Sequences of three consecutive prolines can fold into polyproline helices, structures that join alpha helices and beta pleats as architectural motifs in protein configuration. Triproline helices are participants in protein-protein signaling interactions. Longer spans of repeat prolines also occur, containing as many as 27 consecutive proline residues. Little is known about the frequency, positioning, and functional significance of these proline sequences. Therefore we have undertaken a systematic bioinformatics study of proline residues in proteins. We analyzed the distribution and frequency of 687,434 proline residues among 18,666 human proteins, identifying single residues, dimers, trimers, and longer repeats. Proline accounts for 6.3% of the 10,882,808 protein amino acids. Of all proline residues, 4.4% are in trimers or longer spans. We detected patterns that influence function based on proline location, spacing, and concentration. We propose a classification based on proline-rich, polyproline-rich, and proline-poor status. Whereas singlet proline residues are often found in proteins that display recurring architectural patterns, trimers or longer proline sequences tend be associated with the absence of repetitive structural motifs. Spans of 6 or more are associated with DNA/RNA processing, actin, and developmental processes. We also suggest a role for proline in Kruppel-type zinc finger protein control of DNA expression, and in the nucleation and translocation of actin by the formin complex.

SummaryBreast cancer brain metastases are an increasing clinical problem. Studies have shown that brain metastases from breast cancer have a distinct genomic landscape to that of the primary tumour, including the presence of mutations that are absent in the primary breast tumour. In this Review, we aim to review and evaluate genomic sequencing data for breast cancer brain metastases by searching PubMed, Embase, and Scopus for relevant articles published in English between database inception and May 30, 2020. Extracted information includes data for mutations, receptor status (eg, immunohistochemistry and Prediction Analysis of Microarray 50 [PAM50]), and copy number alterations from published manuscripts and supplementary materials. Of the 431 articles returned by the database search, 13 (3%) breast cancer brain metastases sequencing studies, comprising 164 patients with sequenced brain metastases, met all our inclusion criteria. We identified 268 mutated genes that were present in two or more breast cancer brain metastases samples. Of these 268 genes, 22 (8%) were mutated in five or more patients and pathway enrichment analysis showed their involvement in breast cancer-related signalling pathways, regulation of gene transcription, cell cycle, and DNA repair. Actionability analysis using the Drug Gene Interaction Database revealed that 15 (68%) of these 22 genes are actionable drug targets. In addition, immunohistochemistry and PAM50 data showed receptor discordancy between primary breast cancers and their paired brain metastases. This systematic review provides a detailed overview of the most commonly mutated genes identified in samples of breast cancer brain metastases and their clinical relevance. These data highlight the differences between primary breast cancers and brain metastases and the importance of acquiring and analysing brain metastasis samples for further study.

For decades, a wide variety of products have benefitted from the use of flexible PVC, ranging from healthcare to cable to packaging & household items. The uniqueness of PVC rises from its growth as polymer from monomers and the final structure. Due to the presence of chlorine atoms, PVC is inherently flame retardant, but it cannot always meet all fire safety requirements and maintain a needed balance of properties. One approach to meet this balance of properties is to incorporate flame retardant functionality directly into the plasticizer that is added to PVC. However, the toxicity of current plasticizers has motivated a focus on bio-based plasticizers. In flexible PVC products where flame retardancy is necessary, reports have begun to appear involving bio-plasticizers where flame retardant functionality is included. This focused review presents current research in the flexible PVC field emphasizing development of bio-plasticizers and flame retardants, and an analysis of examples of bio-plasticizers, chemical structures, and effects on flame retardancy. The review concludes with a perspective on the main challenges and future research directions for this exciting fire research field.

Macrophages play a crucial rule in orchestrating immune responses against pathogens and foreign materials. Macrophages have remarkable plasticity in response to environmental cues and are able to acquire a spectrum of activation status, best exemplified by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at the two ends of the spectrum. Characterisation of M1 and M2 subsets is usually carried out by quantification of multiple cell surface markers, transcription factors and cytokine profiles. These approaches are time-consuming, require large numbers of cells and are resource intensive. In this study, we used machine learning algorithms to develop a simple and fast imaging-based approach that enables automated identification of different macrophage functional phenotypes using their cell size and morphology. Fluorescent microscopy was used to assess cell morphology of different cell types which were stained for nucleus and actin distribution using DAPI and phalloidin respectively. By only analysing their morphology we were able to identify M1 and M2 phenotypes effectively and could distinguish them from naïve macrophages and monocytes with an average accuracy of 90%. Thus we suggest high-content and automated image analysis can be used for fast phenotyping of functionally diverse cell populations with reasonable accuracy and without the need for using multiple markers.

The high spatial resolution of secondary ion mass spectrometry and the high resolving power of the Orbitrap mass spectrometer are combined in a single imaging platform, the 3D OrbiSIMS. The instrument's capabilities for resolving lipids and neurotransmitters in the brain with subcellular spatial resolution, and a drug in a single cell in three dimensions is demonstrated. We report the development of a 3D OrbiSIMS instrument for label-free biomedical imaging. It combines the high spatial resolution of secondary ion mass spectrometry (SIMS; under 200 nm for inorganic species and under 2 μm for biomolecules) with the high mass-resolving power of an Orbitrap (>240,000 at m/z 200). This allows exogenous and endogenous metabolites to be visualized in 3D with subcellular resolution. We imaged the distribution of neurotransmitters—gamma-aminobutyric acid, dopamine and serotonin—with high spectroscopic confidence in the mouse hippocampus. We also putatively annotated and mapped the subcellular localization of 29 sulfoglycosphingolipids and 45 glycerophospholipids, and we confirmed lipid identities with tandem mass spectrometry. We demonstrated single-cell metabolomic profiling using rat alveolar macrophage cells incubated with different concentrations of the drug amiodarone, and we observed that the upregulation of phospholipid species and cholesterol is correlated with the accumulation of amiodarone.

Label-free protein characterization at surfaces is commonly achieved using digestion and/or matrix application prior to mass spectrometry. We report the assignment of undigested proteins at surfaces in situ using secondary ion mass spectrometry (SIMS). Ballistic fragmentation of proteins induced by a gas cluster ion beam (GCIB) leads to peptide cleavage producing fragments for subsequent Orbitrap TM analysis. In this work we annotate 16 example proteins (up to 272 kDa) by de novo peptide sequencing and illustrate the advantages of this approach by characterizing a protein monolayer biochip and the depth distribution of proteins in human skin. Label-free protein characterization at surfaces requires digestion or matrix application prior to mass spectrometry. Here, the authors report the assignment of undigested proteins at surfaces by de novo sequencing and apply the methodology to a protein monolayer biochip and for in situ depth profiling of proteins through human skin.

This book focuses on non-halogenated flame retardants with an emphasis on practical and applied issues, and builds upon the 1st edition, but is not just a re-do/re-edit of 1st edition content.  While non-halogenated flame retardants have not greatly changed since the 1st edition was published in 2014, there have been enough advances and changes to merit a 2nd edition.  The book would include chapters on regulation and drivers for non-halogenated flame retardants, specific chapters on each of the major classes of flame retardants, and would include some newer technologies / niche non-halogenated solutions which are either starting to enter the market (coatings / bio-derived flame retardants) or are at least being studied with enough detail to bring to the attention of the reader.  As with the 1st edition, the 2nd edition still takes a practical approach to addressing the narrow subject of non-halogenated flame retardancy.  This includes more emphasis on flame retardant selection for specific plastics, practical considerations in flame retardant material design, and what the strengths and limits of these various technologies are.  Previous flame retardant material science books have covered non-halogenated flame retardants, but they focus more on how they work rather than how to use them.  This book focuses more on the practical uses, hence the title of the book \"Handbook\", which should make it of good use to industrial chemists and material scientists.

The Covid-19 pandemic has brought bioethics back to five topics—justice, autonomy, expert authority, religion, and judicial decisions—that were central during its formative period but has cast a new light on each, while also tangling public health policy in the current, rather radical, reshaping of the role of organized religion in society.

Transcranial alternating current stimulation (tACS) modulates endogenous neural oscillations in healthy human participants by the application of a low-amplitude electrical current with a periodic stimulation waveform. Yet, it is unclear if tACS can modulate and restore neural oscillations that are reduced in patients with psychiatric illnesses such as schizophrenia. Here, we asked if tACS modulates network oscillations in schizophrenia. We performed a randomized, double-blind, sham-controlled clinical trial to contrast tACS with transcranial direct current stimulation (tDCS) and sham stimulation in 22 schizophrenia patients with auditory hallucinations. We used high-density electroencephalography to investigate if a five-day, twice-daily 10Hz-tACS protocol enhances alpha oscillations and modulates network dynamics that are reduced in schizophrenia. We found that 10Hz-tACS enhanced alpha oscillations and modulated functional connectivity in the alpha frequency band. In addition, 10Hz-tACS enhanced the 40Hz auditory steady-state response (ASSR), which is reduced in patients with schizophrenia. Importantly, clinical improvement of auditory hallucinations correlated with enhancement of alpha oscillations and the 40Hz-ASSR. Together, our findings suggest that tACS has potential as a network-level approach to modulate reduced neural oscillations related to clinical symptoms in patients with schizophrenia.

Insecticides are broadly applied in many urban areas of the western United States to control mosquito populations and reduce the prevalence of diseases such as West Nile and Zika Virus. We assessed the extent to which incidental exposure to the insecticide Permethrin affected drifting and benthic invertebrates in Spring Creek, Laramie, WY, USA. We collected drift samples before, immediately after (~ 3–6 h), and 1 day after (~ 28 h) insecticide application. We collected benthic invertebrates with a Hess sampler twice before and twice after spraying began. We measured an 11 × increase in the density of drifting aquatic insects immediately after pesticide application. Additionally, we observed an increase in drifting aquatic invertebrates 2.25 km downstream from treatment. A decrease in the biomass of benthic invertebrates and an increase in taxa richness at the end of the summer suggested that invertebrates are colonizing the stream but may be unable to persist. Fewer aquatic invertebrates in the stream may have cascading effects on the ecosystem by altering resources available to fish and riparian insectivores (e.g., bats, spiders, and amphibians). Understanding the unintended ecological impacts of current pest control practices could lead to more effective and less detrimental management strategies.