The pace of past climate change vs. potential bird distributions and land use in the United States.
Climate change may drastically alter patterns of species distributions and richness, but predicting future species patterns in occurrence is challenging. Significant shifts in distributions have already been observed, and understanding these recent changes can improve our understanding of potential future changes. We assessed how past climate change affected potential breeding distributions for landbird species in the conterminous United States. We quantified the bioclimatic velocity of potential breeding distributions, that is, the pace and direction of change for each species' suitable climate space over the past 60 years. We found that potential breeding distributions for landbirds have shifted substantially with an average velocity of 1.27 km yr(-1) , about double the pace of prior distribution shift estimates across terrestrial systems globally (0.61 km yr(-1) ). The direction of shifts was not uniform. The majority of species' distributions shifted west, northwest, and north. Multidirectional shifts suggest that changes in climate conditions beyond mean temperature were influencing distributional changes. Indeed, precipitation variables that were proxies for extreme conditions were important variables across all models. There were winners and losers in terms of the area of distributions; many species experienced contractions along west and east distribution edges, and expansions along northern distribution edges. Changes were also reflected in the potential species richness, with some regions potentially gaining species (Midwest, East) and other areas potentially losing species (Southwest). However, the degree to which changes in potential breeding distributions are manifested in actual species richness depends on landcover. Areas that have become increasingly suitable for breeding birds due to changing climate are often those attractive to humans for agriculture and development. This suggests that many areas might have supported more breeding bird species had the landscape not been altered. Our study illustrates that climate change is not only a future threat, but something birds are already experiencing.


The mae1 gene of Schizosaccharomyces pombe encodes a permease for malate and other C4 dicarboxylic acids.
The mae1 gene of the yeast Schizosaccharomyces pombe was identified on the basis of its ability to complement a mutant defective in the transport of malic acid. Analysis of the DNA sequence revealed an open reading frame of 1314 base pairs, encoding a polypeptide of 438 amino acids with a predicted molecular weight of 49 kDa. A hydropathy profile of the predicted amino acid sequence revealed a protein with ten membrane-spanning or associated domains and hydrophilic N- and C- termini. The predicted secondary structure of the protein in similar to models proposed for other integral membrane proteins from both prokaryotes and eukaryotes. The S. pombe mae1 gene encodes a single mRNA of 1.5 kb. The mea1 gene is expressed constitutively and is not subject to catabolite repression as was previously reported for the malate permease systems of Candida utilis and Hansenula anomala. The mae1 gene was mapped 2842 bp 5' to the MFml gene on chromosome I. Transport assays revealed that the mae1 gene encodes a permease involved in the uptake of L-malate, succinate and malonic acid.


Rod packings and metal-organic frameworks constructed from rod-shaped secondary building units.
The principal structure possibilities for packing infinite rod-shaped building blocks are described. Some basic nets derived from linking simple rods (helices and ladders) are then enumerated. We demonstrate the usefulness of the concept of rod secondary building units in the design and synthesis of metal-organic frameworks (MOFs). Accordingly, we present the preparation, characterization, and crystal structures of 14 new MOFs (named MOF-69A-C and MOF-70-80) of 12 different structure types, belonging to rod packing motifs, and show how their structures are related to basic nets. The MOFs reported herein are of polytopic carboxylates and contain one of Zn, Pb, Co, Cd, Mn, or Tb. The inclusion properties of the most open members are presented as evidence that MOF structures with rod building blocks can indeed be designed to have permanent porosity and rigid architectures.


Prelabour rupture of membranes: overview of diagnostic methods.
To evaluate diagnostic accuracy studies for rupture of the fetal membranes (ROM). Sample sizes of recent studies are small and studies used different 'silver standard' definitions for ROM. Therefore, reported results should be interpreted with caution. Over the review period the focus of diagnostic studies has been on two bedside test strips: insulin-like growth factor-binding protein-1 (IGFBP-1) and placental α microglobulin-1 (PAMG-1). Bedside tests improve the confidence of the clinician about their diagnosis. Compared to nitrazine or ferning test alone, IGFBP-1 and PAMG-1 are more accurate. However, compared to the conventional testing (combination of history, ferning, nitrazine, speculum and ultrasound) no statistical difference in accuracy was found. In-vitro PAMG-1 is shown to be superior to IGFPB-1. Furthermore, soluble intercellular adhesion molecule-1 and Axl receptor tyrosine kinase (Axl) seem to be promising new specific biomarkers for diagnosing ROM. IGFBP-1 and PAMG-1 are the most commonly used bedside tests for diagnosing ROM. Both tests seem to be sensitive and specific, however, evidence is lacking especially in equivocal cases and comparative studies against the real gold standard (amnio-dye) have still not been published. Further effectiveness research is needed before tests can be applied in practice.


Evaluation of subcortical grey matter abnormalities in patients with MRI-negative cortical epilepsy determined through structural and tensor magnetic resonance imaging.
Although many studies have found abnormalities in subcortical grey matter (GM) in patients with temporal lobe epilepsy or generalised epilepsies, few studies have examined subcortical GM in focal neocortical seizures. Using structural and tensor magnetic resonance imaging (MRI), we evaluated subcortical GM from patients with extratemporal lobe epilepsy without visible lesion on MRI. Our aims were to determine whether there are structural abnormalities in these patients and to correlate the extent of any observed structural changes with clinical characteristics of disease in these patients. Twenty-four people with epilepsy and 29 age-matched normal subjects were imaged with high-resolution structural and diffusion tensor MR scans. The patients were characterised clinically by normal brain MRI scans and seizures that originated in the neocortex and evolved to secondarily generalised convulsions. We first used whole brain voxel-based morphometry (VBM) to detect density changes in subcortical GM. Volumetric data, values of mean diffusivity (MD) and fractional anisotropy (FA) for seven subcortical GM structures (hippocampus, caudate nucleus, putamen, globus pallidus, nucleus accumbens, thalamus and amygdala) were obtained using a model-based segmentation and registration tool. Differences in the volumes and diffusion parameters between patients and controls and correlations with the early onset and progression of epilepsy were estimated. Reduced volumes and altered diffusion parameters of subcortical GM were universally observed in patients in the subcortical regions studied. In the patient-control group comparison of VBM, the right putamen, bilateral nucleus accumbens and right caudate nucleus of epileptic patients exhibited a significantly decreased density Segregated volumetry and diffusion assessment of subcortical GM showed apparent atrophy of the left caudate nucleus, left amygdala and right putamen; reduced FA values for the bilateral nucleus accumbens; and elevated MD values for the left thalamus, right hippocampus and right globus pallidus A decreased volume of the nucleus accumbens consistently related to an early onset of disease. The duration of disease contributed to the shrinkage of the left thalamus. Patients with neocortical seizures and secondary generalisation had smaller volumes and microstructural anomalies in subcortical GM regions. Subcortical GM atrophy is relevant to the early onset and progression of epilepsy.


"It's really no more difficult than putting on fluoride varnish": a qualitative exploration of dental professionals' views of silver diamine fluoride for the management of carious lesions in children.
Despite evidence that Silver Diamine Fluoride (SDF) can be effective in managing carious lesions in primary teeth, the use of SDF in the UK remains limited. This study explored dental professionals' views and experiences of using SDF for managing carious lesions in children. In addition, it explored what they perceived to be the advantages, disadvantages, barriers and enablers to the use of SDF in practice. Fifteen semi-structured face-to-face or over-the-phone interviews were conducted with 14 dental professionals from NHS Tayside and NHS Grampian in Scotland. Interviews were transcribed verbatim, coded and analysed using a thematic approach. Thirteen of 14 dental professionals interviewed were familiar with, or had some existing knowledge of, SDF. Four had used it to treat patients. The majority of participants thought that the main advantage of SDF was that it required minimal patient cooperation. SDF was also perceived as a simple, pain-free and non-invasive treatment approach that could help acclimatise children to the dental environment. However, SDF-induced black staining of arrested carious lesions was most commonly reported as the main disadvantage and greatest barrier to using it in practice. Participants believed that this discolouration would concern some parents who may fear that the black appearance may instigate bullying at school and that others may judge parents as neglecting their child's oral health. Participants thought that education of clinicians about SDF use and information sheets for parents would enhance the uptake of SDF in dental practice. Participants believed that younger children might not be as bothered by the discolouration as older ones and they anticipated greater acceptance of SDF for posterior primary teeth by both parents and children. Dental professionals were aware that SDF can be used for arresting carious lesions. They pointed out that the staining effect of carious lesions is a major disadvantage and had preconceived ideas that this could be a barrier for many parents. Participants considered the application process to be simple and non-invasive and requires a minimum level of child cooperation. Participants appreciated the potential of SDF in paediatric dentistry and suggested actions that could help overcome the barriers they highlighted.


The response to exercise with constant energy intake in identical twins.
Seven pairs of young adult male identical twins completed a negative energy balance protocol during which they exercised on cycle ergometers twice a day, 9 out of 10 days, over a period of 93 days while being kept on a constant daily energy and nutrient intake. The total energy deficit caused by exercise above the estimated energy cost of body weight maintenance reached 244 +/- 9.8 MJ (Mean +/- SEM). Baseline energy intake was estimated over a period of 17 days preceding the negative energy balance protocol. Mean body weight loss was 5.0 kg (SEM = 0.6) (p < 0.001) and it was entirely accounted for by the loss of fat mass (p < 0.001). Fat-free mass was unchanged. Body energy losses reached 191 MJ (SEM = 24) (p < 0.001) which represented about 78% of the estimated energy deficit. Subcutaneous fat loss was slightly more pronounced on the trunk than on the limbs as estimated from skinfolds, circumferences, and computed tomograply (CT). The reduction in CT-assessed abdominal visceral fat was quite striking, from 81 cm2 (SEM = 5) to 52 cm2 (SEM = 6) (p < 0.001). At the same submaximal power output level, subjects oxidized more lipids than carbohydrates after the program as indicated by the changes in the respiratory exchange ratio (p < or = 0.05). Intrapair resemblance was observed for the changes in body weight (p < 0.05), fat mass (P < 0.01), percent fat (p < 0.01), body energy content (p < 0.01), sum of 10 skinfolds (p < 0.01), abdominal visceral fat (p < 0.01), fasting plasma triglycerides (p < 0.05) and cholesterol (p < 0.05), maximal oxygen uptake (p < 0.05), and respiratory exchange ratio during submaximal work (p < 0.01). We conclude that even though there were large individual differences in response to the negative energy balance and exercise protocol, subjects with the same genotype were more alike in responses than subjects with different genotypes particularly for body fat, body energy, and abdominal visceral fat changes. High lipid oxidizers and low lipid oxidizers during submaximal exercise were also seen despite the fact that all subjects had experienced the same exercise and nutritional conditions for about three months.


Modulation of the coffee-ring effect in particle/surfactant mixtures: the importance of particle-interface interactions.
We study the effect of surfactants on the deposits formed after the evaporation of colloidal suspension drops, at initial concentrations lower than the critical micellar concentrations, for various particle/surfactant mixtures. We show that the surfactant-mediated interactions between particles and the liquid-gas (LG) and liquid-solid (LS) interfaces, rather than the flow patterns, primarily define the morphology of the dry deposit in a robust and reproducible manner. For like-charged particle/surfactant mixtures, most of the particles form a ring-shaped deposit (according to the so-called "Coffee-Ring Effect"), but some particles can also be deposited inside the ring in a way that is modulated by electrostatic interactions between the particles and the LS interface. For oppositely charged systems, surfactant adsorption to the particle surface strongly affects particle-LG interface interactions, which in turn control the deposition pattern. For low surfactant concentrations, coffee-rings are systematically observed. For intermediate concentrations, the charge of surfactant-decorated particles becomes nearly neutral, and their hydrophobicity is enhanced, which promotes particle trapping at the LG interface. A particle skin is formed and its deposition upon drying leads to homogeneous disk-like patterns. For high surfactant concentrations, particle charge is reversed, and coffee-rings are observed again. Notably, this ring-disk-ring evolution of the deposition behavior as a function of surfactant concentration is observed in a variety of mixtures, regardless of particle absolute charge and surface chemistry as well as of surfactant charge and hydrophobicity. Its apparent universal character makes it a promising strategy for a robust control of particle deposition from evaporating drops.


First report of Powdery Mildew Caused by Golovinomyces ambrosiae on Cannabis sativa in Oregon.
Oregon is the second largest producer of hemp in the United States with 25,900 ha of hemp licensed to growers in 2019, a nearly six-fold increase over the previous year (Perkowski 2019, Capital Press). Industrial hemp has a wide range of uses including textiles to nutritional supplements; in Oregon, hemp has become one of the most economically promising crops and is mainly cultivated for cannabidiol (CBD) production. Between 2018 and 2019, multiple independent greenhouse growers in western Oregon reported powdery mildew-like signs and symptoms on leaves and buds of several Cannabis sativa cultivars, including 'Cherry Wine'. Signs of the disease started as small, white, powdery patches, typically on the adaxial sides of leaves, and progressed to coalescent colonies on leaves, stems, and buds. Fungi present on diseased tissues had unbranched hyaline conidiophores that measured 140 to 250 µm and grew erect from caulicolous and amphigenous mycelium (n = 15). Foot cells were cylindrical, often tapered at one or both ends, and measured 80 to 117 × 9.5 to 11.9 µm (n = 15). Conidia were catenescent, hyaline, ellipsoidal to barrel-shaped, lacked fibrosin bodies, and measured 24 to 34 × 12 to 18 µm (n = 50). No chasmothecia were observed. Morphological observations overlapped with several Golovinomyces spp. Including G. ambrosiae, G. cichoracearum, and G. spadiceus (Braun and Cook 2012). Identification was confirmed by bidirectional sequencing and phylogenetic analysis of 1,457 nucleotides from the concatenated internal transcribed spacer (ITS), 28S large ribosomal subunit, and beta-tubulin (TUB2) regions of two isolates using primer pairs ITS1/ITS4 and NL1/LR5, and TubF1/TubR1 respectively (Mori et al. 2000, Qiu et al. 2020, Vilgalys and Hester 1990, White et al. 1990; GenBank Acc. No.: MW248121 to MW248124, MW265971 to MW265972). The Oregon hemp isolates grouped (bootstrap value = 100) in a monophyletic clade with G. ambrosiae accessions from Qiu et al. (2020). Pathogenicity was confirmed by transferring conidia by leaf rub inoculation onto 2-to 4-week-old 'Cherry Wine' potted plants and incubated outdoors at 12 to 22°C. Control plants were mock-inoculated using healthy leaves. Powdery mildew symptoms developed on inoculated plants approximately 14 to 21 days later; control plants were asymptomatic. Identification was confirmed by morphological characterization and sequencing using the aforementioned primers. The hemp isolates were also able to infect detached leaves of Humulus lupulus 'Symphony' via similar inoculations; however, colony development on 'Symphony' was slow and sporulation sparse as was reported by Weldon et al. (2020). Golovinomyces spp. have also been reported on hemp in Kentucky (Szarka et al. 2019), Ohio (Farinas and Peduto Hand 2020), and New York (Weldon et al. 2020). Although reported as G. spadiceus, these reports are also likely G. ambrosiae according to new taxonomic revision of the genus (Qiu et al. 2020). This is the first known report of Golovinomyces ambrosiae causing powdery mildew on hemp in Oregon (OSC 171893). While powdery mildew on hemp currently appears most severe in protected cultivation, rapid expansion of hemp cultivation and introduction of new CBD varieties throughout Oregon could lead to increased powdery mildew risk in outdoor cultivation.


Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death.
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and an aggressive malignancy. Galectin-3 (gal-3), the only antiapoptotic member of the galectin family, is overexpressed in DLBCL. While gal-3 can localize to intracellular sites, gal-3 is secreted by DLBCL cells and binds back to the cell surface in a carbohydrate-dependent manner. The major counterreceptor for gal-3 on DLBCL cells was identified as the transmembrane tyrosine phosphatase CD45. Removal of cell-surface gal-3 from CD45 with the polyvalent glycan inhibitor GCS-100 rendered DLBCL cells susceptible to chemotherapeutic agents. Binding of gal-3 to CD45 modulated tyrosine phosphatase activity; removal of endogenous cell-surface gal-3 from CD45 with GCS-100 increased phosphatase activity, while addition of exogenous gal-3 reduced phosphatase activity. Moreover, the increased susceptibility of DLBCL cells to chemotherapeutic agents after removal of gal-3 by GCS-100 required CD45 phosphatase activity. Gal-3 binding to a subset of highly glycosylated CD45 glycoforms was regulated by the C2GnT-1 glycosyltransferase, indicating that specific glycosylation of CD45 is important for regulation of gal-3-mediated signaling. These data identify a novel role for cell-surface gal-3 and CD45 in DLBCL survival and suggest novel therapeutic targets to sensitize DLBCL cells to death.


Microscale imaging of cilia-driven fluid flow.
Cilia-driven fluid flow is important for multiple processes in the body, including respiratory mucus clearance, gamete transport in the oviduct, right-left patterning in the embryonic node, and cerebrospinal fluid circulation. Multiple imaging techniques have been applied toward quantifying ciliary flow. Here, we review common velocimetry methods of quantifying fluid flow. We then discuss four important optical modalities, including light microscopy, epifluorescence, confocal microscopy, and optical coherence tomography, that have been used to investigate cilia-driven flow.


Unraveling the Receptor-Ligand Interactions between Bladder Cancer Cells and the Endothelium Using AFM.
Adhesion of cancer cells to endothelial cells is a key step in cancer metastasis; therefore, identifying the key molecules involved during this process promises to aid in efforts to block the metastatic cascade. We have previously shown that intercellular adhesion molecule-1 (ICAM-1) expressed by endothelial cells is involved in the interactions of bladder cancer cells (BCs) with the endothelium. However, the ICAM-1 ligands have never been investigated. In this study, we combined adhesion assays and atomic force microscopy (AFM) to identify the ligands involved and to quantify the forces relevant in such interactions. We report the expression of MUC1 and CD43 on BCs, and demonstrate that these ligands interact with ICAM-1 to mediate cancer cell-endothelial cell adhesion in the case of the more invasive BCs. This was achieved with the use of adhesion assays, which showed a strong decrease in the attachment of BCs to endothelial cells when MUC1 and CD43 were blocked by antibodies. In addition, AFM measurements showed a similar decrease, by up to 70%, in the number of rupture events that occurred when MUC1 and CD43 were blocked. When we applied a Gaussian mixture model to the AFM data, we observed a distinct force range for receptor-ligand bonds, which allowed us to precisely identify the interactions of ICAM-1 with MUC1 or CD43. Furthermore, a detailed analysis of the rupture events suggested that CD43 is strongly connected to the cytoskeleton and that its interaction with ICAM-1 mainly corresponds to force ramps followed by sudden jumps. In contrast, MUC1 seems to be weakly connected to the cytoskeleton, as its interactions with ICAM-1 are mainly associated with the formation of tethers. This analysis is quite promising and may also be applied to other types of cancer cells.


Met31p and Met32p, two related zinc finger proteins, are involved in transcriptional regulation of yeast sulfur amino acid metabolism.
Sulfur amino acid metabolism in Saccharomyces cerevisiae is regulated by the level of intracellular S-adenosylmethionine (AdoMet). Two cis-acting elements have been previously identified within the 5' upstream regions of the structural genes of the sulfur network. The first contains the CACGTG motif and is the target of the transcription activation complex Cbflp-Met4p-Met28p. We report here the identification of two new factors, Met31p and Met32p, that recognize the second cis-acting element. Met31p was isolated through the use of the one-hybrid method, while Met32p was identified during the analysis of the yeast methionine transport system. Met31p and Met32p are highly related zinc finger-containing proteins. Both LexA-Met31p and LexA-Met32p fusion proteins activate the transcription of a LexAop-containing promoter in a Met4p-dependent manner. Northern blot analyses of cells that do not express either Met31p and/or Met32p suggest that the function of the two proteins during the transcriptional regulation of the sulfur network varies from one gene to the other. While the expression of both the MET3 and MET14 genes was shown to strictly depend upon the presence of either Met31p or Met32p, the transcription of the MET25 gene is constitutive in cells lacking both Met31p and Met32p. These results therefore emphasise the diversity of the mechanisms allowing regulation of the expression of the methionine biosynthetic genes.


BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis.
VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3'UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.


Coproduction of healthcare service.
Efforts to ensure effective participation of patients in healthcare are called by many names-patient centredness, patient engagement, patient experience. Improvement initiatives in this domain often resemble the efforts of manufacturers to engage consumers in designing and marketing products. Services, however, are fundamentally different than products; unlike goods, services are always 'coproduced'. Failure to recognise this unique character of a service and its implications may limit our success in partnering with patients to improve health care. We trace a partial history of the coproduction concept, present a model of healthcare service coproduction and explore its application as a design principle in three healthcare service delivery innovations. We use the principle to examine the roles, relationships and aims of this interdependent work. We explore the principle's implications and challenges for health professional development, for service delivery system design and for understanding and measuring benefit in healthcare services.


Computational challenges, tools, and resources for analyzing co- and post-transcriptional events in high throughput.
Co- and post-transcriptional regulation of gene expression is complex and multifaceted, spanning the complete RNA lifecycle from genesis to decay. High-throughput profiling of the constituent events and processes is achieved through a range of technologies that continue to expand and evolve. Fully leveraging the resulting data is nontrivial, and requires the use of computational methods and tools carefully crafted for specific data sources and often intended to probe particular biological processes. Drawing upon databases of information pre-compiled by other researchers can further elevate analyses. Within this review, we describe the major co- and post-transcriptional events in the RNA lifecycle that are amenable to high-throughput profiling. We place specific emphasis on the analysis of the resulting data, in particular the computational tools and resources available, as well as looking toward future challenges that remain to be addressed.


Longitudinal study of living kidney donor glomerular dynamics after nephrectomy.
Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors. We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post- (median, 0.8 years), and late post- (median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects. Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (Kf), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, Kf) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the Kf. The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria. Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation. Not applicable. FUNDING. NIH (R01DK064697 and K23DK087937); Astellas Pharma US; the John M. Sobrato Foundation; the Satellite Extramural Grant Foundation; and the American Society of Nephrology.


Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors.
For over 40 years, scientists have endeavored to understand the so-called sigma receptors. During this time, the concept of sigma receptors has continuously and significantly evolved. With thousands of publications on the subject, these proteins have been implicated in various diseases, disorders, and physiological processes. Nevertheless, we are just beginning to understand what sigma proteins do and how they work. Two subtypes have been identified, Sigma1 and Sigma2. Whereas Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor, and several other names) was cloned over 20 years ago, Sigma2 (sigma-2 receptor, σ2 receptor) was cloned very recently and had remained a pharmacologically defined entity. In this volume, we will focus primarily on Sigma1. We will highlight several key subject areas in which Sigma1 has been well characterized as well as (re)emerging areas of interest. Despite the large number of publications regarding Sigma1, several fundamental questions remain unanswered or only partially answered. Most of what we know about Sigma1 comes from pharmacological studies; however, a clearly defined molecular mechanism of action remains elusive. One concept has become clear; Sigma1 is not a traditional receptor. Sigma1 is now considered a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. A number of landmark discoveries over the past decade have begun to reshape the concept of sigma receptors. With the rapid emergence of new information, development of new tools, and changing conceptual frameworks, the field is poised for a period of accelerated progress.


Transcriptomic changes underlying EGFR inhibitor resistance in human and mouse models of basal-like breast cancer.
The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for 9 weeks. The PDX was then subjected to long-term erlotinib treatment in vivo. Through serial passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with > 500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Erlotinib effectively inhibited WHIM2 tumor growth for approximately 4 weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 gene expression data revealed a set of 38 overlapping genes that were differentially expressed in the erlotinib-resistant WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Of these five genes, LCN2 was most abundantly expressed in triple-negative breast cancers, and its knockdown restored erlotinib sensitivity in vitro. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. These data could be used to identify a biomarker or develop a gene signature predictive of patient response to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how LCN2 contributes to the development of EGFRi resistance.


DHX15 regulates CMTR1-dependent gene expression and cell proliferation.
CMTR1 contributes to mRNA cap formation by methylating the first transcribed nucleotide ribose at the O-2 position. mRNA cap O-2 methylation has roles in mRNA stabilisation and translation, and self-RNA tolerance in innate immunity. We report that CMTR1 is recruited to serine-5-phosphorylated RNA Pol II C-terminal domain, early in transcription. We isolated CMTR1 in a complex with DHX15, an RNA helicase functioning in splicing and ribosome biogenesis, and characterised it as a regulator of CMTR1. When DHX15 is bound, CMTR1 activity is repressed and the methyl-transferase does not bind to RNA pol II. Conversely, CMTR1 activates DHX15 helicase activity, which is likely to impact several nuclear functions. In HCC1806 breast carcinoma cell line, the DHX15-CMTR1 interaction controls ribosome loading of a subset of mRNAs and regulates cell proliferation. The impact of the CMTR1-DHX15 interaction is complex and will depend on the relative expression of these enzymes and their interactors, and the cellular dependency on different RNA processing pathways.


Exploiting sensitization windows of opportunity in hyper and hypo-fractionated radiation therapy.
In contrast to the conventional radiotherapy/chemoradiotherapy paradigms used in the treatment of majority of cancer types, this review will describe two areas of radiobiology, hyperfractionated and hypofractionated radiation therapy, for cancer treatment focusing on application of novel concepts underlying these treatment modalities. The initial part of the review discusses the phenomenon of hyper-radiation sensitivity (HRS) at lower doses (0.1 to 0.6 Gy), describing the underlying mechanisms and how this could enhance the effects of chemotherapy, particularly, in hyperfractionated settings. The second part examines the radiobiological/physiological mechanisms underlying the effects of high-dose hypofractionated radiation therapy that can be exploited for tumor cure. These include abscopal/bystander effects, activation of immune system, endothelial cell death and effect of hypoxia with re-oxygenation. These biological properties along with targeted dose delivery and distribution to reduce normal tissue toxicity may make high-dose hypofractionation more effective than conventional radiation therapy for treatment of advanced cancers. The novel radiation physics based methods that take into consideration the tumor volume to be irradiated and normal tissue avoidance/tolerance can further improve treatment outcome and post-treatment quality of life. In conclusion, there is enough evidence to further explore novel avenues to exploit biological mechanisms from hyper-fractionation by enhancing the efficacy of chemotherapy and hypo-fractionated radiation therapy that could enhance tumor control and use imaging and technological advances to reduce toxicity.


Forest carbon management in the United States: 1600-2100.
This paper reviews the effects of past forest management on carbon stocks in the United States, and the challenges for managing forest carbon resources in the 21st century. Forests in the United States were in approximate carbon balance with the atmosphere from 1600-1800. Utilization and land clearing caused a large pulse of forest carbon emissions during the 19th century, followed by regrowth and net forest carbon sequestration in the 20th century. Recent data and knowledge of the general behavior of forests after disturbance suggest that the rate of forest carbon sequestration is declining. A goal of an additional 100 to 200 Tg C/yr of forest carbon sequestration is achievable, but would require investment in inventory and monitoring, development of technology and practices, and assistance for land managers.


Breaking the rules: bacteria that use several DNA polymerase IIIs.
Studies using Escherichia coli DNA polymerase (Pol) III as the prototype for bacterial DNA replication have suggested that--in contrast to eukaryotes--one replicase performs all of the main functions at the replication fork. However, recent studies have revealed that replication in other bacteria requires two forms of Pol III, one of which seems to extend RNA primers by only a few nucleotides before transferring the product to the other polymerase--an arrangement analogous to that in eukaryotes. Yet another group of bacteria encode a second Pol III (ImuC), which apparently replaces a Pol Y-type polymerase (Pol V) that is required for induced mutagenesis in E. coli. A complete understanding of complex bacterial replicases will allow the simultaneous biochemical screening of all their components and, thus, the identification of new antibacterial compounds.


Prevalence and Outcomes of Sudden Cardiac Arrest in a University Hospital in the Western Region, Saudi Arabia.
Sudden cardiac arrest (SCA) is a major cause of mortality, yet its epidemiological and outcome data in hospitals from Saudi Arabia are limited. This study aimed to evaluate the prevalence, risk factors and outcomes of SCA in a teaching hospital in Jeddah, Saudi Arabia. This retrospective study included all patients aged ≥18 years with SCA who were resuscitated at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, between January 1 and December 31, 2016. Data were retrieved from the hospital medical records as flow sheets designed in accordance with the Utstein-style recommendations. Factors relating to mortality were analyzed using descriptive analyses and chi-square test. A total of 429 cases of SCA met the inclusion criteria, and its prevalence was 7.76 cases/1000 adult hospital admission. Of these, 61.3% were male, and the mean age was 58.4 years, with 36.6% aged >65 years. Only 3.5% were outside-hospital cardiac arrests. The most common initial rhythm was pulseless electrical activity/asystole (93.2%), while ventricular tachycardia/ventricular fibrillation was documented in only 29 cases (6.8%). The overall rate of return to spontaneous circulation (ROSC) was 56.2%, and 56.8% in cases of in-hospital cardiac arrest (IHCA). Patients with SCA due to sepsis had significantly increased mortality (P < 0.000; odds ratio [OR] = 0.24 [0.12-0.47 95% confidence interval [CI]]), while those with SCA due to respiratory causes had significantly better survival outcomes (P = 0.001; OR = 2.3 [1.5-3.8 95% CI]). No significant differences in outcomes were found between other risk factors, including cardiac causes. In this population, the prevalence of SCA in adults was higher than reported in many similar studies. Further, sepsis was found to affect the survival rate. Although the rate of ROSC for IHCA patients was favorable compared with other studies, it is relatively poor. This finding signifies the need to identify and control risk factors for SCA to improve survival.


Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication.
A high level of transcription has been associated with elevated spontaneous mutation and recombination rates in eukaryotic organisms. To determine whether the transcription level is directly correlated with the degree of genomic instability, we have developed a tetracycline-regulated LYS2 reporter system to modulate the transcription level over a broad range in Saccharomyces cerevisiae. We find that spontaneous mutation rate is directly proportional to the transcription level, suggesting that movement of RNA polymerase through the target initiates a mutagenic process(es). Using this system, we also investigated two hypotheses that have been proposed to explain transcription-associated mutagenesis (TAM): (1) transcription impairs replication fork progression in a directional manner and (2) DNA lesions accumulate under high-transcription conditions. The effect of replication fork progression was probed by comparing the mutational rates and spectra in yeast strains with the reporter gene placed in two different orientations near a well-characterized replication origin. The effect of endogenous DNA damage accumulation was investigated by studying TAM in strains defective in nucleotide excision repair or in lesion bypass by the translesion polymerase Polzeta. Our results suggest that both replication orientation and endogenous lesion accumulation play significant roles in TAM, particularly in terms of mutation spectra.


Electronic Characterization of Au/DNA/ITO Metal-Semiconductor-Metal Diode and Its Application as a Radiation Sensor.
Deoxyribonucleic acid or DNA molecules expressed as double-stranded (DSS) negatively charged polymer plays a significant role in electronic states of metal/silicon semiconductor structures. Electrical parameters of an Au/DNA/ITO device prepared using self-assembly method was studied by using current-voltage (I-V) characteristic measurements under alpha bombardment at room temperature. The results were analyzed using conventional thermionic emission model, Cheung and Cheung's method and Norde's technique to estimate the barrier height, ideality factor, series resistance and Richardson constant of the Au/DNA/ITO structure. Besides demonstrating a strongly rectifying (diode) characteristic, it was also observed that orderly fluctuations occur in various electrical parameters of the Schottky structure. Increasing alpha radiation effectively influences the series resistance, while the barrier height, ideality factor and interface state density parameters respond linearly. Barrier height determined from I-V measurements were calculated at 0.7284 eV for non-radiated, increasing to about 0.7883 eV in 0.036 Gy showing an increase for all doses. We also demonstrate the hypersensitivity phenomena effect by studying the relationship between the series resistance for the three methods, the ideality factor and low-dose radiation. Based on the results, sensitive alpha particle detectors can be realized using Au/DNA/ITO Schottky junction sensor.


Oxygen therapeutics in trauma and surgery.
A number of oxygen therapeutics have completed safety trials and are now undergoing efficacy evaluation in multicenter phase III trials in North America and Europe. There are numerous potential advantages of these solutions when compared with packed red blood cells. They are readily available and have a long shelf life; do not require type and cross-matching; are virtually free of viral or bacterial contamination; have a much lower viscosity than blood; and may lack the immunosuppressive effects of blood. These products may also deliver more oxygen per unit mass than an equivalent amount of hemoglobin from red blood cells, providing the potential to sustain life in certain clinical situations. A few problems remain, including short biologic half-life, which may limit the application to times when the patient is most acutely anemic (i.e., in the intraoperative or immediate perioperative phase) or for emergent use. Nevertheless, a safe, effective alternative therapy providing oxygen delivery characteristics comparable to red blood cells may soon be available that could have significant impact on the way that we resuscitate trauma patients.


Importance of peak height velocity timing in terms of injuries in talented soccer players.
The purpose of this study was to identify differences in traumatic and overuse injury incidence between talented soccer players who differ in the timing of their adolescent growth spurt. 26 soccer players (mean age 11.9 ± 0.84 years) were followed longitudinally for 3 years around Peak Height Velocity, calculated according to the Maturity Offset Protocol. The group was divided into an earlier and later maturing group by median split. Injuries were registered following the FIFA consensus statement. Mann-Whitney tests showed that later maturing players had a significantly higher overuse injury incidence than their earlier maturing counterparts both in the year before Peak Height Velocity (3.53 vs.0.49 overuse injuries/1 000 h of exposure,U = 49.50, z = − 2.049, p < 0.05) and the year of Peak Height Velocity (3.97 vs. 1.56 overuse injuries/1 000 h of exposure, U = 50.5, z = − 1.796,p < 0.05). Trainers and coaches should be careful with the training and match load they put on talented soccer players, especially those physically not (yet) able to handle that load. Players appear to be especially susceptible to injury between 13.5 and 14.5 years of age. Training and match load should be structured relative to maturity such that athletic development is maximized and the risk of injury is minimized.


Design of advanced porous graphene materials: from graphene nanomesh to 3D architectures.
In order to make full utilization of the high intrinsic surface area of graphene, recently, porous graphene materials including graphene nanomesh, crumpled graphene and graphene foam, have attracted tremendous attention and research interest, owing to their exceptional porous structure (high surface area, and high pore volume) in combination with the inherent properties of graphene, such as high electronic conductivity, good thermal stability, and excellent mechanical strength. Interestingly, porous graphene materials and their derivatives have been explored in a wide range of applications in the fields of electronic and photonic devices, energy storage, gas separation/storage, oil absorption and sensors. This article reviews recent progress in the synthesis, characterization, properties, and applications of porous graphene materials. We aim to highlight the importance of designing different porous structures of graphene to meet future challenges, and the trend on future design of porous graphene materials is analyzed.


The impact of Docker containers on the performance of genomic pipelines.
Genomic pipelines consist of several pieces of third party software and, because of their experimental nature, frequent changes and updates are commonly necessary thus raising serious deployment and reproducibility issues. Docker containers are emerging as a possible solution for many of these problems, as they allow the packaging of pipelines in an isolated and self-contained manner. This makes it easy to distribute and execute pipelines in a portable manner across a wide range of computing platforms. Thus, the question that arises is to what extent the use of Docker containers might affect the performance of these pipelines. Here we address this question and conclude that Docker containers have only a minor impact on the performance of common genomic pipelines, which is negligible when the executed jobs are long in terms of computational time.


Improving Patient-Pharmacist Encounters with Over-The-Counter Medications: A Mixed-Methods Pilot Study.
Over-the-counter (OTC) medication use has increased safety risks for adults older than 65. Most older adults purchase OTC medications from community pharmacies, where the considerable distance or visual obstructions between the prescription area and OTC aisles undermine pharmacists' ability to assist patients with OTC medication decisions. An innovative redesign of an abbreviated medication section specifically for older adults (called the Senior SectionTM ) can facilitate pharmacy staff/patient interaction, potentially improving safe medication selection and use. This study evaluated the impact of the Senior Section on the frequency and content of OTC encounters between pharmacy staff and patients. An intervention mixed-methods design generated data from patient OTC encounters, and interviews with two pharmacists and two technicians, throughout the study. NVivo was used to code interview transcripts, and frequencies and chi-square analyses demonstrated pre/post-intervention comparisons for the OTC encounter variables. After Senior Section implementation, pharmacy staff were more likely to initiate (and be involved in) patient encounters, address more topics or problem/symptoms, provide details about OTC products, discuss appropriateness of OTC use, and discuss medication classes highlighted in the Senior Section. Pharmacy staff were less likely to need to leave the prescription department for extended periods; they also had fewer prolonged encounters or encounters about product location. Importantly, the Senior Section did not impede pharmacy workflow. The Senior Section prompted more frequent, effective, and efficient engagements between pharmacy staff and patients, which may substantially reduce OTC-related harms among older adults.


Spatial Distribution of a Large Herbivore Community at Waterholes: An Assessment of Its Stability over Years in Hwange National Park, Zimbabwe.
The spatial structuring of populations or communities is an important driver of their functioning and their influence on ecosystems. Identifying the (in)stability of the spatial structure of populations is a first step towards understanding the underlying causes of these structures. Here we studied the relative importance of spatial vs. interannual variability in explaining the patterns of abundance of a large herbivore community (8 species) at waterholes in Hwange National Park (Zimbabwe). We analyzed census data collected over 13 years using multivariate methods. Our results showed that variability in the census data was mostly explained by the spatial structure of the community, as some waterholes had consistently greater herbivore abundance than others. Some temporal variability probably linked to Park-scale migration dependent on annual rainfall was noticeable, however. Once this was accounted for, little temporal variability remained to be explained, suggesting that other factors affecting herbivore abundance over time had a negligible effect at the scale of the study. The extent of spatial and temporal variability in census data was also measured for each species. This study could help in projecting the consequences of surface water management, and more generally presents a methodological framework to simultaneously address the relative importance of spatial vs. temporal effects in driving the distribution of organisms across landscapes.


Ligands for cannabinoid receptors, promising anticancer agents.
Cannabinoid compounds are unique to cannabis and provide some interesting biological properties. These compounds along with endocannabinoids, a group of neuromodulator compounds in the body especially in brain, express their effects by activation of G-protein-coupled cannabinoid receptors, CB1 and CB2. There are several physiological properties attributed to the endocannabinoids including pain relief, enhancement of appetite, blood pressure lowering during shock, embryonic development, and blocking of working memory. On the other hand, activation of endocannabinoid system may be suppresses evolution and progression of several types of cancer. According to the results of recent studies, CB receptors are over-expressed in cancer cell lines and application of multiple cannabinoid or cannabis-derived compounds reduce tumor size through decrease of cell proliferation or induction of cell cycle arrest and apoptosis along with desirable effect on decrease of tumor-evoked pain. Therefore, modulation of endocannabinoid system by inhibition of fatty acid amide hydrolase (FAAH), the enzyme, which metabolized endocannabinoids, or application of multiple cannabinoid or cannabis-derived compounds, may be appropriate for the treatment of several cancer subtypes. This review focuses on how cannabinoid affect different types of cancers.


A comprehensive phylogeny of birds (Aves) using targeted next-generation DNA sequencing.
Although reconstruction of the phylogeny of living birds has progressed tremendously in the last decade, the evolutionary history of Neoaves--a clade that encompasses nearly all living bird species--remains the greatest unresolved challenge in dinosaur systematics. Here we investigate avian phylogeny with an unprecedented scale of data: >390,000 bases of genomic sequence data from each of 198 species of living birds, representing all major avian lineages, and two crocodilian outgroups. Sequence data were collected using anchored hybrid enrichment, yielding 259 nuclear loci with an average length of 1,523 bases for a total data set of over 7.8 × 10(7) bases. Bayesian and maximum likelihood analyses yielded highly supported and nearly identical phylogenetic trees for all major avian lineages. Five major clades form successive sister groups to the rest of Neoaves: (1) a clade including nightjars, other caprimulgiforms, swifts, and hummingbirds; (2) a clade uniting cuckoos, bustards, and turacos with pigeons, mesites, and sandgrouse; (3) cranes and their relatives; (4) a comprehensive waterbird clade, including all diving, wading, and shorebirds; and (5) a comprehensive landbird clade with the enigmatic hoatzin (Opisthocomus hoazin) as the sister group to the rest. Neither of the two main, recently proposed Neoavian clades--Columbea and Passerea--were supported as monophyletic. The results of our divergence time analyses are congruent with the palaeontological record, supporting a major radiation of crown birds in the wake of the Cretaceous-Palaeogene (K-Pg) mass extinction.


CD169(+) macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes.
Invariant natural killer T cells (iNKT cells) are involved in the host defense against microbial infection. Although it is known that iNKT cells recognize glycolipids presented by CD1d, how and where they encounter antigen in vivo remains unclear. Here we used multiphoton microscopy to visualize the dynamics and activation of iNKT cells in lymph nodes. After antigen administration, iNKT cells became confined in a CD1d-dependent manner in close proximity to subcapsular sinus CD169(+) macrophages. These macrophages retained, internalized and presented lipid antigen and were required for iNKT cell activation, cytokine production and population expansion. Thus, CD169(+) macrophages can act as true antigen-presenting cells controlling early iNKT cell activation and favoring the fast initiation of immune responses.


Potassium diazoacetate-induced p53 mutations in vitro in relation to formation of O6-carboxymethyl- and O6-methyl-2'-deoxyguanosine DNA adducts: relevance for gastrointestinal cancer.
Nitrosated glycine derivatives react with DNA to form O6-carboxymethyl-2'-deoxyguanosine (O6-CMdG) and O6-methyl-2'-deoxyguanosine (O6-MedG) adducts concurrently. O6-CMdG is not repaired by O6-alkylguanine alkyltransferases and might be expected to lead to mutations via a similar mechanism to O6-MedG. Potassium diazoacetate (KDA) is a stable form of nitrosated glycine and its ability to induce mutations in the p53 gene in a functional yeast assay was studied. Treatment of a plasmid containing the human p53 cDNA sequence with KDA afforded readily detectable levels of O6-CMdG and O6-MedG. The treated plasmid was used to transform yeast cells and coloured colonies harbouring a p53 sequence with functional mutations were detected. Recovery of the mutated plasmids followed by DNA sequencing enabled the mutation spectrum of KDA to be characterised. The most common mutations induced by KDA were substitutions with >50% occurring at GC base pairs. In contrast to the methylating agent methylnitrosourea which gives predominantly (>80%) GC-->AT transitions, KDA produced almost equal amounts of transitions (GC-->AT) and transversions (GC-->TA and AT-->TA). This difference is probably due to a different mode of base mispairing for O6-CMdG compared with O6-MedG. The pattern of mutations induced by KDA was very similar to the patterns observed in mutated p53 in human gastrointestinal tract tumours. These results are consistent with the hypothesis that nitrosation of glycine (or glycine derivatives) may contribute to characteristic human p53 mutation profiles. This conclusion is borne out by recent observations that O6-CMdG is present in human DNA both from blood and exfoliated colorectal cells and is consistent with recent epidemiological studies that have concluded that endogenous nitrosation arising from red meat consumption is related to an increased risk of colorectal cancer.


Presence of p53 mutations in primary nasopharyngeal carcinoma (NPC) in non-Asians of Los Angeles, California, a low-risk population for NPC.
Mutatins of the p53 tumor suppressor gene are rare in nasopharyngeal carcinoma (NPC) patients who reside in high-risk areas, such as Southeastern China. Among this high-risk group, a pre-existing infection with the EBV and consumption of Cantonese salted fish are closely associated with NPC. We investigated the prevalence of p53 mutations in 28 primary NPC specimens from white (including Hispanic) and African-American patients in Los Angeles, who are at low risk for NPC. Using PCR-based single-strand conformational polymorphism and direct sequencing, we found four mutations (14%) in exons 5-8 of the p53 gene in four patients. All were C-to-T transition mutations: two were present in exon 5-one at codon 142 [CCT (Pro)-->CTT (Leu)] and another at codon 144 [CAG (Gln)-->TAG (stop codon)]. The other two mutations were identified in exon 8: one at codon 273 [CGT (Arg)-->CAT (His)], a CpG site, and one at codon 271, a silent mutation [GAG (Glu)-->GAA (Glu)]. This is the first report investigating the presence of p53 missense mutations in NPC among a low-risk population. Our data indicate that p53 is also an infrequent event among NPC patients at low risk for the disease.


Covalent immobilization of molecularly imprinted polymer nanoparticles using an epoxy silane.
Molecularly imprinted polymers (MIPs) can be used as antibody mimics to develop robust chemical sensors. One challenging problem in using MIPs for sensor development is the lack of reliable conjugation chemistry that allows MIPs to be fixed on transducer surface. In this work, we study the use of epoxy silane to immobilize MIP nanoparticles on model transducer surfaces without impairing the function of the immobilized nanoparticles. The MIP nanoparticles with a core-shell structure have selective molecular binding sites in the core and multiple amino groups in the shell. The model transducer surface is functionalized with a self-assembled monolayer of epoxy silane, which reacts with the core-shell MIP particles to enable straightforward immobilization. The whole process is characterized by studying the treated surfaces after each preparation step using atomic force microscopy, scanning electron microscopy, fluorescence microscopy, contact angle measurements and X-ray photoelectron spectroscopy. The microscopy results show that the MIP particles are immobilized uniformly on surface. The photoelectron spectroscopy results further confirm the action of each functionalization step. The molecular selectivity of the MIP-functionalized surface is verified by radioligand binding analysis. The particle immobilization approach described here has a general applicability for constructing selective chemical sensors in different formats.


When Parents Take Conflicts to Digital Media.
Over the past decade, there have been numerous cases around the world in which parents have used digital media to orchestrate public opposition to doctors' recommendations. Parents are not always "successful" with such efforts; these cases have mixed outcomes and, sometimes, unintended consequences for parents. In this article, we address the current lack of understanding of parents' goals, motivations, and rationalizations in initiating such campaigns. We analyze 12 cases in which parental digital media campaigns went viral that occurred between 2007 and 2018, with the aim of better understanding parents' motivations for going public. We identify 7 themes raised by parent-initiated digital media campaigns: (1) changing doctors' minds, (2) being heard, (3) feeling empowered, (4) buying more time, (5) raising public awareness, (6) feeling that they have done everything possible, and (7) financial gain. Greater attunement to these themes and what is driving parents in such conflicts may help to disrupt the highly adversarial narrative surrounding such cases. It may also inform how clinicians approach disagreements that cross a certain threshold of public interest at the bedside.


Prevalence of appropriate management of diabetes mellitus in an academic general medicine clinic.
Because diabetes mellitus was not being adequately treated according to guidelines in an academic general medicine clinic, 2 of the authors (W.S.A. and A.H.G.) instituted an educational program to see if we could improve the appropriate management of diabetes mellitus in the academic general medicine clinic. Following this educational program, we investigated the appropriate management of 196 unselected patients with diabetes mellitus, mean age 61 years, who were followed up for at least 1 year in an academic general medicine clinic. The blood pressure was reduced to <130/80 mm Hg in 161 of 196 diabetics (82%). The hemoglobin A1c was reduced to <7.0% in 134 of 196 diabetics (68%). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used to treat 50 of 51 diabetics (98%) with coronary artery disease (CAD), ischemic stroke, or peripheral arterial disease; 33 of 35 diabetics (94%) with a glomerular filtration rate <60 mL/min/1.73 m; 54 of 57 diabetics (94%) with microalbuminuria, and 21 of 22 diabetics (96%) with electrocardiographic left ventricular hypertrophy. Aspirin was used to treat 50 of 51 diabetics (98%) with CAD, ischemic stroke, or peripheral arterial disease. beta-Blockers were used to treat 36 of 39 diabetics (92%) with CAD. Statins were used to treat 168 of 196 diabetics (86%). Smoking cessation counseling was documented in 39 of 53 smokers (74%). Of 196 diabetics, 196 (100%) had a neurological examination, 129 (66%) were referred to an ophthalmologist for an eye examination, and 125 (64%) were referred to a podiatrist for foot care. These data show that an educational program on the appropriate management of diabetes mellitus improved the management of diabetes mellitus in an academic general medicine clinic.


Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton.
Mice in which all members of the Hox10 or Hox11 paralogous group are disrupted provide evidence that these Hox genes are involved in global patterning of the axial and appendicular skeleton. In the absence of Hox10 function, no lumbar vertebrae are formed. Instead, ribs project from all posterior vertebrae, extending caudally from the last thoracic vertebrae to beyond the sacral region. In the absence of Hox11 function, sacral vertebrae are not formed and instead these vertebrae assume a lumbar identity. The redundancy among these paralogous family members is so great that this global aspect of Hox patterning is not apparent in mice that are mutant for five of the six paralogous alleles.


Correlates of viral richness in bats (order Chiroptera).
Historic and contemporary host ecology and evolutionary dynamics have profound impacts on viral diversity, virulence, and associated disease emergence. Bats have been recognized as reservoirs for several emerging viral pathogens, and are unique among mammals in their vagility, potential for long-distance dispersal, and often very large, colonial populations. We investigate the relative influences of host ecology and population genetic structure for predictions of viral richness in relevant reservoir species. We test the hypothesis that host geographic range area, distribution, population genetic structure, migratory behavior, International Union for Conservation of Nature and Natural Resources (IUCN) threat status, body mass, and colony size, are associated with known viral richness in bats. We analyze host traits and viral richness in a generalized linear regression model framework, and include a correction for sampling effort and phylogeny. We find evidence that sampling effort, IUCN status, and population genetic structure correlate with observed viral species richness in bats, and that these associations are independent of phylogeny. This study is an important first step in understanding the mechanisms that promote viral richness in reservoir species, and may aid in predicting the emergence of viral zoonoses from bats.


Improved Serial Sectioning Techniques for Correlative Light-Electron Microscopy Mapping of Human Langerhans Islets.
Combined analysis of immunostaining for various biological molecules coupled with investigations of ultrastructural features of individual cells is a powerful approach for studies of cellular functions in normal and pathological conditions. However, weak antigenicity of tissues fixed by conventional methods poses a problem for immunoassays. This study introduces a method of correlative light and electron microscopy imaging of the same endocrine cells of compact and diffuse islets from human pancreatic tissue specimens. The method utilizes serial sections obtained from Epon-embedded specimens fixed with glutaraldehyde and osmium tetroxide. Double-immunofluorescence staining of thick Epon sections for endocrine hormones (insulin and glucagon) and regenerating islet-derived gene 1 α (REG1α) was performed following the removal of Epoxy resin with sodium ethoxide, antigen retrieval by autoclaving, and de-osmification treatment with hydrogen peroxide. The immunofluorescence images of endocrine cells were superimposed with the electron microscopy images of the same cells obtained from serial ultrathin sections. Immunofluorescence images showed well-preserved secretory granules in endocrine cells, whereas electron microscopy observations demonstrated corresponding secretory granules and intracellular organelles in the same cells. In conclusion, the correlative imaging approach developed by us may be useful for examining ultrastructural features in combination with immunolocalisation of endocrine hormones in the same human pancreatic islets.


The ingi and RIME non-LTR retrotransposons are not randomly distributed in the genome of Trypanosoma brucei.
The ingi (long and autonomous) and RIME (short and nonautonomous) non--long-terminal repeat retrotransposons are the most abundant mobile elements characterized to date in the genome of the African trypanosome Trypanosoma brucei. These retrotransposons were thought to be randomly distributed, but a detailed and comprehensive analysis of their genomic distribution had not been performed until now. To address this question, we analyzed the ingi/RIME sequences and flanking sequences from the ongoing T. brucei genome sequencing project (TREU927/4 strain). Among the 81 ingi/RIME elements analyzed, 60% are complete, and 7% of the ingi elements (approximately 15 copies per haploid genome) appear to encode for their own transposition. The size of the direct repeat flanking the ingi/RIME retrotransposons is conserved (i.e., 12-bp), and a strong 11-bp consensus pattern precedes the 5'-direct repeat. The presence of a consensus pattern upstream of the retroelements was confirmed by the analysis of the base occurrence in 294 GSS containing 5'-adjacent ingi/RIME sequences. The conserved sequence is present upstream of ingis and RIMEs, suggesting that ingi-encoded enzymatic activities are used for retrotransposition of RIMEs, which are short nonautonomous retroelements. In conclusion, the ingi and RIME retroelements are not randomly distributed in the genome of T. brucei and are preceded by a conserved sequence, which may be the recognition site of the ingi-encoded endonuclease.


Dichromats detect colour-camouflaged objects that are not detected by trichromats.
To explain the surprisingly high frequency of congenital red-green colour blindness, the suggestion has been made that dichromats might be at an advantage in breaking certain kinds of colour camouflage. We have compared the performance of dichromats and normal observers in a task in which texture is camouflaged by colour. The texture elements in a target area differed in either orientation or size from the background elements. In one condition, the texture elements were all of the same colour; in the camouflage condition they were randomly coloured red or green. For trichromats, it proved to be more difficult to detect the target region in the camouflage condition, even though colour was completely irrelevant to the task. Dichromats (n = 7) did not show this effect, and indeed performed better than trichromats in the camouflage condition. We conclude that colour can interfere with segregation based upon texture, and that dichromats are less susceptible to such interference.


Covalent attachment of cyclic TAT peptides to GFP results in protein delivery into live cells with immediate bioavailability.
The delivery of free molecules into the cytoplasm and nucleus by using arginine-rich cell-penetrating peptides (CPPs) has been limited to small cargoes, while large cargoes such as proteins are taken up and trapped in endocytic vesicles. Based on recent work, in which we showed that the transduction efficiency of arginine-rich CPPs can be greatly enhanced by cyclization, the aim was to use cyclic CPPs to transport full-length proteins, in this study green fluorescent protein (GFP), into the cytosol of living cells. Cyclic and linear CPP-GFP conjugates were obtained by using azido-functionalized CPPs and an alkyne-functionalized GFP. Our findings reveal that the cyclic-CPP-GFP conjugates are internalized into live cells with immediate bioavailability in the cytosol and the nucleus, whereas linear CPP analogues do not confer GFP transduction. This technology expands the application of cyclic CPPs to the efficient transport of functional full-length proteins into live cells.


Hut lung. A domestically acquired particulate lung disease.
We report an illustrative case of advanced "hut lung," or domestically acquired particulate lung disease (DAPLD), in a recently emigrated nonsmoking Bangladeshi woman with a history of 171 hour-years of exposure to biomass smoke. She presented with symptoms of chronic cough, dyspnea, and early parenchymal lung disease. High-resolution computed tomography (CT) of the chest demonstrated numerous 2- to 3-mm nodules, sparing the pleural surface. To our knowledge, this is the first such report of CT findings in the literature. Bronchoscopy yielded typical anthracotic plaques and diffuse anthracosis with interstitial inflammation on histopathologic examination of biopsy specimens. DAPLD is potentially the largest environmentally attributable disorder in the world, with an estimated 3 billion people at risk. Caused by the inhalation of particles liberated from the combustion of biomass fuel, DAPLD results in significant morbidity from infancy to adulthood. Clinically, DAPLD manifests a broad range of disorders from chronic bronchitis and dyspnea to advanced interstitial lung disease and malignancy. While a detailed environmental history is essential for making the diagnosis in most individuals, for patients with advanced DAPLD, invasive modalities such as bronchoscopy with transbronchial biopsy and examination of bronchoalveolar lavage fluid help differentiate it from other diseases. Recognition of this syndrome and removal of the patient from the environment is the only treatment. The development of well-controlled interventional trials and the commitment of sufficient resources to educate local populaces and develop alternative fuel sources, stove designs, and ventilation are essential toward reducing the magnitude of DAPLD.


Comparison of intraperitoneal and subcutaneous insulin administration on insulin sensitivity and serum lipids in type I diabetic patients on continuous ambulatory peritoneal dialysis treatment.
1. The metabolic effects of intraperitoneal and subcutaneous insulin delivery were compared in a cross-over manner in six C-peptide-negative diabetic patients with end-stage renal disease on continuous ambulatory peritoneal dialysis. Each treatment period lasted at least 3 months. Hyperinsulinaemic euglycaemic clamp was performed and glucose turnover assessed using [3-(3)H]glucose as a tracer. 2. During intraperitoneal delivery the daily insulin dose was 2.4 times higher than during subcutaneous administration and glycaemic control was significantly better (HbA1c 7.63% +/- 0.46% and 9.52% +/- 0.51% during intraperitoneal and subcutaneous insulin respectively, P < 0.01). The number of hypoglycaemic episodes was lower during intraperitoneal insulin than during subcutaneous therapy. 3. Intraperitoneal insulin resulted in an enhanced glucose disposal rate (P < 0.01) and reduced fasting hepatic glucose production (P < 0.01). High-density lipoprotein-cholesterol decreased and the ratio of low-density lipoprotein/high-density lipoprotein-cholesterol increased significantly (P < 0.05) during intraperitoneal insulin delivery. 4. The results suggest that intraperitoneal insulin, while resulting in better glycaemic control and improved insulin sensitivity than subcutaneous insulin, increases serum triacylglycerol and total cholesterol and reduces high-density lipoprotein-cholesterol, possibly via a direct effect on the liver.


Virtually Being Lenin Enhances Presence and Engagement in a Scene From the Russian Revolution.
Virtual Reality (VR) has been widely applied to cultural heritage such as the reconstruction of ancient sites and artifacts. It has hardly been applied to the reprise of specific important moments in history. On the other hand immersive journalism does attempt to recreate current events in VR, but such applications typically give the viewer a disembodied non-participatory role in the scene of interest. Here we show how VR was used to reconstruct a specific historical event, where a famous photograph was brought to life, showing Lenin, the leader of the 1917 October Russian Revolution, giving a speech to Red Army recruits in Moscow 1920. We carried out a between groups experimental study with three conditions: Embodied-where the participant was first embodied as Lenin and then later in the audience watching Lenin; Included-where the participant was not embodied as Lenin but was embodied as part of the audience; and Observing-where the participant mainly viewed the scene from a disembodied third person point of view. Twenty participants were assigned to each of the three conditions in a between-groups design. We found that the level of presence was greatest in the Embodied and Included conditions, and that participants were least likely to later follow up information about the Russian Revolution in the Observing condition. Our conclusion is that if the VR setup allows for a period of embodiment as a character in the scenario then this should be employed in order to maximize the chance of participant presence and engagement with the story.


Applying NGS Data to Find Evolutionary Network Biomarkers from the Early and Late Stages of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a major liver tumor (~80%), besides hepatoblastomas, angiosarcomas, and cholangiocarcinomas. In this study, we used a systems biology approach to construct protein-protein interaction networks (PPINs) for early-stage and late-stage liver cancer. By comparing the networks of these two stages, we found that the two networks showed some common mechanisms and some significantly different mechanisms. To obtain differential network structures between cancer and noncancer PPINs, we constructed cancer PPIN and noncancer PPIN network structures for the two stages of liver cancer by systems biology method using NGS data from cancer cells and adjacent noncancer cells. Using carcinogenesis relevance values (CRVs), we identified 43 and 80 significant proteins and their PPINs (network markers) for early-stage and late-stage liver cancer. To investigate the evolution of network biomarkers in the carcinogenesis process, a primary pathway analysis showed that common pathways of the early and late stages were those related to ordinary cancer mechanisms. A pathway specific to the early stage was the mismatch repair pathway, while pathways specific to the late stage were the spliceosome pathway, lysine degradation pathway, and progesterone-mediated oocyte maturation pathway. This study provides a new direction for cancer-targeted therapies at different stages.


Crowdsourcing in medical research: concepts and applications.
Crowdsourcing shifts medical research from a closed environment to an open collaboration between the public and researchers. We define crowdsourcing as an approach to problem solving which involves an organization having a large group attempt to solve a problem or part of a problem, then sharing solutions. Crowdsourcing allows large groups of individuals to participate in medical research through innovation challenges, hackathons, and related activities. The purpose of this literature review is to examine the definition, concepts, and applications of crowdsourcing in medicine. This multi-disciplinary review defines crowdsourcing for medicine, identifies conceptual antecedents (collective intelligence and open source models), and explores implications of the approach. Several critiques of crowdsourcing are also examined. Although several crowdsourcing definitions exist, there are two essential elements: (1) having a large group of individuals, including those with skills and those without skills, propose potential solutions; (2) sharing solutions through implementation or open access materials. The public can be a central force in contributing to formative, pre-clinical, and clinical research. A growing evidence base suggests that crowdsourcing in medicine can result in high-quality outcomes, broad community engagement, and more open science.


Electrophysiological revelations of trial history effects in a color oddball search task.
In visual oddball search tasks, viewing a no-target scene (i.e., no-target selection trial) leads to the facilitation or delay of the search time for a target in a subsequent trial. Presumably, this selection failure leads to biasing attentional set and prioritizing stimulus features unseen in the no-target scene. We observed attention-related ERP components and tracked the course of attentional biasing as a function of trial history. Participants were instructed to identify color oddballs (i.e., targets) shown in varied trial sequences. The number of no-target scenes preceding a target scene was increased from zero to two to reinforce attentional biasing, and colors presented in two successive no-target scenes were repeated or changed to systematically bias attention to specific colors. For the no-target scenes, the presentation of a second no-target scene resulted in an early selection of, and sustained attention to, the changed colors (mirrored in the frontal selection positivity, the anterior N2, and the P3b). For the target scenes, the N2pc indicated an earlier allocation of attention to the targets with unseen or remotely seen colors. Inhibitory control of attention, shown in the anterior N2, was greatest when the target scene was followed by repeated no-target scenes with repeated colors. Finally, search times and the P3b were influenced by both color previewing and its history. The current results demonstrate that attentional biasing can occur on a trial-by-trial basis and be influenced by both feature previewing and its history.


Mirrored Orthogonal Sampling for Covariance Matrix Adaptation Evolution Strategies.
Generating more evenly distributed samples in high dimensional search spaces is the major purpose of the recently proposed mirrored sampling technique for evolution strategies. The diversity of the mutation samples is enlarged and the convergence rate is therefore improved by the mirrored sampling. Motivated by the mirrored sampling technique, this article introduces a new derandomized sampling technique called mirrored orthogonal sampling. The performance of this new technique is both theoretically analyzed and empirically studied on the sphere function. In particular, the mirrored orthogonal sampling technique is applied to the well-known Covariance Matrix Adaptation Evolution Strategy (CMA-ES). The resulting algorithm is experimentally tested on the well-known Black-Box Optimization Benchmark (BBOB). By comparing the results from the benchmark, mirrored orthogonal sampling is found to outperform both the standard CMA-ES and its variant using mirrored sampling.


Measured energy value of pistachios in the human diet.
Previous studies have suggested that lipid from nuts is more poorly absorbed than that from other food sources. If lipid from nuts is poorly absorbed, then the metabolisable energy contained in the nuts is less than that predicted by the Atwater general factors. A crossover feeding study was conducted in which sixteen volunteers consumed pistachios for 3 weeks as part of a controlled diet. Pistachio doses were 0, 42 and 84 g/d. Urine and faecal samples were collected, and urine, faeces and diet were analysed for N, fat, total dietary fibre, ash and combustible energy. Blood was also collected after each treatment period and analysed for plasma lipids. Energy value of pistachio nuts was calculated from differences in energy excretion during the different dietary treatments. The measured energy density of pistachios was found to be 22·6 kJ/g, which is 5 % less than the currently accepted energy value of 23·7 kJ/g, as calculated using the Atwater general factors. The pistachio nut intervention lowered LDL-cholesterol by 6 %, but did not significantly change plasma total cholesterol, HDL-cholesterol or TAG. In conclusion, pistachio nuts contain less metabolisable energy than that calculated from the Atwater general factors. Accurate information about metabolisable energy content of foods is important for reliable food labelling.


Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions.
It has been previously observed that the intrinsically weak variant GC donor sites, in order to be recognized by the U2-type spliceosome, possess strong consensus sequences maximized for base pair formation with U1 and U5/U6 snRNAs. However, variability in signal strength is a fundamental mechanism for splice site selection in alternative splicing. Here we report human alternative GC-AG introns (for the first time from any species), and show that while constitutive GC-AG introns do possess strong signals at their donor sites, a large subset of alternative GC-AG introns possess weak consensus sequences at their donor sites. Surprisingly, this subset of alternative isoforms shows strong consensus at acceptor exon positions 1 and 2. The improved consensus at the acceptor exon can facilitate a strong interaction with U5 snRNA, which tethers the two exons for ligation during the second step of splicing. Further, these isoforms nearly always possess alternative acceptor sites and exhibit particularly weak polypyrimidine tracts characteristic of AG-dependent introns. The acceptor exon nucleotides are part of the consensus required for the U2AF(35)-mediated recognition of AG in such introns. Such improved consensus at acceptor exons is not found in either normal or alternative GT-AG introns having weak donor sites or weak polypyrimidine tracts. The changes probably reflect mechanisms that allow GC-AG alternative intron isoforms to cope with two conflicting requirements, namely an apparent need for differential splice strength to direct the choice of alternative sites and a need for improved donor signals to compensate for the central mismatch base pair (C-A) in the RNA duplex of U1 snRNA and the pre-mRNA. The other important findings include (i) one in every twenty alternative introns is a GC-AG intron, and (ii) three of every five observed GC-AG introns are alternative isoforms.


Cunea n. g. (Amoebozoa, Dactylopodida) with two cryptic species isolated from different areas of the ocean.
This paper describes a new genus, Cunea n. g., of marine naked amoebae with two cryptic species, Cunea profundata and Cunea thuwala, isolated from distant localities in the ocean and different depths (Brazilian abyssal plain, Western Atlantic Ocean, depth >5km and the Red Sea off the Saudi Arabian coast, depth ca. 58.7m). Both species are very similar to each other in the set of light microscopic and ultrastructural characters and might be described as a single species, yet their genetic divergence based on 3 molecular markers (small-subunit ribosomal RNA, actin and cytochrome c oxidase subunit 1) corresponds to the level of variation typically observed between different morphospecies of Amoebozoa. In addition, the studied strains differ strongly in their temperature tolerance ranges, C. profundata isolated from the cold Atlantic deep-sea habitat being able to reproduce under lower temperatures than C. thuwala isolated from the warm Red Sea benthos. Molecular phylogenetic analysis based on SSU rRNA gene shows that the new genus robustly branches within the Dactylopodida, but forms an independent clade within this order that does not group with any of its known genera.


Aqueous Droplets Used as Enzymatic Microreactors and Their Electromagnetic Actuation.
For the successful implementation of microfluidic reaction systems, such as PCR and electrophoresis, the movement of small liquid volumes is essential. In conventional lab-on-a-chip-platforms, solvents and samples are passed through defined microfluidic channels with complex flow control installations. The droplet actuation platform presented here is a promising alternative. With it, it is possible to move a liquid drop (microreactor) on a planar surface of a reaction platform (lab-in-a-drop). The actuation of microreactors on the hydrophobic surface of the platform is based on the use of magnetic forces acting on the outer shell of the liquid drops which is made of a thin layer of superhydrophobic magnetite particles. The hydrophobic surface of the platform is needed to avoid any contact between the liquid core and the surface to allow a smooth movement of the microreactor. On the platform, one or more microreactors with volumes of 10 µL can be positioned and moved simultaneously. The platform itself consists of a 3 x 3 matrix of electrical double coils which accommodate either neodymium or iron cores. The magnetic field gradients are automatically controlled. By variation of the magnetic field gradients, the microreactors' magnetic hydrophobic shell can be manipulated automatically to move the microreactor or open the shell reversibly. Reactions of substrates and corresponding enzymes can be initiated by merging the microreactors or bringing them into contact with surface immobilized catalysts.


Control, elimination, and eradication of river blindness: scenarios, timelines, and ivermectin treatment needs in Africa.
River blindness (onchocerciasis) causes severe itching, skin lesions, and vision impairment including blindness. More than 99% of all current cases are found in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly reduced morbidity. Studies in Mali and Senegal proved the feasibility of elimination with ivermectin administration. The treatment goal is shifting from control to elimination in endemic African regions. Given limited resources, national and global policymakers need a rigorous analysis comparing investment options. For this, we developed scenarios for alternative treatment goals and compared treatment timelines and drug needs between the scenarios. Control, elimination, and eradication scenarios were developed with reference to current standard practices, large-scale studies, and historical data. For each scenario, the timeline when treatment is expected to stop at country level was predicted using a dynamical transmission model, and ivermectin treatment needs were predicted based on population in endemic areas, treatment coverage data, and the frequency of community-directed treatment. The control scenario requires community-directed treatment with ivermectin beyond 2045 with around 2.63 billion treatments over 2013-2045; the elimination scenario, until 2028 in areas where feasible, but beyond 2045 in countries with operational challenges, around 1.48 [corrected] billion treatments; and the eradication scenario, lasting until 2040, around 1.30 billion treatments. The eradication scenario is the most favorable in terms of the timeline of the intervention phase and treatment needs. For its realization, strong health systems and political will are required to overcome epidemiological and political challenges.


First-principles determination of defect energy levels through hybrid density functionals and GW.
In this topical review, we discuss recent progress in electronic-structure methods for calculating defect energy levels in semiconductors and insulators. We concentrate mainly on two advanced electronic-structure schemes, namely hybrid density functional theory and many-body perturbation theory in the GW approximation. These two schemes go beyond standard density functional theory in the semilocal approximation providing a more realistic description of band gaps. In particular, we address important aspects underlying the GW scheme and highlight the correspondence between the defect levels as obtained in the various schemes. We further assess the quality of the band-edge positions determined with hybrid functionals and GW through the calculation of band-offsets at semiconductor heterojunctions and of ionization potentials at semiconductor surfaces.


Biopsychosocial approach to psychological trauma and possible health consequences.
The diagnostic category of posttraumatic stress disorder (PTSD) has its place in the newest American diagnostic system DSM-V. The authors compare its definition with the former manual DSM-IV and the international classification ICD-10. They reflect difficulties in defining the concept of traumatic event. They summarize epidemiological findings, highlight the possible significant role of traumatogenesis in other psychiatric disorders without PTSD symptoms. The biopsychosocial model seems to be the most adequate for the study of trauma-related disorders, while in therapy the specific shaping of psychotherapy seems to be crucial. Good experiences in relationships before the trauma increase resilience and the availability of supportive empathetic relationships may favourably influence the development of the disorder and its therapy.


Observational Study to Preliminarily Characterize the Audiological Profile of Children With Down Syndrome.
Down syndrome occurs in one of 700 births, and high rates of hearing loss are reported in this population. This puts children with Down syndrome at risk for communication, learning, and social development difficulties, compounding known language and cognitive vulnerabilities in this population. The purpose of this study was to comprehensively characterize audiological profiles in children with Down syndrome, including the use of extended high-frequency sensitivity and speech intelligibility index assessment. Participants were 18 children with Down syndrome between 5 and 17 years of age. Audiological profiles were characterized using behavioral audiometry, tympanometry, and wideband acoustic immittance (WAI). Audibility was characterized using the speech intelligibility index. Of the participants successfully completing behavioral audiometry, hearing loss of a moderate or greater degree was observed in one or both ears for 46% of the participants at conventional audiometric test frequencies and 85% of the participants at frequencies above 8 kHz. Seven children met criteria for amplification based on the speech intelligibility index, but only two wore hearing aids. Abnormal middle ear function was found in approximately 50% of the participants for whom WAI or tympanometry were successfully measured. Consistent with prior research, high rates of hearing loss and middle ear dysfunction were observed. The high prevalence of hearing loss above 8 kHz suggests the importance of including extended high-frequency assessment in audiologic characterization of children with Down syndrome. Few children meeting audibility-based guidelines for amplification wore hearing aids, putting them at additional risk for speech/language and educational difficulties. https://doi.org/10.23641/asha.21200422.


Sleep and wake in rhythmic versus arrhythmic chronotypes of a microphthalmic species of African mole rat (Fukomys mechowii).
The giant Zambian mole rat (Fukomys mechowii) is a subterranean Afrotropical rodent noted for its regressed visual system and unusual patterns of circadian rhythmicity--within this species some individuals exhibit distinct regular circadian patterns of locomotor activity while others have arrhythmic circadian patterns. The current study was aimed at understanding whether differences in circadian chronotypes in this species affect the patterns and proportions of the different phases of the sleep-wake cycle. Physiological parameters of sleep (electroencephalogram and electromyogram) and behaviour (video recording) were recorded continuously for 72 h from 6 mole rats (3 rhythmic and 3 arrhythmic) using a telemetric system and a low-light CCTV camera connected to a DVD recorder. The results indicate that the arrhythmic individuals spend more time in waking with a longer average duration of a waking episode, less time in non-rapid eye movement (NREM) with a shorter average duration of an NREM episode though a greater NREM sleep intensity, and similar sleep cycle lengths. The time spent in rapid eye movement (REM) and the average duration of an REM episode were similar between the chronotypes.


Transcriptome analysis of dominant-negative Brd4 mutants identifies Brd4-specific target genes of small molecule inhibitor JQ1.
The bromodomain protein Brd4 is an epigenetic reader and plays a critical role in the development and maintenance of leukemia. Brd4 binds to acetylated histone tails and activates transcription by recruiting the positive elongation factor P-TEFb. Small molecule inhibitor JQ1 competitively binds the bromodomains of Brd4 and displaces the protein from acetylated histones. However, it remains unclear whether genes targeted by JQ1 are mainly regulated by Brd4 or by other bromodomain proteins such as Brd2 and Brd3. Here, we describe anti-proliferative dominant-negative Brd4 mutants that compete with the function of distinct Brd4 domains. We used these Brd4 mutants to compare the Brd4-specific transcriptome with the transcriptome of JQ1-treated cells. We found that most JQ1-regulated genes are also regulated by dominant-negative Brd4 mutants, including the mutant that competes with the P-TEFb recruitment function of Brd4. Importantly, JQ1 and dominant-negative Brd4 mutants regulated the same set of target genes of c-Myc, a key regulator of the JQ1 response in leukemia cells. Our results suggest that Brd4 mediates most of the anti-cancer effects of JQ1 and that the major function of Brd4 in this process is the recruitment of P-TEFb. In summary, our studies define the molecular targets of JQ1 in more detail.


Numerical investigation of hyperspectral tomography for simultaneous temperature and concentration imaging.
We investigate the simultaneous tomographic reconstruction of temperature and species concentration using hyperspectral absorption spectroscopy. Previous work on absorption tomography has relied on a small number of wavelengths, resulting in the requirement of a large number of projections and limited measurement capability. Here we develop a tomographic inversion method to exploit the increased spectral information content enabled by recent advancement in laser technologies. The simulation results clearly demonstrate that the use of hyperspectral absorption data significantly reduces the number of projections, enables simultaneous mapping of temperature and species concentration, and provides more stable reconstruction compared with traditional absorption tomographic techniques.


Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens.
Macrophages function at the front line of immune defences against incoming pathogens. But the ability of macrophages to internalize bacteria, migrate, recruit other immune cells to the site of infection and influence the nature of the immune response can provide unintended benefits for bacterial pathogens that are able to subvert or co-opt these normally effective defences. This review highlights recent advances in our understanding of the many interference strategies that are used by bacterial pathogens to undermine macrophage signalling.