Use of Technology to Address Substance Use in the Context of HIV: A Systematic Review.
Substance users are at elevated risk for HIV. HIV researchers, particularly at the intersection of HIV and substance use, have requested new methods to better understand and address this important area. New technologies, such as social media and mobile applications, are increasingly being used as research tools in studies on HIV and substance use. These technologies have the potential to build on existing recruitment methods, provide new and improved intervention methods, and introduce novel ways of monitoring and predicting new HIV cases. However, little work has been done to review and broadly explore the types of studies being conducted on the use of technologies to address HIV and substance use. This systematic literature review identified studies on this topic between 2005 and 2015. We identified 33 studies on this topic after excluding studies that did not fit inclusion criteria. Studies were either observational (n = 24) or interventional (n = 9), with the majority being pilot studies exploring the feasibility of using these new technologies to study HIV and substance use. We discuss the implications of this work along with limitations and recommendations for future research on this topic.


Dense core vesicles resemble active-zone transport vesicles and are diminished following synaptogenesis in mature hippocampal slices.
Large dense core vesicles (approximately 100 nm) contain neuroactive peptides and other co-transmitters. Smaller dense core vesicles (approximately 80 nm) are known to contain components of the presynaptic active zone and thought to transport and deliver these components during developmental synaptogenesis. It is not known whether excitatory axons in area CA1 contain such dense core vesicles, and whether they contribute to synaptic plasticity of mature hippocampus. Serial section electron microscopy was used to identify dense core vesicles in presynaptic axons in s. radiatum of area CA1 in adult rat hippocampus. Comparisons were made among perfusion-fixed hippocampus and hippocampal slices that undergo synaptogenesis during recovery in vitro. Dense core vesicles occurred in 26.1+/-3.6% of axonal boutons in perfusion fixed hippocampus, and in only 17.6+/-4.5% of axonal boutons in hippocampal slices (P<0.01). Most of the dense core vesicle positive boutons contained only one dense core vesicle, and no reconstructed axonal bouton had more than a total of 10 dense core vesicles in either condition. Overall the dense core vesicles had average diameters of 79+/-11 nm. These small dense core vesicles were usually located near nonsynaptic membranes and rarely occurred near the edge of a presynaptic active zone. Their size, low frequency, locations, and decrease following recuperative synaptogenesis in slices are novel findings that merit further study with respect to small dense core vesicle content and possible contributions to synapse assembly and plasticity in the mature hippocampus.


Socioeconomic factors and use of secondary preventive therapies for cardiovascular diseases in South Asia: The PURE study.
The purpose of this study was to determine the association of socioeconomic factors on use of cardioprotective medicines in known coronary heart disease (CHD) or stroke in South Asia. We enrolled 33,423 subjects aged 35-70 years (women 56%, rural 53%, low education 51%, low household wealth 25%) in 150 communities in India, Pakistan and Bangladesh during 2003-2009. Information regarding socioeconomic status, disease conditions and treatments was recorded. We studied influence of rural location, educational status and household wealth on use of drug therapies. Odds ratios (ORs) and 95% confidence intervals were calculated. CHD was reported in 683 (2.0%), stroke 316 (0.9%), and CHD/stroke in 970 (2.9%). Median duration since diagnosis was four years. Participants with CHD/stroke were older with greater prevalence of smoking, overweight, hypertension and diabetes (p < 0.01). In patients with CHD, stroke and CHD/stroke, respectively, use (%) of antiplatelets was 11.6, 3.8 and 9.3, beta-blockers 11.9, 7.0 and 10.4, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers 6.4, 1.9 and 5.3 and statins 4.8, 0.6 and 3.5. In CHD/stroke patients any one of these drugs was used in 18.1%, any two in 7.2%, any three in 2.8% and none in 81.5%. Details of drug dose were not available. Use of drugs was significantly lower in rural low education and low wealth index participants (all p < 0.01). Low wealth index participants had the lowest use of these therapies with no attenuation after multiple adjustments. The use of secondary preventive drug therapies in patients with known CHD or stroke in South Asia is low with over 80% receiving none of the effective drug treatments. Low household wealth is the most important determinant.


Mercury Telluride Quantum Dot Based Phototransistor Enabling High-Sensitivity Room-Temperature Photodetection at 2000 nm.
Near-to-mid-infrared photodetection technologies could be widely deployed to advance the infrastructures of surveillance, environmental monitoring, and manufacturing, if the detection devices are low-cost, in compact format, and with high performance. For such application requirements, colloidal quantum dot (QD) based photodetectors stand out as particularly promising due to the solution processability and ease of integration with silicon technologies; unfortunately, the detectivity of the QD photodetectors toward longer wavelengths has so far been low. Here we overcome this performance bottleneck through synergistic efforts between synthetic chemistry and device engineering. First, we developed a fully automated aprotic solvent, gas-injection synthesis method that allows scalable fabrication of large sized HgTe QDs with high quality, exhibiting a record high photoluminescence quantum yield of 17% at the photoluminescence peak close to 2.1 μm. Second, through gating a phototransistor structure we demonstrate room-temperature device response to reach >2 × 1010 cm Hz1/2 W-1 (at 2 kHz modulation frequency) specific detectivity beyond the 2 μm wavelength range, which is comparable to commercial epitaxial-grown photodetectors. To demonstrate the practical application of the QD phototransistor, we incorporated the device in a carbon monoxide gas sensing system and demonstrated reliable measurement of gas concentration. This work represents an important step forward in commercializing QD-based infrared detection technologies.


Repetitive transcranial magnetic stimulation for rehabilitation of poststroke dysphagia: A randomized, double-blind clinical trial.
This randomized, sham-controlled, double-blind study was conducted to investigate the effects of high-frequency versus low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with poststroke dysphagia during early rehabilitation. Forty patients with poststroke dysphagia were randomized to receive five daily sessions of sham, 3-Hz ipsilesional, or 1-Hz contralesional rTMS. Swallowing function, the severity of stroke and functional disability, and cortical excitability were examined before, immediately after five daily sessions, as well as the first, second, and third month after the last session. At baseline, no significant differences between groups were observed in terms of demographic and clinical rating scales. However, a significantly greater improvement in swallowing function as well as functional disability was observed after real rTMS when compared with sham rTMS, which remained 3 months after the end of the treatment sessions. In addition, 1-Hz rTMS increased cortical excitability of the affected hemisphere and decreased that of the non-affected hemisphere; however, 3-Hz rTMS only increased cortical excitability of the affected hemisphere. rTMS (both high and low frequency) improved swallowing recovery in patients with poststroke dysphagia, and the effects lasted for at least 3 months. rTMS appears to be a beneficial therapeutic modality for patients with dysphagia during the early phase of stroke.


The relation between income and mortality in U.S. blacks and whites.
Differential mortality exists in the United States both between racial/ethnic groups and along gradients of socioeconomic status. The specification of statistical models for processes underlying these observed disparities has been hindered by the fact that social and economic quantities are distributed in a highly nonrandom manner throughout the population. We sought to provide a substantive foundation for model development by representing the shape of the income-mortality relation by racial/ethnic group. We used data on black and white men and women from the longitudinal component of the National Health Interview Survey (NHIS), 1986-1990, which provided 1,191,824 person-years of follow-up and 12,165 mortal events. To account for family size when considering income, we used the ratio of annual family income to the federal poverty line for a family of similar composition. To avoid unnecessary categorizations and prior assumptions about model form, we employed kernel smoothing techniques and calculated the continuous mortality surface across dimensions of adjusted income and age for each of the gender and racial/ethnic groups. Representing regions of equal mortality density with contour plots, we observed interactions that need to be accommodated by any subsequent statistical models. We propose two general theories that provide a foundation for more elaborate and testable hypotheses in the future.


Validating tyrosinase homologue melA as a photoacoustic reporter gene for imaging Escherichia coli.
To understand the pathogenic processes for infectious bacteria, appropriate research tools are required for replicating and characterizing infections. Fluorescence and bioluminescence imaging have primarily been used to image infections in animal models, but optical scattering in tissue significantly limits imaging depth and resolution. Photoacoustic imaging, which has improved depth-to-resolution ratio compared to conventional optical imaging, could be useful for visualizing melA-expressing bacteria since melA is a bacterial tyrosinase homologue which produces melanin. Escherichia coli-expressing melA was visibly dark in liquid culture. When melA-expressing bacteria in tubes were imaged with a VisualSonics Vevo LAZR system, the signal-to-noise ratio of a 9×dilution sample was 55, suggesting that ∼20 bacteria cells could be detected with our system. Multispectral (680, 700, 750, 800, 850, and 900 nm) analysis of the photoacoustic signal allowed unmixing of melA-expressing bacteria from blood. To compare photoacoustic reporter gene melA (using Vevo system) with luminescent and fluorescent reporter gene Nano-lantern (using Bruker Xtreme In-Vivo system), tubes of bacteria expressing melA or Nano-lantern were submerged 10 mm in 1% Intralipid, spaced between <1 and 20 mm apart from each other, and imaged with the appropriate imaging modality. Photoacoustic imaging could resolve the two tubes of melA-expressing bacteria even when the tubes were less than 1 mm from each other, while bioluminescence and fluorescence imaging could not resolve the two tubes of Nano-lantern-expressing bacteria even when the tubes were spaced 10 mm from each other. After injecting 100-μL of melA-expressing bacteria in the back flank of a chicken embryo, photoacoustic imaging allowed visualization of melA-expressing bacteria up to 10-mm deep into the embryo. Photoacoustic signal from melA could also be separated from deoxy- and oxy-hemoglobin signal observed within the embryo and chorioallantoic membrane. Our results suggest that melA is a useful photoacoustic reporter gene for visualizing bacteria, and further work incorporating photoacoustic reporters into infectious bacterial strains is warranted.


ACUTE INTERSTITIAL NEPHRITIS.
Acute interstitial nephritis is found in the infectious diseases of children, particularly in diphtheria and scarlet fever, but may be met with in other infectious diseases. The disease is characterized by general and focal infiltration of the interstitial tissue of the kidney with cells which correspond to those which Unna has described under the name of plasma cells. The focal character of the infiltration is marked; even in the cases in which all parts of the kidney show some interstitial cellular infiltration the cells are most abundant in certain foci. These foci are found in three places: in the boundary zone of the pyramids, in the sub-capsular region of the cortex, and around the glomeruli. A considerable number of cases is found in which the blood-vessels of the boundary zone of the pyramids contain nnmbers of lymphoid and plasma cells without any infiltration of the interstitial tissue. The new cells in the interstitial tissue are due to emigration from the blood-vessels and multiplication by mitotic division of the cells which have emigrated. The cells can emigrate as plasma. cells or as lymphoid cells, and the latter may change into plasma cells in the tissues. In the normal individual, plasma cells may be formed in the mucous membrane of the intestine, where they practically form the entire tissue between the epithelium and the muscularis mucosa, and to a limited extent in the spleen. In diphtheria, in scarlet fever, and probably in a number of infectious diseases, plasma cells are formed in great numbers in the spleen and bone-marrow, and to some extent in the lymphatic glands. In the spleen they are formed from the cells of the Malpighian bodies, which are often principally composed of them, and to some extent from the cells in the pulp. They are formed from the lymphoid cells. No adequate explanation is found for the focal character of the lesions in the kidneys. There is some ground for believing that the physical conditions of the circulation may have something to do with their accumulation in the vessels in certain places. It is also possible that in the interstitial foci there may be soluble substances which exert a positive chemotaxis for them. Such substances may be foundin the urine, which may exert its influence on the interstitial tissue in different places. The explanation of the foci cannot be found in primary focal degeneration of the epithelium. Epithclial degeneration in these cases is always present, but it is diffuse. In foci where it is more intense and due to the interstitial changes, polynuclear leucocytes are found in the tissue, in the degenerated epithellum and in the tubules. Folynuclear lencocytes and not plasma cells are attracted by degenerated tissue. The foci are not due in these cases to the local action of bacteria. In a number of the cases in which interstitial nephritis was found the kidneys were shown to be sterile both by cultures and by microscopical examination. In cases where bacteria were present they were found only in small numbers in cultures and not on microscopical examination, and their connection with the foci could not be demonstrated. In three cases plasma cells were found in the interstitial tissue in definite bacterial diseases of the kidney. In these cases they were not found in connection with the lesions produced directly by the bacteria, but in the periphery of the purulent foci.


Extracellular glucose distribution is not altered by insulin: analysis of plasma and interstitial L-glucose kinetics.
We examined the effects of insulin on leg blood flow, whole body extracellular glucose distribution, and glucose diffusion into the interstitial fluid (ISF) surrounding skeletal muscle cells in anesthetized dogs. Extracellular glucose distribution and glucose diffusion into the muscle ISF were assessed by studying the kinetics of L-[1-14C]glucose in plasma and hindlimb lymph. Femoral artery blood flow was not increased with insulin (7.9 +/- 0.7 vs. 7.1 +/- 1.4 ml.min-1.kg-1; P = 0.54). Plasma and lymph dynamics of L-glucose after intravenous administration were superimposable between saline and insulin infusion experiments, indicating that insulin did not affect L-glucose disappearance from plasma or appearance in muscle ISF. Plasma L-glucose kinetics were best described by a four-compartment model, and one of the remote pools (intermediate) predicted the lymph L-glucose dynamics well. Estimation of maximum glucose diffusion capacity indicated that this pool, rather than the slowest pool, represents insulin-sensitive tissues. In conclusion, our data indicate that insulin does not increase transcapillary glucose diffusion to insulin-sensitive cells. In addition, hindlimb lymph represents primarily skeletal muscle ISF, which is represented by an intermediate, rather than the slowest, remote pool from whole body compartmental analysis.


Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours.
An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A person-year methodology was used to compare observed numbers of SPM against expected values generated from age- and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted.


Human leishmaniasis vaccines: Use cases, target population and potential global demand.
The development of vaccines against one or all forms of human leishmaniasis remains hampered by a paucity of investment, at least in part resulting from the lack of well-evidenced and agreed estimates of vaccine demand. Starting from the definition of 4 main use cases (prevention of visceral leishmaniasis, prevention of cutaneous leishmaniasis, prevention of post-kala-azar dermal leishmaniasis and treatment of post-kala-azar dermal leishmaniasis), we have estimated the size of each target population, focusing on those endemic countries where incidence levels are sufficiently high to justify decisions to adopt a vaccine. We assumed a dual vaccine delivery strategy, including a wide age-range catch-up campaign before the start of routine immunisation. Vaccine characteristics and delivery parameters reflective of a target product profile and the likely duration of the clinical development effort were considered in forecasting the demand for each of the four indications. Over a period of 10 years, this demand is forecasted to range from 300-830 million doses for a vaccine preventing visceral leishmaniasis and 557-1400 million doses for a vaccine preventing cutaneous leishmaniasis under the different scenarios we simulated. In a scenario with an effective prophylactic visceral leishmaniasis vaccine, demand for use to prevent or treat post-kala-azar dermal leishmaniasis would be more limited (over the 10 years ~160,000 doses for prevention and ~7,000 doses for treatment). Demand would rise to exceed 330,000 doses, however, in the absence of an effective vaccine for visceral leishmaniasis. Because of the sizeable demand and potential for public health impact, a single-indication prophylactic vaccine for visceral or cutaneous leishmaniasis, and even more so a cross-protective prophylactic vaccine could attract the interest of commercial developers. Continuous refinement of these first-of-their kind estimates and confirmation of country willingness and ability to pay will be paramount to inform the decisions of policy makers and developers in relation to a leishmaniasis vaccine. Positive decisions can provide a much-needed contribution towards the achievement of global leishmaniasis control.


Developmental benzo[a]pyrene (B[a]P) exposure impacts larval behavior and impairs adult learning in zebrafish.
Polycyclic aromatic hydrocarbons (PAHs) are produced from incomplete combustion of organic materials or fossil fuels, and are present in crude oil and coal; therefore, they are ubiquitous environmental contaminants present in urban air, dust, soil, and water. It is widely recognized that PAHs pose risks to human health, especially for the developing fetus and infant where PAH exposures have been linked to in-utero mortality, cardiovascular effects, and lower intelligence. Using the zebrafish model, we evaluated the developmental toxicity of benzo[a]pyrene (B[a]P). Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 0.4 and 4μM B[a]P. The Viewpoint Zebrabox systems were used to evaluate larval photomotor response (LPR) activity and we identified that exposure to 4μM B[a]P resulted in a hyperactive LPR phenotype. To evaluate the role of aryl hydrocarbon receptor (AHR) in this larval phenotype, we exposed ahr2hu2334 null larvae to 4μM B[a]P. Though ahr2hu2334 larvae did not display hyperactive swimming, these larvae had a decrease in LPR activity, suggesting that AHR2 plays a role in B[a]P induced larval hyperactivity. To determine if developmental B[a]P exposures would produce adult behavioral deficits, a subset of exposed animals was raised to adulthood and tested in a conditioned stimulus test using shuttleboxes. Developmentally exposed B[a]P zebrafish exhibited decreased learning and memory. Together this data demonstrates that developmental B[a]P exposure adversely impacts larval behavior, and learning in adult zebrafish.


Disclosure of distress among anxiety-disordered youth: differences in treatment outcome.
The present study evaluated treatment outcome differences in anxiety-disordered youth who differed in their disclosure of internal distress as measured in a structured diagnostic interview. One hundred and seventy-one clinic-referred, anxiety-disordered children served as participants. Participants' primary diagnoses were one of three anxiety disorders: separation anxiety, generalized anxiety/overanxious, or social phobia/avoidance. At a pretreatment assessment, children and their parents were interviewed separately using the Anxiety Disorders Interview Schedule (ADIS) to determine the child's diagnosis. The child's status as a discloser of high distress or discloser of low distress was determined by the parents' endorsement of an anxiety disorder and the child's endorsement or lack of endorsement of an anxiety disorder, respectively. Parents, teachers, and children also completed measures assessing the child's psychopathology (e.g., Revised Children's Manifest Anxiety Scale, Child Behavior Checklist). In general, findings indicated that the level of distress reported by the children moderated treatment outcome. Although both groups benefited from treatment, the children disclosing high distress experienced greater treatment gains than the children disclosing low distress.


Shear dependent red blood cell adhesion in microscale flow.
Non-adherence and deformability are the key intrinsic biomechanical features of the red blood cell (RBC), which allow it to tightly squeeze and pass through even the narrowest of microcirculatory networks. Blockage of microcirculatory flow, also known as vaso-occlusion, is a consequence of abnormal cellular adhesion to the vascular endothelium. In sickle cell disease (SCD), an inherited anaemia, even though RBCs have been shown to be heterogeneous in adhesiveness and deformability, this has not been studied in the context of physiologically relevant dynamic shear gradients at the microscale. We developed a microfluidic system that simulates physiologically relevant shear gradients of microcirculatory blood flow at a constant single volumetric flow rate. Using this system, shear dependent adhesion of RBCs from 28 subjects with SCD and from 11 healthy subjects was investigated using vascular endothelial protein functionalized microchannels. We defined a new term, RBC Shear Gradient Microfluidic Adhesion (SiGMA) index to assess shear dependent RBC adhesion in a subject-specific manner. We have shown for the first time that shear dependent adhesion of RBCs is heterogeneous in a microfluidic flow model, which correlates clinically with inflammatory markers and iron overload in subjects with SCD. This study reveals the complex dynamic interactions between RBC-mediated microcirculatory occlusion and clinical outcomes in SCD. These interactions may also be relevant to other microcirculatory disorders and microvascular diseases.


Predictive Modeling of Microbiome Data Using a Phylogeny-Regularized Generalized Linear Mixed Model.
Recent human microbiome studies have revealed an essential role of the human microbiome in health and disease, opening up the possibility of building microbiome-based predictive models for individualized medicine. One unique characteristic of microbiome data is the existence of a phylogenetic tree that relates all the microbial species. It has frequently been observed that a cluster or clusters of bacteria at varying phylogenetic depths are associated with some clinical or biological outcome due to shared biological function (clustered signal). Moreover, in many cases, we observe a community-level change, where a large number of functionally interdependent species are associated with the outcome (dense signal). We thus develop "glmmTree," a prediction method based on a generalized linear mixed model framework, for capturing clustered and dense microbiome signals. glmmTree uses the similarity between microbiomes, which is defined based on the microbiome composition and the phylogenetic tree, to predict the outcome. The effects of other predictive variables (e.g., age, sex) can be incorporated readily in the regression framework. Additional tuning parameters enable a data-adaptive approach to capture signals at different phylogenetic depth and abundance level. Simulation studies and real data applications demonstrated that "glmmTree" outperformed existing methods in the dense and clustered signal scenarios.


Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing.
Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.


Association of schizophrenia polygenic risk score with manic and depressive psychosis in bipolar disorder.
Bipolar disorder (BD) is highly heterogeneous in symptomatology. Narrowing the clinical phenotype may increase the power to identify risk genes that contribute to particular BD subtypes. This study was designed to test the hypothesis that genetic overlap between schizophrenia (SZ) and BD is higher for BD with a history of manic psychosis. Analyses were conducted using a Mayo Clinic Bipolar Biobank cohort of 957 bipolar cases (including 333 with history of psychosis during mania, 64 with history of psychosis only during depression, 547 with no history of psychosis, and 13 with unknown history of psychosis) and 778 controls. Polygenic risk score (PRS) analysis was performed by calculating a SZ-PRS for the BD cases and controls, and comparing the calculated SZ risk between different psychosis subgroups and bipolar types. The SZ-PRS was significantly higher for BD-I cases with manic psychosis than BD-I cases with depressive psychosis (Nagelkerke's R2 = 0.021; p = 0.045), BD-I cases without psychosis (R2 = 0.015; p = 0.007), BD-II cases without psychosis (R2 = 0.014; p = 0.017), and controls (R2 = 0.065; p = 2 × 10-13). No other significant differences were found. Our results show that BD-I with manic psychosis is genetically more similar to SZ than any other tested BD subgroup. Further investigations on genetics of distinct clinical phenotypes composing major psychoses may help refine the current diagnostic classification system.


Anisotropic microsphere-based approach to damage in soft fibered tissue.
An anisotropic damage model for soft fibered tissue is presented in this paper, using a multi-scale scheme and focusing on the directionally dependent behavior of these materials. For this purpose, a micro-structural or, more precisely, a microsphere-based approach is used to model the contribution of the fibers. The link between micro-structural contribution and macroscopic response is achieved by means of computational homogenization, involving numerical integration over the surface of the unit sphere. In order to deal with the distribution of the fibrils within the fiber, a von Mises probability function is incorporated, and the mechanical (phenomenological) behavior of the fibrils is defined by an exponential-type model. We will restrict ourselves to affine deformations of the network, neglecting any cross-link between fibrils and sliding between fibers and the surrounding ground matrix. Damage in the fiber bundles is introduced through a thermodynamic formulation, which is directly included in the hyperelastic model. When the fibers are stretched far from their natural state, they become damaged. The damage increases gradually due to the progressive failure of the fibrils that make up such a structure. This model has been implemented in a finite element code, and different boundary value problems are solved and discussed herein in order to test the model features. Finally, a clinical application with the material behavior obtained from actual experimental data is also presented.


Higher education and children in immigrant families.
The increasing role that immigrants and their children, especially those from Latin America, are playing in American society, Sandy Baum and Stella Flores argue, makes it essential that as many young newcomers as possible enroll and succeed in postsecondary education. Immigrant youths from some countries find the doors to the nation's colleges wide open. But other groups, such as those from Latin America, Laos, and Cambodia, often fail to get a postsecondary education. Immigration status itself is not a hindrance. The characteristics of the immigrants, such as their country of origin, race, and parental socioeconomic status, in addition to the communities, schools, and legal barriers that greet them in the United States, explain most of that variation. Postsecondary attainment rates of young people who come from low-income households and, regardless of income or immigration status, whose parents have no college experience are low across the board. Exacerbating the financial constraints is the reality that low-income students and those whose parents have little education are frequently ill prepared academically to succeed in college. The sharp rise in demand for skilled labor over the past few decades has made it more urgent than ever to provide access to postsecondary education for all. And policy solutions, say the authors, require researchers to better understand the differences among immigrant groups. Removing barriers to education and to employment opportunities for undocumented students poses political, not conceptual, problems. Providing adequate funding for postsecondary education through low tuition and grant aid is also straightforward, if not easy to accomplish. Assuring that Mexican immigrants and others who grow up in low-income communities have the opportunity to prepare themselves academically for college is more challenging. Policies to improve the elementary and secondary school experiences of all children are key to improving the postsecondary success of all.


Sapayoa aenigma: a New World representative of 'Old World suboscines'.
Passerine birds are very plastic in their adaptations, which has made it difficult to define phylogenetic lineages and correctly allocate all species to these. Sapayoa aenigma, a member of the large group of New World flycatchers, has been difficult to place, and DNA-DNA hybridization experiments have indicated that it may have been misplaced. This is confirmed here, as base sequencing of two nuclear genes places it as a deep branch in the group of broadbills and pittas of the Old World tropics. The peculiar distribution of this lineage may be best explained in terms of a Gondwanic and Late Cretaceous origin of the passerine birds, as this particular lineage dispersed from the Antarctic landmass, reaching the Old World tropics via the drifting Indian plate, and South America via the West Antarctic Peninsula.


Canfam_GSD: De novo chromosome-length genome assembly of the German Shepherd Dog (Canis lupus familiaris) using a combination of long reads, optical mapping, and Hi-C.
The German Shepherd Dog (GSD) is one of the most common breeds on earth and has been bred for its utility and intelligence. It is often first choice for police and military work, as well as protection, disability assistance, and search-and-rescue. Yet, GSDs are well known to be susceptible to a range of genetic diseases that can interfere with their training. Such diseases are of particular concern when they occur later in life, and fully trained animals are not able to continue their duties. Here, we provide the draft genome sequence of a healthy German Shepherd female as a reference for future disease and evolutionary studies. We generated this improved canid reference genome (CanFam_GSD) utilizing a combination of Pacific Bioscience, Oxford Nanopore, 10X Genomics, Bionano, and Hi-C technologies. The GSD assembly is ∼80 times as contiguous as the current canid reference genome (20.9 vs 0.267 Mb contig N50), containing far fewer gaps (306 vs 23,876) and fewer scaffolds (429 vs 3,310) than the current canid reference genome CanFamv3.1. Two chromosomes (4 and 35) are assembled into single scaffolds with no gaps. BUSCO analyses of the genome assembly results show that 93.0% of the conserved single-copy genes are complete in the GSD assembly compared with 92.2% for CanFam v3.1. Homology-based gene annotation increases this value to ∼99%. Detailed examination of the evolutionarily important pancreatic amylase region reveals that there are most likely 7 copies of the gene, indicative of a duplication of 4 ancestral copies and the disruption of 1 copy. GSD genome assembly and annotation were produced with major improvement in completeness, continuity, and quality over the existing canid reference. This resource will enable further research related to canine diseases, the evolutionary relationships of canids, and other aspects of canid biology.


Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1.
A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-β-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.


Chronic fatigue syndrome and fibromyalgia following immunization with the hepatitis B vaccine: another angle of the 'autoimmune (auto-inflammatory) syndrome induced by adjuvants' (ASIA).
The objectives of this study were to gather information regarding demographic and clinical characteristics of patients diagnosed with either fibromyalgia (FM) or chronic fatigue (CFS) following hepatitis B vaccination (HBVv) and furthermore to apply the recently suggested criteria of autoimmune (auto-inflammatory) syndromes induced by adjuvants (ASIA), in the aim of identifying common characteristics that may suggest an association between fibromyalgia, chronic fatigue and HBV vaccination. Medical records of 19 patients with CFS and/or fibromyalgia following HBVv immunization were analyzed. All of which were immunized during 1990-2008 in different centers in the USA. All medical records were evaluated for demographics, medical history, the number of vaccine doses, as well as immediate and long term post-immunization adverse events and clinical manifestations. In addition, available blood tests, imaging results, treatments and outcomes were analyzed. ASIA criteria were applied to all patients. The mean age of patients was 28.6 ± 11 years, of which 68.4 % were females. 21.05 % had either personal or familial background of autoimmune disease. The mean latency period from the last dose of HBVv to onset of symptoms was 38.6 ± 79.4 days, ranging from days to a year. Eight (42.1 %) patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neurological manifestations (84.2 %), musculoskeletal (78.9 %), psychiatric (63.1 %), fatigue (63.1 %), gastrointestinal complains (58 %) and mucocutaneous manifestations (36.8 %). Autoantibodies were detected in 71 % of patients tested. All patients fulfilled the ASIA criteria. This study suggests that in some cases CFS and FM can be temporally related to immunization, as part of ASIA syndrome. The appearance of adverse event during immunization, the presence of autoimmune susceptibility and higher titers of autoantibodies all can be suggested as risk factors. ASIA criteria were fulfilled in all patients eluding the plausible link between ASIA and CFS/FM.


Quantifying the roles of ecology and geography in spatial genetic divergence.
Investigating the properties of ecological landscapes that influence gene flow among populations can provide key insights into the earliest stages of biological divergence. Both ecological and geographical factors can reduce gene flow, which can lead to population divergence, but we know little of the relative strengths of these phenomena in nature. Here, we use a novel application of structural equation modelling to quantify the contributions of ecological and geographical isolation to spatial genetic divergence in 17 species of Anolis lizards. Our comparative analysis shows that although both processes contributed significantly, geographical isolation explained substantially more genetic divergence than ecological isolation (36.3 vs. 17.9% of variance respectively), suggesting that despite the proposed ubiquity of ecological divergence, non-ecological factors play the dominant role in the evolution of spatial genetic divergence.


Causal implications of viscous damping in compressible fluid flows
Classically, a compressible, isothermal, viscous fluid is regarded as a mathematical continuum and its motion is governed by the linearized continuity, Navier-Stokes, and state equations. Unfortunately, solutions of this system are of a diffusive nature and hence do not satisfy causality. However, in the case of a half-space of fluid set to motion by a harmonically vibrating plate the classical equation of motion can, under suitable conditions, be approximated by the damped wave equation. Since this equation is hyperbolic, the resulting solutions satisfy causal requirements. In this work the Laplace transform and other analytical and numerical tools are used to investigate this apparent contradiction. To this end the exact solutions, as well as their special and limiting cases, are found and compared for the two models. The effects of the physical parameters on the solutions and associated quantities are also studied. It is shown that propagating wave fronts are only possible under the hyperbolic model and that the concept of phase speed has different meanings in the two formulations. In addition, discontinuities and shock waves are noted and a physical system is modeled under both formulations. Overall, it is shown that the hyperbolic form gives a more realistic description of the physical problem than does the classical theory. Lastly, a simple mechanical analog is given and connections to viscoelastic fluids are noted. In particular, the research presented here supports the notion that linear compressible, isothermal, viscous fluids can, at least in terms of causality, be better characterized as a type of viscoelastic fluid.


Poly(D, L-lactide/epsilon-caprolactone)/hydroxyapatite composites as bone filler: an in vivo study in rats.
In this study, a novel composite bone substitute was implanted in animal models (rats) and their in vivo characteristics were examined. A D,L-lactide and E-caprolactone copolymer (Mw: 80,000; Mn:40,000, and PI:2.00) was synthesized by ring-opening polymerization of the respective dimers using stannous octoate as the catalyst. The final ratio of D,L-lactide to epsilon-caprolactone obtained by 1NMR was 60/40. Hydroxyapatite (HA) powder was loaded in the copolymer. The HA/copolymer ratio was 60/40 (w/w). These composites were easily shaped by hand. Animal tests were performed on mature wistar rats (n=30). Defects were created on the proximal, the thickest part of the femur. The bone defects of the first group were filled with polymer/HA composite, the second group filled with only HA and the third group was left empty. Histologic examination of bone tissues showed new bone formation around the yellow-green polymer/HA composite material in the first group of animals whereas no evidence of new bone growth was observed in other groups.


Autistic Traits Moderate the Impact of Reward Learning on Social Behaviour.
A deficit in empathy has been suggested to underlie social behavioural atypicalities in autism. A parallel theoretical account proposes that reduced social motivation (i.e., low responsivity to social rewards) can account for the said atypicalities. Recent evidence suggests that autistic traits modulate the link between reward and proxy metrics related to empathy. Using an evaluative conditioning paradigm to associate high and low rewards with faces, a previous study has shown that individuals high in autistic traits show reduced spontaneous facial mimicry of faces associated with high vs. low reward. This observation raises the possibility that autistic traits modulate the magnitude of evaluative conditioning. To test this, we investigated (a) if autistic traits could modulate the ability to implicitly associate a reward value to a social stimulus (reward learning/conditioning, using the Implicit Association Task, IAT); (b) if the learned association could modulate participants' prosocial behaviour (i.e., social reciprocity, measured using the cyberball task); (c) if the strength of this modulation was influenced by autistic traits. In 43 neurotypical participants, we found that autistic traits moderated the relationship of social reward learning on prosocial behaviour but not reward learning itself. This evidence suggests that while autistic traits do not directly influence social reward learning, they modulate the relationship of social rewards with prosocial behaviour.


Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states.
The role in skeletal metabolism of the steroid hormone Vitamin D and its nuclear receptor (VDR) is well known. In addition, however, Vitamin D is also involved in a wide variety of other biological processes including modulation of the immune response and regulation of cell proliferation and differentiation. Variations in the Vitamin D endocrine system have thus been linked to several diseases, including osteoarthritis, diabetes, cancer, cardiovascular disease and tuberculosis. Evidence to support this pleiotropic character of Vitamin D has included epidemiological studies on circulating Vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations which occur frequently in the population are referred to as "polymorphisms" and are usually suspected of having only modest and subtle effects. Recent studies have indicated many polymorphisms to exist in the VDR gene, but the influence of VDR gene polymorphisms on VDR protein function are largely unknown. Sofar, three adjacent restriction fragment length polymorphisms (RFLP) for BsmI, ApaI and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied sofar. But because these polymorphisms are probably non-functional, linkage disequilibrium (LD) with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis, and on trying to understand the functional consequences of the variations. Substantial progress has been made including the discovery of novel polymorphisms in the large promoter region of the VDR gene. Eventually, results of this research will deepen our understanding of variability in the Vitamin D endocrine system and might find applications in risk-assessment of disease and in predicting response-to-treatment.


Experimental evidence that wildflower strips increase pollinator visits to crops.
Wild bees provide a free and potentially diverse ecosystem service to farmers growing pollination-dependent crops. While many crops benefit from insect pollination, soft fruit crops, including strawberries are highly dependent on this ecosystem service to produce viable fruit. However, as a result of intensive farming practices and declining pollinator populations, farmers are increasingly turning to commercially reared bees to ensure that crops are adequately pollinated throughout the season. Wildflower strips are a commonly used measure aimed at the conservation of wild pollinators. It has been suggested that commercial crops may also benefit from the presence of noncrop flowers; however, the efficacy and economic benefits of sowing flower strips for crops remain relatively unstudied. In a study system that utilizes both wild and commercial pollinators, we test whether wildflower strips increase the number of visits to adjacent commercial strawberry crops by pollinating insects. We quantified this by experimentally sowing wildflower strips approximately 20 meters away from the crop and recording the number of pollinator visits to crops with, and without, flower strips. Between June and August 2013, we walked 292 crop transects at six farms in Scotland, recording a total of 2826 pollinators. On average, the frequency of pollinator visits was 25% higher for crops with adjacent flower strips compared to those without, with a combination of wild and commercial bumblebees (Bombus spp.) accounting for 67% of all pollinators observed. This effect was independent of other confounding effects, such as the number of flowers on the crop, date, and temperature. Synthesis and applications. This study provides evidence that soft fruit farmers can increase the number of pollinators that visit their crops by sowing inexpensive flower seed mixes nearby. By investing in this management option, farmers have the potential to increase and sustain pollinator populations over time.


Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF.
Connective tissue growth factor (CTGF) is a growth and chemotactic factor for fibroblasts encoded by an immediate early gene that is transcriptionally activated by transforming growth factor-beta. Previous studies have shown that both CTGF messenger ribonuclear acid (mRNA) and protein are expressed in renal fibrosis and bleomycin-induced pulmonary fibrosis in mice. The aim of the present study was to investigate the localization of CTGF protein and its mRNA expression in the fibrotic lung tissue of patients with idiopathic pulmonary fibrosis (IPF). Using human fibrotic lung tissue obtained from eight autopsy cases and four biopsy cases with IPF, immunohistochemical staining, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) were performed. The cellular immunoreactivity for CTGF was markedly increased in the lung tissue of patients with IPF, compared to normal lungs. The immunolocalization of CTGF was confined predominantly to proliferating type II alveolar epithelial cells and activated fibroblasts. In the normal lung, type II alveolar epithelial cells stained for CTGF were sparsely distributed. CTGF mRNA was localized in proliferating type II alveolar epithelial cells and activated fibroblasts in the interstitium of fibrotic lung tissues. RT-PCR analysis showed that CTGF mRNA was expressed at a higher level in fibrotic lungs than in normal lungs. In both an autocrine and a paracrine manner, type II alveolar epithelial cells and activated fibroblasts may play a critical role in pulmonary fibrosis by producing connective tissue growth factor which modulates fibroblast proliferation and extracellular matrix production.


Use of macrophages to target therapeutic adenovirus to human prostate tumors.
New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells.


Developing a statewide childhood body mass index surveillance program.
Several states have implemented childhood obesity surveillance programs supported by legislation. Representatives from Idaho wished to develop a model for childhood obesity surveillance without the support of state legislation, and subsequently report predictors of overweight and obesity in the state. A coalition comprised of the Idaho State Department of Education and 4 universities identified a randomized cluster sample of schools. After obtaining school administrator consent, measurement teams traveled to each school to measure height and weight of students. Sex and race/ethnicity data were also collected. The collaboration between the universities resulted in a sample of 6735 students from 48 schools and 36 communities. Overall, 29.2% of the youth in the sample were classified as overweight or obese, ranging from 24.0% for grade 1 to 33.8% for grade 5. The prevalence of overweight and obesity across schools was highly variable (31.2 ± 7.58%). Hierarchical logistic regression indicated that sex, age, race/ethnicity, socioeconomic status, and region were all significant predictors of overweight and obesity, whereas school was not. This coalition enabled the state of Idaho to successfully estimate the prevalence of overweight and obesity on a representative sample of children from all regions of the state, and subsequently identify populations at greatest risk.


[Lipids-Diagnosis and therapy in diabetes mellitus (Update 2023)].
Hyper- and dyslipidemia contribute to cardiovascular morbidity and mortality in diabetic patients. Pharmacological therapy to lower LDL cholesterol has convincingly shown to reduce cardiovascular risk in diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the use of lipid-lowering drugs in diabetic patients according to current scientific evidence.


Study protocol: Mother and Infant Nutritional Assessment (MINA) cohort study in Qatar and Lebanon.
The Middle East and North Africa region harbors significant proportions of stunting and wasting coupled with surging rates of non-communicable diseases (NCDs). Recent evidence identified nutrition during the first 1000 days of life as a common denominator not only for optimal growth but also for curbing the risk of NCDs later in life. The main objective of this manuscript is to describe the protocol of the first cohort in the region to investigate the association of nutrition imbalances early in life with birth outcomes, growth patterns, as well as early determinants of non-communicable diseases. More specifically the cohort aims to 1) examine the effects of maternal and early child nutrition and lifestyle characteristics on birth outcomes and growth patterns and 2) develop evidence-based nutrition and lifestyle guidelines for pregnant women and young children. A multidisciplinary team of researchers was established from governmental and private academic and health sectors in Lebanon and Qatar to launch the Mother and Infant Nutritional Assessment 3-year cohort study. Pregnant women (n = 250 from Beirut, n = 250 from Doha) in their first trimester are recruited from healthcare centers in Beirut, Lebanon and Doha, Qatar. Participants are interviewed three times during pregnancy (once every trimester) and seven times at and after delivery (when the child is 4, 6, 9, 12, 18, and 24 months old). Delivery and birth data is obtained from hospital records. Data collection includes maternal socio-demographic and lifestyle characteristics, dietary intake, anthropometric measurements, and household food security data. For biochemical assessment of various indicators of nutritional status, a blood sample is obtained from women during their first trimester. Breastfeeding and complementary feeding practices, dietary intake, as well as anthropometric measurements of children are also examined. The Delphi technique will be used for the development of the nutrition and lifestyle guidelines. The Mother and Infant Nutritional Assessment study protocol provides a model for collaborations between countries of different socio-economic levels within the same region to improve research efficiency in the field of early nutrition thus potentially leading to healthier pregnancies, mothers, infants, and children.


Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex.
Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.


The specificity of the collaterals to the brain through the study and surgical treatment of moyamoya disease.
Moyamoya disease presents clinically as chronic progressive ischemia in the young brain. The brain is surrounded by concentric collateral networks but all of these networks are not available as collaterals in the early stage of cerebral ischemia. The anatomical characteristics precluding their early use include the presence of the watery layer of subarachnoid fluid between the cortical and dural vessels and of a closed bony box intervening between the dural and scalp arterial networks. These barriers isolate the brain from the abundant blood flow of the external carotid system as if they were the moat (the subarachnoid fluid layer) and the walls (the skull) of a castle. Based on these concepts, we have developed a surgical procedure, the encephalo-duro-arterio-synangiosis to treat moyamoya disease in children. This operation surmounts the above mentioned two obstacles to collateral formation to the brain by perforating the castle wall and bridging the moat by granulation tissue, without injuring the collaterals which are already formed. This procedure was performed on 70 sides in 38 pediatric moyamoya patients. Revascularisation of the brain was obtained in 100 percent of the cases with varying improvement in the symptoms.


Modeling and in Situ Probing of Surface Reactions in Atomic Layer Deposition.
Atomic layer deposition (ALD) has matured into a preeminent thin film deposition technique by offering a highly scalable and economic route to integrate chemically dissimilar materials with excellent thickness control down to the subnanometer regime. Contrary to its extensive applications, a quantitative and comprehensive understanding of the reaction processes seems intangible. Complex and manifold reaction pathways are possible, which are strongly affected by the surface chemical state. Here, we report a combined modeling and experimental approach utilizing ReaxFF reactive force field simulation and in situ real-time spectroscopic ellipsometry to gain insights into the ALD process of Al2O3 from trimethylaluminum and water on hydrogenated and oxidized Ge(100) surfaces. We deciphered the origin for the different peculiarities during initial ALD cycles for the deposition on both surfaces. While the simulations predicted a nucleation delay for hydrogenated Ge(100), a self-cleaning effect was discovered on oxidized Ge(100) surfaces and resulted in an intermixed Al2O3/GeOx layer that effectively suppressed oxygen diffusion into Ge. In situ spectroscopic ellipsometry in combination with ex situ atomic force microscopy and X-ray photoelectron spectroscopy confirmed these simulation results. Electrical impedance characterizations evidenced the critical role of the intermixed Al2O3/GeOx layer to achieve electrically well-behaved dielectric/Ge interfaces with low interface trap density. The combined approach can be generalized to comprehend the deposition and reaction kinetics of other ALD precursors and surface chemistry, which offers a path toward a theory-aided rational design of ALD processes at a molecular level.


Stratigraphy of the Anthropocene.
The Anthropocene, an informal term used to signal the impact of collective human activity on biological, physical and chemical processes on the Earth system, is assessed using stratigraphic criteria. It is complex in time, space and process, and may be considered in terms of the scale, relative timing, duration and novelty of its various phenomena. The lithostratigraphic signal includes both direct components, such as urban constructions and man-made deposits, and indirect ones, such as sediment flux changes. Already widespread, these are producing a significant 'event layer', locally with considerable long-term preservation potential. Chemostratigraphic signals include new organic compounds, but are likely to be dominated by the effects of CO(2) release, particularly via acidification in the marine realm, and man-made radionuclides. The sequence stratigraphic signal is negligible to date, but may become geologically significant over centennial/millennial time scales. The rapidly growing biostratigraphic signal includes geologically novel aspects (the scale of globally transferred species) and geologically will have permanent effects.


Effects of Ultrasound Frequency on Nanodroplet-Mediated Histotripsy.
Nanodroplet-mediated histotripsy (NMH) is a targeted ultrasound ablation technique combining histotripsy with nanodroplets that can be selectively delivered to tumor cells for targeted tumor ablation. In a previous study, it was reported that by use of extremely short, high-pressure pulses, histotripsy cavitation bubbles were generated in regions containing nanodroplets at significantly lower pressure (∼10.8 MPa) than without nanodroplets (∼28 MPa) at 500 kHz. Furthermore, it was hypothesized that lower frequency would improve the effectiveness of NMH by increasing the size of the focal region, increasing bubble expansion, and decreasing the cavitation threshold. In this study, we investigated the effects of ultrasound frequency (345 kHz, 500 kHz, 1.5 MHz, and 3 MHz) on NMH. First, the NMH cavitation threshold was measured in tissue phantoms with and without nanodroplets, with results indicating that the NMH threshold was significantly below the histotripsy intrinsic threshold at all frequencies. Results also indicated that the NMH threshold decreased at lower frequency, ranging from 7.4 MPa at 345 kHz to 13.2 MPa at 3 MHz. In the second part of this study, the effects of frequency on NMH bubble expansion were investigated, with results indicating larger expansion at lower frequency, even at a lower pressure. In the final part of this study, the ability of perfluoropentane-encapsulated nanodroplets to act as sustainable cavitation nuclei over multiple pulses was investigated, with results indicating that the nanodroplets are destroyed by the cavitation process and only function as cavitation nuclei for the first few pulses, with this effect being most pronounced at higher frequencies. Overall, the results of this study support our hypothesis that using a lower frequency will improve the effectiveness of NMH by increasing the size of the focal region, increasing bubble expansion and decreasing the cavitation threshold.


Toxoplasma co-opts host cells it does not invade.
Like many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.


Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies.
Considerable controversy exists regarding the association between dietary calcium intake and risk of mortality from cardiovascular disease and all causes. Therefore, we performed a meta-analysis of prospective cohort studies to examine the controversy. We identified relevant studies by searching MEDLINE, Embase, and the Cochrane Library databases between 1 September 2013 and 30 December 2013. Reference lists of relevant articles were also reviewed. Observational prospective studies that reported relative risks and 95% confidence intervals for the association of calcium intake with cardiovascular and all-cause mortality were eligible. Study-specific relative risks were pooled using a random-effects model. In this meta-analysis, 11 prospective studies with 12 independent cohorts, involving 757,304 participants, were eligible. There was evidence of a non-linear association between dietary calcium intake and risk of mortality from cardiovascular disease (P for non-linearity <0.01) and all causes (P for non-linearity <0.01). A dose-response analysis showed a U-shaped relationship between dietary calcium intake and cardiovascular mortality. Intakes that were lower and higher than around 800 mg/day were gradually associated with a higher risk of cardiovascular mortality. For all-cause mortality, we also observed a threshold effect at intakes around 900 mg/day. The risk of all-cause mortality did not decrease further at intakes above 900 mg/day. This meta-analysis of prospective cohort studies suggests that dietary calcium intake is associated with cardiovascular mortality in a U-shaped manner and that high dietary calcium intake (>900 mg/day) is not associated with a decreased risk of all-cause mortality.


Biocontrol of Gray Mold Decay in Pear by Bacillus amyloliquefaciens Strain BA3 and its Effect on Postharvest Quality Parameters.
The economic losses caused by postharvest fruits diseases have attracted global attention. Traditional chemical fungicide could not meet the need of humans. In recent years, microbial agent which has begun to take the place of chemical fungicide comes into people's vision. The aim of this paper was to investigate the potential of Bacillus amyloliquefaciens strain BA3 for its biocontrol capability on gray mold decay of pears and its effect on postharvest quality of pears. Compared with other treatments, the inhibition effect on gray mold of washed cell suspension of B. amyloliquefaciens was the best. Consequently it was utilized in subsequent experiments. Spore germination and germ tube length of Botrytis cinerea was 18.72% and 12.85 μm treated with BA3, while the control group was 62.88% and 30.44 μm. We confirmed that increase of the concentration of B. amyloliquefaciens, improved the efficacy of BA3 in controlling gray mold decay of pears. Colonization variation of BA3 in wounds of pears was recorded. To begin with, the populations of B. amyloliquefaciens increased rapidly and remained stable. On the fourth day, there was a declining trend , after that the population increased to 4 × 10(5) CFU/wound and remained stable. BA3 had no significant effect on mass loss, titratable acidity, firmness and total soluble solids of pears that were stored at 25°C for 7 days comparing with control group. However, the effect of B. amyloliquefaciens on ascorbic acid was significantly higher than that of the control group. Our study indicates that B. amyloliquefaciens has a potential as postharvest biocontrol agent on pears.


Leptin independently predicts development of sepsis and its outcome.
Sepsis is a life-threatening condition and obesity is related to the clinical outcome. The underlying reasons are incompletely understood, but the adipocyte derived hormones leptin and adiponectin may be involved. Patients aged 18 years or more with documented first time sepsis events were included in a nested case-referent study if they had participated in previous health surveys. Two matched referents free of known sepsis were identified. Circulating levels of leptin and adiponectin were determined in stored plasma, and their impact on a future sepsis event and its outcome was evaluated. We identified 152 patients (62% women) with a sepsis event and a previous participation in a health survey. Eighty-three % had also blood samples from the acute event. Hyperleptinemia at health survey associated with a future sepsis event (OR 1.77, 95% CI 1.04-3.00) and with hospital death. After adjustment for BMI leptin remained associated with sepsis in men, but not in women. High levels in the acute phase associated with increased risk for in hospital death in women (OR 4.18, 95% CI 1.17-15.00), while being protective in men (OR 0.05, 95% CI 0.01-0.48). Furthermore, leptin increased more from baseline to the acute phase in men than in women. Adiponectin did not predict sepsis and did not relate to outcome. Hyperleptinemia independently predicted the development of sepsis and an unfavourable outcome in men, and inertia in the acute response related to worse outcome.


Rheumatoid arthritis (RA)-associated HLA-DR alleles form less stable complexes with class II-associated invariant chain peptide than non-RA-associated HLA-DR alleles.
Certain HLA-DR alleles confer strong susceptibility to the autoimmune disease rheumatoid arthritis (RA). We compared RA-associated alleles, HLA-DR*0401, HLA-DR*0404, and HLA-DR*0405, with closely related, non-RA-associated alleles, HLA-DR*0402 and HLA-DR*0403, to determine whether they differ in their interactions with the class II chaperone, invariant chain (Ii). Ii binds to class II molecules in the endoplasmic reticulum, inhibits binding of other ligands, and directs class II-Ii complexes to endosomes, where Ii is degraded to class II-associated Ii peptide (CLIP). To evaluate the interaction of Ii and CLIP with these DR4 alleles, we introduced HLA-DR*0401, *0402, and *0404 alleles into a human B cell line that lacked endogenous HLA-DR or HLA-DM molecules. In a similar experiment, we introduced HLA-DR*0403 and *0405 into an HLA-DM-expressing B cell line, 8.1.6, and its DM-negative derivative, 9.5.3. Surface abundance of DR4-CLIP peptide complexes and their susceptibility to SDS-induced denaturation suggested that the different DR4-CLIP complexes had different stabilities. Pulse-chase experiments showed CLIP dissociated more rapidly from RA-associated DR molecules in B cell lines. In vitro assays using soluble rDR4 molecules showed that DR-CLIP complexes of DR*0401 and DR*0404 were less stable than complexes of DR*0402. Using CLIP peptide variants, we mapped the reduced CLIP interaction of RA-associated alleles to the shared epitope region. The reduced interaction of RA-associated HLA-DR4 molecules with CLIP may contribute to the pathophysiology of autoimmunity in RA.


OBSTRUCTIVE LUNG DISEASE AND EXPOSURE TO BURNING BIOMASS FUEL IN THE INDOOR ENVIRONMENT.
It is estimated that up to half of the world's population burns biomass fuel (wood, crop residues, animal dung and coal) for indoor uses such as cooking, lighting and heating. As a result, a large proportion of women and children are exposed to high levels of household air pollution (HAP). The short and long term effects of these exposures on the respiratory health of this population are not clearly understood. On May 9-11, 2011 NIH held an international workshop on the "Health Burden of Indoor Air Pollution on Women and Children," in Arlington, VA. To gather information on the knowledge base on this topic and identify research gaps, ahead of the meeting we conducted a literature search using PubMed to identify publications that related to HAP, asthma, and chronic obstructive pulmonary disease (COPD). Abstracts were all analyzed and we report on those considered by the respiratory sub study group at the meeting to be most relevant to the field. Many of the studies published are symptom-based studies (as opposed to objective measures of lung function or clinical examination etc.) and measurement of HAP was not done. Many found some association between indoor exposures to biomass smoke as assessed by stove type (e.g., open fire vs. liquid propane gas) and respiratory symptoms such as wheeze and cough. Among the studies that examined objective measures (e.g. spirometry) as a health outcome, the data supporting an association between biomass smoke exposure and COPD in adult women are fairly robust, but the findings for asthma are mixed. If an association was observed between the exposures and lung function, most data seemed to demonstrate mild to moderate reductions in lung function, the pathophysiological mechanisms of which need to be investigated. In the end, the group identified a series of scientific gaps and opportunities for research that need to be addressed to better understand the respiratory effects of exposure to indoor burning of the different forms of biomass fuels.


Integrative analysis of metabolite and transcript abundance during the short-term response to saline and oxidative stress in the brown alga Ectocarpus siliculosus.
The model brown alga Ectocarpus siliculosus undergoes extensive transcriptomic changes in response to abiotic stress, many of them related to primary metabolism and particularly to amino acid biosynthesis and degradation. In this study we seek to improve our knowledge of the mechanisms underlying the stress tolerance of this alga, in particular with regard to compatible osmolytes, by examining the effects of these changes on metabolite concentrations. We performed extensive metabolic profiling (urea, amino acids, sugars, polyols, organic acids, fatty acids) of Ectocarpus samples subjected to short-term hyposaline, hypersaline and oxidative stress, and integrated the results with previously published transcriptomic data. The most pronounced changes in metabolite concentrations occurred under hypersaline stress: both mannitol and proline were accumulated, but their low final concentrations indicate that, in this stress condition, both compounds are not likely to significantly contribute to osmoregulation at the level of the entire cell. Urea and trehalose were not detected in any of our samples. We also observed a shift in fatty acid composition from n-3 to n-6 fatty acids under high salinities, and demonstrated the salt stress-induced accumulation of small amounts of γ-aminobutyric acid (GABA). GABA could be synthesized in E. siliculosus through a salt stress-induced putrescine-degradation pathway.


Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Eli Lilly and Company. For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.


Effects of synthetic iron and aluminium oxide surface charge and hydrophobicity on the formation of bacterial biofilm.
In this research, bacterial cell attachments to hematite, goethite and aluminium hydroxide were investigated. The aim was to study the effects of these minerals' hydrophobicity and pH-dependent surface charge on the extent of biofilm formation using six genetically diverse bacterial strains: Rhodococcus spp. (RC92 & RC291), Pseudomonas spp. (Pse1 & Pse2) and Sphingomonas spp. (Sph1 & Sph2), which had been previously isolated from contaminated environments. The surfaces were prepared in a way that was compatible with the naturally occurring coating process in aquifers: deposition of colloidal particles from the aqueous phase. The biofilms were evaluated using a novel, in situ and non-invasive technique developed for this purpose. A manufactured polystyrene 12-well plate was used as the reference surface to be coated with synthesized minerals by deposition of their suspended particles through evaporation. Planktonic phase growth indicates that it is independent of the surface charge and hydrophobicity of the studied surfaces. The hydrophobic similarities failed to predict biofilm proliferation. Two of the three hydrophilic strains formed extensive biofilms on the minerals. The third one, Sph2, showed anomalies in contrast to the expected electrostatic attraction between the minerals and the cell surface. Further research showed how the solution's ionic strength affects Sph2 surface potential and shapes the extent of its biofilm formation; reducing the ionic strength from ≈200 mM to ≈20 mM led to a tenfold increase in the number of cells attached to hematite. This study provides a technique to evaluate biofilm formation on metal-oxide surfaces, under well-controlled conditions, using a simple yet reliable method. The findings also highlight that cell numbers in the planktonic phase do not necessarily show the extent of cell attachment, and thorough physicochemical characterization of bacterial strains, substrata and the aquifer medium is fundamental to successfully implementing any bioremediation projects.


Prevalence of Preoperative Lower Urinary Tract Symptoms in Patients Undergoing Elective Lumbar Spine Surgery.
Cross-sectional cohort study. To determine the prevalence of moderate-to-severe lower urinary tract symptoms (LUTS) in patients undergoing elective lumbar spine surgery, and to describe associations between prevalence, severity of symptoms, demographic variables, and spine pathology. The prevalence of LUTS is unknown in patients with lumbar spine disease. Furthermore, the extent of LUTS severity and the relationship between spine pathology and LUTS is not well documented. We used the validated International Prostate Symptom Score (IPSS) to assess LUTS severity among elective lumbar spine surgery patients from October 2015 to April 2017 at a single academic institution. Moderate-to-severe LUTS was defined as IPSS score of 8 or more. The IPSS also includes a question to assess urinary bother, for which a score of 4 or more indicates clinically significant bother. Prevalence estimates and 95% confidence intervals were computed in the sample overall, and according to sex, age, and lumbar spine diagnosis. IPSS data were obtained from 373 patients (97% of those eligible) undergoing elective lumbar spine surgery. Moderate-to-severe urinary symptoms were reported by 46% of these patients, and by 51% of women and 42% of men. Prevalence of moderate-to-severe urinary symptoms increased with age, rising from 38% in patients younger than 40 years to 57% in patients 70 years or older. LUTS prevalence according to spondylolisthesis, stenosis, scoliosis, and herniated nucleus pulposus diagnostic groups were 51%, 50%, 50%, and 31%, respectively. Clinically significant urinary bother was reported by 14% overall, 10% of men, and 18% of women, and prevalence also increased with age. Moderate-to-severe LUTS were highly prevalent in this sample. Urinary symptoms are more prevalent with increasing age, in women, and in patients with stenosis, spondylolisthesis, and scoliosis. Proportionally, fewer patients reported clinically significant urinary bother, which may impact patient reporting and physician identification of urinary symptoms. 3.


Nutrition metabolism plays an important role in the alternate bearing of the olive tree (Olea europaea L.).
The olive tree (Olea europaea L.) is widely known for its strong tendency for alternate bearing, which severely affects the fruit yield from year to year. Microarray based gene expression analysis using RNA from olive samples (on-off years leaves and ripe-unripe fruits) are particularly useful to understand the molecular mechanisms influencing the periodicity in the olive tree. Thus, we carried out genome wide transcriptome analyses involving different organs and temporal stages of the olive tree using the NimbleGen Array containing 136,628 oligonucleotide probe sets. Cluster analyses of the genes showed that cDNAs originated from different organs could be sorted into separate groups. The nutritional control had a particularly remarkable impact on the alternate bearing of olive, as shown by the differential expression of transcripts under different temporal phases and organs. Additionally, hormonal control and flowering processes also played important roles in this phenomenon. Our analyses provide further insights into the transcript changes between "on year" and "off year" leaves along with the changes from unrpipe to ripe fruits, which shed light on the molecular mechanisms underlying the olive tree alternate bearing. These findings have important implications for the breeding and agriculture of the olive tree and other crops showing periodicity. To our knowledge, this is the first study reporting the development and use of an olive array to document the gene expression profiling associated with the alternate bearing in olive tree.


Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes.
It is established that mutations in viral antigenic epitopes, or antigenic drifts, allow viruses to escape recognition by both Ab's and T lymphocytes. It is unclear, however, whether tumor cells can escape immune recognition via antigenic drift. Here we show that adoptive therapy with both monoclonal and polyclonal transgenic CTLs, specific for a natural tumor antigen, P1A, selects for multiple mutations in the P1A antigenic epitope. These mutations severely diminish T cell recognition of the tumor antigen by a variety of mechanisms, including modulation of MHC:peptide interaction and TCR binding to MHC:peptide complex. These results provide the first evidence for tumor evasion of T cell recognition by antigenic drift, and thus have important implications for the strategy of tumor immunotherapy.


Complex Medial Meniscus Tears Are Associated With a Biconcave Medial Tibial Plateau.
To determine whether an association exists between a biconcave medial tibial plateau and complex medial meniscus tears. A consecutive series of stable knees undergoing arthroscopy were evaluated retrospectively with the use of preoperative magnetic resonance imaging (MRI), radiographs, and arthroscopy documented by intraoperative videos. Investigators independently performed blinded reviews of the MRI or videos. Based on the arthroscopy findings, medial tibial plateaus were classified as either biconcave or not biconcave. A transverse coronal plane ridge, separating the front of the tibial plateau from the back near the inner margin of the posterior body of the medial meniscus, was defined as biconcave. The medial plateau slope was calculated with MRI sagittal views. General demographic information, body mass index, and arthroscopically confirmed knee pathology were recorded. A total of 179 consecutive knees were studied from July 2014 through August 2015; 49 (27.2%) biconcave medial tibial plateaus and 130 (72.8%) controls were identified at arthroscopy. Complex medial meniscus tears were found in 103. Patients with a biconcave medial tibial plateau were found to have more complex medial meniscus tears (69.4%) than those without a biconcavity (53.1%) (P = .049) despite having lower body mass index (P = .020). No difference in medial tibial plateau slope was observed for biconcavities involving both cartilage and bone, bone only, or an indeterminate group (P = .47). Biconcave medial tibial plateaus were present in 27.4% of a consecutive series of patients undergoing knee arthroscopy. A biconcave medial tibial plateau was more frequently associated with a complex medial meniscus tear. Level III, case-control study.


Core formation and core composition from coupled geochemical and geophysical constraints.
The formation of Earth's core left behind geophysical and geochemical signatures in both the core and mantle that remain to this day. Seismology requires that the core be lighter than pure iron and therefore must contain light elements, and the geochemistry of mantle-derived rocks reveals extensive siderophile element depletion and fractionation. Both features are inherited from metal-silicate differentiation in primitive Earth and depend upon the nature of physiochemical conditions that prevailed during core formation. To date, core formation models have only attempted to address the evolution of core and mantle compositional signatures separately, rather than seeking a joint solution. Here we combine experimental petrology, geochemistry, mineral physics and seismology to constrain a range of core formation conditions that satisfy both constraints. We find that core formation occurred in a hot (liquidus) yet moderately deep magma ocean not exceeding 1,800 km depth, under redox conditions more oxidized than present-day Earth. This new scenario, at odds with the current belief that core formation occurred under reducing conditions, proposes that Earth's magma ocean started oxidized and has become reduced through time, by oxygen incorporation into the core. This core formation model produces a core that contains 2.7-5% oxygen along with 2-3.6% silicon, with densities and velocities in accord with radial seismic models, and leaves behind a silicate mantle that matches the observed mantle abundances of nickel, cobalt, chromium, and vanadium.


Regulation of epithelial cell growth factor receptor protein and gene expression using a rat periodontitis model.
Regulation of epithelial cell behavior associated with periodontitis is not well elucidated but many responses will ultimately be regulated by growth factor receptors. Using a rat experimental periodontitis model, protein and gene expression of select growth factor receptors in junctional and pocket epithelium were examined. Periodontal disease was induced by daily topical application of lipopolysaccharide using an established protocol. Animals were killed at time 0 (control), and at 2 and 8 wk. Frozen tissue samples were collected from the right palatal gingival soft tissue, and the left periodontal tissues were decalcified and embedded in paraffin. Laser microdissection and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to quantify keratinocyte growth factor receptor (KGFR), hepatocyte growth factor receptor (HGFR), epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor 1 (FGFR1) gene expression, and in situ RT-PCR localized these increases to specific epithelial cells. Receptor protein expression was examined immunohistochemically. In cell culture, induction of HGFR and KGFR protein expression by serum, lipopolysaccharide and pro-inflammatory cytokines were examined using flow cytometry. Eight-week tissue samples exhibited histological changes consistent with periodontitis. KGFR and HGFR gene and protein expression were significantly induced at the 8 wk time point. KGFR expression was significantly up-regulated in basal and parabasal pocket epithelial cells, but HGFR was up-regulated throughout the pocket epithelium. In cell culture serum, lipopolysaccharide and pro-inflammatory cytokines, interleukin-1beta and tumour necrosis factor-alpha significantly induced KGFR protein receptor expression, but HGFR expression was only induced by serum. KGFR and HGFR are highly up-regulated in this model of periodontal disease and may play a significant role in regulating the proliferation and migration of pocket epithelium.


Analysis of a generic model of eukaryotic cell-cycle regulation.
We propose a protein interaction network for the regulation of DNA synthesis and mitosis that emphasizes the universality of the regulatory system among eukaryotic cells. The idiosyncrasies of cell cycle regulation in particular organisms can be attributed, we claim, to specific settings of rate constants in the dynamic network of chemical reactions. The values of these rate constants are determined ultimately by the genetic makeup of an organism. To support these claims, we convert the reaction mechanism into a set of governing kinetic equations and provide parameter values (specific to budding yeast, fission yeast, frog eggs, and mammalian cells) that account for many curious features of cell cycle regulation in these organisms. Using one-parameter bifurcation diagrams, we show how overall cell growth drives progression through the cell cycle, how cell-size homeostasis can be achieved by two different strategies, and how mutations remodel bifurcation diagrams and create unusual cell-division phenotypes. The relation between gene dosage and phenotype can be summarized compactly in two-parameter bifurcation diagrams. Our approach provides a theoretical framework in which to understand both the universality and particularity of cell cycle regulation, and to construct, in modular fashion, increasingly complex models of the networks controlling cell growth and division.


[Analysis of demand for family medical care in Brazil using the International Classification of Primary Care].
In various countries, motives for contact of patients with Primary Health Care (PHC) is classified by the International Classification of Primary Care (ICPC-2). This instrument enables the assessment of why people seek care, thereby assisting in planning strategies to attend the population's health needs. The scope of this study was to identify the main reasons for same-day appointments in PHC units of a medium-sized Brazilian city. The methodology used was to examine all records of a typical month of three family practice residents. Data were extracted from a secondary database of same-day appointments during the spring of 2010, classified with ICPC and then statistically analyzed. 1222 records were considered; 32 motives accounted for 50% of contacts. Most common motives were related to the General and Unspecific chapter of the ICPC. About 20% of visits occurred for administrative reasons. Female sex and greater age were determinants of greater motives for consultation. Knowing the motives for appointments by gender and age may help PHC teams in tackling health problems at the critical point of access to PHC.


Cancer Stem Cell Signaling during Repopulation in Head and Neck Cancer.
The aim of the study was to investigate cancer stem signaling during the repopulation response of a head and neck squamous cell cancer (HNSCC) xenograft after radiation treatment. Xenografts were generated from low passage HNSCC cells and were treated with either sham radiation or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21, after irradiation, 3 tumors per group were harvested for global gene expression, pathway analysis, and immunohistochemical evaluation. 316 genes were identified that were associated with a series of stem cell-related genes and were differentially expressed (p ≤ 0.01 and 1.5-fold) at a minimum of one time point in UT-SCC-14 xenografts after radiation. The largest network of genes that showed significant changes after irradiation was associated with CD44, NOTCH1, and MET. c-MET and ALDH1A3 staining correlated with the changes in gene expression. A clear pattern emerged that was consistent with the growth inhibition data in that genes associated with stem cell pathways were most active at day 7 and day 12 after irradiation. The MET/CD44 axis seemed to be an important component of the repopulation response.


Pharmacokinetics and tolerability of cediranib, a potent VEGF signalling inhibitor, in cancer patients with hepatic impairment.
Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid tumours received a single 45 mg dose of cediranib, followed by 30 mg continuous once-daily oral dosing for 21 days after a 7-day washout period (clinicaltrials.gov identifier NCT00621725). The primary objective was to compare the single-dose pharmacokinetics (PK) of cediranib in patients with different levels of hepatic impairment classified according to the bilirubin level. Safety, tolerability, multiple-dose PK and PK stratified according to the Child-Pugh criteria were also assessed. Thirty patients received cediranib: 18 with normal-mild hepatic impairment and 12 with moderate hepatic impairment. Single-dose PK parameters were similar between the group with normal-mild hepatic impairment and the group with moderate hepatic impairment [ratio of geometric least square means: area under the curve (AUC) 1.12, 90% confidence interval (CI) 0.77-1.61; Cmax 0.95, 90% CI 0.69-1.31]. Hepatic impairment did not influence PK results in multiple dosing. After continuous once-daily dosing, the geometric least square means ratio was 0.72 (90% CI 0.51-1.03) for AUCSS and 0.67 (90% CI 0.47-0.94) for CSS,max. Similar results were obtained when patients were classified for hepatic impairment according to the Child-Pugh criteria. There was no clear difference in the incidence or the severity of adverse events between hepatic impairment groups. Moderate hepatic impairment does not appear to affect the PK profile or the tolerability of cediranib. Dose adjustments are not necessary in this patient population.