Living as a person using a lower-limb prosthesis in Nepal.
The purpose of this study is to explore experiences of persons in Nepal using lower-limb prostheses, in relation to specific articles in the Convention on the Rights of Persons with Disabilities that consider mobility, education, health, rehabilitation, and work and employment. Qualitative interviews were conducted with 16 persons using lower limb prostheses. Content analysis was applied to the data. Six themes emerged: The lower-limb prosthesis is essential for mobility and daily life; Limited mobility in challenging terrain and request for reduced pain when using prosthesis; Difficulties in finding and sustaining employment emphasized the importance of vocational training; Appreciation of comprehensive rehabilitation together with other persons with amputations, but covering related costs is a struggle; Satisfied with health care, but concerned that it creates debt and dependence upon others; and finally, Limited ability creates negative self-image and varied attitudes in other people. Persons with lower-limb amputations were restricted by poverty and wanted increased independence. Rehabilitation and prosthetic services in Nepal need to increase proportionally as they contribute to enabling those persons to a better daily life. Prostheses were essential but more advanced technology was requested. Access to education and vocational training has the potential to improve the socio-economic status of those with lower-limb amputations due lack of employment not requiring physical effort. Implications for rehabilitation To increase access for persons with lower-limb amputations in Nepal to rehabilitation services, these services need to increase proportionally, and the policy for financial compensation to enable those persons to afford transportation to the rehabilitation center should be implemented. The design and manufacture of the low-cost polypropylene technology for prostheses used in Nepal needs to be improved, directed towards increasing the ability to ambulate on uneven surfaces and hilly terrain, and the ability to walk long distances. Adjustments of employment for persons with physical disabilities in Nepal have the potential to strengthen their socio-economic status. Vocational training programs and educational opportunities for persons with physical disabilities have the potential to improve income-generating employment and need to increase proportionally in Nepal. The policies developed in accordance with the Convention on the Rights of Persons with Disabilities need to be further implemented to decrease existing barriers to access to general health care and rehabilitation and prosthetic services for persons with disabilities in Nepal.


Endoplasmic reticulum-associated mitochondria-cortex tether functions in the distribution and inheritance of mitochondria.
To elucidate the functional roles of mitochondrial dynamics in vivo, we identified genes that become essential in cells lacking the dynamin-related proteins Fzo1 and Dnm1, which are required for mitochondrial fusion and division, respectively. The screen identified Num1, a cortical protein implicated in mitochondrial division and distribution that also functions in nuclear migration. Our data indicate that Num1, together with Mdm36, forms a physical tether that robustly anchors mitochondria to the cell cortex but plays no direct role in mitochondrial division. Our analysis indicates that Num1-dependent anchoring is essential for distribution of the static mitochondrial network in fzo1 dnm1 cells. Consistently, expression of a synthetic mitochondria-cortex tether rescues the viability of fzo1 dnm1 num1 cells. We find that the cortical endoplasmic reticulum (ER) also is a constituent of the Num1 mitochondria-cortex tether, suggesting an active role for the ER in mitochondrial positioning in cells. Thus, taken together, our findings identify Num1 as a key component of a mitochondria-ER-cortex anchor, which we termed "MECA," that functions in parallel with mitochondrial dynamics to distribute and position the essential mitochondrial network.


Considerations for the use of cellular electrophysiology models within cardiac tissue simulations.
The use of mathematical models to study cardiac electrophysiology has a long history, and numerous cellular scale models are now available, covering a range of species and cell types. Their use to study emergent properties in tissue is also widespread, typically using the monodomain or bidomain equations coupled to one or more cell models. Despite the relative maturity of this field, little has been written looking in detail at the interface between the cellular and tissue-level models. Mathematically this is relatively straightforward and well-defined. There are however many details and potential inconsistencies that need to be addressed, in order to ensure correct operation of a cellular model within a tissue simulation. This paper will describe these issues and how to address them. Simply having models available in a common format such as CellML is still of limited utility, with significant manual effort being required to integrate these models within a tissue simulation. We will thus also discuss the facilities available for automating this in a consistent fashion within Chaste, our robust and high-performance cardiac electrophysiology simulator. It will be seen that a common theme arising is the need to go beyond a representation of the model mathematics in a standard language, to include additional semantic information required in determining the model's interface, and hence to enhance interoperability. Such information can be added as metadata, but agreement is needed on the terms to use, including development of appropriate ontologies, if reliable automated use of CellML models is to become common.


Analysis of rhythmic gene expression in adult Drosophila using the firefly luciferase reporter gene.
The study of circadian clock function in Drosophila relies heavily on the analysis of rhythmic gene expression. Typically, individuals or groups of flies collected during a specific time of the circadian day need to be sacrificed, followed by the extraction of clock gene products. This procedure makes it impossible to analyze molecular rhythms in an individual over time. To measure clock gene expression within the living animal, firefly luciferase can be used as real-time reporter gene. This chapter describes how rhythmic expression of clock or clock-controlled genes can be measured in living adult Drosophila. A survey of all existing clock-related luciferase transgenics is given.


The cerebellum in cognitive processes: supporting studies in children.
Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome or William's syndrome. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also focal lesions during childhood or adolescence such as cerebellar tumour or stroke are related with neuropsychological abnormalities, which are most pronounced in visuo-spatial, language and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukaemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal IQ and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions especially in learning. There is a suggestion that the earlier the incorrect influence the more pronounced the problems.


Editorial: New frontiers in the scientific study of developmental language disorders.
Developmental language disorders (DLD) are common and have far-reaching developmental consequences. Nevertheless, public awareness of DLD is poor, and one goal of this special issue is to showcase a set of papers that provide a clear and coherent message about the nature and impact of DLD, and the potential of intervention to mitigate these impacts. In this editorial, we highlight seminal papers JCPP has published on language disorders over the last 40 years. Many of the issues raised then are still relevant now; however, the papers that comprise this special issue exemplify how far the field has come in achieving consensus on terminology and diagnostic criteria, and producing highly consistent findings on the stability and impact of DLD, and the potential for language change in response to targeted interventions. The editorial concludes with a road map for future research and clinical priorities that includes the need for randomised controlled trials that specifically address the impact of co-morbidities on response to treatment, impacts of intervention on broader developmental outcomes, and the experiences of adults with DLD.


Prevalence of glucose intolerance among Native Hawaiians in two rural communities. Native Hawaiian Health Research (NHHR) Project.
To estimate prevalence of type 2 diabetes and impaired glucose tolerance (IGT) among a population of native Hawaiians in two rural communities. Prevalence of glucose intolerance was assessed in two rural communities by history (confirmed by record review) or with a 75-g oral glucose tolerance test according to World Health Organization criteria. Anthropometric and demographic data were also obtained. A short survey was used to estimate the prevalence of known diabetes among nonparticipants. Prevalence rates were adjusted using the standard world population of Segi. A total of 574 native Hawaiians age > or = 30 years participated. The crude prevalence of IGT and type 2 diabetes were 15.5 and 20.4%, respectively. Only IGT prevalence was significantly higher (P = 0.03) among women (18.7%) than among men (10.9%). Prevalence of glucose intolerance was significantly associated with BMI, waist circumference, and waist-to-hip ratio (WHR). After adjusting for age and BMI, waist circumference and WHR were significantly and independently associated with type 2 diabetes prevalence only among women. Prevalence of type 2 diabetes was not significantly associated with the percentage of Hawaiian ancestry after adjusting for age. This study observed a high prevalence of glucose intolerance associated with being overweight among native Hawaiians. Age-adjusted type 2 diabetes prevalence was four times higher than among the U.S. National Health and Nutrition Examination Survey (NHANES) II population. Prevalence was high despite high rates of admixture with other ethnic groups of Hawaii, suggesting that these other Asian and Pacific Island populations share similar susceptibility to type 2 diabetes risk.


Yeast artificial chromosomes for the molecular analysis of the familial polyposis APC gene region.
Two yeast artificial chromosomes (YACs) spanning a total distance of 1.1 megabase pairs of DNA around the MCC (for mutated in colorectal carcinoma) and APC (for adenomatous polyposis coli) genes at 5q21 have been isolated and characterized. Starting from the MCC gene, a strategy was undertaken to identify constitutional submicroscopic deletions in familial adenomatous polyposis patients that might considerably narrow down the position of the APC gene. To this end, YACs identified by the MCC gene were screened across a chromosome 5-specific cosmid library to provide a source of DNA probes for genomic scanning. The cosmids isolated from these experiments were used to screen a panel of somatic cell hybrids containing chromosome 5 segregated from patients suspected to carry putative interstitial deletions. This screening approach led to the confirmation of a small heterozygous deletion in a polyposis patient that overlaps one of the two isolated YACs. This YAC has been shown to contain the entire APC gene, in addition to a significant portion of DNA flanking the 5' end of the gene, and should therefore prove a valuable resource for functional studies by transfer to colorectal tumor-derived cell lines.


Palliative splenic irradiation for symptomatic splenomegaly in non-Hodgkin lymphoma.
Splenic marginal zone lymphoma, an uncommon subtype of non-Hodgkin lymphoma (NHL), is usually present with symptomatic splenomegaly. Although splenectomy has long been considered the first-line therapy in symptomatic or cytopenic patients, it can lead to significant morbidity and mortality. Splenic irradiation is an option for patients who have a poor response to systemic therapy and/or are not surgical candidates. In this paper, we present a case report of a patient who received splenic radiotherapy for symptomatic splenomegaly. An 85-year-old Caucasian man with a 4 year history of low-grade NHL presented with progressive pancytopenia, significant weight loss and symptomatic splenomegaly (abdominal discomfort, sense of fullness and limitation of mobility due to spleen size). The patient refused splenectomy and, in December 2017, was referred to palliative splenic radiotherapy. He was initially treated with five fractions of one Grey (Gy) in order to evaluate clinical and haematology response. After that, 1.5 Gy daily, 5 days a week for 3 weeks. 3D conformal radiotherapy, multiple fields and mixed energy (6 and 15 Mv) were used. Radiotherapy allowed significant splenic reduction to almost half the size, resolving abdominal discomfort and improving quality of life. There was no decline of haemoglobin, leukocytes and platelet counts; in fact, there was a marginal increase. Palliative splenic irradiation was well tolerated confirming that it is a safe treatment option for palliation of symptomatic splenomegaly. Thereby, splenic irradiation should be strongly considered in the management of symptomatic splenomegaly, for selected patients who are refractory to or unsuitable for other options or when the patient refuses other treatments.


Single-center trials show larger treatment effects than multicenter trials: evidence from a meta-epidemiologic study.
A recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings. To perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs). MEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched. All individual RCTs included in the meta-analyses were selected. Data were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration. The primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I(2) = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]). Despite sensitivity analyses, meta-confounding cannot be fully excluded. Single-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted. Academic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).


Ultrafast exciton transfers in DNA and its nonlinear optical spectroscopy.
We have calculated the nonlinear response function of a DNA duplex helix including the contributions from the exciton population and coherence transfers by developing an appropriate exciton theory as well as by utilizing a projector operator technique. As a representative example of DNA double helices, the B-form (dA)10-(dT)10 is considered in detail. The Green functions of the exciton population and coherence transfer processes were obtained by developing the DNA exciton Hamiltonian. This enables us to study the dynamic properties of the solvent relaxation and exciton transfers. The spectral density describing the DNA base-solvent interactions was obtained by adjusting the solvent reorganization energy to reproduce the absorption and steady-state fluorescence spectra. The time-dependent fluorescence shift of the model DNA system is found to be ultrafast and it is largely determined by the exciton population transfer processes. It is further shown that the nonlinear optical spectroscopic techniques such as photon echo peak shift and two-dimensional photon echo can provide important information on the exciton dynamics of the DNA double helix. We have found that the exciton-exciton coherence transfer plays critical roles in the peculiar energy transfer and ultrafast memory loss of the initially created excitonic state in the DNA duplex helix.


The structural features of Trask that mediate its anti-adhesive functions.
Trask/CDCP1 is a transmembrane protein with a large extracellular and small intracellular domains. The intracellular domain (ICD) undergoes tyrosine phosphorylation by Src kinases during anchorage loss and, when phosphorylated, Trask functions to inhibit cell adhesion. The extracellular domain (ECD) undergoes proteolytic cleavage by serine proteases, although the functional significance of this remains unknown. There is conflicting evidence regarding whether it functions to signal the phosphorylation of the ICD. To better define the structural determinants that mediate the anti-adhesive functions of Trask, we generated a series of deletion mutants of Trask and expressed them in tet-inducible cell models to define the structural elements involved in cell adhesion signaling. We find that the ECD is dispensable for the phosphorylation of the ICD or for the inhibition of cell adhesion. The anti-adhesive functions of Trask are entirely embodied within its ICD and are specifically due to tyrosine phosphorylation of the ICD as this function is completely lost in a phosphorylation-defective tyrosine-phenylalanine mutant. Both full length and cleaved ECDs are fully capable of phosphorylation and undergo phosphorylation during anchorage loss and cleavage is not an upstream signal for ICD phosphorylation. These data establish that the anti-adhesive functions of Trask are mediated entirely through its tyrosine phosphorylation. It remains to be defined what role, if any, the Trask ECD plays in its adhesion functions.


Patterns of funerary variability, diet, and developmental stress in a Celtic population from NE Italy (3rd-1st c BC).
Little is known about the types of social organization characterizing the pre-Roman Celtic populations of Italy. Here, we explore the funerary variability characterizing the late Iron Age site of Seminario Vescovile (SV: Verona, Italy, 3rd-1st c. BC), and test its possible correlation to diet and relative exposure to developmental stressors. Patterns on funerary treatment (N = 125), δ13C and δ15N (N = 90), and linear enamel hypoplasia (N = 47) from SV are compared, and their possible association with sex and age-at-death further discussed. Results point to the presence at SV of variable funerary customs while at the same time demonstrating a rather homogenous diet and exposure to developmental stressors: funerary treatment is mainly correlated to age-at-death but do not appear to be associated to either isotopic patterns or hypoplasia frequencies. Accordingly, even if some weak social differentiation may have characterized the individuals buried at SV, this was not reflected in markedly differing living conditions. Our study is the first to attempt an exploration of the links between age, sex, funerary variability, and diet in a pre-Roman Celtic community from Italy. While highlighting the potential of a multifaceted approach in bioarcheology, it also points to a series of analytical and theoretical issues relevant when trying to disentangle the cultural and biological dimensions of social differentiation in the past.


Sleep-related sweating in obstructive sleep apnoea: association with sleep stages and blood pressure.
The aim of this study was to investigate sleep-related sweating as a symptom of obstructive sleep apnoea (OSA). Fifteen otherwise healthy male non-smoking patients with untreated moderate-to-severe OSA underwent polysomnography, including measurements of skin and core body temperature and electrodermal activity (EDA) as an objective indicator of sweating. Evening and morning blood pressure was measured as well as catecholamines in nocturnal urine. All measurements were repeated after 3 months on successful continuous positive airway pressure (CPAP) treatment. The untreated OSA subjects had a mean (+/-SD) apnoea-hypopnoea index of 45.3 +/- 3.9 and a mean EDA index during sleep of 131.9 +/- 22.4 events per hour. Patients with higher EDA indices had higher systolic blood pressure in the evening and morning (P = 0.001 and 0.006) and lower rapid eye movement (REM) sleep percentage (P = 0.003). The EDA index decreased significantly to 78.5 +/- 17.7 in the patients on CPAP treatment (P = 0.04). The decrease correlated with lower evening systolic and diastolic blood pressure (P = 0.05 and 0.006) and an increase in REM% (P = 0.02). No relationship was observed between EDA and skin or core body temperature, or to catecholamine levels in urine. OSA patients who experience sleep-related sweating may have increased blood pressure and decreased REM sleep compared with other OSA patients. CPAP treatment appears to lower blood pressure and increase REM sleep to a higher extent in these patients compared with other OSA patients.


Anti-hyperlipidemic effect of rice bran polysaccharide and its potential mechanism in high-fat diet mice.
Hyperlipidemia occurs very often in modern society along with a high calorie intake and is regarded as one of the greatest risk factors for the prevalence of cardiac vascular disease (CVD). In this study, we investigated the anti-hyperlipidemic effect of the rice bran polysaccharides (RBP) and its mechanism in a high fat diet animal model. 60 ICR mice were randomly divided into 3 groups, which included Control, HFD (high fat diet) and HFD + RBP, and each group included 20 mice. The control group was fed with a standard diet while the other two groups were fed with HFD. In addition, the HFD + RBP group was fed with 500 mg kg-1 of rice bran polysaccharides by intragastric administration while the other two groups were intragastrically administered with water. The results showed that RBP treatment for 10 weeks obviously decreased the body weight, liver weight and adipose tissues of mice; and it decreased the levels of total cholesterol (TC), triglycerides (TG) and low density lipoprotein-cholesterol (LDL-c) in the plasma. H&E staining of the liver tissues showed that RBP treatment decreased the size of fat droplets compared with the HFD group. Microarray analysis revealed that RBP treatment results in 80 genes being up-regulated while 72 genes were down-regulated in the tissues of liver. IPA software analysis suggested that NF-κB may play a vital role in the lipid-lowering effect of RBP. Real-time quantitative PCR confirmed that the mRNA levels of PPAR-α, PPAR-γ, PPAR-δ, SREBP-1C, FASN, ACC, SIRT and CD36, which are related to lipid metabolism, were significantly regulated by RBP supplementation compared to HFD. The western blot analysis further confirmed these altered expressions after RBP treatment. Taken together, these results suggest that the oral administration of RBP exerts lipid-lowering in high fat diet mice via regulating the lipid metabolism-related gene expression.


Dismantling the present and future threats of testicular cancer: a grounded theory of positive and negative adjustment trajectories.
Testicular cancer commonly affects men in the prime of their lives. While survival rates are excellent, little previous research has examined men's experiences of adjustment to survivorship. We aimed to explore this issue in younger testicular cancer survivors. In-depth qualitative interviews were conducted with testicular cancer survivors over two time points approximately 6 months apart in the year following treatment completion. Interviews were analysed using a grounded theory approach. The sample included 18 testicular cancer survivors between 22 and 44 years (mean age 34). A grounded theory was developed, which explained the process of positive adjustment over the first year following the treatment completion in terms of men's ability to dismantle the present and future threats of cancer, involving the key transitions of gaining a sense of perspective and striving to get on with life and restore normality. These were facilitated by six key processes. The processes that explained a negative adjustment trajectory are also presented. These findings contribute to the understanding of the psychosocial impact of testicular cancer on younger men's lives and have implications for the provision of support to testicular cancer survivors. Further investigation into the feasibility of one-on-one peer support interventions is warranted, as well as informal support that respects men's desire for independence. Understanding the processes involved in adjustment highlights ways in which health professionals can offer support to those struggling to adjust through challenging illness beliefs, encouraging emotional disclosure and facilitating peer mentoring.


Patterns and functional implications of rare germline variants across 12 cancer types.
Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.


Langerin+ dermal dendritic cells are critical for CD8+ T cell activation and IgH γ-1 class switching in response to gene gun vaccines.
The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin(+) dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin(+) DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin(+) DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin(+) cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin(+) DC abrogated the activation of IFN-γ-producing and cytolytic CD8(+) T cells after gene gun vaccination. Moreover, we identified migratory langerin(+) dermal DC as the subset that directly activated CD8(+) T cells in lymph nodes. Langerin(+) DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4(+) T helper cells by langerin(+) or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin(+) DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation.


Human paternal lineages, languages, and environment in the Caucasus.
Publications that describe the composition of the human Y-DNA haplogroup in diffferent ethnic or linguistic groups and geographic regions provide no explicit explanation of the distribution of human paternal lineages in relation to specific ecological conditions. Our research attempts to address this topic for the Caucasus, a geographic region that encompasses a relatively small area but harbors high linguistic, ethnic, and Y-DNA haplogroup diversity. We genotyped 224 men that identified themselves as ethnic Georgian for 23 Y-chromosome short tandem-repeat markers and assigned them to their geographic places of origin. The genotyped data were supplemented with published data on haplogroup composition and location of other ethnic groups of the Caucasus. We used multivariate statistical methods to see if linguistics, climate, and landscape accounted for geographical diffferences in frequencies of the Y-DNA haplogroups G2, R1a, R1b, J1, and J2. The analysis showed significant associations of (1) G2 with wellforested mountains, (2) J2 with warm areas or poorly forested mountains, and (3) J1 with poorly forested mountains. R1b showed no association with environment. Haplogroups J1 and R1a were significantly associated with Daghestanian and Kipchak speakers, respectively, but the other haplogroups showed no such simple associations with languages. Climate and landscape in the context of competition over productive areas among diffferent paternal lineages, arriving in the Caucasus in diffferent times, have played an important role in shaping the present-day spatial distribution of patrilineages in the Caucasus. This spatial pattern had formed before linguistic subdivisions were finally shaped, probably in the Neolithic to Bronze Age. Later historical turmoil had little influence on the patrilineage composition and spatial distribution. Based on our results, the scenario of postglacial expansions of humans and their languages to the Caucasus from the Middle East, western Eurasia, and the East European Plain is plausible.


The moderating role of peer norms in the associations of social withdrawal and aggression with peer victimization.
This study examined the moderating role of classroom injunctive norms salience regarding social withdrawal and regarding aggression in the longitudinal association between these behaviors and peer victimization. A total of 1,769 fourth through sixth graders (895 girls, M = 10.25 years, SD = 1.03) from 23 schools (67 classrooms) completed a peer nomination inventory in the fall (T1) and spring (T2) of the same academic year. Participants circled the name of each student who fit the description provided for social withdrawal, aggression, and peer victimization at T1 and T2. The salience of injunctive norms was sex-specific and operationalized by the extent to which children displaying the behavior were socially rewarded or sanctioned by their classmates. Generalized estimation equations (GEE) showed that the association between social withdrawal at T1 and peer victimization at T2 was moderated by injunctive norms. Social withdrawal at T1 was positively associated with peer victimization at T2 in classrooms where injunctive norms for this behavior were salient and unfavorable, as well as in classrooms where injunctive norms for aggression were salient and favorable, albeit for girls only. The association between aggression at T1 and peer victimization at T2 was also moderated by the injunctive norms regarding this behavior. Aggressive children were less likely to be victimized in classrooms where this behavior was rewarded. These results support bullying interventions that target factors related to the larger peer context, including social norms. (PsycINFO Database Record


Early stages of oxidative stress-induced membrane permeabilization: a neutron reflectometry study.
Neutron reflectometry was used to probe in situ the structure of supported lipid bilayers at the solid-liquid interface during the early stages of UV-induced oxidative degradation. Single-component supported lipid bilayers composed of gel phase, dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and fluid phase, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), phospholipids were exposed to low-dose oxidative stress generated by UV light and their structures were examined by neutron reflectometry. An interrupted illumination mode, involving exposures in 15 min increments with 2 h intervals between subsequent exposures, and a continuous mode involving a single 60 (or 90) min exposure period were employed. In both cases, pronounced differences in the structure of the lipid bilayer after exposure were observed. Interrupted exposure led to a substantial decrease in membrane coverage but preserved its total thickness at reduced scattering length densities. These results indicate that the initial phase during UV-induced membrane degradation involves the formation of hydrophilic channels within the membrane. This is consistent with the loss of some lipid molecules we observe and attendant reorganization of residual lipids forming hemimicellar edges of the hydrophilic channels. In contrast, continuous illumination produced a graded interface of continuously varied scattering length density (and hence hydrocarbon density) extending 100-150 A into the liquid phase. Exposure of a DPPC bilayer to UV light in the presence of a reservoir of unfused vesicles showed low net membrane disintegration during oxidative stress, presumably because of surface back-filling from the bulk reservoir. Chemical evidence for membrane degradation was obtained by mass spectrometry and Fourier transform infrared spectroscopy. Further evidence for the formation of hydrophilic channels was furnished by fluorescence microscopy and imaging ellipsometry data.


Musculoskeletal pain in Malaysia: a COPCORD survey.
To assess the nature and extent of rheumatic complaints in a semirural area in a multiracial (Malay, Indian, Chinese) community in Malaysia using the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) protocol initiated by ILAR and the WHO. All members of a community of 2700 persons over the age of 15 years were offered a questionnaire based interview in Phase 1 of the study. Those with rheumatic complaints (pain in the last 1 week) were invited for a physical examination by a rheumatologist in Phase 2. In total, 2594 (96%) persons agreed to a questionnaire based interview. Of those interviewed, 21.1% had a current rheumatic complaint. The pain rate was higher in women (23.8%) than in men (17.8%). Chinese men had the lowest age-standardized pain rate (9.9%), while Indian women had the highest rate (28.4%). In the study population, 14.4% complained of pain in the joints and/or musculoskeletal pain and 11.6% had low back pain. The knee was responsible for 64.8% of all complaints pertaining to the joints, and more than half those examined with knee pain had clinical evidence of osteoarthritis (OA). The complaint rate increased with age, up to 53.4% in the group age > 65 years. The major disability encountered was the inability to squat (3.1%). Fibromyalgia, soft tissue lesions, and localized OA of the knees were the main clinical diagnoses. Inflammatory arthritis was uncommon. Both Western and traditional sources of healthcare were used, often together. Self-medication was common (58.8%). Knee and back pain are the main rheumatic complaints in Malaysia, with complaint rates differing according to race and gender.


Screening mammographies in Switzerland: what makes female and male physicians prescribe them?
Physicians play a key role in motivating women to undergo mammography screening. In 1998 we assessed Swiss physicians' attitudes to mammography screening and their prescription behaviour in this regard. All female physicians and every second male physician aged 50-69 who were either not board-certified or board-certified in general practice, internal medicine, or obstetrics/gynaecology were sent a questionnaire. The response rate was 50% and thus 738 questionnaires were included in this study. Of the study population 39% were female and 61% male physicians. The distribution of professional backgrounds was: 27% board-certified general practitioners; 23% board-certified internists; 11% board-certified gynaecologists; 39% not board-certified. 55% of all study participants were in favour of a mammography screening programme for women aged over 50 in Switzerland, but breast self-examination and clinical breast examination were judged to have a more positive impact on breast cancer survival. Among clinically practising physicians, 22% reported generally prescribing biannual screening mammographies for women aged 50-69. Irrespective of other determinants, physicians from the Italian- and French-speaking parts of Switzerland prescribed screening mammographies more often than their colleagues from the German-speaking part (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.5-4.2). Clinical practice in obstetrics/gynaecology (OR 2.4; CI 1.3-4.2) and a self-reported high level of knowledge concerning mammography screening (OR 1.9; CI 1.1-3.2) were also positively associated with the prescription of screening mammography. Since mammography screening programmes exist in only three French-speaking cantons of Switzerland (VS; VD; GE), the gap in prescription of screening mammographies between French/Italian- and German-speaking regions must be narrowed to prevent a higher prevalence of side effects from opportunistic screening among German-speaking women. There is a need to educate physicians and the political community regarding the risks and benefits of mammography screening.


Wertheim's association theory applied to one site patchy colloids: beyond the single bonding condition.
We apply Wertheim's theory to develop an equation of state for one site patchy colloids where the patch can bond multiple times. We allow for the possibility of ring formation without the introduction of empirical parameters and show that for moderate patch coverage the infinite series of chain graphs is well represented by the first two terms. The theory is found to be in excellent agreement with new NVT and NPT Monte Carlo simulations. The approach described here can easily be converted to the form of a density functional theory to describe inhomogeneous patchy colloid systems.


Quantification of patient fears regarding dental injections and patient perceptions of a local noninjectable anesthetic gel.
Data have shown that 30% of all Americans do not seek dental care and/or treatment unless a problem arises that causes them severe pain. Similar study results have been found in Europe as well. While some studies indicate that cost concerns prevent people from seeking dental care, the fear of pain has been identified as a factor in keeping people from seeing a dentist. A random sample of US and European patients who had recently undergone a scaling and root planing procedure was surveyed via telephone interview to quantify data on patient concerns and fears regarding anesthesia administered by injection, as well as to determine patient interest and price perception of an anesthetic gel product. The survey also provided data on the patient's experience and perception about the scaling and root planing procedure. Responses from the study population showed that patients find the injection painful and do not like the prolonged numbness. Additionally, based on the patients surveyed, they experience injection anxiety before appointments, and a significant number of them cancel appointments or simply do not seek treatment because they are afraid of the injection. Finally, the study also demonstrated that, while not eliminating dental anxiety completely, the availability of a new noninjectable anesthetic would assist in relieving patient fear, with almost half of the patients surveyed being more likely to seek treatment if only the new noninjectable anesthetic was used. Additionally, most patients surveyed would be willing to pay for the noninjectable anesthetic out of their own pockets if it was not covered by their health insurance.


Endoluminal fundoplication (ELF)--evolution of EsophyX, a new surgical device for transoral surgery.
A novel endoluminal fundoplication (ELF) technique using a trans-oral and fastener-deploying device (EsophyX, EndoGastric Solutions) was developed and evaluated for feasibility, safety and the treatment of gastroesophageal reflux disease (GERD) in a series of bench, animal, human (phase 1, phase 2, commercial registry) studies. The studies verified biological compatibility, durability and non-toxicity of the polypropylene fasteners as well as the feasibility of the ELF technique. The results of the preclinical testing indicated that the EsophyX device was shown to be safe, and capable of deploying fasteners directly into tissue and forming an interrupted suture line at the base of the gastro-esophageal valve (GEV). Moreover, the studies demonstrated that the ELF technique performed using the EsophyX device resulted in the creation of new GEVs of 3-5 cm in length and a circumference of 200 degrees -310 degrees , which maintained their anatomical aspects at six months. The ELF-created GEVs appeared similar to those created by laparoscopic anti-reflux surgery (LARS). The ELF procedure also resulted in reduction of all small hiatal hernias (2 cm in size) and restoration of the angle of His. The ELF procedure provides an anatomical approach similar to that of LARS for the treatment of GERD.


How funding structures for HIV/AIDS research shape outputs and utilization: a Swiss case study.
Research policy in the field of HIV has changed substantially in recent decades in Switzerland. Until 2004, social science research on HIV/AIDS was funded by specialized funding agencies. After 2004, funding of such research was "normalized" and integrated into the Swiss National Science Foundation as the main funding agency for scientific research in Switzerland. This paper offers a longitudinal analysis of the relationship between the changing nature of funding structures on the one hand and the production and communication of policy-relevant scientific knowledge in the field of HIV on the other hand. The analysis relies on an inventory of all social sciences research projects on HIV in Switzerland that were funded between 1987 and 2010, including topics covered and disciplines involved, as well as financial data. In addition, in-depth interviews were conducted with 18 stakeholders. The analysis highlights that the pre-2004 funding policy ensured good coverage of important social science research themes. Specific incentives and explicit promotion of social science research related to HIV gave rise to a multidisciplinary, integrative and health-oriented approach. The abolition of a specific funding policy in 2004 was paralleled by a drastic reduction in the number of social science research projects submitted for funding, and a decline of public money dedicated to such research. Although the public administration in charge of HIV policy still acknowledges the relevance of findings from social sciences for the development of prevention, treatment and care, HIV-related social science research does not flourish under current funding conditions. The Swiss experience sheds light on the difficulties of sustaining social science research and multidisciplinary approaches related to HIV without specialized funding agencies. Future funding policy might not necessarily require specialized agencies, but should better take into account research dynamics and motivations in the field of social sciences.


Further characterisation of cytokines in macropod marsupials: IL-10 and IL-10Δ3.
Interleukin-10 is an immunomodulatory cytokine that has been implicated, along with IFN-γ, in the disease sequelae of mycobacterial infection. In order to investigate the role of IL-10 in marsupial disease models we sequenced and characterised the IL10 gene in the tammar wallaby (Macropus eugenii) and rufous hare-wallaby (Lagorchestes hirsutus). An isoform IL-10Δ3, in which an in-frame deletion of exon 3 occurs, was discovered in both macropod species. Analysis of wallaby and other reported marsupial IL-10 homologs suggests that while marsupial IL-10 is comparable to that of human IL-10, the predicted IL-10Δ3 protein may play a more complicated role in the modulation of IL-10-directed responses. Expression of the canonical gene and splicing variant was confirmed in both wallabies, and the rufous hare-wallaby showed differential expression across lymph node, spleen and liver, with isoform expression detected in the lymph node. This characterisation and expression of IL-10 in de novo tissues provides a basis for further study into the role of IL-10 in disease models in marsupials.


State-of-the-art lentiviral vectors for research use: risk assessment and biosafety recommendations.
Lentiviral vectors (LV) are competent gene transfer vehicles, as used for both research and gene therapy applications, because of their stable integration in non-dividing and dividing cells and long-term transgene expression. Along with our understanding that LV offer solutions for gene therapy, biosafety concerns have uncovered risks due to insertional mutagenesis, the generation of replication competent lentiviruses (RCL) and vector mobilization. Researchers therefore continue to devote significant efforts in designing LV with improved efficacy and biosafety features. The choice of a particular LV system for experimental studies is often driven by functional considerations, including increased productivity and/or transduction efficiency. The design of safer vectors has also directly benefited researchers allowing them to conduct experimental studies with lower risk. Currently, vectors combine improved safety features (that decrease the risk of recombination and vector mobilization) with increased transduction efficiency. Hence, risks associated with the inadvertent transduction of cells of the investigator gain greater importance in assessing the overall risk of these vectors and become an important biosafety concern. This review outlines the different strategies used to improve LV biosafety by comparing state-of-the-art and emerging LV production systems and highlighting biosafety issues that can arise during their contained use. The few existing national and international biosafety recommendations that specifically address the use of LV in research are discussed and recommendations for most common research activities using LV are proposed.


Role of Hcp, a type 6 secretion system effector, of Aeromonas hydrophila in modulating activation of host immune cells.
Recently, we reported that the type 6 secretion system (T6SS) of Aeromonas hydrophila SSU plays an important role in bacterial virulence in a mouse model, and immunization of animals with the T6SS effector haemolysin co-regulated protein (Hcp) protected them against lethal infections with wild-type bacteria. Additionally, we showed that the mutant bacteria deleted for the vasH gene within the T6SS gene cluster did not express the hcp gene, while the vasK mutant could express and translocate Hcp, but was unable to secrete it into the extracellular milieu. Both of these A. hydrophila SSU mutants were readily phagocytosed by murine macrophages, pointing to the possible role of the secreted form of Hcp in the evasion of the host innate immunity. By using the ΔvasH mutant of A. hydrophila, our in vitro data showed that the addition of exogenous recombinant Hcp (rHcp) reduced bacterial uptake by macrophages. These results were substantiated by increased bacterial virulence when rHcp was added along with the ΔvasH mutant in a septicaemic mouse model of infection. Analysis of the cytokine profiling in the intraperitoneal lavage as well as activation of host cells after 4 h of infection with the ΔvasH mutant supplemented with rHcp indicated that this T6SS effector inhibited production of pro-inflammatory cytokines and induced immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β, which could circumvent macrophage activation and maturation. This mechanism of innate immune evasion by Hcp possibly inhibited the recruitment of cellular immune components, which allowed bacterial multiplication and dissemination in animals, thereby leading to their mortality.


Challenges and promise for the development of human immune monitoring.
The immune system is critical for protection and health maintenance and is likely required for a long lifespan. Yet, despite its importance for health, the ability to assess its quality of function has been poor, nor is much known on its variation between individuals. Hence direct assessment of immune health has largely been missing from medicine, and metrics of immune health are not well defined, especially in non-extreme states. This is chiefly due to the high complexity of the immune system. Recently emerging technologies now enable broad surveying of many immune system components at high resolution, setting forth a transformation of immunology and, through it, medicine. Such technologies enable, for the first time, high-resolution monitoring of an individual's immune system. The resulting information can be used for diagnostic and prognostic purposes, as well as to provide a quantitative, global view of the immune system, i.e. "systems immunology." This is especially relevant in the context of aging, in which the immune system exhibits profound alterations in state and function.


Plasma miR-601 and miR-760 are novel biomarkers for the early detection of colorectal cancer.
Colorectal cancer (CRC) is a major cause of death worldwide. Sensitive, non-invasive diagnostic screen methods are urgently needed to improve its survival rates. Stable circulating microRNA offers unique opportunities for the early diagnosis of several diseases, including cancers. Our aim has been to find new plasma miRNAs that can be used as biomarkers for the detection of CRC. According to the results of miRNA profiling performed on pooling plasma samples form 10 CRC patients or 10 healthy controls, a panel of miRNAs (hsa-miR-10a, -19a, -22*, -24, -92a, 125a-5p, -141, -150, -188-3p, -192, -210, -221, -224*, -376a, -425*, -495, -572, -601, -720, -760 and hsa-let-7a, -7e) were deregulated in CRC plasma with fold changes >5. After large scale validation by qRT-PCR performed on another 191 independent individuals (90 CRC, 43 advanced adenoma and 58 healthy participants), we found that the levels of plasma miR-601 and miR-760 were significantly decreased in colorectal neoplasia (carcinomas and advanced adenomas) compared with healthy controls. ROC curve analysis showed that plasma miR-601 and miR-760 were of significant diagnostic value for advanced neoplasia. These two miRNAs together yield an AUC of 0.792 with 83.3% sensitivity and 69.1% specificity for separating CRC from normal controls, and yield an AUC of 0.683 with 72.1% sensitivity and 62.1% specificity in discriminating advanced adenomas from normal controls. Plasma miR-601 and miR-760 can potentially serve as promising non-invasive biomarkers for the early detection of CRC.


Genome sequence of the cellulolytic gliding bacterium Cytophaga hutchinsonii.
The complete DNA sequence of the aerobic cellulolytic soil bacterium Cytophaga hutchinsonii, which belongs to the phylum Bacteroidetes, is presented. The genome consists of a single, circular, 4.43-Mb chromosome containing 3,790 open reading frames, 1,986 of which have been assigned a tentative function. Two of the most striking characteristics of C. hutchinsonii are its rapid gliding motility over surfaces and its contact-dependent digestion of crystalline cellulose. The mechanism of C. hutchinsonii motility is not known, but its genome contains homologs for each of the gld genes that are required for gliding of the distantly related bacteroidete Flavobacterium johnsoniae. Cytophaga-Flavobacterium gliding appears to be novel and does not involve well-studied motility organelles such as flagella or type IV pili. Many genes thought to encode proteins involved in cellulose utilization were identified. These include candidate endo-beta-1,4-glucanases and beta-glucosidases. Surprisingly, obvious homologs of known cellobiohydrolases were not detected. Since such enzymes are needed for efficient cellulose digestion by well-studied cellulolytic bacteria, C. hutchinsonii either has novel cellobiohydrolases or has an unusual method of cellulose utilization. Genes encoding proteins with cohesin domains, which are characteristic of cellulosomes, were absent, but many proteins predicted to be involved in polysaccharide utilization had putative D5 domains, which are thought to be involved in anchoring proteins to the cell surface.


Ebola outbreak killed 5000 gorillas.
Over the past decade, the Zaire strain of Ebola virus (ZEBOV) has repeatedly emerged in Gabon and Congo. Each human outbreak has been accompanied by reports of gorilla and chimpanzee carcasses in neighboring forests, but both the extent of ape mortality and the causal role of ZEBOV have been hotly debated. Here, we present data suggesting that in 2002 and 2003 ZEBOV killed about 5000 gorillas in our study area. The lag between neighboring gorilla groups in mortality onset was close to the ZEBOV disease cycle length, evidence that group-to-group transmission has amplified gorilla die-offs.


Ponatinib in refractory Philadelphia chromosome-positive leukemias.
Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).


Intracavity diamond heatspreaders in lasers: the effects of birefringence.
The birefringence of a number of commercially-available diamond platelets is assessed in the context of their use for intracavity thermal management in lasers. Although diamond is normally thought of as isotropic, significant birefringence is found to be present in some samples, with considerable variation from batch to batch, and in some cases across an individual sample. Nonetheless, low-loss operation is achieved in a laser cavity containing a Brewster element, either by rotating the sample or by using a diamond platelet with low birefringence.


Macrophage migration is differentially regulated by distinct ECM components.
Macrophages are indispensable for proper immune surveillance and inflammatory regulation. They also exhibit dramatic phenotypic plasticity and are highly responsive to their local microenvironment, which includes the extracellular matrix (ECM). The present work demonstrates that two fibrous ECM glycoproteins, fibronectin (FN) and laminin (LAM), elicit distinct morphological and migratory responses to macrophages in 2D environments. Laminin 111 inhibits macrophage cell spreading, but drives them to migrate rapidly and less persistently compared to cells on fibronectin. Differential integrin engagement and ROCK/myosin II organization helps explain why macrophages alter their morphology and migration character on these two ECM components. The present study also demonstrates that laminin 111 exerts a suppressive effect toward fibronectin, as macrophages plated on a LAM/FN mixture adopt a morphology and migratory character almost identical to LAM alone. This suggests that distinct responses can be initiated downstream of receptor-ECM engagement, and that one component of the microenvironment may affect the cell's ability to sense another. Overall, macrophages appear intrinsically poised to rapidly switch between distinct migratory modes based on their ECM environments. The role of ECM composition in dictating motile and inflammatory responses in 3D and in vivo contexts warrants further study.


Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation.
The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8(+) T cells. During influenza virus infection in vivo, naive T cells enter a CD62L(intermediate) state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62L(hi) central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62L(hi) memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways.


Vinasse application and cessation of burning in sugarcane management can have positive impact on soil carbon stocks.
Bioenergy crops, such as sugarcane, have the potential to mitigate greenhouse gas emissions through fossil fuel substitution. However, increased sugarcane propagation and recent management changes have raised concerns that these practices may deplete soil carbon (C) stocks, thereby limiting the net greenhouse gas benefit. In this study, we use both a measured and modelled approach to evaluate the impacts of two common sugarcane management practices on soil C sequestration potential in Brazil. We explore how transitions from conventional (mineral fertiliser/burning) to improved (vinasse application/unburned) practices influence soil C stocks in total and in physically fractionated soil down to one metre. Results suggest that vinasse application leads to an accumulation of soil C of 0.55 Mg ha-1yr-1 at 0-30 cm depth and applying unburned management led to gains of ∼0.7 Mg ha-1yr-1 at 30-60 cm depth. Soil C concentration in the Silt+Clay fraction of topsoil (0-20 cm) showed higher C content in unburned management but it did not differ under vinasse application. The CENTURY model was used to simulate the consequences of management changes beyond the temporal extent of the measurements. Simulations indicated that vinasse was not the key factor driving increases in soil C stocks but its application may be the most readily available practice to prevent the soil C losses under burned management. Furthermore, cessation of burning may increase topsoil C by 40% after ∼50 years. These are the first data comparing different sugarcane management transitions within a single area. Our findings indicate that both vinasse application and the cessation of burning can play an important role in reducing the time required for sugarcane ethanol production to reach a net C benefit (payback time).


Assay of heparan-N-sulfamidase in dried leukocytes impregnated in filter paper: a new tool for the identification of mucopolisaccharidosis IIIA and potentially other lysosomal disorders.
Diagnosis of lysosomal storage disorders (LSDs) is mainly based on specific enzyme assays in leucocytes. Dried blood spots have also been used as sample for the enzyme assays. However, some lysosomal enzymes such as heparan-N-sulfamidase (HNS) and others cannot be assayed by this material. We developed an assay for HNS using dried leukocytes impregnated in filter paper (DLFP) as source of enzyme, and the results allowed the correct identification of Mucopolisaccharidosis IIIA. From this proof of concept we predict that the assay of lysosomal enzymes in DLFP samples, which still needs further development, could be a useful tool for the diagnosis of LSDs, especially in regions where transportation of liquid blood samples in appropriate conditions for long distances and/or across country borders is challenging.


A prototype hand-held tri-modal instrument for in vivo ultrasound, photoacoustic, and fluorescence imaging.
Multi-modality imaging is beneficial for both preclinical and clinical applications as it enables complementary information from each modality to be obtained in a single procedure. In this paper, we report the design, fabrication, and testing of a novel tri-modal in vivo imaging system to exploit molecular/functional information from fluorescence (FL) and photoacoustic (PA) imaging as well as anatomical information from ultrasound (US) imaging. The same ultrasound transducer was used for both US and PA imaging, bringing the pulsed laser light into a compact probe by fiberoptic bundles. The FL subsystem is independent of the acoustic components but the front end that delivers and collects the light is physically integrated into the same probe. The tri-modal imaging system was implemented to provide each modality image in real time as well as co-registration of the images. The performance of the system was evaluated through phantom and in vivo animal experiments. The results demonstrate that combining the modalities does not significantly compromise the performance of each of the separate US, PA, and FL imaging techniques, while enabling multi-modality registration. The potential applications of this novel approach to multi-modality imaging range from preclinical research to clinical diagnosis, especially in detection/localization and surgical guidance of accessible solid tumors.


The Neurokinins: Peptidomimetic Ligand Design and Therapeutic Applications.
The neurokinins are indisputably essential neurotransmitters in numerous pathoand physiological events. Being widely distributed in the Central Nervous System (CNS) and peripheral tissues, their discovery rapidly promoted them to drugs targets. As a necessity for molecular tools to understand the biological role of this class, endogenous peptides and their receptors prompted the scientific community to design ligands displaying either agonist and antagonist activity at the three main neurokinin receptors, called NK1, NK2 and NK3. Several strategies were implemented for this purpose. With a preference to small non-peptidic ligands, many research groups invested efforts in synthesizing and evaluating a wide range of scaffolds, but only the NK1 antagonist Aprepitant (EMENDT) and its prodrug Fosaprepitant (IVEMENDT) have been approved by the Food Drug Administration (FDA) for the treatment of Chemotherapy-Induced and Post-Operative Nausea and Vomiting (CINV and PONV, respectively). While non-peptidic drugs showed limitations, especially in side effect control, peptidic and pseudopeptidic compounds progressively regained attention. Various strategies were implemented to modulate affinity, selectivity and activity of the newly designed ligands. Replacement of canonical amino acids, incorporation of conformational constraints, and fusion with non-peptidic moieties gave rise to families of ligands displaying individual or dual NK1, NK2 and NK3 antagonism, that ultimately were combined with non-neurokinin ligands (such as opioids) to target enhanced biological impact.


Costs and benefits of multifactorial falls prevention in nursing homes in the Netherlands.
To investigate whether the implementation of a multifactorial falls intervention in nursing homes is cost-beneficial and alleviates the professional workload. A comprehensive quantitative model was developed to calculate the impact of investments in multifactorial falls prevention in nursing homes in the Netherlands, comparing the fall incidence using intervention strategies in 1000 nursing home residents with the conditions of usual care over a five-year timeline. We built a model combining several data sources regarding falls and injury prevalence in nursing home residents, health care costs, intervention costs and effectiveness, and demographic statistics. The primary outcomes were number of falls and injuries, treatment hours and cost. In the nursing home setting, a baseline scenario was calculated with 1471 falls incidents resulting in 345 injuries per year. The mean cost of injury related treatment and care was calculated 860 thousand euro per year and €4.63 million in five years. Implementing multifactorial intervention over five years, costing 702 thousand euro, resulted in savings in health care costs of €2.0 million, of which €1.6 million was saved in nursing home injury care. The benefits outweighed the costs: each euro invested was compensated by 2.86 euro benefit in total care, 2.31 benefit in nursing home care. Yearly 3050 nursing hours, 3100 paramedical care hours and 760 h of physician care were saved. Implementation of customized multifactorial interventions provided by multidisciplinary teams is cost-beneficial in reduction of falls in nursing homes. The CBA model gives valuable information about the advantageous consequences (i.e. health benefits, financial benefits and reduced workload of staff) of falls prevention in nursing homes and can provide guidance to the management in structural implementation of multifactorial falls prevention.


Patterns of Sedentary Behaviour in Female Office Workers.
Prolonged sedentary behaviour is associated with poor health outcomes. Office workers often engage in excessive sedentary behaviour, however limited research reports on how this sedentary behaviour is accumulated. This study examines objectively measured patterns of prolonged sedentary behaviour in female office workers during weekdays and weekend days and across time of day. Full time female office workers from a Scottish University participated (N = 27 mean age 43.0 ± 11.5 yrs; BMI 25.8 ± 4.1 kg/m2). Participants wore an activPAL™ for 7 days and completed a diary of waking and working hours. Average week and weekend time sitting, standing and stepping was calculated and also expressed as a proportion of waking day. Average week and weekend daily step count and sit to stand transitions were calculated. Continuous bouts of sedentary behaviour were categorised as: 20-40, 40-60 and > 60 minutes and compared between week and weekend days and across time of day. Average weekday sitting time and proportion was higher (P < 0.05) than weekend days [9.1 hrs (66%) vs 8.1 hrs (56%)]. Time and proportion spent standing was higher (P < 0.01) at weekends than weekdays [4.6 hrs (32%) vs 3.8 hrs (27%)]. Time spent stepping [weekday 1.8 hrs (12%) vs weekend 1.7 hrs (12%)] and total daily step count (weekday 8903 vs weekend day 8014) were not significanlty different (P > 0.05) on weekdays vs weekend days. The pattern of sedentary behaviour bouts was different between week and weekend days. Week days were dominated by a consistent pattern of shorter (20-40 mins) sedentary behaviour bouts. The longest continuous sedentary behaviour bouts occurred in the evening, particularly at weekends. In office workers the most prolonged sedentary behaviour occurred in the evening, particularly at weekends. Interventions need to target these highly saturated periods of sedentary behaviour.


Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin.
Culturing DOV 13 ovarian carcinoma cells on three-dimensional collagen lattice but not on thin-layer collagen induces processing of promatrix metalloproteinase (MMP)-2 to a M(r) 62,000 form, suggesting that multivalent integrin aggregation may participate in proteinase regulation. To address the role of collagen-binding integrins in this event, we treated DOV 13 cells with soluble beta1 integrin antibodies (clones P4C10 or 21C8) or beta1 integrin antibodies immobilized on latex beads to promote integrin aggregation. Divalent ligation of beta1 integrins with soluble P4C10 antibodies stimulated expression of pro-MMP-2 and its inhibitor, tissue inhibitor of metalloproteinase-2, whereas soluble 21C8 antibodies had no effect. Aggregation of beta1 integrins with immobilized 21C8 or P4C10 antibodies stimulated MMP-dependent pro-MMP-2 activation and accumulation of a M(r) 43,000 form of membrane type 1 MMP (MT1-MMP), a cell surface activator of pro-MMP-2, in cell extracts. beta1 integrin-mediated MMP-2 activation required protein synthesis and tyrosine kinase signaling and was reduced by an inhibitor of gene transcription. Treatment of control cells with concanavalin A stimulated MMP-dependent pro-MMP-2 activation and accumulation of M(r) 55,000 and 43,000 forms of MT1-MMP in cell extracts. Addition of either the MMP inhibitor GM-6001-X or exogenous tissue inhibitor of metalloproteinase-2 to concanavalin A-treated cells resulted in loss of the M(r) 43,000 form of MT1-MMP and accumulation of the M(r) 55,000 form of the enzyme in cell extracts, suggesting that the M(r) 43,000 form is a product of MMP-dependent M(r) 55,000 MT1-MMP proteolysis. Together, these data suggest that beta1 integrin stimulation of pro-MMP-2 activation involves MT1-MMP posttranslational processing and requires multivalent integrin aggregation.


Reflecting upon the years of political violence in Peru: An experimental study to promote a culture of peace in higher education.
This article analyzes the effect of a pedagogic module, designed to help reflect on political violence in Peru, facilitating political and social attitudes directed toward promoting a culture of peace in higher education settings. As a main source of information for developing the module, Truth and Reconciliation Commission (TRC) report was used. The effects of the module implementation were assessed with a 2 × 2 experimental design, with an experimental group (n = 59) and a control group (n = 62), with pre and post evaluations. Results show the effectiveness of the intervention with significant increases in self-reported knowledge about the TRC and its work, and an agreement that the CVR represented a viable and integrative view of the era of violence. Even more, the pedagogic module attained a reduction of attitudes favorable to violence, and also a reduction of conservative ideological discourses that appear as a risk factor in the expression of new conflicts due to collective motives in post-conflict societies. Nevertheless, the effects observed were limited in some aspects, and the article discusses the need for new dissemination mechanisms about the era of violence to complement the positive effects of the module in the aim of generating a culture of peace.


Exposure to combustion generated environmentally persistent free radicals enhances severity of influenza virus infection.
Exposures to elevated levels of particulate matter (PM) enhance severity of influenza virus infection in infants. The biological mechanism responsible for this phenomenon is unknown. The recent identification of environmentally persistent free radicals (EPFRs) associated with PM from a variety of combustion sources suggests its role in the enhancement of influenza disease severity. Neonatal mice (< seven days of age) were exposed to DCB230 (combustion derived PM with a chemisorbed EPFR), DCB50 (non-EPFR PM sample), or air for 30 minutes/day for seven consecutive days. Four days post-exposure, neonates were infected with influenza intranasally at 1.25 TCID50/neonate. Neonates were assessed for morbidity (% weight gain, peak pulmonary viral load, and viral clearance) and percent survival. Lungs were isolated and assessed for oxidative stress (8-isoprostanes and glutathione levels), adaptive immune response to influenza, and regulatory T cells (Tregs). The role of the EPFR was also assessed by use of transgenic mice expressing human superoxide dismutase 2. Neonates exposed to EPFRs had significantly enhanced morbidity and decreased survival following influenza infection. Increased oxidative stress was also observed in EPFR exposed neonates. This correlated with increased pulmonary Tregs and dampened protective T cell responses to influenza infection. Reduction of EPFR-induced oxidative stress attenuated these effects. Neonatal exposure to EPFR containing PM resulted in pulmonary oxidative stress and enhanced influenza disease severity. EPFR-induced oxidative stress resulted in increased presence of Tregs in the lungs and subsequent suppression of adaptive immune response to influenza.


Heterogeneity in the induction and expression of carcinoembryonic antigen-related antigens in human colon cancer cell lines.
Sodium butyrate induces morphological and biochemical changes consistent with a more differentiated phenotype in some colon cancer cell lines. These changes include increased expression of carcinoembryonic antigen (CEA) and other oncodevelopmental markers. We utilized domain-specific probes and polyclonal antibodies against CEA-related antigens to study sodium butyrate-induced expression of the CEA gene family in a villous adenoma-derived cell line, which is nontumorigenic in nude mice (VACO 235), and two colonic carcinoma cell lines known to respond to sodium butyrate exposure by phenotypic differentiation (HT-29 and LS 174T). The induction begins as quickly as 24 h after exposure and occurs primarily at a transcriptional level, although some translational control is also evident. No evidence was found for gene amplification, rearrangement, or methylation to account for the mechanism of this transcriptional control. [35S]Cysteine pulse-labeled cell lysate immunoblots and polyadenylated RNA blot hybridization suggest that increases in mRNA transcript and CEA-related glycoprotein levels are primarily due to increased synthesis rather than decreased degradation. A considerable amount of heterogeneity is seen in the biosynthesis of the CEA-related glycoproteins, with each cell line showing a distinct pattern of CEA-related antigen expression from a limited number of mRNA transcripts.


The sarcoplasmic reticulum plays a major role in isometric contraction in atrial muscle of yellowfin tuna
We used an isometric muscle preparation to test the hypothesis that yellowfin tuna Thunnus albacares utilize the intracellular Ca2+ storage sites of the sarcoplasmic reticulum (SR) during routine contractions. Ryanodine (a blocker of SR Ca2+ release) reduced the force of contraction by approximately 50 % and the rates of contraction and relaxation by 60 % in yellowfin tuna atrium. High levels of adrenaline were unable to ameliorate the effects of ryanodine. We conclude that the SR is active in contributing Ca2+ to force development at physiological contraction frequencies. Further, we suggest that, by using intracellular Ca2+ cycling, the yellowfin tuna is able to increase the maximum contraction frequency of its cardiac muscle beyond that of most other fishes.


Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.
Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.


Identification of crucial bottlenecks in engineered polyketide biosynthesis.
The concept of combinatorial biosynthesis promises access to compound libraries based on privileged natural scaffolds. Ever since the elucidation of the biosynthetic pathway towards the antibiotic erythromycin A in 1990, the predictable manipulation of type I polyketide synthase megaenzymes was investigated. However, this goal was rarely reached beyond simplified model systems. In this study, we identify the intermediates in the biosynthesis of the polyether monensin and numerous mutated variants using a targeted metabolomics approach. We investigate the biosynthetic flow of intermediates and use the experimental setup to reveal the presence of selectivity filters in polyketide synthases. These obstruct the processing of non-native intermediates in the enzymatic assembly line. Thereby we question the concept of a truly modular organization of polyketide synthases and highlight obstacles in substrate channeling along the cascade. In the search for the molecular origin of a selectivity filter, we investigate the role of different thioesterases in the monensin gene cluster and the connection between ketosynthase sequence motifs and incoming substrate structures. Furthermore, we demonstrate that the selectivity filters do not apply to new-to-nature side-chains in nascent polyketides, showing that the acceptance of these is not generally limited by downstream modules.


The Baltimore pregnancy prevention program for urban teenagers. II. What did it cost?
An experimental pregnancy prevention program for junior and senior high school students consisted of classroom lectures, informal discussion groups and individual counseling in the schools and group education, individual counseling and reproductive health care in a nearby clinic. The structure of the program allowed for extensive individual counseling for students who desired it, and the reported costs are thus considered generous. School-based services utilized 40 percent of a total three-year budget of $409,250, and clinic services, 60 percent. The average cost per student served was $122, with the average per female student almost four times that per male and the average per senior high student more than twice that per junior high student. Students who utilized more expensive types of services, such as individual counseling and medical services in the clinic, also used other program offerings more frequently. Services to students who attended only class lectures cost an average of $13.20 to deliver, while students who utilized all services cost the program an average of $546 each.


Clinical management of chronic mercury intoxication secondary to skin lightening products: A proposed algorithm.
Mercury is a toxic substance that is commonly used in skin lightening products. Various effects on humans have been observed, which affect both users and non-users. Many studies reported delayed diagnosis and treatment, even after weeks of hospitalization. The possible reasons are non-specific clinical manifestation and lack of awareness and knowledge regarding chronic mercury intoxication secondary to skin lightening products. A thorough history of mercury exposure is crucial. Physical assessment and relevant supporting tests are indicated to establish a diagnosis. Blood and urine mercury levels are an essential examination for diagnosis and monitoring of the progress and response to treatment. The primary treatment is the discontinuation of the skin lightening products. Chelation therapy is not mandatory and is usually indicated for symptomatic patients. The prognosis depends on the duration of the product use, concentration of mercury in the skin product, and the severity of clinical presentation.


Elevated fetal haemoglobin levels are associated with decreased incidence of retinopathy in adults with sickle cell disease.
Among the many vascular complications of sickle cell disease (SCD), retinopathy is the most prevalent and represents a leading cause of blindness. Hydroxycarbamide therapy ameliorates many symptoms of SCD, and high fetal haemoglobin (HbF) levels have been shown to protect against the development of retinopathy in children with HbSS. Its effect on adults with SCD, who are at a much higher risk of developing retinopathy, has not been studied. We aimed to investigate the effect of hydroxycarbamide use and HbF level on sickle cell retinopathy development in adults. We performed a retrospective cross-sectional study and collected demographics, comorbidities, and ocular and haematological data from 300 adult sickle cell subjects examined at the Henkind Eye Institute at Montefiore Medical Center during a 5-year period, from October 2012 to November 2017. The cohort was comprised mainly of Black and Hispanic subjects with all SCD genotypes, aged 18-71 years. Results show that in HbSS patients treated with hydroxycarbamide, those with retinopathy had significantly lower HbF levels compared to patients without retinopathy (P = 0·018). Our study identified the optimal HbF cut-off point for retinopathy protection to be 14·87%. Thus, a HbF level of 15% appears to be the threshold above which the odds for developing retinopathy in SS patients are reduced by 50%.


Modelling approaches to the dewetting of evaporating thin films of nanoparticle suspensions.
We review recent experiments on dewetting thin films of evaporating colloidal nanoparticle suspensions (nanofluids) and discuss several theoretical approaches to describe the ongoing processes including coupled transport and phase changes. These approaches range from microscopic discrete stochastic theories to mesoscopic continuous deterministic descriptions. In particular, we describe (i) a microscopic kinetic Monte Carlo model, (ii) a dynamical density functional theory and (iii) a hydrodynamic thin film model. Models (i) and (ii) are employed to discuss the formation of polygonal networks, spinodal and branched structures resulting from the dewetting of an ultrathin 'postcursor film' that remains behind a mesoscopic dewetting front. We highlight, in particular, the presence of a transverse instability in the evaporative dewetting front, which results in highly branched fingering structures. The subtle interplay of decomposition in the film and contact line motion is discussed. Finally, we discuss a simple thin film model (iii) of the hydrodynamics on the mesoscale. We employ coupled evolution equations for the film thickness profile and mean particle concentration. The model is used to discuss the self-pinning and depinning of a contact line related to the 'coffee-stain' effect. In the course of the review we discuss the advantages and limitations of the different theories, as well as possible future developments and extensions.


What humanlike errors do autonomous vehicles need to avoid to maximize safety?
The final failure in the causal chain of events in 94% of crashes is driver error. It is assumed most crashes will be prevented by autonomous vehicles (AVs), but AVs will still crash if they make the same mistakes as humans. By identifying the distribution of crashes among various contributing factors, this study provides guidance on the roles AVs must perform and errors they must avoid to realize their safety potential. Using the NMVCCS database, five categories of driver-related contributing factors were assigned to crashes: (1) sensing/perceiving (i.e., not recognizing hazards); (2) predicting (i.e., misjudging behavior of other vehicles); (3) planning/deciding (i.e., poor decision-making behind traffic law adherence and defensive driving); (4) execution/performance (i.e., inappropriate vehicle control); and (5) incapacitation (i.e., alcohol-impaired or otherwise incapacitated driver). Assuming AVs would have superior perception and be incapable of incapacitation, we determined how many crashes would persist beyond those with incapacitation or exclusively sensing/perceiving factors. Thirty-three percent of crashes involved only sensing/perceiving factors (23%) or incapacitation (10%). If they could be prevented by AVs, 67% could remain, many with planning/deciding (41%), execution/performance (23%), and predicting (17%) factors. Crashes with planning/deciding factors often involved speeding (23%) or illegal maneuvers (15%). Errors in choosing evasive maneuvers, predicting actions of other road users, and traveling at speeds suitable for conditions will persist if designers program AVs to make errors similar to those of today's human drivers. Planning/deciding factors, such as speeding and disobeying traffic laws, reflect driver preferences, and AV design philosophies will need to be consistent with safety rather than occupant preferences when they conflict. Practical applications: This study illustrates the complex roles AVs will have to perform and the risks arising from occupant preferences that AV designers and regulators must address if AVs will realize their potential to eliminate most crashes.


Facile Generation of Biomimetic-Supported Lipid Bilayers on Conducting Polymer Surfaces for Membrane Biosensing.
Membrane biosensors that can rapidly sense pathogen interaction and disrupting agents are needed to identify and screen new drugs to combat antibiotic resistance. Bioelectronic devices have the capability to read out both ionic and electrical signals, but their compatibility with biological membranes is somewhat limited. Supported lipid bilayers (SLBs) have served as useful biomimetics for a myriad of research topics involving biological membranes. However, SLBs are traditionally made on inert, rigid, inorganic surfaces. Here, we demonstrate a versatile and facile method for generating SLBs on a conducting polymer device using a solvent-assisted lipid bilayer (SALB) technique. We use this bioelectronic device to form both mammalian and bacterial membrane mimetics to sense the membrane interactions with a bacterial toxin (α-hemolysin) and an antibiotic compound (polymyxin B), respectively. Our results show that we can form high quality bilayers of both types and sense these particular interactions with them, discriminating between pore formation, in the case of α-hemolysin, and disruption of the bilayer, in the case of polymyxin B. The SALB formation method is compatible with many membrane compositions that will not form via common vesicle fusion methods and works well in microfluidic devices. This, combined with the massive parallelization possible for the fabrication of electronic devices, can lead to miniaturized multiplexed devices for rapid data acquisition necessary to identify antibiotic targets that specifically disrupt bacterial, but not mammalian membranes, or identify bacterial toxins that strongly interact with mammalian membranes.


Challenges to the Pair Bond: Neural and Hormonal Effects of Separation and Reunion in a Monogamous Primate.
Social monogamy at its most basic is a group structure in which two adults form a unit and share a territory. However, many socially monogamous pairs display attachment relationships known as pair bonds, in which there is a mutual preference for the partner and distress upon separation. The neural and hormonal basis of this response to separation from the adult pair mate is under-studied. In this project, we examined this response in male titi monkeys (Callicebus cupreus), a socially monogamous New World primate. Males underwent a baseline scan, a short separation (48 h), a long separation (approximately 2 weeks), a reunion with the female pair mate and an encounter with a female stranger (with nine males completing all five conditions). Regional cerebral glucose metabolism was measured via positron emission tomography (PET) imaging using [18F]-fluorodeoxyglucose (FDG) co-registered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. In addition, plasma was collected and assayed for cortisol, oxytocin (OT), vasopressin (AVP), glucose and insulin concentrations. Cerebrospinal fluid (CSF) was collected and assayed for OT and AVP. We used generalized estimating equations (GEE) to examine significant changes from baseline. Short separations were characterized by decreases in FDG uptake, in comparison to baseline, in the lateral septum (LS), ventral pallidum (VP), paraventricular nucleus of the hypothalamus (PVN), periaqueductal gray (PAG), and cerebellum, as well as increases in CSF OT, and plasma cortisol and insulin. Long separations differed from baseline in reduced FDG uptake in the central amygdala (CeA), reduced whole brain FDG uptake, increased CSF OT and increased plasma insulin. The response on encounter with a stranger female depended on whether or not the male had previously reproduced with his pair mate, suggesting that transitions to fatherhood contribute to the neurobiology underlying response to a novel female. Reunion with the partner appeared to stimulate coordinated release of central and peripheral OT. The observed changes suggest the involvement of OT and AVP systems, as well as limbic and striatal areas, during separation and reunion from the pair mate.


Regional metabolite concentrations in the brain of healthy dogs measured by use of short echo time, single voxel proton magnetic resonance spectroscopy at 3.0 Tesla.
To investigate regional differences of relative metabolite concentrations in the brain of healthy dogs with short echo time, single voxel proton magnetic resonance spectroscopy ((1)H MRS) at 3.0 T. 10 Beagles. Short echo time, single voxel (1)H MRS was performed at the level of the right and left basal ganglia, right and left thalamus, right and left parietal lobes, occipital lobe, and cerebellum. Data were analyzed with an automated fitting method (linear combination model). Metabolite concentrations relative to water content were obtained, including N-acetyl aspartate, total choline, creatine, myoinositol, the sum of glutamine and glutamate (glutamine-glutamate complex), and glutathione. Metabolite ratios with creatine as the reference metabolite were calculated. Concentration differences between right and left hemispheres and sexes were evaluated with a Wilcoxon signed rank test and among various regions of the brain with an independent t test and 1-way ANOVA. No significant differences were detected between sexes and right and left hemispheres. All metabolites, except the glutamine-glutamate complex and glutathione, had regional concentrations that differed significantly. The creatine concentration was highest in the basal ganglia and cerebellum and lowest in the parietal lobes. The N-acetyl aspartate concentration was highest in the parietal lobes and lowest in the cerebellum. Total choline concentration was highest in the basal ganglia and lowest in the occipital lobe. Metabolite concentrations differed among brain parenchymal regions in healthy dogs. This study may provide reference values for clinical and research studies involving (1)H MRS performed at 3.0 T.


Channel modeling and estimation for intrapage equalization in pixel-matched volume holographic data storage.
We present two different channel models (the magnitude model and the intensity model) for a pixel-matched volume holographic data storage system that employs the 4-focal-length architecture. First, a framework to describe the channel models is developed. We evaluate the linearity of the channel models by comparing data values obtained from diffraction-limited interference with data values predicted by the channel models. The models are evaluated for linearity and equalization gain under different storage and read-back conditions, such as fill factors, apertures, and contrast ratios. Bit error rate results obtained by use of linear equalization methods in conjunction with the channel models developed are also presented. Our results suggest that the magnitude model leads to better performance when the fill factors are small, whereas the intensity model appears to be more appropriate for the high-fill-factor cases. The magnitude model, when suitable, appears to provide a storage density improvement of as great as 65%, whereas the intensity model seems capable of providing as much as 15% density gain through deconvolution. The optimum aperture for storage seems to be close to the Nyquist aperture.


Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.
Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.


Clinical considerations for optimal dentinal bonding.
A review of current clinical research has demonstrated that successful attachment with resin-based bonding systems is achieved through brief acidic conditions of dentin, followed by thorough coverage with resin priming and bonding agents. This article discusses factors of clinical relevance in achieving optimal results. Effective priming, using multiple coats to enhance resin penetration to the full depth of dentinal demineralization, is crucial. A thin, uniform layer of bonding resin is a critical, elastic intermediary for absorbing stresses of polymerization shrinkage. An air stream should be used only for evaporation of solvent and not for spreading bonding resin, because use of an air stream causes uneven thinning of this valuable intermediate layer. Contamination of the dentinal surface with excessive moisture or solvent or the presence of air voids will make bonding unpredictable under clinical conditions. Adequate etching of peripheral enamel continues to be an important factor in the long-term retention of adhesive restorations.