Distribution of ticks, tick-borne pathogens and the associated local environmental factors including small mammals and livestock, in two French agricultural sites: the OSCAR database.
In Europe, ticks are major vectors of both human and livestock pathogens (e.g. Lyme disease, granulocytic anaplasmosis, bovine babesiosis). Agricultural landscapes, where animal breeding is a major activity, constitute a mosaic of habitat types of various quality for tick survival and are used at different frequencies by wild and domestic hosts across seasons. This habitat heterogeneity, in time and space, conditions the dynamics of these host-vector-pathogen systems and thus drives acarological risk (defined as the density of infected ticks). The principal objective of the OSCAR project (2011-2016) was to examine the links between this heterogeneity and acarological risk for humans and their domestic animals. Here, we present the data associated with this project. This paper reports a database on the distribution and densities of I. ricinus ticks - the most common tick species in French agricultural landscapes - and the prevalence of three tick-borne pathogens (Anaplasma phagocytophilum, Borrelia spp. and Babesia spp.) in two sites in north-western ("Zone Atelier Armorique": ZA site) and south-western ("Vallées et Coteaux de Gascogne": VG site) France. The distribution and density of ticks along a gradient of wooded habitats, as well as biotic variables, such as the presence and abundance of their principal domestic (livestock) and wild hosts (small mammals), were measured from forest cores and edges to more or less isolated hedges, all bordering meadows. Ticks, small mammals and information on local environmental conditions were collected along 90 transects in each of the two sites in spring and autumn 2012 and 2013 and in spring 2014, corresponding to the main periods of tick activity. Local environmental conditions were recorded along each tick and small mammal transect: habitat type, vegetation type and characteristics, slope and traces of livestock presence. Samples consisted of questing ticks collected on the vegetation (mainly I. ricinus nymphs), biopsies of captured small mammals and ticks fixed on small mammals. In the VG site, livestock occurrence and abundance were recorded each week along each tick transect.A total of 29004 questing ticks and 1230 small mammals were captured during the study across the two sites and over the five field campaigns. All questing nymphs (N = 12287) and questing adults (N = 646) were identified to species. Ticks from small mammals (N = 1359) were also identified to life stage. Questing nymphs (N = 4518 I. ricinus) and trapped small mammals (N = 908) were analysed for three pathogenic agents: A. phagocytophilum, Borrelia spp. and Babesia spp.In the VG site, the average prevalence in I. ricinus nymphs for A. phagocytophilum, Borrelia spp. and Babesia spp. were, respectively 1.9% [95% CI: 1.2-2.5], 2.5% [95% CI: 1.8-3.2] and 2.7% [95% CI: 2.0-3.4]. In small mammals, no A. phagocytophilum was detected, but the prevalence for Borrelia spp. was 4.2% [95% CI: 0.9-7.5]. On this site, there was no screening of small mammals for Babesia spp. In ZA site, the average prevalence in nymphs for A. phagocytophilum, Borrelia spp. and Babesia were, respectively 2.2% [95% CI: 1.6-2.7], 3.0% [95% CI: 2.3-3.6] and 3.1% [95% CI: 2.5-3.8]. In small mammals, the prevalence of A. phagocytophilum and Borrelia spp. were, respectively 6.9% [95% CI: 4.9-8.9] and 4.1% [95% CI: 2.7-5.9]. A single animal was found positive for Babesia microti at this site amongst the 597 tested.


Transmitted effect of purebred versus crossbred rams on rate and variability of lamb growth.
The performance of 457 fall-, 510 winter-and 640 summer-born lambs from several years was examined to compare the progeny of purebred Hampshire (H) or Suffolk (S) and crossbred (S X H or H X S) rams for mean and variability of growth rate. Eight rams (four crossbred and four purebred) were mated to white-faced crossbred ewes each season with a total of 37 rams represented in the study. Individual rams were exposed to approximately 30 ewes each season. Purebred-sired lambs were slightly heavier at birth than crossbred-sired lambs averaged over seasons (P = .10). The differences in birth weight between purebred- and crossbred-sired lambs were .08 kg (P = .28); .15 kg (P = .20) and .13 kg (P = .03) for fall, winter and summer seasons, respectively. For 70-d weight and average daily gain from weaning to market weight (ADG), the differences between purebred- and crossbred-sired lambs were not consistent over seasons. Purebred-sired lambs were 1.62 kg heavier (P = .02) at 70 d of age for the winter season, but were .26 (P = .44) and .27 kg (P = .48) lighter than crossbred-sired lambs for the fall and summer lambing seasons, respectively. Differences in ADG between lambs sired by purebred and crossbred rams were -27 (P = .01), 35 (P = .01) and 5 g/d (P = .28) for fall, winter and summer seasons, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Gut microflora associated characteristics in first-degree relatives of children with celiac disease.
In celiac disease (CD), enteropathy of the small bowel results from a T-cell-mediated reaction to gluten in the diet. In addition to gluten, other environmental and genetic factors participate in the disease pathogenesis. We have recently reported the finding of a significantly different short-chain fatty acid (SCFA) profile in fecal samples from children with CD compared to healthy controls reflecting an aberrant gut microflora. The aim of the present study was to make a functional evaluation of the gut microflora status in non-celiac 1st degree relatives of children with CD. Fecal samples from 76 symptom-free, non-celiac, 1st degree CD relatives and from 91 aged-matched healthy controls were analyzed for fecal tryptic activity (FTA) and a number of SCFAs. There was a significantly lower level of acetic acid and total SCFAs as well as a significantly increased level of i-butyric acid and FTA in relatives compared to healthy controls. The FTA and the SCFA profiles in fecal samples from 1st degree relatives of children with CD are different from those of healthy individuals. The implication of this observation provides insight into the pathogenesis of CD and opens up the possibility of future new diagnostic, therapeutic and prophylactic strategies.


Understanding the role of zinc dithiocarbamate complexes as single source precursors to ZnS nanomaterials.
Zinc sulfide is an important wide-band gap semi-conductor and dithiocarbamate complexes [Zn(S2CNR2)2] find widespread use as single-source precursors for the controlled synthesis of ZnS nanoparticulate modifications. Decomposition of [Zn(S2CNiBu2)2] in oleylamine gives high aspect ratio wurtzite nanowires, the average length of which was increased upon addition of thiuram disulfide to the decomposition mixture. To provide further insight into the decomposition process, X-ray absorption spectroscopy (XAS) of [Zn(S2CNMe2)2] was performed in the solid-state, in non-coordinating xylene and in oleylamine. In the solid-state, dimeric [Zn(S2CNMe2)2]2 was characterised in accord with the single crystal X-ray structure, while in xylene this breaks down into tetrahedral monomers. In situ XAS in oleylamine (RNH2) shows that the coordination sphere is further modified, amine binding to give five-coordinate [Zn(S2CNMe2)2(RNH2)]. This species is stable to ca. 70 °C, above which amine dissociates and at ca. 90 °C decomposition occurs to generate ZnS. The relatively low temperature onset of nanoparticle formation is associated with amine-exchange leading to the in situ formation of [Zn(S2CNMe2)(S2CNHR)] which has a low temperature decomposition pathway. Combining these observations with the previous work of others allows us to propose a detailed mechanistic scheme for the overall process.


Effect of a Multifaceted Quality Improvement Intervention on the Prescription of Evidence-Based Treatment in Patients at High Cardiovascular Risk in Brazil: The BRIDGE Cardiovascular Prevention Cluster Randomized Clinical Trial.
Studies have found that patients at high cardiovascular risk often fail to receive evidence-based therapies in community practice. To evaluate whether a multifaceted quality improvement intervention can improve the prescription of evidence-based therapies. In this 2-arm cluster randomized clinical trial, patients with established atherothrombotic disease from 40 public and private outpatient clinics (clusters) in Brazil were studied. Patients were recruited from August 2016 to August 2017, with follow-up to August 2018. Data were analyzed in September 2018. Case management, audit and feedback reports, and distribution of educational materials (to health care professionals and patients) vs routine practice. The primary end point was prescription of evidence-based therapies (ie, statins, antiplatelet therapy, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) using the all-or-none approach at 12 months after the intervention period in patients without contraindications. Of the 1619 included patients, 1029 (63.6%) were male, 1327 (82.0%) had coronary artery disease (843 [52.1%] with prior acute myocardial infarction), 355 (21.9%) had prior ischemic stroke or transient ischemic attack, and 197 (12.2%) had peripheral vascular disease, and the mean (SD) age was 65.6 (10.5) years. Among randomized clusters, 30 (75%) were cardiology sites, 6 (15%) were primary care units, and 26 (65%) were teaching institutions. Among eligible patients, those in intervention clusters were more likely to receive a prescription of evidence-based therapies than those in control clusters (73.5% [515 of 701] vs 58.7% [493 of 840]; odds ratio, 2.30; 95% CI, 1.14-4.65). There were no differences between the intervention and control groups with regards to risk factor control (ie, hyperlipidemia, hypertension, or diabetes). Rates of education for smoking cessation were higher among current smokers in the intervention group than in the control group (51.9% [364 of 701] vs 18.2% [153 of 840]; odds ratio, 11.24; 95% CI, 2.20-57.43). The rate of cardiovascular mortality, acute myocardial infarction, and stroke was 2.6% for patients from intervention clusters and 3.4% for those in the control group (hazard ratio, 0.76; 95% CI, 0.43-1.34). Among Brazilian patients at high cardiovascular risk, a quality improvement intervention resulted in improved prescription of evidence-based therapies. ClinicalTrials.gov identifier: NCT02851732.


Backward wave optical amplification by an asymmetric active interference filter.
Equations are given for reflectance, bandwidth and root gain-bandwidth of an active interference filter having unequal mirror reflectances and operating in the reflecting mode. Gain for various configurations is compared keeping the product of the mirror reflectances constant. It is shown that the reflectance gain of an asymmetric configuration can be greater than the transmittance gain while the bandwidths are identical. Specific examples are treated to show how device gain depends on single-pass gain and input and output mirror reflectances.


Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats.
The autocrine modulation of cardiac K(+) currents was compared in ventricular and atrial cells (V and A cells, respectively) from Type 1 diabetic rats. K(+) currents were measured by using whole cell voltage clamp. ANG II was measured by ELISA and immunofluorescent labeling. Oxidative stress was assessed by immunofluorescent labeling with dihydroethidium, a measure of superoxide ions. In V cells, K(+) currents are attenuated after activation of the renin-angiotensin system (RAS) and the resulting ANG II-mediated oxidative stress. In striking contrast, these currents are not attenuated in A cells. Inhibition of the angiotensin-converting enzyme (ACE) also has no effect, in contrast to current augmentation in V cells. ANG II levels are enhanced in V, but not in A, cells. However, the high basal ANG II levels in A cells suggest that in these cells, ANG II-mediated pathways are suppressed, rather than ANG II formation. Concordantly, superoxide ion levels are lower in diabetic A than in V cells. Several findings indicate that high atrial natriuretic peptide (ANP) levels in A cells inhibit RAS activation. In male diabetic V cells, in vitro ANP (300 nM-1 muM, >5 h) decreases oxidative stress and augments K(+) currents, but not when excess ANG II is present. ANP has no effect on ventricular K(+) currents when the RAS is not activated, as in control males, in diabetic males treated with ACE inhibitor and in diabetic females. In conclusion, the modulation of K(+) currents and oxidative stress is significantly different in A and V cells in diabetic rat hearts. The evidence suggests that this is largely due to inhibition of RAS activation and/or action by ANP in A cells. These results may underlie chamber-specific arrhythmogenic mechanisms.


Somatosensory and motor representations following bilateral transplants of the hands: A 6-year longitudinal case report on the first pediatric bilateral hand transplant patient.
A vascularized composite tissue allotransplantation (VCA) was performed at the Children's Hospital of Philadelphia (CHOP), on an 8-year-old patient in 2015, six years after bilateral hand and foot amputation. Hand VCA resulted in reafferentation of the medial, ulnar, and radial nerves serving hand somatosensation and motor function. We used magnetoencephalography (MEG) to assess somatosensory cortical plasticity following the post-transplantation recovery of the peripheral sensory nerves of the hands. Our 2-year postoperative MEG showed that somatosensory lip representations, initially observed at "hand areas", reverted to canonical, orthotopic lip locations with recovery of post-transplant hand function. Here, we continue the assessment of motor and somatosensory responses up to 6-years post-transplant. Magnetoencephalographic somatosensory responses were recorded eight times over a six-year period following hand transplantation, using a 275-channel MEG system. Somatosensory tactile stimuli were presented to the right lower lip (all 8 visits) as well as right and left index fingers (visits 3-8) and fifth digits (visits 4-8). In addition, left and right-hand motor responses were also recorded for left index finger and right thumb (visit 8 only).During the acute recovery phase (visits 3 and 4), somatosensory responses of the digits were observed to be significantly larger and more phasic (i.e., smoother) than controls. Subsequent measures showed that digit responses maintain this atypical response profile (evoked-response magnitudes typically exceed 1 picoTesla). Orthotopic somatosensory localization of the lip, D2, and D5 was preserved. Motor beta-band desynchrony was age-typical in localization and response magnitude; however, the motor gamma-band response was significantly larger than that observed in a reference population.These novel findings show that the restoration of somatosensory input of the hands resulted in persistent and atypically large cortical responses to digit stimulation, which remain atypically large at 6 years post-transplant; there is no known perceptual correlate, and no reports of phantom pain. Normal somatosensory organization of the lip, D2, and D5 representation remain stable following post-recovery reorganization of the lip's somatosensory response.


Exploring Causes and Potential Solutions for Food Waste among Young Consumers.
Young consumers are often described as innovative and concerned about the environment. However, their practices sometimes are not strong enough, which are described as the attitude-behavior gap and are seen in significant amounts of food waste. The objective of this study is to focus on food waste among young consumers in high-income countries and to outline the main determinants of food waste generation. Qualitative data gathered from nine focus groups in Lithuania, Finland and Denmark (2021-2022) contribute to formulating potential intervention to decrease food waste behavior within this segment. The article provides a substantial literature review on food waste and discusses recommendations for possible interventions and further research to solve the attitude-behavior gap. The findings show four specific fields for potential solutions, related to (1) special occasions, (2) assessing food quality, (3) kitchen habits, and (4) shopping habits. Our contribution is discussed at the end of the article.


Virus-Mediated Metalloproteinase 1 Induction Revealed by Transcriptome Profiling of Bovine Herpesvirus 4-Infected Bovine Endometrial Stromal Cells.
Viral infections can cause genital tract disorders (including abortion) in cows, and bovine herpesvirus 4 (BoHV-4) is often present in endometritis-affected animals. A major problem with cattle uterine viral infections in general, and BoHV-4 in particular, is our limited understanding of the pathogenic role(s) that these infections play in the endometrium. A similar lack of knowledge holds for the molecular mechanisms utilized, and the host cell pathways affected, by BoHV-4. To begin to fill these gaps, we set up optimized conditions for BoHV-4 infection of a pure population of bovine endometrial stromal cells (BESCs) to be used as source material for RNA sequencing-based transcriptome profiling. Many genes were found to be upregulated (417) or downregulated (181) after BoHV-4 infection. As revealed by enrichment functional analysis on differentially expressed genes, BoHV-4 infection affects various pathways related to cell proliferation and cell surface integrity, at least three of which were centered on upregulation of matrix metalloproteinase 1 (MMP1) and interleukin 8 (IL8). This was confirmed by reverse transcription PCR, real-time PCR, Western-immunoblot analysis, and a luciferase assay with a bovine MMP1-specific promoter reporter construct. Further, it was found that MMP1 transcription was upregulated by the BoHV-4 transactivator IE2/RTA, leading to abnormally high metalloproteinase tissue levels, potentially leading to defective endometrium healing and unresolved inflammation. Based on these findings, we propose a new model for BoHV-4 action centered on IE2-mediated MMP1 upregulation and novel therapeutic interventions based on IFN gamma-mediated MMP1 downregulation.


Three polymorphisms associated with low hepatic lipase activity are common in African Americans.
We have shown previously that a hepatic lipase allele (designated -514T) is common among African Americans and contributes to low hepatic lipase activity in this population. To identify other hepatic lipase alleles associated with low hepatic lipase activity in this population, the coding region and intron-exon boundaries of the hepatic lipase gene were sequenced in 20 African American men with low hepatic lipase activity. Two polymorphisms (N193S and L334F) were associated with low post-heparin plasma hepatic lipase activity and were much more common in African Americans than in whites. This finding, together with our previous data on the -514T allele, indicates that at least three different hepatic lipase polymorphisms associated with low hepatic lipase activity are common among African Americans. Analysis of hepatic lipase haplotypes revealed that 97% of African Americans have at least one hepatic lipase allele that is associated with low hepatic lipase activity.


[Increased erythrocyte membrane permeability to sodium--a risk factor for hypertension].
Monitoring the sodium-lithium counter transport, the authors examined the membrane permeability of red cells for sodium in 70 females and 127 males aged 20 to 70 years. In subjects with normal arterial pressure, the membrane permeability of the red cells showed no age-specific changes or differences in males and females at the age of 20 to 31 years and those over 40 years. Arterial hypertension (AH) according to the WHO criteria was diagnosed in 31% of those studied. The individuals with an increased permeability of the red cell membrane for sodium, exhibited AH twice as frequently as the individuals with the normal or decreased permeability. The rate of AH was found to rise (from 46 to 68%) with age in the subjects with the elevated permeability of the red cell membrane whilst there was no such tendency in the individuals with normal and decreased permeability of the red cell membrane.


[Surgical treatment of traumatic madarosis].
Traumatic madarosis is a cosmetic and anatomo-functional problem. Besides the repair of the eyelashes proper, the clinical status of the patient requires repair of the carcass of the damaged eyelid in order to prevent lagophthalmos. The technique of transplanting a free hairy graft from the eyebrows is described. The results of treatment were assessed by the following parameters: the flap taking in, thickness and direction of the new lashes growth, and stability of the eyelid. Complete healing of the graft and stability of the eyelid were attained in all the cases. Good thickness of the eyelashes and the ideal direction of their growth were more difficult to achieve. The causes of failures are discussed. Despite the shortcomings, the method of treating traumatic madarosis proved to be effective and is recommended for clinical use.


Single-molecule force-unfolding of titin I27 reveals a correlation between the size of the surrounding anions and its mechanical stability.
Each cellular protein is surrounded by a biochemical milieu that affects its stability and the associated function. The role of this surrounding milieu in the proteins' mechanical stability remains largely unexplored. Herein, we report an as yet unknown correlation between the size of the surrounding anions and the mechanical stability of a protein. Using single-molecule force spectroscopy of the 27th domain (I27) of human cardiac muscle protein titin, we show that the average unfolding force of the protein decreases with increase in the ionic radii of the surrounding anions in the order Cl- > Br- > NO3- > I- > SO42- ≈ ClO4-, indicating an inverse correlation between anion size and the mechanical stability of I27. The destabilizing effect was attributed to the combined effect of increase in the unfolding rate constant and unfolding distance upon incubation with the anion. These findings reveal that anion size can significantly affect the mechanical resistance of proteins and thus could be a convenient and promising tool for regulating the mechanical stability of proteins.


[Use of music in palliative care].
Man is mortal, which means that as the earthly body perishes being, final. Disease and death will always be an inevitable and integral part of human experience. The way in which we try to identify and respond to the unique and individual needs of the dying is an indication of our maturity as a society. The number of people requiring palliative care is growing. Palliative care does not intend to either accelerate or postpone death she emphasizes the life and looks at dying as a normal process. It is an active form of care for patients with advanced, progressive illness, with the aim of suppressing pain and other symptoms in addition to providing psychological, social and spiritual support which ensures the best possible quality of life for patients and their families. Therefore requires a coordinated and interdisciplinary contribution team. The variety of professions in a team, and determine the needs of patients should be ready to provide physical, psychological, social and spiritual support using methods that result from an interdisciplinary, collaborative team approach. Development of a holistic approach and awareness in the medical and allied professions has led to a renewal of interest in the inclusion of music and other expressive media in contemporary concepts of palliative care, which are consistent with problem areas, clinical manifestations and the needs of patients. Music offers a direct and uncomplicated medium of intimacy, living in a man who listens to her, has a place where words lose their power. Music is like our existence, constantly polarizing and emotionally stimulating, as it touches the medium of the earliest layers of our becoming. The use of music in palliative care has proved very effective for a variety of effects that music creates in patients. These effects are achieved through the use of various musical techniques, such as musical improvisation, songwriting, receiving creative techniques, guided by imagination and music. These techniques allow the diversity of objectives in treating patients such as reducing anxiety and stress, relaxation, pain control, reducing confusion spiritual, emotional expression, experience, self-awareness, encourage creative expression, causing mood swings - emotional, cognitive and behavioral, inducing the patient's imagination, enabling patient's chronological classification of life experiences, and the elaboration of unresolved pain, sorrow or errors. Adequate selection and use of musical techniques in palliative care in the service of achieving the best possible quality of life for patients at the end of life.


Does Freeze-Thawing Influence the Effects of Platelet Concentrates? An In Vitro Study on Human Adipose-Derived Stem Cells.
Human adipose-derived stem cells (hASCs) have been proposed as a possible therapy for tissue regeneration in aesthetic, plastic, and reconstructive surgery. Today, platelet concentrates are used in a wide range of disciplines, but their storage has become a controversial aspect. The purpose of this in vitro study was to evaluate the effect of plasma rich in growth factors (PRGF), after a freeze-thawing cycle, on the proliferation and biological activity of progenitor cells involved in soft tissue healing. Different formulations of activated PRGF were added to hASCs cultured in serum-free medium. Cell proliferation was assessed by MTT test and cell count up to 7 and 12-day incubation. Osteo-differentiation ability of hASCs was also tested after 7 and 14-day incubation by alkaline phosphatase assay. The effects of 4 PRGF preparations (fresh/frozen and with/without platelets) were compared with corresponding formulations of plasma poor in growth factors and with standard medium. hASCs cultured in the presence of platelet concentrates increased proliferation rate with respect to cells grown in standard medium without significant differences among all the tested plasma formulations on cell viability up to 12 days of culture. PRGF activity is preserved after cryopreservation and platelet-rich preparations promoted osteo-differentiation of hASCs at day 7. In conclusion, PRGF supports the proliferation and the differentiation of progenitor cells in vitro also when applied after cryopreservation. Platelet concentrates, either alone or in combination with mesenchymal stem cells, might be a valuable tool in the field of tissue regeneration.


[Detection and quantitative determination of antigen to the human immunodeficiency virus during development of a test-system for the serodiagnosis of AIDS].
One of the variants of IFA using a conjugate on the basis of anti-HIV-IgG was used for control of the content of human immunodeficiency virus (HIV) antigen at different stages of production of a test system for serodiagnosis of AIDS. This method permits HIV antigen quantitation in virus lysates, its nonpurified concentrates, and in native culture fluid in titres from 2000 to 60,000 and from less than 27 to greater than 729, respectively. In most cases, high titres of antigen in the liquid fraction of the culture corresponded to high values of the antigen-containing cells on the basis of immunofluorescence data and signs of intensive HIV production in electron microscopic culture control. The authors developed a method allowing to determine the antigen titre in the study material using only one dilution (1:9) of it in IFA technique.


Biochemical and mutational analysis of the polyomavirus core promoter: involvement of nuclear factor-1 in early promoter function.
The polyomavirus enhancer is separated from the early RNA initiation sites by a 120 bp promoter region. To identify the core promoter elements, we introduced base-substitution mutations within the potential elements in the vicinity of the RNA initiation site. Three of these mutants, two with mutations within a putative nuclear factor-1 (NF-1) binding site and the other within the TATA box, exhibited reduced promoter activity by about threefold in the mouse NIH 3T3 cell line. The activity of the other three mutants was either little affected or remained unchanged. Mobility shift assays using specific competitors and antibodies against NF-1 demonstrated the binding of a protein of the NF-1 family at a site adjacent to the TATA box, suggesting a role for NF-1 binding in early promoter function. The effect of these mutations was also evaluated in undifferentiated mouse embryonal carcinoma (F9) cells in the presence of an additional mutation (F441) at nucleotide position 5233. This additional mutation creates a strong binding site for a transcription factor, TEF-1, and helps the virus to grow in this cell line. While the TATA box and the GC box mutants behaved qualitatively in a similar fashion, the NF-1 motif now played a minor role in F9 cells. Western blot experiments demonstrated low levels of NF-1 protein in this cell line. The NF-1 motif partially overlaps a T-antigen binding motif and this motif is not involved in T-antigen-mediated regulation of the early promoter. Our results suggest that a protein of the NF-1 family binds to the core promoter and is important for early transcription in vivo. We further demonstrate that undifferentiated F9 cells contain a very low level of NF-1 and the F441 mutant possibly follows a different mechanism for promoter function in these cells.


High mitochondrial diversity of domesticated goats persisted among Bronze and Iron Age pastoralists in the Inner Asian Mountain Corridor.
Goats were initially managed in the Near East approximately 10,000 years ago and spread across Eurasia as economically productive and environmentally resilient herd animals. While the geographic origins of domesticated goats (Capra hircus) in the Near East have been long-established in the zooarchaeological record and, more recently, further revealed in ancient genomes, the precise pathways by which goats spread across Asia during the early Bronze Age (ca. 3000 to 2500 cal BC) and later remain unclear. We analyzed sequences of hypervariable region 1 and cytochrome b gene in the mitochondrial genome (mtDNA) of goats from archaeological sites along two proposed transmission pathways as well as geographically intermediary sites. Unexpectedly high genetic diversity was present in the Inner Asian Mountain Corridor (IAMC), indicated by mtDNA haplotypes representing common A lineages and rarer C and D lineages. High mtDNA diversity was also present in central Kazakhstan, while only mtDNA haplotypes of lineage A were observed from sites in the Northern Eurasian Steppe (NES). These findings suggest that herding communities living in montane ecosystems were drawing from genetically diverse goat populations, likely sourced from communities in the Iranian Plateau, that were sustained by repeated interaction and exchange. Notably, the mitochondrial genetic diversity associated with goats of the IAMC also extended into the semi-arid region of central Kazakhstan, while NES communities had goats reflecting an isolated founder population, possibly sourced via eastern Europe or the Caucasus region.


[Subcutaneous injection chambers for central venous access: a multicenter clinical trial. The Interhospital Group of Valencia (GIHV)].
A multicentric clinical trial was performed to evaluate two routes of access for implantable subcutaneous central venous devices: by way of the subclavian vein (group A) and peripheral access by way of the veins of the flexion side of the elbow (group B). The indications for implantation were: antineoplastic treatment of solid tumors, myelo- and lymphoproliferative syndromes, antiviral treatment, and parenteral nutrition at home. The study was composed of 87 patients, 48 men and 39 women, with a mean age of 57.1 years (SD = 12.6). Group A was made up of 48 patients, and group B of 39. Implantation failure was 8.3% in group A and 5.1% in group B (p = n.s.). Complications of implantation were 23.4% in group A and 15.4% in group B (p = n.s.). The complications of permanence were diagnosed at 27.6% in group A and at 15.4% in group B (p = n.s.). We have not been able to find significant differences between the two groups, probably due to the fact that the series is still short. Nevertheless, the manageability, comfort for the nursing staff and for the patients, appears to be greater with the devices implanted in the infraclavicular region, by means of a subclavian vein puncture.


Prediction of the Development of Pulmonary Fibrosis Using Serial Thin-Section CT and Clinical Features in Patients Discharged after Treatment for COVID-19 Pneumonia.
To identify predictors of pulmonary fibrosis development by combining follow-up thin-section CT findings and clinical features in patients discharged after treatment for COVID-19. This retrospective study involved 32 confirmed COVID-19 patients who were divided into two groups according to the evidence of fibrosis on their latest follow-up CT imaging. Clinical data and CT imaging features of all the patients in different stages were collected and analyzed for comparison. The latest follow-up CT imaging showed fibrosis in 14 patients (male, 12; female, 2) and no fibrosis in 18 patients (male, 10; female, 8). Compared with the non-fibrosis group, the fibrosis group was older (median age: 54.0 years vs. 37.0 years, p = 0.008), and the median levels of C-reactive protein (53.4 mg/L vs. 10.0 mg/L, p = 0.002) and interleukin-6 (79.7 pg/L vs. 11.2 pg/L, p = 0.04) were also higher. The fibrosis group had a longer-term of hospitalization (19.5 days vs. 10.0 days, p = 0.001), pulsed steroid therapy (11.0 days vs. 5.0 days, p < 0.001), and antiviral therapy (12.0 days vs. 6.5 days, p = 0.012). More patients on the worst-state CT scan had an irregular interface (59.4% vs. 34.4%, p = 0.045) and a parenchymal band (71.9% vs. 28.1%, p < 0.001). On initial CT imaging, the irregular interface (57.1%) and parenchymal band (50.0%) were more common in the fibrosis group. On the worst-state CT imaging, interstitial thickening (78.6%), air bronchogram (57.1%), irregular interface (85.7%), coarse reticular pattern (28.6%), parenchymal band (92.9%), and pleural effusion (42.9%) were more common in the fibrosis group. Fibrosis was more likely to develop in patients with severe clinical conditions, especially in patients with high inflammatory indicators. Interstitial thickening, irregular interface, coarse reticular pattern, and parenchymal band manifested in the process of the disease may be predictors of pulmonary fibrosis. Irregular interface and parenchymal band could predict the formation of pulmonary fibrosis early.


Cissus quadrangularis extract enhances biomineralization through up-regulation of MAPK-dependent alkaline phosphatase activity in osteoblasts.
Cissus quadrangularis Linn. has been implicated as therapeutic agent for enhancing bone healing. Though its osteogenic activity has been suggested, the underlying mechanism still remains unclear. In the present study, the effects of ethanol extract of C. quadrangularis (CQ-E) on osteoblast differentiation and function were analyzed using murine osteoblastic cells. The results indicated that mRNA expressions of osteoblast-related genes were not affected by the CQ-E treatment. However, alkaline phosphatase (ALP) activity and the extent of mineralized nodules were significantly increased in treated cells compared with controls. The addition of an extracellular regulated kinase 1/2 inhibitor, a Jun N-terminal kinase 1/2/3 inhibitor and a p38 mitogen-activated protein kinase (MAPK) inhibitor resulted in significantly decreased ALP activity, preferentially by p38 MAPK inhibitor. These results suggested that CQ-E may regulate osteoblastic activity by enhancing ALP activity and mineralization process, and the increased ALP activity effect of CQ-E is likely mediated by MAPK-dependent pathway.


Effects of exercise on periodontal parameters in obese women.
Several studies have demonstrated an association between obesity, periodontitis, and exercise. This study aimed to investigate the effects of regular exercise on obese women with periodontal disease, using serum, saliva, and gingival crevicular fluid (GCF) samples. A before-after study design was adopted to evaluate the effects of 12 weeks of regular exercise on obese women grouped according to periodontal status, without a control group (no exercise). The study sample comprised of 15 patients without periodontitis (NP group) and 10 patients with chronic periodontitis (CP group), from whom periodontal parameters were measured and serum, saliva, and GCF samples were collected. Body mass index (BMI), anthropometric measurements, somatotype-motoric tests, and maximal oxygen consumption (VO2max) were recorded at baseline and after exercise. Med Calc was used for statistical analysis. After exercise, a significant decrease in BMI and a significant increase in VO2max were observed in both groups. A significant decrease in probing depth and clinical attachment loss, serum leptin, GCF tumor necrosis factor-α(TNF-α) and leptin, and a significant increase in GCF resistin were observed in the CP group. A significant decrease in serum TNF-α and leptin levels and a significant increase in serum resistin and GCF TNF-α, leptin, resistin, and adiponectin levels were observed in the NP group. Significant correlations between bleeding on probing and levels of interleukin-1β and leptin in GCF were observed in the CP group. This study showed that regular exercise exerts different impacts with respect to clinical and biochemical aspects of periodontal and systemic conditions in obese women.


The architecture of the accessory reproductive glands of the male desert locust. 5: ultrastructure during maturation.
The accessory reproductive glands of the male desert locust were studied with the electron microscope from the time of adult emergence until full sexual maturity was attained (10 days). Observations on the changes in the nucleus and the cytoplasm of the glandular epithelium, particularly those organelles involved in the elaboration of cell secretions, were made during the maturation of the accessory glands. Cells of gland 16 (the functional seminal vesicle) exhibit numerous ribosomal aggregates, have a concentration of mitochondria along their luminal surface, and show some secretory activity, even at the time of adult emergence. On the other hand, all other accessory glands show very little development of the secretory apparatus (rough-surfaced endoplasmic reticulum, polyribosomes, Golgi elements, elaborate mitochondria, etc.) until after the fifth adult day. These changes parallel changes in the secretory activity of the adult corpus allatum; and it is suggested that the corpus allatum hormone regulates the maturation of the truly glandular accessory glands of the locust, but not that of the functional vesicle.


Role of the insulin-like growth factors and their binding proteins in lactation.
Insulin-like growth factor (IGF)-I is thought to mediate a portion of the effects of bST on lactation in dairy cows. Serum concentrations of IGF-I are increased in lactating cows that were treated with bST, and IGF-I receptors are present in bovine mammary tissue. In addition, close arterial infusion of IGF-I into the mammary gland of goats increases milk yield. Little evidence exists to support a direct galactopoietic effect of IGF-I in ruminants. However, IGF-I is a potent mitogen for mammary epithelial cells and may also influence the inhibition of apoptosis of this cell type. The IGF are found in association with a family of individual binding proteins. The high affinity of the IGF for these proteins relative to the IGF receptor allows them to modulate IGF-I bioactivity in the mammary gland at the cellular level. Mammary epithelial cells synthesize multiple forms of IGF binding proteins, and one of these, IGF binding protein-3, is specifically regulated by the IGF. Stimulation of DNA synthesis by IGF-I is enhanced in bovine mammary epithelial cells that overexpress the IGF binding protein-3. These data indicate that IGF-I can stimulate the synthesis of an IGF binding protein, which enhances its own mitogenic activity. However, whether this mechanism is operative in the lactating mammary gland in vivo is unknown. Given the complexity of the interactions between the IGF and their binding proteins, more information is needed before the role of these growth factors in regulating growth, differentiation, and apoptosis of mammary epithelial cells is delineated.


Withaferin A Promotes White Adipose Browning and Prevents Obesity Through Sympathetic Nerve-Activated Prdm16-FATP1 Axis.
The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis, and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.


Advances in dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is a clinical diagnosis representing a specific presentation of a pathological α-synucleinopathy (Lewy body disease). DLB is one entity under the broader term Lewy body dementia, which also includes Parkinson's disease dementia. Recent advances in DLB include publication of updated diagnostic criteria and recognition of prodromal DLB states, including mild cognitive impairment, delirium-onset, and psychiatric-onset forms. Research criteria for the mild cognitive impairment form of DLB were published in 2020. Increasing research shows that concomitant Alzheimer's disease pathology in individuals with DLB is common in addition to the α-synucleinopathy pathology. This has implications for biomarker use and expected progression. Identifying biomarkers for DLB is an area of active research. Cerebrospinal fluid and skin biopsy tests are now commercially available in the United States, but their role in routine clinical care is not yet established. Additional research and biomarkers are needed. Research suggests that median survival after DLB diagnosis is 3-4 years, but there are rapidly and slowly progressive forms. Most individuals with DLB die of complications of the disease. Clinical trials for individuals with DLB have increased over the last 5 years, targeting both symptoms and underlying pathology. Effective therapies remain an unmet need, however. This review focuses on recent advances with an emphasis on literature that informs clinical care.


Oral Candida Infection in Psoriatic Patients Treated with IL17A Inhibitors: Report of 3 Cases and a Comprehensive Review of the Literature.
An intact and fully functional immune system plays a crucial role in the prevention of several infectious diseases. Interleukin (IL)17 is significantly involved in oral mucosa immunity against several antigens and microorganisms, including Candida albicans (CA). Herein, we present three cases of oral candidiasis (OC) related to the use of an IL17A inhibitor for psoriasis. Three psoriatic individuals presented for evaluation of widespread symptomatic oral lesions temporally correlated with the onset of IL17A inhibitors (secukinumab in two patients and brodalumab in one patient). Clinical examination revealed either partially removable white plaques in an erythematous background (case #1) or diffuse erythematous lesions (cases #2 and 3) involving several areas of the oral mucosa. Cytology smear, accompanied by histopathologic examination in case #1, confirmed the clinical impression of OC in all three cases. All patients received antifungal therapy with satisfactory clinical response. No discontinuation of the antipsoriatic regimen was recommended, but all patients were advised to remain under monitoring for possible OC relapses. During the last few years, new systemic biologic agents targeting IL17 have been used for the management of variable immune-mediated diseases. Few clinical trials and scarce case reports have shown that these medications place individuals at high risk of developing candidiasis. We propose that patients treated with these medications should be at close monitoring for the development of OC and, if it occurs, receive appropriate management.


Acute respiratory distress syndrome: diagnosis and management.
Acute respiratory distress syndrome manifests as rapidly progressive dyspnea, tachypnea, and hypoxemia. Diagnostic criteria include acute onset, profound hypoxemia, bilateral pulmonary infiltrates, and the absence of left atrial hypertension. Acute respiratory distress syndrome is believed to occur when a pulmonary or extrapulmonary insult causes the release of inflammatory mediators, promoting neutrophil accumulation in the microcirculation of the lung. Neutrophils damage the vascular endothelium and alveolar epithelium, leading to pulmonary edema, hyaline membrane formation, decreased lung compliance, and difficult air exchange. Most cases of acute respiratory distress syndrome are associated with pneumonia or sepsis. It is estimated that 7.1 percent of all patients admitted to an intensive care unit and 16.1 percent of all patients on mechanical ventilation develop acute lung injury or acute respiratory distress syndrome. In-hospital mortality related to these conditions is between 34 and 55 percent, and most deaths are due to multiorgan failure. Acute respiratory distress syndrome often has to be differentiated from congestive heart failure, which usually has signs of fluid overload, and from pneumonia. Treatment of acute respiratory distress syndrome is supportive and includes mechanical ventilation, prophylaxis for stress ulcers and venous thromboembolism, nutritional support, and treatment of the underlying injury. Low tidal volume, high positive end-expiratory pressure, and conservative fluid therapy may improve outcomes. A spontaneous breathing trial is indicated as the patient improves and the underlying illness resolves. Patients who survive acute respiratory distress syndrome are at risk of diminished functional capacity, mental illness, and decreased quality of life; ongoing care by a primary care physician is beneficial for these patients.


[The mechanisms underlying the formation of systemic hemodynamic reactions: role of initial vessel tone and arterial pressure].
A review of the experimental materials describing the relationships between the initial (background) vascular tone and arterial pressure, on the one hand, and reactivity of the arterial system, on the other. Experiments were carried out on anesthetized rats under arterial hypotension caused by orthostasis or vasoactive agents, such as papaverin and sodium nitroprusside, and arterial hypertension resulting from volume expansion. It has been proposed that these relationships are based on changes in the amplitude of transmural pressure in arterial vessles.


Two- and three-photon absorption of organic ionic pyrylium based materials.
Pyrylium dyes having the same basic chemical structure, differing only to a specific substituent, have been used as novel materials for multiphoton three-dimensional data storage. Electronic absorption spectra, two-photon and three-photon absorption properties of this class of pyrylium dyes, have been studied theoretically and compared to experimental results. The effects of the counteranion, the surrounding solvent, and electron releasing and electron withdrawing groups in specific positions of the basic structure have been explored in detail. It is argued that on grounds of the quality of experimental spectroscopic agreement, the computed two- and three-photon data may be used in pulse propagation simulations of three-dimensional recording in optical memories.


Osteoporosis treatment for patients with stroke.
Little is known about the frequency of use of medications to maintain bone health for patients with stroke. This study was undertaken at an urban academic rehabilitation center to determine the prevalence of use of agents that could reduce bone loss in the stroke population. A clinical database was searched for all patients 18 years old and over with stroke. The sample included 1,219 inpatients and 2,776 outpatients. Demographic information (age, gender, and race) and medications were obtained for each patient. Among inpatients with stroke, 7.1% were taking osteoporosis medications (bisphosphonates, calcitonin, parathyroid hormone, or hormone replacement therapy), 11.3% were taking calcium supplements, 5.9% were taking vitamin D supplements, and 45.1% were taking multivitamin supplements. Among outpatients with stroke, 5.7% were taking osteoporosis medication, 5.8% were taking calcium supplements, 2.2% were taking vitamin D supplements, and 16.0% were taking multivitamin supplements. Patients being treated with specific osteoporosis therapies tended to be older and female by calculated odds ratios. The use of multivitamins was not related to age, gender, or race. Overall, relatively few stroke patients were taking osteoporosis medications or supplements. There is a need to increase the recognition, prevention, and treatment of bone loss in this high-risk population.


Clinical and economic outcomes in patients with type 2 diabetes initiating insulin glargine disposable pen versus exenatide BID.
To evaluate clinical and economic outcomes in patients with type 2 diabetes mellitus (T2DM) who failed oral anti-diabetic drug (OAD) therapy and initiated either insulin glargine with disposable pen (GLA-P) or exenatide BID (EXE). This retrospective study used data from a large US-managed care claims database and included adult T2DM patients initiating treatment with GLA-P or EXE in 2007 or 2008. Propensity score matching was used to control observed baseline differences between treatment groups. Primary study end-points included treatment persistence, A1C, healthcare utilization, and healthcare costs during the 1-year follow-up period. Two thousand three hundred and thirty nine patients were included in the study (GLA-P: 381; EXE: 1958); 626 patients were in the 1:1 matched cohort (54% male; mean age: 54 years; mean A1C: 9.2%). At follow-up, patients in the GLA-P group were significantly more persistent in treatment than EXE patients (48% vs 15% in persistence rate and 252 vs 144 days in persistence days; both p<0.001). GLA-P patients also had significantly lower A1C at follow-up (8.02% vs 8.32%; p=0.042) and greater A1C reduction from baseline (-1.23% vs -0.92%; p=0.038). There were no significant differences in claims-based hypoglycemia rates and overall diabetes-related healthcare utilization and cost. Since this was a retrospective analysis, causality of treatment benefits cannot be established. The study was specific to two treatments and may not generalize to other models of insulin administration. Some of the results, although statistically significant, may not be found clinically important. In a real-world setting among T2DM patients who failed to achieve or sustain glycemic goal with OADs, initiation of GLA-P instead of EXE may be a more effective option because it was associated with greater treatment persistence, greater A1C reduction without a significantly higher rate of hypoglycemia, and similar healthcare costs.


Political uncertainty moderates neural evaluation of incongruent policy positions.
Uncertainty has been shown to impact political evaluation, yet the exact mechanisms by which uncertainty affects the minds of citizens remain unclear. This experiment examines the neural underpinnings of uncertainty in political evaluation using functional magnetic resonance imaging (fMRI). During fMRI, participants completed an experimental task where they evaluated policy positions attributed to hypothetical political candidates. Policy positions were either congruent or incongruent with candidates' political party affiliation and presented with varying levels of certainty. Neural activity was modelled as a function of uncertainty and incongruence. Analyses suggest that neural activity in brain regions previously implicated in affective and evaluative processing (anterior cingulate cortex, insular cortex) differed as a function of the interaction between uncertainty and incongruence, such that activation in these areas was greatest when information was both certain and incongruent, and uncertainty influenced processing differently as a function of the valence of the attached information. These findings suggest that individuals are attuned to uncertainty in the stated issue positions of politicians, and that the neural processing of this uncertainty is dependent on congruence of these positions with expectations based on political party identification. Implications for the study of emotion and politics and political cognition are discussed. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.


[Once more about interstitial nephritis].
A comparative study was made of 25 patients (Group 2, control) with documented pyelonephritis and 55 patients (Group 1) who had a morphological picture of chronic interstitial inflammation without signs of abnormal urodynamics, bacteriuria, urographic and sonographic evidence of pyelonephritis. All the patients underwent life-time morphological study, their immunological spectrum (IgA, IgG, IgM, IgE) was explored. They had a test for sensitization of a peripheral blood mononuclear fraction to one or several drugs which had been given to the patients. The patients from Group 1 displayed significantly elevated IgE levels and a regularly detected sensitization of mononuclears to one or several drugs. Morphologically, there were signs of congenital renal tissue dysplasia in the presence of diffuse interstitial inflammation. Positive immunofluorescence findings were seen in the tubular wall of 10 (18%) patients. The findings made it possible to define diagnostic criteria for interstitial nephritis, a nosological entity.


"Every step counts!": effects of a structured walking intervention in a community-based senior organization.
This study evaluated "Every Step Counts!"- a 10-wk, structured walking intervention in a community-based senior organization - on promoting physical activity participation, fitness, and well-being among older adults (age ≥ 55 yr). The intervention prescribed pedometer-defined walks in weekly walking schedules. These were fitness-tailored and structured in walking load (intensity/volume) according to the principles of training progression. This intervention was offered as a social activity at meeting points of a community-based senior organization. Twenty-nine meeting points (n = 432) constituted the intervention condition. Ten meeting points (n = 148) formed the wait-list control condition. Measurements were organized at intervention start (pretest) and end (posttest). Intention-to-treat linear mixed models showed small positive intervention effects on physical activity, fitness, and aspects of well-being. These results confirm the effectiveness of structured walking interventions with systematic training progression and underscore the value of community-based senior organizations as intervention settings for older adults.


HIV-TB coinfection: Clinico-epidemiological determinants at an antiretroviral therapy center in Southern India.
HIV-TB (tuberculosis) coinfection has emerged as a major public health threat. Given the multifactorial enabling environment in a resource-constrained setting like India, the consequences are of epidemic proportions. This study was aimed at identifying the clinical and epidemiological determinants underlying HIV-TB coinfection. A retrospective review of patient records was done from the antiretroviral therapy center (ART) center at a district hospital in southern India between May and August 2012. Secondary data of 684 patients on ART as well as pre-ART were collected between July 2008 and June 2012 and were analyzed. Descriptive analysis, χ(2), and Wilcoxon signed rank tests were used with SPSS version 15.0 to draw significant statistical inferences. HIV-TB coinfection was diagnosed in 18.9% with higher prevalence among males (75.3%), in the sexually active age group 31-45 years (61.3%), with less than primary education (44.15%), who were married (56.1%), laborers (42.4%), from rural backgrounds (88.2%), and having low income-earning capacity (94.4%). Transmission was predominantly through the heterosexual route. The key entry point was the integrated counseling and testing center (ICTC) (47.4%). Pulmonary tuberculosis (58.8%) was predominantly found followed by extrapulmonary tuberculosis (38.2%) and both in 3.1%. A favorable outcome was observed in 69.3% of coinfected patients with 89.2% on ART and 97.2% currently on DOTS therapy. The Wilcoxon signed-rank test found significant association between rises in CD4 counts after the 6(th)-month follow up (P < 0.05). Coinfected patients had a case fatality rate of 25%. The prevalence of HIV-TB coinfection recorded in this sample was 18.86%. ICTC implemented by NACO emerged as an effective entry point, while Revised National Tuberculosis Control Program referred 1.6% (n = 11) of the patients to the ART center. Coinfection is associated with lower CD4 counts than those with HIV alone, which could translate into increased morbidity and progression of HIV to AIDS.


Fetal outcome in murine Lyme disease.
Lyme disease is an inflammatory syndrome caused by infection with Borrelia burgdorferi. Although this syndrome has important implications for human pregnancy, little is known about gestational infection with B. burgdorferi. Fetal death occurred in 33 of 280 gestational sacs (12%) in 39 C3H/HeN female mice infected by intradermal injection of B. burgdorferi 4 days after mating (acute infection), compared with 0 of 191 sacs in 25 control mice (P = 0.0001). Forty-six percent of acutely infected mice suffered at least one fetal death, compared with none of the control animals (P = 0.0002). There were no fetal deaths in 18 C3H/HeN mice infected 3 weeks prior to mating (chronic infection). A sensitive PCR technique detected B. burgdorferi DNA in the uteri of acutely infected mice but did not detect DNA in the uteri of controls or chronically infected mice. Spirochete DNA was only rarely detected in fetal tissues, and its presence was not required for fetal death. The inclusion of an internal competitive PCR target indicated that the lack of B. burgdorferi sequences in fetal DNA was not due to the presence of a PCR inhibitor. Histologic analysis of gestational tissues from infected animals demonstrated nonspecific pathology consistent with fetal death. These findings indicate an association between murine fetal death and acute infection with B. burgdorferi early in gestation but not with chronic infection. Our data suggest that fetal death is due to a maternal response to infection rather than fetal infection. These findings could provide an explanation for observations in humans in which sporadic cases of fetal death in women infected with B. burgdorferi during pregnancy have been reported, while previous infection has not been associated with fetal death.


A field study of the microbiological quality of fresh produce.
The Centers for Disease Control and Prevention has reported that foodborne disease outbreaks associated with fruits and vegetables increased during the past decade. This study was conducted to characterize the routes of microbial contamination in produce and to identify areas of potential contamination from production through postharvest handling. We report here the levels of bacterial indicator organisms and the prevalence of selected pathogens in produce samples collected from the southern United States. A total of 398 produce samples (leafy greens, herbs, and cantaloupe) were collected through production and the packing shed and assayed by enumerative tests for total aerobic bacteria, total coliforms, total Enterococcus, and Escherichia coli. These samples also were analyzed for Salmonella, Listeria monocytogenes, and E. coli O157:H7. Microbiological methods were based on methods recommended by the U.S. Food and Drug Administration. For all leafy greens and herbs, geometric mean indicator levels ranged from 4.5 to 6.2 log CFU/g (aerobic plate count); less than 1 to 4.3 log CFU/g (coliforms and Enterococcus); and less than 1 to 1.5 log CFU/g (E. coli). In many cases, indicator levels remained relatively constant throughout the packing shed, particularly for mustard greens. However, for cilantro and parsley, total coliform levels increased during the packing process. For cantaloupe, microbial levels significantly increased from field through packing, with ranges of 6.4 to 7.0 log CFU/g (aerobic plate count); 2.1 to 4.3 log CFU/g (coliforms); 3.5 to 5.2 log CFU/g (Enterococcus); and less than 1 to 2.5 log CFU/g (E. coli). The prevalence of pathogens for all samples was 0, 0, and 0.7% (3 of 398) for L. monocytogenes, E. coli O157:H7, and Salmonella, respectively. This study demonstrates that each step from production to consumption may affect the microbial load of produce and reinforces government recommendations for ensuring a high-quality product.


All-nanoparticle concave diffraction grating fabricated by self-assembly onto magnetically-recorded templates.
Using the enormous magnetic field gradients present near the surface of magnetic recording media, we assemble diffraction gratings with lines consisting entirely of self-assembled magnetic nanoparticles that are transferred to flexible polymer thin films. These nanomanufactured gratings have line spacings programmed with commercial magnetic recording and are inherently concave with radii of curvature controlled by varying the polymer film thickness. This manufacturing approach offers a low-cost alternative for realizing concave gratings and more complex optical materials assembled with single-nanometer precision.


Advances of surface-enhanced Raman and IR spectroscopies: from nano/microstructures to macro-optical design.
Raman and infrared (IR) spectroscopy are powerful analytical techniques, but have intrinsically low detection sensitivity. There have been three major steps (i) to advance the optical system of the light excitation, collection, and detection since 1920s, (ii) to utilize nanostructure-based surface-enhanced Raman scattering (SERS) and surface-enhanced infrared absorption (SEIRA) since 1990s, and (iii) to rationally couple (i) and (ii) for maximizing the total detection sensitivity since 2010s. After surveying the history of SERS and SEIRA, we outline the principle of plasmonics and the different mechanisms of SERS and SEIRA. We describe various interactions of light with nano/microstructures, localized surface plasmon, surface plasmon polariton, and lightning-rod effect. Their coupling effects can significantly increase the surface sensitivity by designing nanoparticle-nanoparticle and nanoparticle-substrate configuration. As the nano/microstructures have specific optical near-field and far-field behaviors, we focus on how to systematically design the macro-optical systems to maximize the excitation efficiency and detection sensitivity. We enumerate the key optical designs in particular ATR-based operation modes of directional excitation and emission from visible to IR spectral region. We also present some latest advancements on scanning-probe microscopy-based nanoscale spectroscopy. Finally, prospects and further developments of this field are given with emphasis on emerging techniques and methodologies.


KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells.
Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.


Purification and properties of 2,3-dihydroxy-p-cumate-3,4-dioxygenase from Bacillus species.
2,3-Dihydroxy-p-cumate-3,4-dioxygenase, an enzyme involved in the catabolism of p-cymene, was purified to homogeneity from Bacillus species by affinity chromatography. Purification of the dioxygenase allowed the observation of the immediate ring cleavage product of 2,3-dihydroxy-p-cumate. The enzyme was optimally active at pH 8.2 and at 35 degrees C. The Km value for 2,3-dihydroxy-p-cumate was 32 microM. The enzyme had a broad substrate specificity for 3-substituted catechols. The activity of the enzyme was inhibited by heavy metals, sulphydryl inhibitors, iron-chelating agents, and substrate analogues. Fe2+ was suggested as a cofactor.


Association of chronic obstructive pulmonary disease with mild cognitive impairment and dementia.
As age expectancy increases, both dementia and chronic obstructive pulmonary disease (COPD) have become more prevalent. Dementia and COPD together, however, occur more commonly than would be predicted from the incidence of either alone, suggesting a link between these two common senescent diseases. The purpose of this article is to review the extant literature and report findings in a clinically meaningful manner. We will look at the level of evidence, the risk factors for co-occurrence of the two diseases and the differential effects upon cognitive domains in the population with dementia and COPD. Cognitive impairment in patients with COPD may be 'dose-dependent' with the duration of COPD. Patients with COPD appear to develop nonamnestic mild cognitive impairment (MCI) as opposed to amnestic MCI. Newer studies exploring the impact of oxygen therapy and pulmonary rehabilitation upon cognitive function have reported some positive findings. Higher prevalence of MCI/dementia is seen in patients with COPD compared with age-matched controls. Imaging findings and dementia/MCI biomarkers provide preliminary evidence for an indirect association of the two conditions. Although no causality can be drawn with the available data, there is some indication that the severity of hypoxemia correlates with the severity of cognitive dysfunction.


The effect of vitamin C and/or E supplementations on type 2 diabetic adult males under metformin treatment: A single-blinded randomized controlled clinical trial.
Recently, there has been an increasing interest in the influence of antioxidant vitamins on the efficacy of oral hypoglycemic therapy in type 2 diabetic patients (T2DM). This single-blinded randomized controlled clinical trial aimed to investigate the effect of vitamin C and/or E supplementation on the efficacy of oral hypoglycemic therapy in T2DM Palestinian male patients from the Gaza Strip. Forty T2DM male patients aged 40-60 years on metformin treatment were randomly divided into four groups, each group received an additional one of the following daily oral supplements for 90 days: placebo; vitamin C; vitamin E and vitamin C plus vitamin E. After overnight fasting, venous blood specimens were collected from all individuals into K3-EDTA tubes and serum tubes for measuring the biochemical and hematological parameters of the study at baseline and after 90 days of vitamins supplementation. The results revealed that vitamin C and/or E improve fasting blood sugar (FBS), HbA1c, lipid profile, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), reduced glutathione (GSH); and Quantitative Insulin Sensitivity Check Index (QISCI) compared with diabetic patients group that received placebo. This study provided additional evidence on the beneficial effects of supplementing antioxidant vitamins in T2DM which could improve the clinical condition and attenuate or prevent diabetic pathogenesis and complications that, secondly to poor glycemic control, could attribute to the imbalance between the decline in the endogenous antioxidants and increasing production of the reactive oxygen species leading to the oxidant-mediated damage present in the diabetic context.


To accept or reject heterospecific mates: behavioural decisions underlying premating isolation.
Premating isolation in animals involves decision-making processes that affect whether individuals accept or reject heterospecific mates. An integrative understanding of the behavioural processes underlying heterospecific acceptance can clarify the conditions under which premating isolation evolves. As an illustration, we review how Reeve's (Reeve 1989 Am. Nat.133, 407-435. (doi:10.1086/284926)) acceptance threshold model can help make sense of patterns of premating isolation in nature. This model derives a threshold trait value for acceptance for rejection of recipients of an action (e.g. mating) based on the fitness consequences of these decisions. We show that the maintenance of partial reproductive isolation can be an outcome of optimal acceptance thresholds, even in the face of reinforcement. We also use this model to clarify how the composition of multispecies communities can shape premating isolation. The acceptance threshold model can also be viewed as the behavioural underpinning of reproductive character displacement and cascading reinforcement. Finally, we highlight potential limitations of the acceptance threshold model with respect to investigating the role of sexual selection in speciation, and we propose that integration of behavioural models in speciation research will help us gain a full picture of the mechanisms underlying premating isolation. This article is part of the theme issue 'Signal detection theory in recognition systems: from evolving models to experimental tests'.


Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidylethanolamine of platelet membrane and microvesicles.
Protein C inhibitor (PCI) was detected in human platelets (2.9 ng/10(9) cells) and megakaryocytic cells (1.5 ng/10(6) cells). PCI mRNA was also detected in both platelets and megakaryocytic cells using nested polymerase chain reaction. PCI was found to be located in the alpha-granules of resting platelets. Approximately 30% of the total amount of PCI in platelets was released after stimulation with ADP, collagen, adrenalin, thrombin, or thrombin receptor-activating peptide. Secreted PCI was detected on the surface of activated platelets and phospholipid microvesicles. PCI secreted from thrombin receptor-activating peptide-stimulated platelets inhibited activated protein C (APC) efficiently. PCI significantly inhibited APC in the presence of phospholipid vesicles prepared using rabbit brain cephalin (RBC) or a mixture of 40% phosphatidylethanolamine (PE), 20% phosphatidylserine (PS), and 40% phosphatidylcholine (PC) with a second order rate constant of 1.0 x 10(6) M-1.min-1. Of these phospholipids, PE was critical for this inhibition. The dissociation constants of the binding of APC or PCI to solid phase phospholipids showed that APC binds more preferably to PE than to RBC or PS, and PCI to PE or RBC than to PS or PC. PCI binding to solid phase phospholipids depended on the presence of PE. RBC- or PE-bound PCI inhibited APC significantly but only weakly the gamma-carboxyglutamic acid domainless APC. The gamma-carboxyglutamic acid fragment of protein C suppressed the PCI-mediated inhibition of APC on solid phase RBC or PE. Most of the APC.PCI complex formed on solid phase RBC or PE was released into the soluble phase. These findings suggest that PCI secreted from activated platelets binds preferably to PE of platelet membrane and microvesicles and that it inhibits phospholipid-bound APC efficiently.


Pre-treatment expectations and their influence on subjective symptom change in Crohn's disease.
Treatment expectations reportedly shape treatment outcomes, but have not been studied in the context of multimodal therapy in Crohn's disease (CD). Therefore, the current study investigated the role of treatment expectations for subjective symptom changes in CD patients who have undergone an integrative multimodal therapy program. Validated questionnaires were completed at the start of the treatment program and post intervention. Pre-treatment expectations and experienced symptom change were assessed with the Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effects (GEEE); stress levels were quantified with the Perceived Stress Scale (PSS-10) and disease specific quality of life was quantified with the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). We performed multiple linear and Bayesian regression to determine how expectations related to symptom change. N = 71 CD patients (66.2% female) were included. Stronger expectations regarding symptom improvement (b = 0.422, t = 3.70, p < .001) were associated with higher experienced symptom improvement. Additionally, Bayesian analysis provided strong evidence for including improvement expectations as a predictor of improvement experience (BFinclusion = 13.78). In line with research in other disorders, we found that positive treatment expectations were associated with experienced symptom improvement. In contrast, we found no indication that an experience of symptom worsening was associated with positive or negative baseline treatment expectations. Induction of positive expectations might be a potential avenue for improving treatment outcomes in CD therapy.


Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.
In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.


Predicting gene regulatory networks from cell atlases.
Recent single-cell RNA-sequencing atlases have surveyed and identified major cell types across different mouse tissues. Here, we computationally reconstruct gene regulatory networks from three major mouse cell atlases to capture functional regulators critical for cell identity, while accounting for a variety of technical differences, including sampled tissues, sequencing depth, and author assigned cell type labels. Extracting the regulatory crosstalk from mouse atlases, we identify and distinguish global regulons active in multiple cell types from specialised cell type-specific regulons. We demonstrate that regulon activities accurately distinguish individual cell types, despite differences between individual atlases. We generate an integrated network that further uncovers regulon modules with coordinated activities critical for cell types, and validate modules using available experimental data. Inferring regulatory networks during myeloid differentiation from wild-type and Irf8 KO cells, we uncover functional contribution of Irf8 regulon activity and composition towards monocyte lineage. Our analysis provides an avenue to further extract and integrate the regulatory crosstalk from single-cell expression data.


Clinical benefit of systemic therapies for recurrent ovarian cancer-ESMO-MCBS scores.
Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse.


Morbid obesity leads to increased skin autofluorescence independent of metabolic syndrome components.
Obesity, diabetes mellitus, and metabolic syndrome (MetS) are associated with increased accumulated skin advanced glycation end products. We aimed to evaluate the association of MetS components with skin autofluorescence (SAF) in patients with morbid obesity. Eight hundred and one patients with morbid obesity and 94 age-matched controls with normal body mass index (BMI) and normal glucose metabolism were included. Advanced glycation end products (AGEs) were measured using SAF in the forearm, with an AGE reader. The prevalence of MetS in patients with morbid obesity was 65.5% (n = 525). Type 2 diabetes mellitus (type 2 DM) and hypertension were present in 40.9% (n = 328) and 43.7% (n = 357). Patients with morbid obesity and those with MetS had higher SAF measurements compared with the control group, 1.85 ± 0.44 arbitrary unit (AU) and 1.86 ± 0.43 AU vs. 1.72 ± 0.30 AU, respectively (p = 0.016). There was no difference in SAF levels between patients with and without MetS. SAF measurements of patients without MetS were not statistically different from the control group (p = 0.076). Patients with five MetS criteria had higher SAF measurements compared with patients with fewer MetS components (p = 0.019). There was no difference in SAF levels between patients with type 2 DM, impaired glucose metabolism, and patients with normal glucose metabolism (p = 0.513). Although MetS and type 2 DM are known as factors related to increased SAF levels, obesity can cause elevated SAF measurements in different ways independent of concomitant comorbid diseases. Larger studies with longer follow-ups are needed to enlighten the underlying mechanism.


Differential effects of X-irradiation and cyclosporin-A administration on the thymus with respect to the generation of cyclosporin-A-induced autoimmunity.
Cyclosporin A (CsA), a potent inhibitor of T-cell activation, has been shown to have several effects on thymocyte maturation, thymic stromal cells, and the generation of autoreactive T cells. In Lewis rats, the combination of lethal irradiation, syngeneic bone marrow transplantation, and a 4-week course of CsA administration causes the development of an autoimmune disease (CsA-AI) resembling allogeneic graft-versus-host disease. This occurs upon withdrawal of CsA, provided the thymus receives irradiation and is present during CsA treatment. In this study, the separate effects of irradiation or CsA treatment on thymic stromal cells and thymocytes, compared to the combinatory effects, were examined using immunohistochemistry and tricolor flow cytometric analysis. CsA treatment causes an involution of the thymic medulla and a strong reduction of the cell number of thymocytes and stromal cells residing in the medulla. However, within the remaining medullary area, changes in cell distribution and antigen density on these cells were not observed. Irradiation on the other hand causes a strong depletion of thymocytes. The thymocyte population is recovered within 2 weeks and a cortical and medullary region can be distinguished. CsA treatment in combination with irradiation results in a strongly inhibited recovery of the medulla during CsA treatment, whereas the cortex recovers to normal size and morphology. The presence of the medullary IDC and epithelial cells is reduced proportionally to the small size of the medulla. However, the distribution of these stromal cells is normal. During the CsA administration, the thymuses from irradiated and CsA-treated rats are very similar to thymuses from CsA-treated rats. In conclusion, no changes specific for irradiation plus CsA treatment have been observed. Regarding the distribution and size of medullary stromal cells and residing thymocytes, thymuses from irradiated and CsA-treated rats hardly differ from the thymuses from rats treated only with CsA. Therefore, irradiation seems essential in the generation of CsA-AI by eliminating suppressor-cell circuits in the periphery.


A double-blind placebo controlled trial of fluoxetine in fibromyalgia.
42 women were randomized to receive either placebo or fluoxetine at 20 mgs per day. Inter and intra group differences in clinical variables were evaluated after 3 and 6 weeks of treatment. Except for self rated anxiety which improved in the placebo treated group at 3 weeks, no differences between groups were noted. For those receiving fluoxetine both AIMS Anxiety (4.0 baseline vs. 3.3, p = 0.04) and Depression scores (2.6 baseline vs. 1.9, p = 0.03) improved at 3 weeks; however, improvement in the Beck Depression Scale did not reach significance (11.8 vs. 9.4, p = 0.34). At 6 weeks, both AIMS Depression (2.6 at baseline and 1.5 at 6 weeks, p = 0.03) and Beck Depression Scales (11.8 at baseline vs. 8.3 at 6 weeks, p = 0.04) showed improvement, as did sleep quality (9.6 vs. 7.6, p = 0.03). But no other variable had a significant change from baseline at either the 3 or 6 week point. Our data do not suggest that fluoxetine improves the signs and symptoms of fibromyalgia.


Association between organisational and workplace cultures, and patient outcomes: systematic review protocol.
Despite widespread interest in the topic, no current synthesis of research is available analysing the linkages between organisational or workplace cultures on the one hand, and patient outcomes on the other. This protocol proposes a systematic review to analyse and synthesise the literature to date on this topic. The resulting review will discuss characteristics of included studies in terms of the type of healthcare settings researched, the measurements of organisational and workplace culture, patient outcomes measured and the influence of these cultures on patient outcomes. A systematic review will be conducted aiming to examine the associations between organisational and workplace cultures, and patient outcomes, guided by the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. An English language search of abstracts will be executed using the following academic databases: CINAHL, EMBASE, Ovid MEDLINE, Web of Science and PsycINFO. The review will include relevant peer-reviewed articles from randomised controlled trials (RCTs), non-RCTs, controlled before and after studies, interrupted time series studies, cross-sectional analyses, qualitative studies and mixed-method studies. Multiple researchers will be involved in assessing the quality of articles for inclusion in the review. This protocol documents a detailed search strategy, including terms and inclusion criteria, which will form the basis of the subsequent systematic review. Ethics approval is not required as no primary data will be collected. Results will be disseminated through a peer-reviewed publication and conference presentations.


Elevated expression of the adhesion GPCR ADGRL4/ELTD1 promotes endothelial sprouting angiogenesis without activating canonical GPCR signalling.
ADGRL4/ELTD1 is an orphan adhesion GPCR (aGPCR) expressed in endothelial cells that regulates tumour angiogenesis. The majority of aGPCRs are orphan receptors. The Stachel Hypothesis proposes a mechanism for aGPCR activation, in which aGPCRs contain a tethered agonist (termed Stachel) C-terminal to the GPCR-proteolytic site (GPS) cleavage point which, when exposed, initiates canonical GPCR signalling. This has been shown in a growing number of aGPCRs. We tested this hypothesis on ADGRL4/ELTD1 by designing full length (FL) and C-terminal fragment (CTF) ADGRL4/ELTD1 constructs, and a range of potential Stachel peptides. Constructs were transfected into HEK293T cells and HTRF FRET, luciferase-reporter and Alphascreen GPCR signalling assays were performed. A stable ADGRL4/ELTD1 overexpressing HUVEC line was additionally generated and angiogenesis assays, signalling assays and transcriptional profiling were performed. ADGRL4/ELTD1 has the lowest GC content in the aGPCR family and codon optimisation significantly increased its expression. FL and CTF ADGRL4/ELTD1 constructs, as well as Stachel peptides, did not activate canonical GPCR signalling. Furthermore, stable overexpression of ADGRL4/ELTD1 in HUVECs induced sprouting angiogenesis, lowered in vitro anastomoses, and decreased proliferation, without activating canonical GPCR signalling or MAPK/ERK, PI3K/AKT, JNK, JAK/HIF-1α, beta catenin or STAT3 pathways. Overexpression upregulated ANTXR1, SLC39A6, HBB, CHRNA, ELMOD1, JAG1 and downregulated DLL4, KIT, CCL15, CYP26B1. ADGRL4/ELTD1 specifically regulates the endothelial tip-cell phenotype through yet undefined signalling pathways.


Should tobacco and alcohol companies be allowed to influence Australia's National Drug Strategy?
Formation of Australia's National Drug Strategy (NDS) included an extensive consultation process that was open not only to community and public health stakeholders, but also to representatives of the tobacco and alcohol industries. Australia is bound by the World Health Organization Framework Convention on Tobacco Control, which requires governments to protect tobacco control measures from interference by the tobacco industry. NDS consultation submissions made by these conflicted industries are not publicly available for scrutiny. The NDS goals are at odds with the commercial agenda of industries that support regulatory stagnation, oppose and undermine effective action, ignore and distort evidence, and prioritise profits over health.


p16 and Ki-67 immunostaining in atypical immature squamous metaplasia of the uterine cervix: correlation with human papillomavirus detection.
Atypical immature squamous metaplasia (AIM) of the cervix is a loosely defined entity characterized by immature metaplastic cells with mild cytologic atypia. To examine whether a combination of immunostaining for p16 and Ki-67 could be used to stratify AIM cases into 3 categories: benign, cases with nondiagnostic atypia, and high-grade squamous intraepithelial lesion (HSIL). The study consisted of 37 cases of AIM, 23 cases of benign cervical mucosa (NEG), and 36 cases of HSIL. All cases were tested for high-risk human papillomaviruses using SPF 10 polymerase chain reaction and immunostained for p16 and Ki-67. All cases of HSIL were positive for both p16 and Ki-67. All but 2 benign control cases were negative for both p16 and Ki-67. Seven cases of AIM (19%) displayed a pattern of immunostaining identical to HSIL, and these most likely represent a spectrum of HSIL. A total of 54% of cases of AIM were negative for both p16 and Ki-67, consistent with benign reactive atypia. Two AIM cases (5%) were negative for p16 and positive for Ki-67 in the area adjacent to an ulcer, representing regeneration. Finally, 22% of AIM cases were positive for p16 and negative for Ki-67; such cases may represent a precursor of HSIL or, alternatively, a regressing HSIL. The combination of immunostaining for p16 and Ki-67 is helpful in limiting of the number of cases with nondiagnostic atypia of the cervix.


Understanding the basis for the association of apoE4 with Alzheimer's disease: opening the door for therapeutic approaches.
Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease (AD) by an as yet to be defined mechanism. Since the structure or biophysical properties of a protein directly determines function, our approach to addressing mechanism is structure:function based. Domain interaction a structural property of apoE4 that distinguishes it from apoE3 is predicted to contribute to the association of apoE4 with AD. We developed a mouse model, the Arg-61 apoE model, which is specific for domain interaction. These mice display synaptic, functional, and cognitive deficits, demonstrating domain interaction is the causative factor. We present evidence that domain interaction results in stressed astrocytes that are dysfunctional and propose that dysfunctional astrocytes are an early player in apoE4-associated AD and that domain interaction is a potential therapeutic target.


Pathway Processor 2.0: a web resource for pathway-based analysis of high-throughput data.
Pathway Processor 2.0 is a web application designed to analyze high-throughput datasets, including but not limited to microarray and next-generation sequencing, using a pathway centric logic. In addition to well-established methods such as the Fisher's test and impact analysis, Pathway Processor 2.0 offers innovative methods that convert gene expression into pathway expression, leading to the identification of differentially regulated pathways in a dataset of choice. Pathway Processor 2.0 is available as a web service at http://compbiotoolbox.fmach.it/pathwayProcessor/. Sample datasets to test the functionality can be used directly from the application. firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


A monoclonal antibody specific for Candida albicans Als4 demonstrates overlapping localization of Als family proteins on the fungal cell surface and highlights differences between Als localization in vitro and in vivo.
The Candida albicans agglutinin-like sequence (ALS) family encodes large cell surface glycoproteins that function in adhesion of the fungus to host and abiotic surfaces. Monoclonal antibodies (mAbs) specific for each Als protein were developed to study Als localization on the C. albicans surface. An anti-Als4 mAb demonstrated that Als4 covers the surface of yeast cells, with a greater abundance of Als4 on cells grown at 30 °C compared to 37 °C. On germ tubes, Als4 is localized in a restricted area proximal to the mother yeast. Immunolabeling with several anti-Als mAbs showed overlapping localization of Als1 and Als4 on yeast cells and Als1, Als3 and Als4 on germ tubes. Overlapping localization of Als proteins was also observed on yeast and hyphae recovered from mouse models of disseminated and oral candidiasis. Differences between Als localization in vivo and in vitro suggested changes in regulation of Als production in the host compared to the culture flask. Characterization with the anti-Als mAbs reveals the simultaneous presence and differences in relative abundance of Als proteins, creating an accurate image of Als representation and localization that can be used to guide conclusions regarding individual and collective Als protein function.


Genome-wide identification of regulatory elements in Sertoli cells.
A current goal of molecular biology is to identify transcriptional networks that regulate cell differentiation. However, identifying functional gene regulatory elements has been challenging in the context of developing tissues where material is limited and cell types are mixed. To identify regulatory sites during sex determination, we subjected Sertoli cells from mouse fetal testes to DNaseI-seq and ChIP-seq for H3K27ac. DNaseI-seq identified putative regulatory sites around genes enriched in Sertoli and pregranulosa cells; however, active enhancers marked by H3K27ac were enriched proximal to only Sertoli-enriched genes. Sequence analysis identified putative binding sites of known and novel transcription factors likely controlling Sertoli cell differentiation. As a validation of this approach, we identified a novel Sertoli cell enhancer upstream of Wt1, and used it to drive expression of a transgenic reporter in Sertoli cells. This work furthers our understanding of the complex genetic network that underlies sex determination and identifies regions that potentially harbor non-coding mutations underlying disorders of sexual development.


Levels, sources and chemical fate of persistent organic pollutants in the atmosphere and snow along the western Antarctic Peninsula.
The Antarctic continent is among the most pristine regions; yet various organic contaminants have been measured there routinely. Air and snow samples were collected during the austral spring (October-November, 2010) along the western Antarctic Peninsula and analyzed for organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) to assess the relative importance of long-range transport versus local primary or secondary emissions. Highest concentrations of PCBs, PBDEs and DDTs were observed in the glacier's snow sample, highlighting the importance of melting glaciers as a possible secondary source of legacy pollutants to the Antarctic. In the atmosphere, contaminants were mainly found in the vapor phase (>65%). Hexachlorobenzene (33.6 pg/m(3)), PCBs (11.6 pg/m(3)), heptachlor (5.64 pg/m(3)), PBDEs (4.22 pg/m(3)) and cis-chlordane (2.43 pg/m(3)) were the most abundant contaminants. In contrast to other compounds, PBDEs seem to have originated from local sources, possibly the research station itself. Gas-particle partitioning for analytes were better predicted using the adsorption partitioning model than an octanol-based absorption approach. Diffusive flux calculations indicated that net deposition is the dominant pathway for PBDEs and chlordanes, whereas re-volatilization from snow (during melting or metamorphosis) was observed for PCBs and some OCPs.


Study of fluid and transport properties of porous anodic aluminum membranes by dynamic atomic force microscopy.
Recent work on carbon nanotubes (CNT) has focused on their potential application in water treatment as a result of their predicted and observed enhanced flow rates. Recent work on the lesser-known porous anodic alumina membranes (PAAMs) has also shown flow enhancement, albeit at only a fraction of what has been observed in CNTs. Despite their potential applications, little research has been conducted on PAAMs' hydrodynamic properties, and in this Article we present experimental results and theoretical models that explore the fluid flow behavior around and through these membranes. The experiments were conducted using an atomic force microscope (AFM) that pushed a solid silica particle against PAAMs that were characterized with different pore diameters. Furthermore, the PAAMs were classified as either closed or open, with the latter allowing fluid to pass through. The theoretical model developed to describe the experimental data incorporates Derjaguin-Landau-Verwey-Overbeek (DLVO) effects, cantilever drag, and hydrodynamic forces. By using the slip boundary condition for the hydrodynamic forces, we were able to fit the model to experimental findings and also demonstrate that the difference between closed and open PAAMs was negligible. The slip lengths did not correspond to any physical feature of the PAAMs, but our model does provide a simple yet effective means of describing the hydrodynamics for not only PAAMs but for membranes in general.