Temporal Trends in Cardiovascular Hospital Discharges Following a Mass Chlorine Exposure Event in Graniteville, South Carolina.
Background: On January 6, 2005, a train derailed in Graniteville, South Carolina, releasing nearly 60,000 kg of toxic chlorine gas. The disaster left nine people dead and was responsible for hundreds of hospitalizations and outpatient visits in the subsequent weeks. While chlorine gas primarily affects the respiratory tract, a growing body of evidence suggests that acute exposure may also cause vascular injury and cardiac toxicity. Here, we describe the incidence of cardiovascular hospitalizations among residents of the zip codes most affected by the chlorine gas plume, and compare the incidence of cardiovascular discharges in the years leading up to the event (2000-2004) to the incidence in the years following the event (2005-2014). Methods: De-identified hospital discharge information was collected from the South Carolina Revenue and Fiscal Affairs Office for individuals residing in the selected zip codes for the years 2000 to 2014. A quasi-experimental study design was utilized with a population-level interrupted time series model to examine hospital discharge rates for Graniteville-area residents for three cardiovascular diagnoses: hypertension (HTN), acute myocardial infarction (AMI), and coronary heart disease (CHD). We used linear regression with autoregressive error correction to compare slopes for pre- and post-spill time periods. Data from the 2000 and 2010 censuses were used to calculate rates and to provide information on potential demographic shifts over the course of the study. Results: A significant increase in hypertension-related hospital discharge rates was observed for the years following the Graniteville chlorine spill (slope 8.2, p < 0.001). Concurrent changes to CHD and AMI hospital discharge rates were in the opposite direction (slopes -3.2 and -0.3, p < 0.01 and 0.14, respectively). Importantly, the observed trend cannot be attributed to an aging population. Conclusions: An unusual increase in hypertension-related hospital discharge rates in the area affected by the Graniteville chlorine spill contrasts with national and state-level trends. A number of factors related to the spill may be contributing the observation: disaster-induced hypertension, healthcare services access issues, and, possibly, chlorine-induced susceptibility to vascular pathologies. Due to the limitations of our data, we cannot determine whether the individuals who visited the hospital were the ones exposed to chlorine gas, however, the finding warrants additional research. Future studies are needed to determine the etiology of the increase and whether individuals exposed to chlorine are at a heightened risk for hypertensive heart disease.


Temperature trends over the past five centuries reconstructed from borehole temperatures
For an accurate assessment of the relative roles of natural variability and anthropogenic influence in the Earth's climate, reconstructions of past temperatures from the pre-industrial as well as the industrial period are essential. But instrumental records are typically available for no more than the past 150 years. Therefore reconstructions of pre-industrial climate rely principally on traditional climate proxy records, each with particular strengths and limitations in representing climatic variability. Subsurface temperatures comprise an independent archive of past surface temperature changes that is complementary to both the instrumental record and the climate proxies. Here we use present-day temperatures in 616 boreholes from all continents except Antarctica to reconstruct century-long trends in temperatures over the past 500 years at global, hemispheric and continental scales. The results confirm the unusual warming of the twentieth century revealed by the instrumental record, but suggest that the cumulative change over the past five centuries amounts to about 1 K, exceeding recent estimates from conventional climate proxies. The strength of temperature reconstructions from boreholes lies in the detection of long-term trends, complementary to conventional climate proxies, but to obtain a complete picture of past warming, the differences between the approaches need to be investigated in detail.


Glycosphingolipids in endocytic membrane transport.
Endocytosis leads to the internalisation of both lipids and proteins and their delivery to specific subcellular locations. This involves sorting processes that are not completely understood, but may involve interactions between lipids and proteins as well as pH and calcium gradients. This article discusses the importance of endocytosis in glycosphingolipid (GSL) synthesis as well as the potential roles of GSLs in endocytic membrane transport. Although the accumulation of GSLs in storage diseases clearly disrupts endocytic transport, increasing evidence also supports a role for GSLs in endocytosis in normal cells.


Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14.
Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


OmpA is the critical component for Escherichia coli invasion-induced astrocyte activation.
Escherichia coli is the major Gram-negative bacterial pathogen in neonatal meningitis. Outer membrane protein A (OmpA) is a conserved major protein in the E. coli outer membrane and is involved in several host-cell interactions. To characterize the role of OmpA in the invasion of astrocytes by E. coli, we investigated OmpA-positive and OmpA-negative E. coli strains. Outer membrane protein A E44, E105, and E109 strains adhered to and invaded C6 glioma cells 10- to 15-fold more efficiently than OmpA-negative strains. Actin rearrangement, protein tyrosine kinase, and phosphoinositide 3-kinase activation were required for OmpA-mediated invasion by E. coli. In vitro infection of C6 cells and intracerebral injection into mice of the E44 strain induced expression of the astrocyte differentiation marker glial fibrillary acidic protein and the inflammatory mediators cyclooxygenase 2 and nitric oxide synthase 2. After intracerebral infection with E44, all C57BL/6 mice died within 36hours, whereas 80% of mice injected with E44 premixed with recombinant OmpA protein survived. Astrocyte activation and neutrophil infiltration were reduced in brain tissue sections in the mice given OmpA. Taken together, these data suggest that OmpA-mediated invasion plays an important role in the early stage of E.coli-induced brain damage, and that it may have therapeutic use in E. coli meningitis.


Tunable negative-tap photonic microwave filter based on a cladding-mode coupler and an optically injected laser of large detuning.
A tunable negative-tap photonic microwave filter using a cladding-mode coupler together with optical injection locking of large wavelength detuning is demonstrated. Continuous and precise tunability of the filter is realized by physically sliding a pair of bare fibers inside the cladding-mode coupler. Signal inversion for the negative tap is achieved by optical injection locking of a single-mode semiconductor laser. To couple light into and out of the cladding-mode coupler, a pair of matching long-period fiber gratings is employed. The large bandwidth of the gratings requires injection locking of an exceptionally large wavelength detuning that has never been demonstrated before. Experimentally, injection locking with wavelength detuning as large as 27 nm was achieved, which corresponded to locking the 36-th side mode. Microwave filtering with a free-spectral range tunable from 88.6 MHz to 1.57 GHz and a notch depth larger than 35 dB was obtained.


Regulation of ABCG2 expression at the 3' untranslated region of its mRNA through modulation of transcript stability and protein translation by a putative microRNA in the S1 colon cancer cell line.
ABCG2 is recognized as an important efflux transporter in clinical pharmacology and is potentially important in resistance to chemotherapeutic drugs. To identify epigenetic mechanisms regulating ABCG2 mRNA expression at its 3' untranslated region (3'UTR), we performed 3' rapid amplification of cDNA ends with the S1 parental colon cancer cell line and its drug-resistant ABCG2-overexpressing counterpart. We found that the 3'UTR is >1,500 bp longer in parental cells and, using the miRBase TARGETs database, identified a putative microRNA (miRNA) binding site, distinct from the recently reported hsa-miR520h site, in the portion of the 3'UTR missing from ABCG2 mRNA in the resistant cells. We hypothesized that the binding of a putative miRNA at the 3'UTR of ABCG2 suppresses the expression of ABCG2. In resistant S1MI80 cells, the miRNA cannot bind to ABCG2 mRNA because of the shorter 3'UTR, and thus, mRNA degradation and/or repression on protein translation is relieved, contributing to overexpression of ABCG2. This hypothesis was rigorously tested by reporter gene assays, mutational analysis at the miRNA binding sites, and forced expression of miRNA inhibitors or mimics. The removal of this epigenetic regulation by miRNA could be involved in the overexpression of ABCG2 in drug-resistant cancer cells.


Ancient DNA suggests modern wolves trace their origin to a Late Pleistocene expansion from Beringia.
Grey wolves (Canis lupus) are one of the few large terrestrial carnivores that have maintained a wide geographical distribution across the Northern Hemisphere throughout the Pleistocene and Holocene. Recent genetic studies have suggested that, despite this continuous presence, major demographic changes occurred in wolf populations between the Late Pleistocene and early Holocene, and that extant wolves trace their ancestry to a single Late Pleistocene population. Both the geographical origin of this ancestral population and how it became widespread remain unknown. Here, we used a spatially and temporally explicit modelling framework to analyse a data set of 90 modern and 45 ancient mitochondrial wolf genomes from across the Northern Hemisphere, spanning the last 50,000 years. Our results suggest that contemporary wolf populations trace their ancestry to an expansion from Beringia at the end of the Last Glacial Maximum, and that this process was most likely driven by Late Pleistocene ecological fluctuations that occurred across the Northern Hemisphere. This study provides direct ancient genetic evidence that long-range migration has played an important role in the population history of a large carnivore, and provides insight into how wolves survived the wave of megafaunal extinctions at the end of the last glaciation. Moreover, because Late Pleistocene grey wolves were the likely source from which all modern dogs trace their origins, the demographic history described in this study has fundamental implications for understanding the geographical origin of the dog.


Trichostatin A attenuates airway inflammation in mouse asthma model.
Histone deacetylase (HDAC) inhibition has been demonstrated to change the expression of a restricted set of cellular genes. T cells are essential in the pathogenesis of allergen-induced airway inflammation. It was recently reported that treatment with HDAC inhibitors induces a T cell-suppressive effect. The purpose of this study was to determine whether treatment with trichostatin A (TSA), a representative HDAC inhibitor, would reduce allergen-induced airway inflammation in a mouse asthma model. BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA) and challenged with an aerosol of OVA. TSA (1 mg/kg body weight) was injected intraperitoneally every 2 days beginning on day 1. Mouse lungs were assayed immunohistochemically for HDAC1, a major HDAC subtype, and for infiltration of CD4+ cells. The effect of TSA on airway hyper-responsiveness (AHR) was determined, and the bronchoalveolar lavage fluid (BALF) of these mice was assayed for the number and types of inflammatory cells, and for the concentrations of IL-4, IL-5, and IgE. HDAC1 was localized within most airway cells and infiltrating inflammatory cells of asthmatic lungs. Treatment with TSA significantly attenuated AHR, as well as the numbers of eosinophils and lymphocytes in BALF. TSA also reduced infiltration of CD4+ and inflammatory cells and mucus occlusions in lung tissue, and decreased the concentrations of IL-4, IL-5, and IgE in BALF. TSA attenuated the development of allergic airway inflammation by decreasing expression of the Th2 cytokines, IL-4 and IL-5, and IgE, which resulted from reduced T cell infiltration. Our results suggest that HDAC inhibition may attenuate the development of asthma by a T cell suppressive effect.


Cardiac magnetic resonance imaging in normal dogs and two dogs with heart base tumor.
We describe the technique for in vivo cardiac-gated magnetic resonance imaging (MRI) in normal dogs and its application in two dogs with a large right atrial tumor. The dogs with a cardiac tumor were also imaged using contrast-enhanced magnetic resonance angiography (CE-MRA). Cardiac-gated MRI and CE-MRA are both feasible in animals with short acquisition times compatible with breath-hold imaging under anesthesia, and provide detailed two- and three-dimensional (3D) depiction of the cardiac anatomy and great vessels with or without contrast medium. Although cardiac MRI will not replace echocardiography, it is a powerful alternative technique to use when knowledge of the 3D anatomy of the vasculature is required, when precise volume measurements are needed or when myocardial characterization is indicated. As opposed to contrast-enhanced computed tomography angiography, cardiac MRI does not use ionizing radiation or iodinated contrast medium.


Regional brain metabolism during auditory hallucinations in chronic schizophrenia.
Regions of the brain involved in language and attention were studied using [18F]-fluorodeoxy-glucose in PET. In nine chronic DSM-III schizophrenic patients who had persistent auditory hallucinations, ten who had recovered from hallucinations and ten normal controls. In none of the regions examined was metabolic activity significantly different in hallucinating patients compared with that in other groups. However, a pattern of seven significant correlations of metabolic activity between language regions and between frontal and parietal cortex characterised the hallucinating but not the other groups. Three of the seven correlations were significantly greater in hallucinating patients than in the two other groups, and six were greater in hallucinating patients than controls. Metabolism in Broca's region and its right-hemisphere homologue correlated positively and significantly in the hallucinating group, as it did in anterior cingulate and left superior temporal areas, and in right frontal and parietal areas. Hallucination ratings correlated with metabolism in the anterior cingulate region.


Accelerated prompt gamma estimation for clinical proton therapy simulations.
There is interest in the particle therapy community in using prompt gammas (PGs), a natural byproduct of particle treatment, for range verification and eventually dose control. However, PG production is a rare process and therefore estimation of PGs exiting a patient during a proton treatment plan executed by a Monte Carlo (MC) simulation converges slowly. Recently, different approaches to accelerating the estimation of PG yield have been presented. Sterpin et al (2015 Phys. Med. Biol. 60 4915-46) described a fast analytic method, which is still sensitive to heterogeneities. El Kanawati et al (2015 Phys. Med. Biol. 60 8067-86) described a variance reduction method (pgTLE) that accelerates the PG estimation by precomputing PG production probabilities as a function of energy and target materials, but has as a drawback that the proposed method is limited to analytical phantoms. We present a two-stage variance reduction method, named voxelized pgTLE (vpgTLE), that extends pgTLE to voxelized volumes. As a preliminary step, PG production probabilities are precomputed once and stored in a database. In stage 1, we simulate the interactions between the treatment plan and the patient CT with low statistic MC to obtain the spatial and spectral distribution of the PGs. As primary particles are propagated throughout the patient CT, the PG yields are computed in each voxel from the initial database, as a function of the current energy of the primary, the material in the voxel and the step length. The result is a voxelized image of PG yield, normalized to a single primary. The second stage uses this intermediate PG image as a source to generate and propagate the number of PGs throughout the rest of the scene geometry, e.g. into a detection device, corresponding to the number of primaries desired. We achieved a gain of around 103 for both a geometrical heterogeneous phantom and a complete patient CT treatment plan with respect to analog MC, at a convergence level of 2% relative uncertainty in the 90% yield region. The method agrees with reference analog MC simulations to within 10-4, with negligible bias. Gains per voxel range from 102 to 104. The presented generic PG yield estimator is drop-in usable with any geometry and beam configuration. We showed a gain of three orders of magnitude compared to analog MC. With a large number of voxels and materials, memory consumption may be a concern and we discuss the consequences and possible tradeoffs. The method is available as part of Gate 7.2.


Changes in Lean Muscle Mass Associated with Neoadjuvant Platinum-Based Chemotherapy in Patients with Muscle Invasive Bladder Cancer.
Baseline sarcopenia or severe lean muscle deficiency is independently associated with increased mortality after cystectomy for muscle-invasive urothelial carcinoma of the bladder (MIUC). The impact of chemotherapy on muscle mass in MIUC patients remains undefined. To describe preoperative changes in body composition in MIUC patients receiving platinum-based neoadjuvant chemotherapy (NC). Patients with cT2-4 N0-1 M0 UC of the bladder who received NC were identified. Lumbar skeletal muscle index (SMI, cm2/m2), visceral adipose index (VAI, cm2/m2), and the subcutaneous and intramuscular adipose index (SAI, cm2/m2) were calculated using validated methodology (cross sectional area of skeletal muscle/height2 at L3) from measurement of soft tissue areas on pre- (pre-NC) and post-NC (post-NC) computed tomography. Patients were classified as sarcopenic according to consensus definitions: Male: SMI <55 cm2/m2, Female: SMI <38.5 cm2/m2. Pre-NC and post-NC median body mass index (BMI kg/m2), SMI, and adipose indices were compared. The study cohort consisted of 26 patients, with a median age 70 years, including 7 females (27%). Chemotherapy regimens included dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (31%), gemcitabine/cisplatin (62%) and gemcitabine/carboplatin (3.8%) with a median of 3.5 (range 2-6) cycles. Median pre- and post-NC BMI were 27.1 kg/m2 and 27.2 kg/m2 (p = 0.36). Median pre- and post-NC SMI were 49.1 cm2/m2 and 44.5 (p < 0.001) respectively. Median percent change in SMI was -6.4% (range -30% to 10%). Pre-NC, 18 (69%) patients were sarcopenic vs. 21 (81%, p = 0.002) post-NC. Median time between initiation of chemotherapy and cystectomy was 110 days. We observed a significant decrease in lean muscle mass among MIUC patients treated with platinum-based NC prior to cystectomy, with an associated increase in the prevalence of sarcopenia. Patients undergoing NC may benefit from pre-habilitative interventions to mitigate lean muscle loss prior to cystectomy.


The role of phosphatidylinositol 3-kinase in vascular endothelial growth factor signaling.
Vascular endothelial growth factor (VEGF) receptor Flk-1/KDR in endothelial cells is activated during vasculogenesis and angiogenesis upon ligand-receptor interaction. Activated Flk-1/KDR has been shown to recruit Src homology 2 domain-containing signaling molecules that are known to serve as links to the activation of the mitogen-activated protein (MAP) kinase signaling pathway. To define the functional significance of phosphatidylinositol (PI) 3-kinase in VEGF signaling, we have examined its role in human umbilical vein endothelial cell (HUVEC) cycle progression. We show herein that p85, the regulatory subunit of PI 3-kinase, is constitutively associated with Flk-1/KDR. The treatment of HUVECs with VEGF promoted tyrosine autophosphorylation of Flk-1/KDR and also induced phosphorylation of p85. This was followed by an increase in the PI 3-kinase activity, which was sensitive to wortmannin, a potent PI 3-kinase inhibitor. VEGF also induced a striking activation of MAP kinase in a time-dependent manner. Inhibition studies with both a dominant-negative p85 mutant and the PI 3-kinase inhibitor, wortmannin, were employed to show for the first time that VEGF-stimulated PI 3-kinase modulates MAP kinase activation and nuclear events such as transcription from c-fos promoter and entry into the synthesis (S)-phase. Our data demonstrate the importance of PI 3-kinase as a necessary signaling component of VEGF-mediated cell cycle progression.


Carbon-11-thymidine and FDG to measure therapy response.
This study was performed to determine if PET imaging with 11C-thymidine could measure tumor response to chemotherapy early after the initiation of treatment. Imaging of deoxyriboneucleic acid biosynthesis, quantitated with 11C-thymidine, was compared with measurements of tumor energetics, obtained by imaging with 18F-fluorodeoxyglucose (FDG). We imaged four patients with small cell lung cancer and two with high-grade sarcoma both before and approximately 1 wk after the start of chemotherapy. Thymidine and FDG studies were done on the same day. Tumor uptake was quantified by standardized uptake values (SUVs) for both tracers by the metabolic rate of FDG and thymidine flux constant (K(TdR)) using regions of interest placed on the most active part of the tumor. In the four patients with clinical response to treatment, both thymidine and FDG uptake markedly declined 1 wk after therapy. Thymidine measurements of SUV and K(TdR) declined by 64% +/- 15% and 84% +/- 33%, respectively. FDG SUV and the metabolic rate of FDG declined by 51% +/- 9% and 63% +/- 23%, respectively. In the patient with metastatic small cell lung cancer who had disease progression, the thymidine SUV decreased by only 8% (FDG not done). In a patient with abdominal sarcoma and progressive disease, thymidine SUV was essentially unchanged (declined by 3%), whereas FDG SUV increased by 69%. Images show a decline in both cellular energetics and proliferative rate after successful chemotherapy. In the two patients with progressive disease, thymidine uptake was unchanged 1 wk after therapy. In our limited series, K(TdR) measurements showed a complete shutdown in tumor proliferation in patients in whom FDG showed a more limited decrease in glucose metabolism.


Apoptosis in a rodent model of cranial suture fusion: in situ imaging and gene expression analysis.
Craniosynostosis, the premature fusion of cranial sutures, is one of the most common craniofacial anomalies, with a reported incidence of up to one in 2500 live births. Despite its prevalence, the cause of craniosynostosis remains unknown. Previously, apoptosis has been postulated to be a contributing factor in the pathogenesis of craniosynostosis, although the role of programmed cell death in cranial sutures is poorly understood. To address this problem, the authors used an established rodent model of posterior-frontal suture fusion and sagittal suture patency to globally examine apoptosis in cranial sutures. Apoptosis was evaluated by systemically coinjecting Sprague-Dawley rats with both fluorescent and technetium-99m-labeled annexin V at time points before, during, and after the period of predicted posterior-frontal suture fusion to determine the magnitude and time course of overall apoptotic activity in both fusing and patent sutures. Using these novel in situ imaging techniques, the authors observed a significant increase in the overall levels of apoptosis in both the posterior-frontal and sagittal suture complexes during the period of predicted posterior-frontal suture fusion. To further explore this increase in apoptotic activity, they used microarray technology to study apoptosis-related genes within the suture complex. Interestingly, there was activation of distinct apoptotic pathways in the posterior-frontal and sagittal sutures during the period of predicted posterior-frontal suture fusion. Whereas increased transcription of genes associated with the mitochondria-mediated apoptotic pathway occurred in the posterior-frontal suture during fusion, activation of genes associated with the death receptor-mediated apoptotic pathway predominated in the patent sagittal suture during the same time period. These data suggest that although overall apoptotic activity in rat patent and fusing sutures is similar, the pathways mediating apoptosis within each suture are distinct.


Adsorption of prion and tissue proteins to surgical stainless steel surfaces and the efficacy of decontamination following dry and wet storage conditions.
Iatrogenic transmission of the infectious prion protein (PrP(Sc)) is a potential threat due to its resistance to many chemical and enzymatic decontamination protocols and its strong adhesive properties to stainless steel. The conditions in which surgical instruments are handled during and after surgery may affect the level of tissue protein, prion attachment and the efficacy of subsequent decontamination regimes. This study investigated the adhesion of tissue protein and prion-associated amyloid to surgical stainless steel with respect to time and various storage conditions, and the subsequent outcome on the efficacy of enzymatic cleaning chemistries. Surfaces were contaminated with ME7-infected brain homogenate and left to dry between 0 and 120 min at room temperature or 24 h, in dry or moist conditions. Residual contamination before and after cleaning was visualised using sensitive fluorescent staining and episcopic differential interference contrast/epifluorescence microscopy. Longer drying times increased both protein and prion amyloid adsorption and affected the efficacy of the cleaning chemistries tested. A moist environment post-contamination significantly reduced the attachment of both protein and prion amyloid to the surgical stainless steel surface. Maintaining moist conditions could potentially improve the subsequent decontamination of reusable surgical instruments, also reducing process time and cost.


Hypoxia modulates the effect of dihydroartemisinin on endothelial cells.
Artemisinin derivatives, the current cornerstone of malaria treatment, possess also anti-angiogenic and anti-tumor activity. Hypoxia plays a crucial role both in severe malaria (as a consequence of the cytoadherence of infected erythrocytes to the microvasculature) and in cancer (due to the restricted blood supply in the growing tumor mass). However, the consequences of hypoxia onto the effects of artemisinins is under-researched. This study aimed at assessing how the inhibition of microvascular endothelial cell (HMEC-1) growth induced by dihydroartemisinin (DHA, an antimalarial drug and the active metabolite of currently in-use artemisinins) is affected by oxygen tension. Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents.


Examining the Potential Synergistic Effects Between Mindfulness Training and Psychedelic-Assisted Therapy.
Mindfulness-based interventions and psychedelic-assisted therapy have been experimentally utilised in recent years as alternative treatments for various psychopathologies with moderate to great success. Both have also demonstrated significant post-acute and long-term decreases in clinical symptoms and enhancements in well-being in healthy participants. These two therapeutic interventions share various postulated salutogenic mechanisms, such as the ability to alter present-moment awareness and anti-depressive action, via corresponding neuromodulatory effects. Recent preliminary evidence has also demonstrated that psychedelic administration can enhance mindfulness capacities which has already been demonstrated robustly as a result of mindfulness-based interventions. These shared mechanisms between mindfulness-based interventions and psychedelic therapy have led to scientists theorising, and recently demonstrating, synergistic effects when both are used in combination, in the form of potentiated therapeutic benefit. These synergistic results hold great promise but require replication in bigger sample groups and better controlled methodologies, to fully delineate the effect of set and setting, before they can be extended onto clinical populations.


Conjugated-polyelectrolyte-functionalized reduced graphene oxide with excellent solubility and stability in polar solvents.
Conjugated-polyelectrolyte (CPE)-functionalized reduced graphene oxide (rGO) sheets are synthesized for the first time by taking advantage of a specially designed CPE, PFVSO(3), with a planar backbone and charged sulfonate and oligo(ethylene glycol) side chains to assist the hydrazine-mediated reduction of graphene oxide (GO) in aqueous solution. The resulting CPE-functionalized rGO (PFVSO(3)-rGO) shows excellent solubility and stability in a variety of polar solvents, including water, ethanol, methanol, dimethyl sulfoxide, and dimethyl formamide. The morphology of PFVSO(3)-rGO is studied by atomic force microscopy, X-ray diffraction, and transmission electron microscopy, which reveal a sandwich-like nanostructure. Within this nanostructure, the backbones of PFVSO(3) stack onto the basal plane of rGO sheets via strong pi-pi interactions, while the charged hydrophilic side chains of PFVSO(3) prevent the rGO sheets from aggregating via electrostatic and steric repulsions, thus leading to the solubility and stability of PFVSO(3)-rGO in polar solvents. Optoelectronic studies show that the presence of PFVSO(3) within rGO induces photoinduced charge transfer and p-doping of rGO. As a result, the electrical conductivity of PFVSO(3)-rGO is not only much better than that of GO, but also than that of the unmodified rGO.


Elastic deformations of the rotary double motor of single F(o)F(1)-ATP synthases detected in real time by Förster resonance energy transfer.
Elastic conformational changes of the protein backbone are essential for catalytic activities of enzymes. To follow relative movements within the protein, Förster-type resonance energy transfer (FRET) between two specifically attached fluorophores can be applied. FRET provides a precise ruler between 3 and 8nm with subnanometer resolution. Corresponding submillisecond time resolution is sufficient to identify conformational changes in FRET time trajectories. Analyzing single enzymes circumvents the need for synchronization of various conformations. F(O)F(1)-ATP synthase is a rotary double motor which catalyzes the synthesis of adenosine triphosphate (ATP). A proton-driven 10-stepped rotary F(O) motor in the Escherichia coli enzyme is connected to a 3-stepped F(1) motor, where ATP is synthesized. To operate the double motor with a mismatch of step sizes smoothly, elastic deformations within the rotor parts have been proposed by W. Junge and coworkers. Here we extend a single-molecule FRET approach to observe both rotary motors simultaneously in individual F(O)F(1)-ATP synthases at work. We labeled this enzyme with two fluorophores specifically, that is, on the ε- and c-subunits of the two rotors. Alternating laser excitation was used to select the FRET-labeled enzymes. FRET changes indicated associated transient twisting within the rotors of single enzyme molecules during ATP hydrolysis and ATP synthesis. Supported by Monte Carlo simulations of the FRET experiments, these studies reveal that the rotor twisting is greater than 36° and is largely suppressed in the presence of the rotation inhibitor DCCD. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).


Doped and disclosed Anatomopolitics, biopower, and sovereignty in the Russian sports industry.
In this article, we scrutinize a policy area in which the Russian government has had to react to negative publicity in the last few years, namely, the doping scandal surrounding the 2014 Sochi Winter Olympics. This scandal uncovered important aspects of Russia's vulnerability in the global sports milieu, yet so far, it has remained almost unnoticed in the literature on mega sports events in Russia. Our analysis is premised on the convergence of two types and techniques of control and regulation: anatomopolitics, which presupposes, in Michel Foucault's interpretation of the term, measures of control over individual bodies, and biopolitics, which refers to policy practices that target and concern the entire population. Their conflation in the Russian context results in a controversial effect: it strengthens relations of hegemony yet also exposes the sovereign power to the regulations of global sports organizations.


Evaluation of respiratory parameters at presentation as clinical indicators of the respiratory localization in dogs and cats with respiratory distress.
To describe clinical respiratory parameters in cats and dogs with respiratory distress and identify associations between respiratory signs at presentation and localization of the disease with particular evaluation between the synchrony of abdominal and chest wall movements as a clinical indicators for pleural space disease. Design - Prospective observational clinical study. Emergency service in a university veterinary teaching hospital. Cats and dogs with respiratory distress presented to the emergency service between April 2008 and July 2009. None. The following parameters were systematically determined at time of admission: respiratory rate, heart rate, temperature, type of breathing, movement of the thoracic and abdominal wall during inspiration, presence of stridor, presence and type of dyspnea, and results of thoracic auscultation. Abdominal and chest wall movement was categorized as synchronous, asynchronous, or inverse. Diagnostic test results, diagnosis, and outcome were subsequently recorded. Based on the final diagnoses, animals were assigned to 1 or more of the following groups regarding the anatomical localization of the respiratory distress: upper airways, lower airways, lung parenchyma, pleural space, thoracic wall, nonrespiratory causes, and normal animals. One hundred and seventy-six animals (103 cats and 73 dogs) were evaluated. Inspiratory dyspnea was associated with upper airway disease in dogs and expiratory dyspnea with lower airway disease in cats. Respiratory noises were significantly associated and highly sensitive and specific for upper airway disease. An asynchronous or inverse breathing pattern and decreased lung auscultation results were significantly associated with pleural space disease in both dogs and cats (P<0.001). The combination is highly sensitive (99%) but not very specific (45%). Fast and shallow breathing was not associated with pleural space disease. Increased or moist pulmonary auscultation findings were associated with parenchymal lung disease. Cats and dogs with pleural space disease can be identified by an asynchronous or inverse breathing pattern in combination with decreased lung sounds on auscultation.


Spatially dependent biotic and abiotic factors drive survivorship and physical structure of green roof vegetation.
Plant survivorship depends on biotic and abiotic factors that vary at local and regional scales. This survivorship, in turn, has cascading effects on community composition and the physical structure of vegetation. Survivorship of native plant species is variable among populations planted in environmentally stressful habitats like urban roofs, but the degree to which factors at different spatial scales affect survivorship in urban systems is not well understood. We evaluated the effects of biotic and abiotic factors on survivorship, composition, and physical structure of two native perennial species assemblages, one characterized by a mixture of C4 grasses and forbs (Hempstead Plains, HP) and one characterized by a mixture of C3 grasses and forbs (Rocky Summit, RS), that were initially sown at equal ratios of growth forms (5:1:4; grass, N-fixing forb and non-N-fixing forb) in replicate 2-m2 plots planted on 10 roofs in New York City (New York, USA). Of 24 000 installed plants, 40% survived 23 months after planting. Within-roof factors explained 71% of variation in survivorship, with biotic (species identity and assemblage) factors accounting for 54% of the overall variation, and abiotic (growing medium depth and plot location) factors explaining 17% of the variation. Among-roof factors explained 29% of variation in survivorship and increased solar radiation correlated with decreased survivorship. While growing medium properties (pH, nutrients, metals) differed among roofs there was no correlation with survivorship. Percent cover and sward height increased with increasing survivorship. At low survivorship, cover of the HP assemblage was greater compared to the RS assemblage. Sward height of the HP assemblage was about two times greater compared to the RS assemblage. These results highlight the effects of local biotic and regional abiotic drivers on community composition and physical structure of green roof vegetation. As a result, initial green roof plant composition and roof microclimate may have long-term effects on community dynamics, ecosystem function, and urban biodiversity.


Unraveling dynamics of human physical activity patterns in chronic pain conditions.
Chronic pain is a complex disabling experience that negatively affects the cognitive, affective and physical functions as well as behavior. Although the interaction between chronic pain and physical functioning is a well-accepted paradigm in clinical research, the understanding of how pain affects individuals' daily life behavior remains a challenging task. Here we develop a methodological framework allowing to objectively document disruptive pain related interferences on real-life physical activity. The results reveal that meaningful information is contained in the temporal dynamics of activity patterns and an analytical model based on the theory of bivariate point processes can be used to describe physical activity behavior. The model parameters capture the dynamic interdependence between periods and events and determine a 'signature' of activity pattern. The study is likely to contribute to the clinical understanding of complex pain/disease-related behaviors and establish a unified mathematical framework to quantify the complex dynamics of various human activities.


Positive and negative influences of regulatory T cells on tumour immunity.
Clinicians and scientists have long questioned whether the immune system has a role in destroying cancerous tissue. Studies performed in animal models have, however, recently revealed that the immune system can, at least in principle, effectively control tumours. In parallel with these findings, a large body of evidence indicates that although the immune system has the capacity to control tumours, there are also regulatory mechanisms that subdue these responses. A major challenge of tumour immunotherapy, therefore, is to find ways of disabling these regulatory functions while restoring or priming any immune responses that are protective.


Endogenous nitric oxide downregulates the Bcl-2 expression of eosinophils through mitogen-activated protein kinase in bronchial asthma.
Eosinophil apoptosis might play a crucial role in the maintenance of persistent airway inflammation in asthma. Nitric oxide (NO) synthase activity is upregulated in eosinophils of asthmatic patients. Mitogen-activated protein kinase (MAPK) is implicated in regulating eosinophil apoptosis by modulating Bcl-2 expression. NO-induced cell apoptosis is associated with an inhibition of Bcl-2 expression. We sought to study whether NO might induce eosinophil apoptosis through extracellular signal-regulated protein kinase (ERK) or p38 MAPK pathways and Bcl-2 expression. Eosinophils were freshly isolated from peripheral blood of 16 asthmatic patients and 12 healthy subjects and then cultured with or without the NO synthase inhibitor N-nitro-l-arginine methyl ester (L-NAME) at 1 and 10 mmol/L for 16 hours. The expression of Bcl-2 and induced NO synthase on eosinophils was analyzed by means of flow cytometry. Apoptosis was assessed by means of propidium iodide and DNA ladder. The activity of ERK and p38 MAPK was determined by means of Western blotting. The induced NO synthase immunoreactivities and the spontaneous release of nitrite from the eosinophils of asthmatic patients were higher compared with those of healthy subjects. Eosinophils of asthmatic patients were found to express more highly constitutive Bcl-2 than those of healthy subjects. After incubation for 16 hours, the expression of Bcl-2 on eosinophils from patients with asthma was significantly enhanced by L-NAME. The percentage of apoptosis was decreased by the addition of 1 mmol/L L-NAME in patients with asthma. The activity of p38 MAPK and ERK in eosinophils from patients with asthma was enhanced in the presence of L-NAME. An inhibition of MAPK reduced the Bcl-2 expression and increased eosinophil apoptosis in patients with asthma. We concluded that inhibition of endogenous NO might increase the expression of Bcl-2 in eosinophils from patients with asthma through the signaling pathway of ERK or p38 MAPK, which in turn decrease the apoptosis.


Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production.
Studies of cell-surface molecules involved in human T cell interaction reveal that differential expression of each of three adhesion molecules (LFA-3, CD2, and LFA-1) subdivides human peripheral blood T cells into major subpopulations. Systematic analysis of the relationship between expression of these and other markers of T cell subsets demonstrates a single major subset of human peripheral blood T lymphocytes distinguished by enhanced expression of LFA-3, CD2, LFA-1, and three other markers (CDw29 [4B4], UCHL1, and Pgp-1). Large differences in relative expression are observed for UCHL1 (29-fold) and LFA-3 (greater than 8-fold), and smaller differences (2- to 4-fold) are seen for CDw29, CD2, LFA-1, and Pgp-1. Bimodal distribution of LFA-3 is found on both CD4+ cells and on CD8+ cells as well as on B lymphocytes (CD19+). Neonatal T cells (CD3+) are comprised almost exclusively of the subset expressing low LFA-3, CD2, LFA-1, CDw29, and UCHL1. Activation of cord peripheral blood mononuclear leukocytes with PHA leads to uniform enhanced expression of each of these molecules on CD3+ cells. Functional analyses of these T cell subsets were performed after sorting of adult T cells based on differential LFA-3 expression. Only the LFA-3+ subset proliferated in response to the Ag tetanus toxoid, even though the LFA-3- subset proliferated more strongly to PHA. Furthermore, the LFA-3+ subset made greater than fivefold more IFN-gamma than the LFA-3- subset in response to PHA, despite the fact that both subsets made equivalent amounts of IL-2. This phenotypic and functional analysis of resting and activated newborn and adult T cells indicates that human memory T cells express enhanced levels of LFA-3, CD2, LFA-1, UCHL1, CDw29, and Pgp-1; we speculate that the increase in expression of T cell adhesion molecules LFA-3, CD2, and LFA-1 on memory cells is functionally important in their enhanced responsiveness.


Establishment and cryptic transmission of Zika virus in Brazil and the Americas.
Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.


Rickettsial infection in murine models activates an early anti-rickettsial effect mediated by NK cells and associated with production of gamma interferon.
Natural killer (NK) cell activity was significantly increased on days 2-6 of infection in the Rickettsia conorii-infected C3H/HeN mice and on day 2 in the Rickettsia typhi-infected C57BL/6 mice. Depletion of NK cell activity utilizing anti-NK1.1 monoclonal antibody enhanced the susceptibility of normally resistant C57BL/6 mice to infection with R. typhi, and depletion of NK cell activity with antibody to asialo GM1 enhanced the susceptibility of C3H/HeN mice to infection with R. conorii. Serum gamma interferon was increased in R. conorii-infected C3H/HeN mice compared with NK cell-depleted, infected mice during the early course of infection. Additionally, the NK cell activating cytokine IL-12 was elevated in the sera of infected mice during the time period representing enhanced NK cell activity compared with uninfected mice. Thus, it appears that NK cells contribute to the early anti-rickettsial immune response, likely via a mechanism involving gamma interferon.


Surface-plasmon-induced modification on the spontaneous emission spectrum via subwavelength-confined anisotropic Purcell factor.
The mechanism of using the anisotropic Purcell factor to control the spontaneous emission linewidths in a four-level atom is theoretically demonstrated; if the polarization angle bisector of the two dipole moments lies along the axis of large/small Purcell factor, destructive/constructive interference narrows/widens the fluorescence center spectral lines. Large anisotropy of the Purcell factor, confined in the subwavelength optical mode volume, leads to rapid spectral line narrowing of atom approaching a metallic nanowire, nanoscale line width pulsing following periodically varying decay rates near a periodic metallic nanostructure, and dramatic modification on the spontaneous emission spectrum near a custom-designed resonant plasmon nanostructure. The combined system opens a good perspective for applications in ultracompact active quantum devices.


Tackling Indigenous smoking: a good news story in Australian tobacco control.
There is good news to tell about Aboriginal and Torres Strait Islander tobacco control: smoking prevalence is falling and government funding has been secured in a climate of under-investment in prevention. The Australian Government has committed to funding the Tackling Indigenous Smoking program until 2022. The program continues to fund 37 regional teams with a focus on localised health promotion. This localised activity has been supported by two national Indigenous mass-media campaigns, individual cessation advice provided by Aboriginal Community Controlled Health Organisations and via the Australian quit-smoking helpline, Quitline. But some state governments could do more to support Aboriginal and Torres Strait Islander tobacco control. National Aboriginal and Torres Strait Islander smoking prevalence is falling, with significant falls in urban and regional areas where most Aboriginal and Torres Strait Islander people live. However, there has been little improvement in remote areas and this has become an area of future focus, with three additional Tackling Indigenous Smoking teams announced in remote areas in 2020. We can celebrate the recent achievements of Aboriginal and Torres Strait Islander tobacco control and the current and emerging leaders who are ready for future challenges from the tobacco industry.


Alcohol use trajectories among adults in an urban area after a disaster: evidence from a population-based cohort study.
Alcohol use increased in the New York City (NYC) metropolitan area in the first months after the 11 September 2001 terrorist attacks. To investigate alcohol use trajectories in the NYC metropolitan area in the 3 years after 11 September and examine the relative contributions of acute exposure to the attacks and ongoing stressors to these trajectories. We used a population-based cohort of adults recruited through a random-digit-dial telephone survey in 2002; participants completed three follow-up interviews over 30 months. The NYC metropolitan area. A total of 2752 non-institutionalized adult residents of NYC. We used growth mixture models to assess trajectories in levels of total alcohol consumption and bingeing in the past 30 days, and predictors of these trajectories. We identified five trajectories of alcohol consumption levels and three bingeing trajectories. Predictors of higher levels of use over time included ongoing stressors, traumatic events and lower income. Ongoing exposure to stressors and low income also play a central role in bingeing trajectories. While point-in-time mass traumatic events may matter in the short term, their contribution subsides over time. Accumulated stressors and traumatic events, in contrast, lead to higher levels of consumption among respondents already vulnerable to high alcohol use. Interventions to mitigate post-disaster stressors may have substantial benefit in reducing alcohol abuse in the medium- to long term.


Size, rarity and charisma: valuing African wildlife trophies.
We explore variation in the prices paid by recreational hunters of trophy animals in Africa and its possible causes, including perceived rarity. Previous work has raised the possibility that extinction can result if demand rises fast enough as a species becomes rarer. We attempt to disentangle this from other inter-correlated influences affecting price. Species with larger body sizes and larger trophies were more valuable. Value increased less steeply as a function of size for bovids than for felids and the effect was consistent across countries. Power laws, ubiquitous in physical and social systems, described the trends. The exponent was approximately 0.4 for bovids, compared with approximately 1.0 for felids. Rarity (as indexed by IUCN score) influenced the value of bovid trophies - price was higher for species in categories denoting higher global threat. There was substantial variation in price among and within families not explained by either size or rarity. This may be attributable to a 'charisma' effect, which seems likely to be a general attribute of human perceptions of wildlife. Species where prices were higher than predicted by size or rarity are ranked high in published accounts of desirability by hunters. We conclude that the valuation of these species is explicable to a large extent by body size and perceived rarity, and that differences in valuation between taxonomic groups are related to less easily quantified 'charisma' effects. These findings are relevant for conservationists considering the threat status of species exploited in open access markets, and where license quotas are adjusted in response to changes in perceived rarity.


Redescription of Spinitectus tabascoensis (Nematoda: Cystidicolidae) from fishes of the Lacandon rain forest in Chiapas, southern Mexico, with remarks on Spinitectus macrospinosus and S. osorioi.
Two little-known species of Spinitectus (Nematoda: Cystidicolidae) were, for the first time, recorded from fishes of the Lacantún River (Usumacinta River basin) in the Lacandon rain forest, Chiapas, southern Mexico: S. tabascoensis Moravec, Garcia-Magaña et Salgado-Maldonado, 2002 in intestines of Ictalurus furcatus (Valenciennes) (Ictaluridae) (adults and juveniles), Cathorops aguadulce (Meek) and Potamarius nelsoni (Evermann et Goldsborough) (both Ariidae) (in both only juveniles), and S. osorioi Choudhury et Pérez-Ponce de León, 2001 in Atherinella alvarezi (Díaz-Pardo) (Atherinopsidae) (adults in intestine) and Eugerres mexicanus (Steindachner) (Gerreidae) (adults and juveniles in stomach). Eugerres mexicanus, C. aguadulce and P. nelsoni represent new host records. Detailed light and electron microscopical studies of S. tabascoensis revealed some taxonomically important, previously not observed features, such as cuticular spines arranged in four sectors, the cephalic structure, the number (2) of ventral precloacal ridges or the structure of the male caudal end. Therefore, Spinitectus tabascoensis is redescribed. Spinitectus macrospinosus Choudhury et Perryman, 2003, described from ictalurids in Canada and the USA, is considered its junior synonym. Spinitectus tabascoensis seems to be a specific parasite of Ictalurus spp., whereas C. aguadulce and P. nelsoni, as well as some other fishes, serve only as its paratenic hosts. The definitive hosts of S. osorioi are atherinopsid fish (A. alvarezi, Chirostoma spp.), whereas the gerreid E. mexicanus probably serves only as its postcyclic host.


Biomedical applications of nanodiamond (Review).
The interest in nanodiamond applications in biology and medicine is on the rise over recent years. This is due to the unique combination of properties that nanodiamond provides. Small size (∼5 nm), low cost, scalable production, negligible toxicity, chemical inertness of diamond core and rich chemistry of nanodiamond surface, as well as bright and robust fluorescence resistant to photobleaching are the distinct parameters that render nanodiamond superior to any other nanomaterial when it comes to biomedical applications. The most exciting recent results have been related to the use of nanodiamonds for drug delivery and diagnostics-two components of a quickly growing area of biomedical research dubbed theranostics. However, nanodiamond offers much more in addition: it can be used to produce biodegradable bone surgery devices, tissue engineering scaffolds, kill drug resistant microbes, help us to fight viruses, and deliver genetic material into cell nucleus. All these exciting opportunities require an in-depth understanding of nanodiamond. This review covers the recent progress as well as general trends in biomedical applications of nanodiamond, and underlines the importance of purification, characterization, and rational modification of this nanomaterial when designing nanodiamond based theranostic platforms.


Predicting the impact of climate change on threatened species in UK waters.
Global climate change is affecting the distribution of marine species and is thought to represent a threat to biodiversity. Previous studies project expansion of species range for some species and local extinction elsewhere under climate change. Such range shifts raise concern for species whose long-term persistence is already threatened by other human disturbances such as fishing. However, few studies have attempted to assess the effects of future climate change on threatened vertebrate marine species using a multi-model approach. There has also been a recent surge of interest in climate change impacts on protected areas. This study applies three species distribution models and two sets of climate model projections to explore the potential impacts of climate change on marine species by 2050. A set of species in the North Sea, including seven threatened and ten major commercial species were used as a case study. Changes in habitat suitability in selected candidate protected areas around the UK under future climatic scenarios were assessed for these species. Moreover, change in the degree of overlap between commercial and threatened species ranges was calculated as a proxy of the potential threat posed by overfishing through bycatch. The ensemble projections suggest northward shifts in species at an average rate of 27 km per decade, resulting in small average changes in range overlap between threatened and commercially exploited species. Furthermore, the adverse consequences of climate change on the habitat suitability of protected areas were projected to be small. Although the models show large variation in the predicted consequences of climate change, the multi-model approach helps identify the potential risk of increased exposure to human stressors of critically endangered species such as common skate (Dipturus batis) and angelshark (Squatina squatina).


Ultra-small lipid-polymer hybrid nanoparticles for tumor-penetrating drug delivery.
Lipid-polymer hybrid nanoparticles, consisting of a polymeric core coated by a layer of lipids, are a class of highly scalable, biodegradable nanocarriers that have shown great promise in drug delivery applications. Here, we demonstrate the facile synthesis of ultra-small, sub-25 nm lipid-polymer hybrid nanoparticles using an adapted nanoprecipitation approach and explore their utility for targeted delivery of a model chemotherapeutic. The fabrication process is first optimized to produce a monodisperse population of particles that are stable under physiological conditions. It is shown that these ultra-small hybrid nanoparticles can be functionalized with a targeting ligand on the surface and loaded with drug inside the polymeric matrix. Further, the in vivo fate of the nanoparticles after intravenous injection is characterized by examining the blood circulation and biodistribution. In a final proof-of-concept study, targeted ultra-small hybrid nanoparticles loaded with the cancer drug docetaxel are used to treat a mouse tumor model and demonstrate improved efficacy compared to a clinically available formulation of the drug. The ability to synthesize a significantly smaller version of the established lipid-polymer hybrid platform can ultimately enhance its applicability across a wider range of applications.


Caregivers' perceived adequacy of support in end-stage lung disease: results of a population survey.
End-stage lung disease (ESLD) is a frequent cause of death. What are the differences in the supports needed by caregivers of individuals with ESLD at end of life versus other life-limiting diagnoses? The South Australian Health Omnibus is an annual, random, face-to-face, cross-sectional survey. In 2002, 2003 and 2005-2007, respondents were asked a range of questions about end-of-life care; there were approximately 3000 survey participants annually (participation rate 77.9%). Responses were standardised for the whole population. The families and friends who cared for someone with ESLD were the focus of this analysis. In addition to describing caring, respondents reported additional support that would have been helpful. Of 1504 deaths reported, 145 (9.6%) were due to ESLD. The ESLD cohort were older than those with other 'expected' causes of death (> 65 years of age; 92.6% versus 70.6%; p < 0.0001) and were less likely to access specialised palliative care services (38.4% versus 61.9%; p < 0.0001). For those with ESLD, the mean caring period was significantly longer at 25 months (standard deviation (SD) 24) than for 'other diagnoses' (15 months; SD 18; p < 0.0001). Domains where additional support would have been useful included physical care, information provision, and emotional and spiritual support. Caregiver needs were similar regardless of the underlying diagnosis although access to palliative care specialist services occurred less often for ESLD patients. This was despite significantly longer periods of time for which care was provided.


Design and psychometric properties of willingness to mobile learning scale for medical sciences students: A mixed-methods study.
Given the absence of a scale specially designed to measure willingness to mobile learning (m-learning) in medical sciences students, the present study was conducted to design and evaluate the psychometric properties of "willingness to m-learning" scale for medical sciences students. The study was carried out as a mixed-method study in two phases at Saveh University of Medical Sciences in 2019. Phase one was a qualitative study to elaborate on the students' perception of m-learning. Then, the statements were extracted, and statement pool was completed through reviewing the text. In the second phase, the psychometric properties including face, content, and construct validities (using explorative factor analysis), internal consistency (Cronbach's alpha), and test-retest reliability (intercluster correlation test) were measured. A total of 482 students who were selected randomly participated in the second phase. Data analysis was done with MAXQDA software (VERBI Software 2019, Berlin, Germany) for qualitative data and SPSS 19 software (SPSS Inc., Chicago, IL, USA) for quantitative data. Based on qualitative content analysis and literature review, 92 statements were extracted. After checking face and content validity, 55 statements remained in the study. Construct validity of the questionnaire based on explorative factor analysis removed 10 more statements and the remaining 45 statements were categorized into nine factors, namely technophilia, perceived attraction, perceived ease, perceived conflict, self-management, attitude, behavioral intention to use, educational use, and efficacy of m-learning. Reliability of the scale was obtained as 0.95 based on Cronbach's alpha and stability was checked using test-retest method (intercluster correlation coefficient; r = 0.92). Willingness to m-learning scale had an acceptable reliability and validity in medical sciences students. Therefore, it can be used for medical sciences students for improve learning and education.


Silicon/III-V laser with super-compact diffraction grating for WDM applications in electronic-photonic integrated circuits.
We have demonstrated a heterogeneously integrated III-V-on-Silicon laser based on an ultra-large-angle super-compact grating (SCG). The SCG enables single-wavelength operation due to its high-spectral-resolution aberration-free design, enabling wavelength division multiplexing (WDM) applications in Electronic-Photonic Integrated Circuits (EPICs). The SCG based Si/III-V laser is realized by fabricating the SCG on silicon-on-insulator (SOI) substrate. Optical gain is provided by electrically pumped heterogeneous integrated III-V material on silicon. Single-wavelength lasing at 1550 nm with an output power of over 2 mW and a lasing threshold of around 150 mA were achieved.


Mass Spectrometric Quantification of Arousal Associated Neurochemical Changes in Single Honey Bee Brains and Brain Regions.
Honey bee foragers show a strong diurnal rhythm of foraging activity, and such behavioral changes are likely under the control of specific neuromodulators. To identify and quantify neuromodulators involved in regulating rest and arousal in honey bees, we established a mass spectrometric method for quantifying 14 different neurochemicals and precursor molecules. We measured forager type and brain region specific differences in amine levels from individual honey bee brains and brain regions. The observed differences in amine levels between resting and aroused foragers resemble findings in other species indicating a conserved molecular mechanism by glutamate and GABA in regulating arousal. Subesophageal ganglion specific changes in the histaminergic system and global increases in aspartate during arousal suggest a possible role of histamine and aspartate in feeding and arousal, respectively. More aminergic systems were significantly affected due to arousal in nectar foragers than in pollen foragers, implying that forager phenotypes differ not only in their food preference but also in their neuromodulatory signaling systems (brain states). Finally, we found that neurotransmitter precursors were better at distinguishing brain states in the central brain, while their end products correlated with arousal associated changes in sensory regions like the optic and antennal lobes.


The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO).
Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbach's-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5% were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH = 47.35) differed mainly by accredited training (P = 0.003). The training-satisfaction score (TSS) had high reliability (Cronbach's alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P = 0.001) and salary (P = 0.002). The TSS was independent of age (P = 0.360), working hours (P = 0.620), overtime-pay (P = 0.318), annual leave (P = 0.933), gender (P = 0.545) and marital status (P = 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology training within Europe.


Interventions to reduce suicidal thoughts and behaviours among people in contact with the criminal justice system: A global systematic review.
People who experience incarceration die by suicide at a higher rate than those who have no prior criminal justice system contact, but little is known about the effectiveness of interventions in other criminal justice settings. We aimed to synthesise evidence regarding the effectiveness of interventions to reduce suicide and suicide-related behaviours among people in contact with the criminal justice system. We searched Embase, PsycINFO, MEDLINE, and grey literature databases for articles published between 1 January 2000 and 1 June 2021. The protocol was registered with PROSPERO (CRD42020185989). Thirty-eight studies (36 primary research articles, two grey literature reports) met our inclusion criteria, 23 of which were conducted in adult custodial settings in high-income, Western countries. Four studies were randomised controlled trials. Two-thirds of studies (n=26, 68%) were assessed as medium quality, 11 (29%) were assessed as high quality, and one (3%) was assessed as low quality. Most had considerable methodological limitations and very few interventions had been rigorously evaluated; as such, drawing robust conclusions about the efficacy of interventions was difficult. More high-quality evidence from criminal justice settings other than adult prisons, particularly from low- and middle-income countries, should be considered a priority for future research. This work was funded by the Australian government's National Suicide Prevention Taskforce. RB is supported by a National Health and Medical Research Council (NHMRC) Emerging Leader Investigator Grant (EL2; GNT2008073). MW is supported by a NHMRC Postgraduate Scholarship (GNT1151103). SF was funded by the NIHR HTA Programme (HTA Project:16/159/09).


Mapping of DNase I-hypersensitive sites in the upstream DNA of human embryonic epsilon-globin gene in K562 leukemia cells.
We have mapped the DNase I-hypersensitive sites around the epsilon-globin and c-myc genes in two human leukemia cell lines K562 and HL60. In K562 cells in which the epsilon-globin gene is transcribed, six DNase I-hypersensitive sites are found in 6 kilobases (kb) of upstream flanking DNA; in HL60 cells in which the c-myc gene is expressed, two DNase I-hypersensitive sites are observed in 2 kb of upstream DNA. Neither the inactive epsilon-globin gene in HL60 cells nor the inactive c-myc gene in K562 cells displays such upstream DNase I-hypersensitive sites. Our results are consistent with previous studies that have shown DNase I-hypersensitive sites within 1 kb of the 5' end of other expressed genes. In addition, we have found sites displaying even more DNase I sensitivity further upstream of expressed epsilon-globin and c-myc genes. Among the six DNase I-hypersensitive sites of the expressed epsilon-globin gene in K562 cells, the most sensitive site is located about 6 kb upstream of the epsilon-globin gene. When correlated with the DNA sequence upstream of the epsilon-globin gene, this site was found to correspond to a region that contains a stretch of 28 consecutive Ts, three enhancer core-like sequences, and a stretch of consecutive (C-A)15(T-A)6 alternating purine and pyrimidine bases. These findings suggest the possibility that an enhancer element for epsilon-globin gene expression resides within this DNase I-hypersensitive site.


Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis.
Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05-0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance, hypertriglyceridemia, and hypercholesterolemia. Prolonged feeding (6-22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did not induce beta-cell dysfunction. Metabolic changes induced by the diet, including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a high-fructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.


Interspecific primate associations in Amazonian flooded and unflooded forests.
Stable associations between two or more primate species are a prominent feature of neotropical forest vertebrate communities and many studies have addressed their prevalence, and their costs and benefits. However, little is known about the influence of different habitat types on the frequency, seasonality, and composition of mixed-species groups in Amazonian forest primates. Here we examine the features of interspecific primate groups in a large mosaic of flooded (várzea and igapó) and unflooded (terra firme) forest in central Amazonia. In total, 12 primate species occurred in the study area, nine of which were observed in mixed-species associations. Primates were more than twice as likely to form associations in várzea forest than in terra firme forest. Squirrel monkeys were most frequently found in mixed-species groups in all forest types, most commonly in association with brown capuchins. Another frequent member of interspecific associations was the buffy saki, which often formed mixed-species groups with tamarins or brown capuchins. There was no seasonality in the frequency of associations in terra firme forest whereas associations in várzea forest were twice as frequent during the late-dry and early-wet seasons than in the late-wet and early-dry seasons. Interspecific primate associations were common in all forest types, but the degrees to which different species associate varied between these environments. We suggest that the temporal variation of várzea forest associations is connected with seasonal changes in habitat structure and resource abundance. However, more work is needed to pinpoint the underlying causes of mixed-species associations in all forest types and their strong seasonality in várzea forest.


Arthroscopically assisted fibular strut allograft for treatment of osteonecrosis of proximal humerus.
Fourteen patients (17 shoulders) were identified who had been treated by one surgeon from 1992 to 2008 for symptomatic shoulder osteonecrosis using proximal humerus core decompression with fibular allograft strut placement. Pre- and postoperative radiographs were available, along with active range of motion and postoperative function: SPADI, ASES, SF-12. Two patients (two shoulders) were lost to follow-up. Radiographs were staged using the Cruess classification system as eight precollapse (stages I and II) (mean age 44 years) and six postcollapse shoulders (stages III and IV) (mean age 30 years). Groups had similar preoperative and postoperative flexion, external rotation, and functional scores. Two stage II shoulders and one stage IV shoulder were subsequently converted to hemiarthroplasty. This minimally invasive surgical technique could expand indications for strut grafting and joint salvage to treatment of patients with advanced osteonecrosis.


Importance of antibody and complement for oxidative burst and killing of invasive nontyphoidal Salmonella by blood cells in Africans.
Bacteremia caused by nontyphoidal strains of Salmonella is endemic among African children. Case-fatality rates are high and antibiotic resistance increasing, but no vaccine is currently available. T cells are important for clearance of Salmonella infection within macrophages, but in Africa, invasive Salmonella disease usually manifests in the blood and affects children between 4 months and 2 y of age, when anti-Salmonella antibody is absent. We have previously found a role for complement-fixing bactericidal antibody in protecting these children. Here we show that opsonic activity of antibody and complement is required for oxidative burst and killing of Salmonella by blood cells in Africans. Induction of neutrophil oxidative burst correlated with anti-Salmonella IgG and IgM titers and C3 deposition on bacteria and was significantly lower in African children younger than 2 y compared with older children. Preopsonizing Salmonella with immune serum overcame this deficit, indicating a requirement for antibody and/or complement. Using different opsonization procedures, both antibody and complement were found to be necessary for optimal oxidative burst, phagocytosis and killing of nontyphoidal Salmonella by peripheral blood cells in Africans. Although most strains of African nontyphoidal Salmonella can be killed with antibody and complement alone, phagocytes in the presence of specific antibody and complement can kill strains resistant to killing by immune serum. These findings increase the likelihood that an antibody-inducing vaccine will protect against invasive nontyphoidal Salmonella disease in African children.


Prenatal stress inhibits neuronal maturation through downregulation of mineralocorticoid receptors.
Prenatal stress (PS) increases the risk of depressive disorders in adult offspring. The pathophysiology of depressive disorders has been linked to hippocampal dysfunction; however, whether and how PS attenuates the development and function of hippocampal networks remains unknown. Using a rat model of PS, in which pregnant mothers receive daily restraint stress during late gestation and their offspring exhibit depressive-like behavior later in life, we show that PS impairs the morphological and functional maturation of hippocampal granule cells in adult offspring via the downregulated expression of mineralocorticoid receptors. PS reduced the dendritic complexity and spine density of neonatal-generated granule cells, which persists into adulthood. These granule cells exhibited depressed synaptic responses to stimulation of the medial perforant path. We further revealed that the expression of mineralocorticoid receptors, which we found is necessary for proper dendritic maturation in this study, was significantly downregulated in granule cells after PS. These results suggest that PS-induced downregulation of mineralocorticoid receptors attenuates neuronal maturation, which results in dysfunction of neuronal network in adulthood.


Mechanical thrombectomy following intravenous thrombolysis in the treatment of acute stroke.
The efficacy of intravenous thrombolytics in acute stroke is limited by low rates of recanalization of occluded arteries. Treatment with intravenous thrombolytics followed by mechanical thrombectomy is a novel approach that may increase recanalization rates without compromising time to initiation of treatment. To report our experience with 2 patients who received this combination therapy and outline plans for a prospective pilot study. Case studies at a university hospital. Patients treated with intravenous thrombolytics within 3 hours of symptom onset subsequently underwent computed tomographic angiography. If an occlusion of a proximal cerebral vessel was shown by a computed tomographic angiogram, mechanical thrombectomy was performed. Patients were observed for 1 month after treatment. National Institutes of Health Stroke Scale (NIHSS) score. The computed tomographic angiography of 2 patients showed complete occlusion of the M1 branch of the middle cerebral artery following administration of intravenous thrombolytics. The NIHSS scores were 21 and 13. In both cases, blood flow through the occluded artery was restored with mechanical thrombectomy and dramatic neurologic improvement occurred. There were no complications. The NIHSS scores were 0 and 2 at 1-month follow-up. Treatment with intravenous thrombolytics followed by mechanical thrombectomy may improve outcomes in acute stroke patients and a pilot safety trial is warranted.


Poly(ADP-ribose) polymerase contributes to the development of myocardial infarction in diabetic rats and regulates the nuclear translocation of apoptosis-inducing factor.
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury during myocardial infarction. Because diabetes mellitus can substantially alter cellular signal transduction pathways, we have now investigated whether the PARP pathway also contributes to myocardial ischemia/reperfusion (MI/R) injury in diabetes mellitus in rodents. Myocardial ischemia/reperfusion in control and streptozotocin-diabetic rats was induced by transient ligation of the left anterior descending coronary artery. PARP activation was inhibited by the isoindolinone derivative PARP inhibitor INO-1001. In diabetic rats, a more pronounced degree of myocardial contractile dysfunction developed, which also was associated with a larger infarct size, and significant mortality compared with nondiabetic rats. Inhibition of PARP provided a similar degree of myocardial protective effect in diabetic and nondiabetic animals and reduced infarct size and improved myocardial contractility. In diabetic rats, PARP inhibition reduced mortality during the reperfusion phase. There was marked activation of PARP in the ischemic/reperfused myocardium, which was blocked by INO-1001. In addition, there was a significant degree of mitochondrial-to-nuclear translocation of the cell death effector apoptosis-inducing factor (AIF) in myocardial infarction, which was blocked by pharmacological inhibition of PARP. The role of PARP in regulating AIF translocation in myocytes also was confirmed in an isolated perfused heart preparation. Overall, the current results demonstrate the importance of the PARP pathway in diabetic rats subjected to myocardial infarction and demonstrate the role of PARP in regulating AIF translocation in MI/R.


Development and Validation of an Inflammatory Bowel Disease Severity Index Using US Administrative Claims Data: A Retrospective Cohort Study.
Clinical indices to characterize the severity of inflammatory bowel disease (IBD) are widely used in clinical trials and real-world practice. However, there are few validated instruments for assessing IBD severity in administrative claims-based studies. Patients (18-89 years) diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) and receiving ≥1 prescription claim for IBD therapy were identified using administrative claims data from the Optum Clinformatics, IMS PharMetrics, and Truven MarketScan databases (January 1, 2013-September 30, 2017). Regression modeling identified independent predictors of IBD-related hospitalization (inpatient stay or emergency department visit resulting in hospitalization), which were used to develop IBD severity indices. The index was validated against all-cause hospitalization and total cost and IBD-related hospitalization and total cost. There were 51,767 patients diagnosed with UC (n = 30,993) or CD (n = 20,774) who were initiated treatment with IBD therapy. Independent predictors of IBD-related hospitalization were Charlson Comorbidity Index score >1, anemia, weight loss, intravenous corticosteroid use, prior gastrointestinal-related emergency department visit and hospitalization, and unspecified disease location or more extensive disease. Female sex, renal comorbidities, intestinal fistula, and stricture were additional risk factors for patients with CD, whereas age <40 years was a UC-specific risk factor. Median IBD severity scores were 8 and 13 for UC and CD, respectively, from possible total scores of 51 and 37. Inflammatory bowel disease severity score correlated with significantly higher all-cause hospitalization and cost, all-cause total cost, IBD-related hospitalization cost, and total cost. These validated UC and CD severity indices can be used to predict IBD-related outcomes using administrative claims databases.


aeGEPUCI: a database of gene expression in the dengue vector mosquito, Aedes aegypti.
Aedes aegypti is the principal vector of dengue and yellow fever viruses. The availability of the sequenced and annotated genome enables genome-wide analyses of gene expression in this mosquito. The large amount of data resulting from these analyses requires efficient cataloguing before it becomes useful as the basis for new insights into gene expression patterns and studies of the underlying molecular mechanisms for generating these patterns. We provide a publicly-accessible database and data-mining tool, aeGEPUCI, that integrates 1) microarray analyses of sex- and stage-specific gene expression in Ae. aegypti, 2) functional gene annotation, 3) genomic sequence data, and 4) computational sequence analysis tools. The database can be used to identify genes expressed in particular stages and patterns of interest, and to analyze putative cis-regulatory elements (CREs) that may play a role in coordinating these patterns. The database is accessible from the address http://www.aegep.bio.uci.edu. The combination of gene expression, function and sequence data coupled with integrated sequence analysis tools allows for identification of expression patterns and streamlines the development of CRE predictions and experiments to assess how patterns of expression are coordinated at the molecular level.


Role of pancreatoscopy in management of pancreatic disease: A systematic review.
Per-oral pancreatoscopy (POP) plays a role in the diagnosis and therapy of pancreatic diseases. With recent technological advances, there has been renewed interest in this modality. To evaluate the efficacy and safety of POP in management of pancreatic stone disease and pancreatic ductal neoplasia. To determine the safety and efficacy of POP in the management of pancreatic diseases, a systematic search was conducted in MEDLINE, EMBASE and Ovid. Articles in languages other than English and case reports were excluded. All published case series were eligible. Data specific to POP were extracted from studies, which combined cholangiopancreatoscopy. Ten studies were included in the analysis of POP therapy for pancreatic stone disease, and 15 case series satisfied the criteria for inclusion for the role of POP in the management of pancreatic ductal neoplasia. The examined data were subcategorized according to adjunctive modalities, such as direct tissue sampling, cytology, the role of intraoperative POP, intraductal ultrasound (IDUS) and POP combined with image-enhancing technology. The success rate for complete ductal stone clearance ranged from 37.5%-100%. Factors associated with failure included the presence of strictures, multiple stones and the inability to visualize the target area. Although direct visualization can identify malignant and premalignant conditions, there is significant overlap with benign diseases. Visually-directed biopsies provide a high degree of accuracy, and represent a unique approach for tissue acquisition in patients with ductal abnormalities. Addition of pancreatic fluid cytology increases diagnostic yield for indeterminate lesions. Protrusions larger than 3 mm noted on IDUS are significantly more likely to be associated with malignancy. The rate of adverse events associated with POP ranged from 0%-35%. Current evidence supports wider adoption of pancreatoscopy, as it is safe and effective. Improved patient selection and utilization of novel technologies may further enhance its role in managing pancreatic disease.


Biomarkers for the Early Detection of Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and the cancer with the fastest increase in mortality in the United States, with more than 39,000 cases and 29,000 deaths in 2018. As with many cancers, survival is significantly improved by early detection. The median survival of patients with early HCC is >60 months but <15 months when detected at an advanced stage. Surveillance of at-risk patients improves outcome, but fewer than 20% of those at risk for HCC receive surveillance, and current surveillance strategies have limited sensitivity and specificity. Ideally, blood-based biomarkers with adequate sensitivity or specificity would be available for early detection of HCC; however, the most commonly used biomarker for HCC, alpha-fetoprotein, has inadequate performance characteristics. There are several candidate serum proteomic, glycomic, and genetic markers that have gone through early stages of biomarker validation and have shown promise for the early detection of HCC, but these markers require validation in well-curated cohorts. Ongoing prospective cohort studies will permit retrospective longitudinal (phase III biomarker study) validation of biomarkers. In this review, we highlight promising candidate biomarkers and biomarker panels that have completed phase II evaluation but require further validation prior to clinical use.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."


Sign-tunable Poisson's ratio in semi-fluorinated graphene.
Poisson's ratio is a fundamental property of a material which reflects the transverse strain response to the applied axial strain. Negative Poisson's ratio is allowed theoretically, but is rare in nature. Besides the discovery and tailoring of bulk auxetic materials, recent studies have also found a negative Poisson's ratio in nanomaterials, while their negative Poisson's ratio is mainly based on conventional rigid mechanical models as bulk auxetic materials. In this work, we report the existence of in-plane negative Poisson's ratio in a two-dimensional convex structure of newly synthesized semi-fluorinated graphene by using first-principles calculations. In addition, the sign of the Poisson's ratio can be tuned by the applied strain. Interestingly, we find that this unconventional negative Poisson's ratio cannot be explained by conventional rigid mechanical models but originates from the enhanced bond angle strain over the bond strain due to chemical functionalization. This new mechanism of auxetics extends the scope of auxetic nanomaterials and can serve as design principles for future discovery and design of new auxetic materials.


Platinum-based chemotherapy for advanced transitional cell carcinoma of the upper urinary tract.
To report the results of platinum-based chemotherapy used at one medical center in patients with advanced transitional cell carcinomas (TCCs) of the upper urinary tract. Between July 1981 and February 1993, 28 patients (mean age, 59.3 years) with advanced TCC of the upper urinary tract received cisplatin-based chemotherapy. Of the 28 patients, 14 received a median of 4 cycles of cisplatin, methotrexate, and vinblastine sulfate, 8 received a median of 4.5 cycles of methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin, 5 received a median of 5 cycles of etoposide and cisplatin, and 1 was treated with 7 cycles of only cisplatin. Overall survival estimates were constructed from nonparametric analysis with the Kaplan-Meier method. The overall response rate (partial and complete) to chemotherapy was 54%. The most responsive metastatic sites were the lung and lymph nodes-78 and 47% overall response rate, respectively. The estimated median duration of survival for the entire study group was 14 months. In the study population, only three patients were long-term survivors. A significant survival advantage was noted only in the few patients (with limited metastatic tumor volume) who had a complete response to therapy. Initial dose reductions in chemotherapy because of decreased baseline renal function were necessary in 79% of the patients. Removal of the primary lesion in the presence of metastatic or locally advanced disease does not apparently improve chemotherapy response rates or patient survival. In addition, many patients do not receive optimal dosing of systemic chemotherapy after nephrectomy. Therefore, by avoiding dose modifications, the overall response rates and survival may conceivably be improved. A diagnostic biopsy or nephron-sparing surgical procedure and neoadjuvant systemic therapy may be considered in patients with advanced TCC at the time of initial assessment in order to allow optimal dosing of chemotherapy.


Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis.
BACKGROUND Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. MATERIAL AND METHODS Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. RESULTS DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. CONCLUSIONS The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.


Analysis of Two CDKN2B-AS Polymorphisms in Relation to Coronary Artery Disease Patients in North of Iran.
Coronary artery disease (CAD) including myocardial infarction (MI) as its complication, is one of the most common heart diseases worldwide and also in Iran, with extremely elevated mortality. CAD is a multifactorial disorder. Twin and family studies at different loci have demonstrated that genetic factors have an important role in the progression of CAD. Many studies have reported a significant association of CDKN2B-AS, also known as ANRIL which is located within the p15, p16, p14 gene cluster at 9p21 locus, with cardiovascular diseases as well as many other diseases like diabetes and cancers. This study investigated two polymorphisms rs10757274 and rs1333042 of CDKN2B-AS gene at 9p21 locus. 205 subjects, comprising 102 controls and 103 CAD patients were genotyped by TaqMan probe real time PCR technique and haplotypes were examined. This study confirmed the association of rs10757274 variants with CAD in Iranian patients (P= 0.003) but genotype and allele distributions of CAD and control groups showed no significant association for the rs1333042. However, frequency of the [G;G] haplotype of these two SNPs was significantly higher in CAD group (P= 0.0002, Odds Ratio = 3.1, 95% CI = 1.7-5.7). Our finding suggests that [G; G] haplotype of rs10757274 and rs1333042 may be considered as a genetic risk factor for susceptibility to CAD in Iranian patients.