Photodynamic effect of curcumin on NPC/CNE2 cells.
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southern China. Radiotherapy is the primary treatment of NPC, but the rate of tumor recurrence is significant. Photodynamic therapy (PDT) and the use of natural compounds become one of the new approaches in the investigation of NPC treatment. PDT is an alternate method of cancer treatment while curcumin (CUR) is a compound derived from the traditional Chinese medicinal (TCM) herbs. The purpose of the study focuses on the photodynamic effect of CUR on one of the NPC cell lines, NPC/CNE2. Cytotoxicity and photocytotoxicity of CUR were evaluated by 3-(4,5-dimthyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Uptake kinetics of CUR in NPC/CNE2 was examined by flow cytometry. The mode of cell death induced by CUR was studied by fluorescence microscopy. Summarizing the results, CUR showed dark cytotoxicity as well as photocytotoxic effects on NPC/CNE2 cells. LC50 of CUR in the dark was about 16 microM. The cytotoxicity of CUR was enhanced by the irradiation of visible light and blue filtered light (maximum transmittance at 300 approximately 400 nm) with light doses of 300 kJ/m2 and 60 kJ/m2 respectively. NPC/CNE2 was found to rapidly take up CUR in the first hour of incubation, and the uptake kinetics steadily increased to a plateau level after 20 hr of incubation. Cell shrinkage and membrane bledding appeared under the observation of fluorescence microscopy. Such evidences proved that CUR might induce apoptosis on NPC/CNE2 cells. The preliminary study confirmed that CUR demonstrated dark cytotoxicity and photocytotoxicty to NPC/CNE2. The mode of action is likely to be induced by apoptotic pathway. CUR may be developed as a potential photosensitizer as well as a chemotherapeutic agent in clinical application.


A singular PpaA/AerR-like protein in Rhodospirillum rubrum rules beyond the boundaries of photosynthesis in response to the intracellular redox state.
Rhodospirillum rubrum vast metabolic versatility places it as a remarkable model bacterium and an excellent biotechnological chassis. The key component of photosynthesis (PS) studied in this work (HP1) stands out among the other members of PpaA/AerR anti-repressor family since it lacks the motif they all share: the cobalamin B-12 binding motif. Despite being reduced and poorly conserved, HP1 stills controls PS as the other members of the family, allowing a fast response to changes in the redox state of the cell. This work also shows that HP1 absence affects genes from relevant biological processes other than PS, including nitrogen fixation and stress response. From a biotechnological perspective, HP1 could be manipulated in approaches where PS is not necessary, such as hydrogen or polyhydroxyalkanoates production, to save energy.


Short-term effects of nitrate-rich green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure.
Evidence for a beneficial effect of dietary nitrate, through the nitrate-nitrite-NO pathway, on measures of cardiovascular function in healthy individuals is accumulating. It is less clear whether increased dietary nitrate intake from green leafy vegetables would have similar beneficial vascular effects in those at increased risk of developing hypertension. Our aim was to assess the effects of short-term regular consumption of increased nitrate from green leafy vegetables on blood pressure and arterial stiffness in individuals with high-normal blood pressure. Thirty-eight men and women ages 30-70 years with systolic blood pressure 120 to 139 mm Hg were recruited to a randomized controlled crossover trial. The effects of a 7-day high-nitrate diet intervention (increased nitrate intake by at least 300 mg/day from green leafy vegetables) were compared to a 7-day low-nitrate diet intervention. Outcome measures included pre- and postintervention salivary and plasma nitrate and nitrite concentrations; ambulatory, home, and office blood pressure; augmentation index; and carotid-femoral pulse wave velocity. The high-nitrate diet intervention resulted in at least a fourfold increase in salivary and plasma nitrate and nitrite (P<0.001). Ambulatory, home, and office blood pressure and arterial stiffness were not different between the high-nitrate diet and the low-nitrate diet. Increasing dietary nitrate intake in those with high-normal blood pressure and at increased risk of hypertension may not be an effective short-term strategy to lower blood pressure.


Initial experience with a novel EUS-guided core biopsy needle (SharkCore): results of a large North American multicenter study.
The ability to safely and effectively obtain sufficient tissue for pathologic evaluation by using endoscopic ultrasound (EUS) guidance remains a challenge. Novel designs in EUS needles may provide for improved ability to obtain such core biopsies. The aim of this study was to evaluate the diagnostic yield of core biopsy specimens obtained using a novel EUS needle specifically designed to obtain core biopsies. Multicenter retrospective review of all EUS-guided fine-needle biopsies obtained using a novel biopsy needle (SharkCore FNB needle, Medtronic, Dublin, Ireland). Data regarding patient demographics, lesion type/location, technical parameters, and diagnostic yield was obtained. A total of 250 lesions were biopsied in 226 patients (Median age 66 years; 113 (50 %) male). Median size of all lesions (mm): 26 (2 - 150). Overall, a cytologic diagnosis was rendered in 81 % specimens with a median number of 3 passes. When rapid onsite cytologic evaluation (ROSE) was used, cytologic diagnostic yield was 126/149 (85 %) with a median number of 3 passes; without ROSE, cytologic diagnostic yield was 31/45 (69 %, P = 0.03) with a median number of 3 passes. Overall, a pathologic diagnosis was rendered in 130/147 (88 %) specimens with a median number of 2 passes. Pathologic diagnostic yield for specific lesion types: pancreas 70/81 (86 %), subepithelial lesion 13/15 (87 %), lymph node 26/28 (93 %). Ten patients (10/226, 4 %) experienced adverse events: 4 acute pancreatitis, 5 pain, 1 fever/cholangitis. Initial experience with a novel EUS core biopsy needle demonstrates excellent pathologic diagnostic yield with a minimum number of passes.


Multiple Loci Control Variation in Plasticity to Foliar Shade Throughout Development in Arabidopsis thaliana.
The shade avoidance response is a set of developmental changes exhibited by plants to avoid shading by competitors, and is an important model of adaptive plant plasticity. While the mechanisms of sensing shading by other plants are well-known and appear conserved across plants, less is known about the developmental mechanisms that result in the diverse array of morphological and phenological responses to shading. This is particularly true for traits that appear later in plant development. Here we use a nested association mapping (NAM) population of Arabidopsis thaliana to decipher the genetic architecture of the shade avoidance response in late-vegetative and reproductive plants. We focused on four traits: bolting time, rosette size, inflorescence growth rate, and inflorescence size, found plasticity in each trait in response to shade, and detected 17 total QTL; at least one of which is a novel locus not previously identified for shade responses in Arabidopsis Using path analysis, we dissected each colocalizing QTL into direct effects on each trait and indirect effects transmitted through direct effects on earlier developmental traits. Doing this separately for each of the seven NAM populations in each environment, we discovered considerable heterogeneity among the QTL effects across populations, suggesting allelic series at multiple QTL or interactions between QTL and the genetic background or the environment. Our results provide insight into the development and variation in shade avoidance responses in Arabidopsis, and emphasize the value of directly modeling the relationships among traits when studying the genetics of complex developmental syndromes.


The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating.
WIN 51711 and WIN 52084 are structurally related, antiviral compounds that inhibit the replication of rhino (common cold) viruses and related picornaviruses. They prevent the pH-mediated uncoating of the viral RNA. The compounds consist of a 3-methylisoxazole group that inserts itself into the hydrophobic interior of the VP1 beta-barrel, a connecting seven-membered aliphatic chain, and a 4-oxazolinylphenoxy group (OP) that covers the entrance to an ion channel in the floor of the "canyon." Viral disassembly may be inhibited by preventing the collapse of the VP1 hydrophobic pocket or by blocking the flow of ions into the virus interior.


Perceptions, knowledge, and practices of breastfeeding in indigenous regions of Mexico during Covid-19 pandemic.
To explore the perceptions, knowledge, and practices of breastfeeding in the context of Covid-19 of pregnant and postpartum women, midwives, and health providers in an indigenous region of Chiapas, Mexico. Qualitative thematic analysis study involving semi-structured interviews (n = 46) with pregnant women (n = 19), postpartum women (n = 6), health providers (n = 10, i.e., doctors/nurses), and midwives (n = 11). Among mothers, 47% (n = 11) did not know if Covid-19 is transmitted through breastfeeding. They mentioned that they would stay away from their newborns if infected. Health providers and midwives have not received education or any supporting material on the value of breastfeeding during Covid-19 infection. Breastfeeding mothers' promotion and counseling remain poor in indigenous communities and have worsened during the Covid-19 pandemic. Breastfeeding training among health providers and midwives should be provided or strengthened even more in emergency situations.


The Soybean Laccase Gene Family: Evolution and Possible Roles in Plant Defense and Stem Strength Selection.
Laccase is a widely used industrial oxidase for food processing, dye synthesis, paper making, and pollution remediation. At present, laccases used by industries come mainly from fungi. Plants contain numerous genes encoding laccase enzymes that show properties which are distinct from that of the fungal laccases. These plant-specific laccases may have better potential for industrial purposes. The aim of this work was to conduct a genome-wide search for the soybean laccase genes and analyze their characteristics and specific functions. A total of 93 putative laccase genes (GmLac) were identified from the soybean genome. All 93 GmLac enzymes contain three typical Cu-oxidase domains, and they were classified into five groups based on phylogenetic analysis. Although adjacent members on the tree showed highly similar exon/intron organization and motif composition, there were differences among the members within a class for both conserved and differentiated functions. Based on the expression patterns, some members of laccase were expressed in specific tissues/organs, while some exhibited a constitutive expression pattern. Analysis of the transcriptome revealed that some laccase genes might be involved in providing resistance to oomycetes. Analysis of the selective pressures acting on the laccase gene family in the process of soybean domestication revealed that 10 genes could have been under artificial selection during the domestication process. Four of these genes may have contributed to the transition of the soft and thin stem of wild soybean species into strong, thick, and erect stems of the cultivated soybean species. Our study provides a foundation for future functional studies of the soybean laccase gene family.


A unifying modeling of plant shoot gravitropism with an explicit account of the effects of growth.
Gravitropism, the slow reorientation of plant growth in response to gravity, is a major determinant of the form and posture of land plants. Recently a universal model of shoot gravitropism, the AC model, was presented, in which the dynamics of the tropic movement is only determined by the conflicting controls of (1) graviception that tends to curve the plants toward the vertical, and (2) proprioception that tends to keep the stem straight. This model was found to be valid for many species and over two orders of magnitude of organ size. However, the motor of the movement, the elongation, was purposely neglected in the AC model. If growth effects are to be taken into account, it is necessary to consider the material derivative, i.e., the rate of change of curvature bound to expanding and convected organ elements. Here we show that it is possible to rewrite the material equation of curvature in a compact simplified form that directly expresses the curvature variation as a function of the median elongation and of the distribution of the differential growth. By using this extended model, called the ACĖ model, growth is found to have two main destabilizing effects on the tropic movement: (1) passive orientation drift, which occurs when a curved element elongates without differential growth, and (2) fixed curvature, when an element leaves the elongation zone and is no longer able to actively change its curvature. By comparing the AC and ACĖ models to experiments, these two effects are found to be negligible. Our results show that the simplified AC mode can be used to analyze gravitropism and posture control in actively elongating plant organs without significant information loss.


Xolotl: An Intuitive and Approachable Neuron and Network Simulator for Research and Teaching.
Conductance-based models of neurons are used extensively in computational neuroscience. Working with these models can be challenging due to their high dimensionality and large number of parameters. Here, we present a neuron and network simulator built on a novel automatic type system that binds object-oriented code written in C++ to objects in MATLAB. Our approach builds on the tradition of uniting the speed of languages like C++ with the ease-of-use and feature-set of scientific programming languages like MATLAB. Xolotl allows for the creation and manipulation of hierarchical models with components that are named and searchable, permitting intuitive high-level programmatic control over all parts of the model. The simulator's architecture allows for the interactive manipulation of any parameter in any model, and for visualizing the effects of changing that parameter immediately. Xolotl is fully featured with hundreds of ion channel models from the electrophysiological literature, and can be extended to include arbitrary conductances, synapses, and mechanisms. Several core features like bookmarking of parameters and automatic hashing of source code facilitate reproducible and auditable research. Its ease of use and rich visualization capabilities make it an attractive option in teaching environments. Finally, xolotl is written in a modular fashion, includes detailed tutorials and worked examples, and is freely available at https://github.com/sg-s/xolotl, enabling seamless integration into the workflows of other researchers.


Gastrodin Rescues Autistic-Like Phenotypes in Valproic Acid-Induced Animal Model.
Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized by impaired social interaction, restricted/repetitive behavior, and anxiety. GABAergic dysfunction has been postulated to underlie these autistic symptoms. Gastrodin is widely used clinically in the treatment of neurological disorders and showed to modulate GABAergic signaling in the animal brain. The present study aimed to determine whether treatment with gastrodin can rescue valproic acid (VPA) induced autistic-like phenotypes, and to determine its possible mechanism of action. Our results showed that administration of gastrodin effectively alleviated the autistic-associated behavioral abnormalities as reflected by an increase in social interaction and decrement in repetitive/stereotyped behavior and anxiety in mice as compared to those in untreated animals. Remarkably, the amelioration in autistic-like phenotypes was accompanied by the restoration of inhibitory synaptic transmission, α5 GABAA receptor, and type 1 GABA transporter (GAT1) expression in the basolateral amygdala (BLA) of VPA-treated mice. These findings indicate that gastrodin may alleviate the autistic symptoms caused by VPA through regulating GABAergic synaptic transmission, suggesting that gastrodin may be a potential therapeutic target in autism.


The influence of dietary lutein and zeaxanthin on visual performance.
The idea that normal constituents of the diet can influence visual function is not new. As early as 1782, Buzzi identified the yellow of the macula and Schulze (1866) specifically postulated that the yellow pigments led to improvements in human vision. These pigments were later found to be derived from dietary lutein and zeaxanthin that are known to be oxygenated carotenoids (xanthophylls). Walls and Judd (1933) postulated that these yellow intraocular pigments could improve visual performance by absorbing light scattered both within (for example, glare) and outside of the eye (increasing visual range by absorbing blue light scattered in the atmosphere), and by improving spatial vision through enhancing contrast and reducing chromatic blur. In this article, evidence for these ideas is reviewed with particular emphasis towards more recent data on glare effects.


Antigen-specific suppression of delayed type hypersensitivity to murine cytomegalovirus in MCMV-infected mice.
When primary infection with murine cytomegalovirus (MCMV) was by the intravenous route, the resulting delayed type hypersensitivity (DTH) to MCMV was reduced compared with subcutaneous or intraperitoneal infection. Intravenous injection of 10(3) or more p.f.u. of MCMV also reduced the DTH response to virus injected at the same time subcutaneously. When spleen cells from mice injected intravenously with MCMV 1 to 3 weeks earlier were transferred to subcutaneously infected mice, the resulting DTH response was suppressed. The cells responsible were T cells, being non-adherent and Thy-1 positive; they were not destroyed by complement plus antibody to either Lyt-1 or Lyt-2. Suppression was not transferred by serum. The suppression was antigen-specific; DTH responses induced by sheep red blood cells and by a thymidine kinase-negative strain of herpes simplex virus type 1 were not significantly suppressed by concurrent intravenous infection with MCMV. Suppression of DTH to MCMV caused by intravenously injected MCMV was reduced in mice given 50 mg/kg cyclophosphamide, but not in those given 200 mg/kg. Deoxyguanosine had no effect on the induction of DTH to MCMV.


Sensorimotor and Cognitive Abilities Associated With Touchscreen Tablet App Performance to Support Self-Management of Type 2 Diabetes.
Self-management programs (facilitated by mobile devices) may improve health and prevent secondary complications for older adults with diabetes. However, older adults may have difficulties using mobile devices because of neuropathy or cognitive dysfunction. To identify sensorimotor and cognitive abilities associated with touchscreen tablet app performance to support self-management of diabetes in older adults. Cross-sectional study. Outpatient Center for Successful Aging With Diabetes. Forty-five older adults with Type 2 diabetes. Dexterity (Purdue Pegboard Test), touch sensation (Semmes-Weinstein monofilaments), pinch strength (pinch gauge), cognition (Montreal Cognitive Assessment), and executive functioning (Trail Making Test) were assessed. Two apps were then used: Dexteria and SuCare. Demographic data, prior mobile device use, and diabetes severity (hemoglobin A1C [HbA1C]) were collected. Age and HbA1C accounted for 29.8% and 9.7%, respectively, of the total variance of Dexteria performance time (dominant hand). Dexterity (dominant hand) accounted for an additional 5.4% of the total variance of 45.1%, F(4, 40) = 10.021, p < .001. Prior mobile device use, age, and diabetes severity accounted for 6.4%, 11.8%, and 26.4%, respectively, of the total variance of SuCare performance time. Executive functioning and dominant-hand dexterity accounted for an additional 9.5% and 9.4%, respectively, of the total variance of 61.0%, F(5, 39) = 14.75, p < .001. Beyond age and diabetes severity, executive functioning and dominant-hand dexterity contributed to app performance, highlighting the importance of diabetes self-management. These findings may help determine suitable candidates for tablet use for self-management. App performance is explained by the executive functioning and dexterity of older adults with Type 2 diabetes. These factors, in addition to age and diabetes severity, should be taken into consideration by occupational therapy practitioners in future mobile self-management programs.


Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers.
Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis. Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation. We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22-2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring. Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.


Modified methodology to improve flow cytometric DNA histograms from paraffin-embedded material.
Flow Cytometric (FCM) DNA content analysis of paraffin-embedded tissues has become a widely accepted procedure in assessing the biologic course in some tumors from archival material. Difficulty in interpreting histograms is frequently due to high levels of debris, and wide coefficients of variation (CV). These may lead to underestimating near-diploid abnormality. Although the clinical significance of low-degree aneuploidy has yet to be established, the procedure reported here improved our endeavor to detect DNA Indices (DI) of at least 1.1%. Experience has shown that careful technique can result in overall improvement of DNA histograms by lowering levels of debris and % CV, dramatically so in some cases. Archival histograms can be generated that rival in quality fresh tissue results. Archival material is currently employed for diagnostic and research purposes.


Peer-assisted learning after onsite, low-dose, high-frequency training and practice on simulators to prevent and treat postpartum hemorrhage and neonatal asphyxia: A pragmatic trial in 12 districts in Uganda.
An urgent need exists to improve and maintain intrapartum skills of providers in sub-Saharan Africa. Peer-assisted learning may address this need, but few rigorous evaluations have been conducted in real-world settings. A pragmatic, cluster-randomized trial in 12 Ugandan districts provided facility-based, team training for prevention and management of postpartum hemorrhage and birth asphyxia at 125 facilities. Three approaches to facilitating simulation-based, peer assisted learning were compared. The primary outcome was the proportion of births with uterotonic given within one minute of birth. Outcomes were evaluated using observation of birth and supplemented by skills assessments and service delivery data. Individual and composite variables were compared across groups, using generalized linear models. Overall, 107, 195, and 199 providers were observed at three time points during 1,716 births across 44 facilities. Uterotonic coverage within one minute increased from: full group: 8% (CI 4%‒12%) to 50% (CI 42%‒59%); partial group: 19% (CI 9%‒30%) to 42% (CI 31%‒53%); and control group: 11% (5%‒7%) to 51% (40%‒61%). Observed care of mother and newborn improved in all groups. Simulated skills maintenance for postpartum hemorrhage prophylaxis remained high across groups 7 to 8 months after the intervention. Simulated skills for newborn bag-and-mask ventilation remained high only in the full group. For all groups combined, incidence of postpartum hemorrhage and retained placenta declined 17% and 47%, respectively, from during the intervention period compared to the 6‒9 month period after the intervention. Fresh stillbirths and newborn deaths before discharge decreased by 34% and 62%, respectively, from baseline to after completion, and remained reduced 6‒9 months post-implementation. Significant improvements in uterotonic coverage remained across groups 6 months after the intervention. Findings suggest that while short, simulation-based training at the facility improves care and is feasible, more complex clinical skills used infrequently such as newborn resuscitation may require more practice to maintain skills. Trial Registration: ClinicalTrials.gov NCT03254628.


CD137 (ILA/4-1BB), a member of the TNF receptor family, induces monocyte activation via bidirectional signaling.
CD137 (ILA/4-1BB), a member of the TNF receptor family, was shown previously to inhibit proliferation and to induce apoptosis in T lymphocytes. In this study, we identify CD137 as a novel and potent monocyte activation factor. CD137 protein induces expression of IL-6, IL-8, and TNF-alpha, and inhibits expression of IL-10. Furthermore, CD137 differentially regulates expression of cell surface receptors. It induces expression of ICAM and reduces expression of FcgammaRIII, while levels of HLA-DR remain unchanged. CD137 also promotes adherence of monocytes. These effects of CD137 require immobilization of CD137 protein, indicating that they are mediated by cross-linking of a corresponding ligand/coreceptor expressed on monocytes.


Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses.
The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.


Abscisic acid-induced stomatal closure mediated by cyclic ADP-ribose.
Abscisic acid (ABA) is a plant hormone involved in the response of plants to reduced water availability. Reduction of guard cell turgor by ABA diminishes the aperture of the stomatal pore and thereby contributes to the ability of the plant to conserve water during periods of drought. Previous work has demonstrated that cytosolic Ca2+ is involved in the signal transduction pathway that mediates the reduction in guard cell turgor elicited by ABA. Here we report that ABA uses a Ca2+-mobilization pathway that involves cyclic adenosine 5'-diphosphoribose (cADPR). Microinjection of cADPR into guard cells caused reductions in turgor that were preceded by increases in the concentration of free Ca2+ in the cytosol. Patch clamp measurements of isolated guard cell vacuoles revealed the presence of a cADPR-elicited Ca2+-selective current that was inhibited at cytosolic Ca2+ >/= 600 nM. Furthermore, microinjection of the cADPR antagonist 8-NH2-cADPR caused a reduction in the rate of turgor loss in response to ABA in 54% of cells tested, and nicotinamide, an antagonist of cADPR production, elicited a dose-dependent block of ABA-induced stomatal closure. Our data provide definitive evidence for a physiological role for cADPR and illustrate one mechanism of stimulus-specific Ca2+ mobilization in higher plants. Taken together with other recent data [Wu, Y., Kuzma, J., Marechal, E., Graeff, R., Lee, H. C., Foster, R. & Chua, N.-H. (1997) Science 278, 2126-2130], these results establish cADPR as a key player in ABA signal transduction pathways in plants.


Competition between pyrimorph-sensitive and pyrimorph-resistant isolates of Phytophthora capsici.
Phytophthora capsici causes significant losses to vegetable production worldwide. Pyrimorph, a new carboxylic acid amide fungicide, has been registered to control P. capsici in China. A mutation (Q1077K) in cellulose synthase 3 has been reported to confer resistance to pyrimorph. In this study, we measured the competition between pyrimorph-resistant and pyrimorph-sensitive isolates of P. capsici. Mixed zoospore suspensions of resistant (R) and sensitive (S) isolates at five ratios (1R:9S, 3R:7S, 5R:5S, 7R:3S, and 9R:1S) were applied to carrot agar in vitro test (with five successive transfers) and to the soil surface around pepper plants in planta test (with 10 successive disease cycles). The proportion of resistant isolates was measured by a conventional assay in which single zoospore isolates recovered after transfers or disease cycles were grown on agar medium with a discriminatory concentration of pyrimorph. The results were then compared with those of a real-time polymerase chain reaction (PCR)-based method developed here, the results were similar. Both assays showed that the competitive ability of the resistant isolates was similar to or less than that of the sensitive isolates. The real-time PCR assay developed will be useful for high-throughput analysis and monitoring the development of pyrimorph resistance in field populations of P. capsici.


Compact diode-laser based rubidium frequency reference.
The performance of a simple microwave frequency reference based on Raman scattering in an atomic vapor is examined. This reference has the potential to be compact, low-power, and insensitive to acceleration. Several design architectures have been evaluated with a table-top experiment in order to guide the future development of a compact system. Fractional frequency deviations of </=5x10(-11) appear to be feasible.


Improving population representation through geographic health information systems: mapping the MURDOCK study.
This paper highlights methods for using geospatial analysis to assess, enhance, and improve recruitment efforts to ensure representativeness in study populations. We apply these methods to the Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) study, a longitudinal population health study focused on the city of Kannapolis and Cabarrus County, NC. Although efforts have been made to recruit a participant registry that is representative of the 18 ZIP code catchment region inclusive of Cabarrus County and Kannapolis, bias in such recruitment is inevitable. Participants in the MURDOCK study are geospatially referenced at entry, providing information that can be used to monitor and guide recruitment efforts. MURDOCK participant population representativeness was assessed using chi-squared tests to compare the MURDOCK population with 2010 Census data, relative to both the entire 18 ZIP code catchment area and for individual Census tracts. A logistic regression model was fit to characterize Census tracts with low recruitment, defined by fewer than 56 participants from that tract. The distance to the site at which participants enrolled was calculated, and median distance to enrollment site was used in the logistic regression. Tracts with low recruitment rates contained higher minority and younger populations, suggesting specific strategies for improving recruitment in these areas. Areal units farther away from enrollment sites were also not well-sampled, despite being in the specified study area, indicating that distance traveled to enrollment may be a barrier. These results have implications for targeting recruitment efforts and representative samples more generally, including in other population-based studies.


Evaluation of the relationship between shear wave elastography measurements with laboratory and Doppler US parameters in patients with adult Hashimoto's thyroiditis
Hashimoto thyroiditis (HT) is an autoimmune disease that leads to tissue stiffening secondary to lymphocyte infiltration of the thyroid gland. Gray-scale ultrasound (US) is widely used in its diagnosis. Numerous studies have been conducted comparing elastography findings of HT with tissue stiffness and immunoreactivity levels. This study aims to reveal the relationship between shear wave elastography (SWE) and Doppler parameters in patients with HT. The study group consisted of 45 patients diagnosed with HT, and 20 control patients without thyroid pathology. Thyroid-stimulating hormone (TSH) and antithyroid peroxidase (TPO) values were examined in patients with HT. Thyroid gland volume and echo patterns were evaluated in the gray-scale US. Doppler measurements –peak systolic velocity (Vmax), end-diastolic velocity (Vmin), pulsatility index (PI), resistivity index (RI)– from the superior thyroidal artery and SWE measurements were taken from both thyroid lobes. The mean age of men and women in the HT group was 44.8 and 43.4 years. The mean TSH value (normal value: 0.3–4.2 uIU/ mL) was 3.90 ± 6.6 uIU/mL, and the anti-TPO value (normal value: < 35 IU/mL) was 235.47 ± 271.12 IU/mL. The average thyroid gland volume was 10.12 ± 2.71 mL in the HT group and 6.62 ± 2.11 mL in the control group (P = 0.034). HT group mean Vmax, mean Vmin, mean PI and RI values were significantly lower compared to normal subjects (P = 0.022, P = 0.026, P = 0.042, P = 0.046, respectively). The average SWE value of the thyroid gland was 24.56 ± 18.04 kPa in the experimental group and 7.34 ± 3.54 (P < 0.05) in the control group. A positive correlation was found between PI and RI values and elastography values. An increase in SWE and decreases in Vmax and Vmin were found as high diagnostic value for HT.


Human-rhesus reassortant rotavirus vaccines: safety and immunogenicity in adults, infants, and children.
Human-rhesus reassortant rotavirus vaccines derived from rhesus rotavirus and human rotavirus serotypes 1, 2, or 4 were administered to adults, children, and infants after they had been given sodium bicarbonate buffer. Over 70% of infants and children developed antibody responses to or shed the candidate vaccine viruses. Individuals with prevaccination serum neutralization antibody titers less than or equal to 1:160 had significantly (P less than .0001) higher response rates than did individuals with prevaccination titers greater than or equal to 1:320. Similarly, shedding of vaccine viruses occurred significantly (P = .03) more often in children than adults and was inversely correlated with prevaccination antibody titers. No illnesses were observed in adults, and the vaccines were well tolerated in children. An increased rate of low-grade, transient fever (38.0-38.8 C) was noted only in children given serotype 2 vaccine, compared with controls (P = .006). No significant differences in the average number of unformed stools passed during the seven days after vaccination were noted in vaccinees versus controls. These vaccine strains are currently undergoing further evaluation in expanded clinical trials.


Improved ergonomic layout design of metro control center based on virtual simulation technology and genetic algorithm.
For the existing control center layout methods do not have targeted measures to implement human factors requirements, this paper puts forward a specific human factors design method for metro control center layout. This method covers the overall process of ergonomic standards and actual engineering requirements in personal space determination, overall location design, and personnel post layout. It introduces discrete personnel simulation to assist in physical control center layout design for the controllers' safety. To make the posts between the unified lines and the connections between the lines more reasonable, an improved genetic algorithm is used to solve the Systematic Layout Planning. This design flow and algorithm can be quickly adapted according to the project's actual needs and the application of human factors guidelines. This method is also suitable for the layout planning and design of similar large spaces, large numbers of people, and complex associated control centers.


Extrafine Versus Fine Inhaled Corticosteroids in Relation to Asthma Control: A Systematic Review and Meta-Analysis of Observational Real-Life Studies.
The particle size of inhaled corticosteroids (ICSs) may affect airway drug deposition and effectiveness. To compare the effectiveness of extrafine ICSs (mass median aerodynamic diameter, <2 μm) versus fine-particle ICSs administered as ICS monotherapy or ICS-long-acting β-agonist combination therapy by conducting a meta-analysis of observational real-life asthma studies to estimate the treatment effect of extrafine ICSs. MEDLINE and EMBASE databases were reviewed for asthma observational comparative effectiveness studies from January 2004 to June 2016. Studies were included if they reported odds and relative risk ratios and met all inclusion criteria (Respiratory Effectiveness Group/European Academy of Allergy and Clinical Immunology quality standards, comparison of extrafine ICSs with same or different ICS molecule, ≥12-month follow-up). End-point data (asthma control, exacerbations, prescribed ICS dose) were pooled. Random-effects meta-analysis modeling was used. The study protocol is published in the PROSPERO register CRD42016039137. Seven studies with 33,453 subjects aged 5 to 80 years met eligibility criteria for inclusion. Six studies used extrafine beclometasone propionate and 1 study used both extrafine beclometasone propionate and extrafine ciclesonide as comparators with fine-particle ICSs. The overall odds of achieving asthma control were significantly higher for extrafine ICSs compared with fine-particle ICSs (odds ratio, 1.34; 95% CI, 1.22-1.46). Overall exacerbation rate ratios (0.84; 95% CI, 0.73-0.97) and ICS dose (weighted mean difference, -170 μg; 95% CI, -222 to -118 μg) were significantly lower for extrafine ICSs compared with fine-particle ICSs. This meta-analysis demonstrates that extrafine ICSs have significantly higher odds of achieving asthma control with lower exacerbation rates at significantly lower prescribed doses than fine-particle ICSs.


Separation of two phenotypically similar cell types via a single common marker in microfluidic channels.
To isolate clinically and biologically relevant cell types from a heterogeneous population, fluorescent or magnetic tagging together with knowledge of surface biomarker profiles represents the state of the art. To date, it remains exceedingly difficult to separate phenotypically and physically similar cell types from a mixed population. We report a microfluidic platform engineered to separate two highly similar cell types using a single antibody by taking advantage of subtle variations in surface receptor density and cell size. This platform utilizes antibody-conjugated surfaces in microfluidic channels together with precise modulation of fluid shear stresses to accomplish selective fractionation in a continuous flow process. Antibody conjugation density variation on the adhesive surfaces is achieved by covalently immobilizing an antibody in the presence of poly(ethylene glycol). This platform is used to demonstrate separation of two CD31 positive cell types, human umbilical vein endothelial cells and human micro vascular endothelial cells.


Does spinal chloroprocaine pharmacokinetic profile actually translate into a clinical advantage in terms of clinical outcomes when compared to low-dose spinal bupivacaine? A systematic review and meta-analysis.
Spinal anesthesia is well suited for day-care surgery, however a persisting motor block after surgery can delay discharge. Among the new drugs available, chloroprocaine has been associated with a short onset time, and motor block duration and a quicker discharge. However, it is not clear if those outcomes are clinically significantly superior compared to those associated with the use of low-dose hyperbaric bupivacaine. Aim of the study was to determine if spinal 2-chloroprocaine was superior to low-dose spinal bupivacaine regarding the following outcomes: onset time, block duration, time to ambulation and time to discharge. We performed a systematic literature search of the last 30 years using PubMed Embase and the Cochrane Controlled Trials Register. We included only blinded, prospective trials comparing chloroprocaine with a low dose of bupivacaine for spinal anesthesia. Low dose bupivacaine was defined as a dose of 10 mg or less. Outcomes of interest were time to motor block regression (primary outcome), time to ambulation and time to discharge (secondary outcomes), as indirect indicators of a complete recovery after spinal anesthesia. Compared to a low dose bupivacaine, spinal 2-chloroprocaine was associated with significantly faster motor and sensory block regression (pMD = -57 min-140.3 min; P = 0.015 and <0.001 respectively), a significantly shorter time to ambulation and an earlier discharge (pMD = -84.6 min; P < 0.001 and pMD = -88.6 min and <0.001 respectively). Onset time did not differ between the two drugs (pMD = -1.1 min; P = 0.118). Spinal 2-chloroprocaine has a shorter motor block duration, a significantly quicker time to ambulation and time to discharge compared to low dose hyperbaric bupivacaine and may be advantageous when spinal anesthesia is performed for day case surgery.


[A new type of electrochemical immunosensor based on ion-selective field effect transistors].
A new type of an electrochemical sensor based on the use of ion-selective field effect transistors (ISFETs) and conjugates of horse radish peroxidase with specific monoclonal antibodies was developed for the express determination of myoglobine in a solution. For this purpose a simple method of covalent immobilization of myoglobine on the surface of ISFET gate was worked out, an appropriate biochemical approach which allowed potentiometrical registration of the peroxidase activity was used, and an immune chemical analysis was accomplished in competitive way. It was shown that the sensitivity of the analysis with the help of the electrochemical immune sensor corresponds to the demands of medical practice to reveal early stages of myocardial infarction. This sensitivity was significantly higher then that which can be obtained by the traditional ELISA-method. Moreover, overall time of the analysis by the immune sensor was almost one order shorter than this by the ELISA-method. It is concluded that the proposed electrochemical immune sensor based on the ISFETs was very perspective for the express analysis of the level of different types of antigens and antibodies.


Long-term placement of dependent children from the client's point of view.
This article presents data regarding the backgrounds and attitudes of 396 dependent children in Israel who had been living in boarding institutions for almost three years, and were at least 10 years old at the time of the research interview. Parents of the children were also interviewed, and background [corrected] information regarding the family and its experience with placement was abstracted from welfare department records. This detailed information, collected nearly a decade ago, was then compared with several very recent Israeli studies of institutionalized dependent children and it was found that many problematic features of placement still persist. Among these are lack of long or short-term planning by welfare agencies, poor agency follow-up after placement, and little personal contact with either the child or his family. More older children were accepting placement than were younger children, and the majority of the parents did not contemplate the child's return home, being quite satisfied with placement in the institution. The findings from this study should have direct implications for child welfare policy and practices.


Blood taurine concentrations in dogs with exocrine pancreatic insufficiency.
To determine whether blood taurine concentrations in dogs with exocrine pancreatic insufficiency (EPI) were lower than the reference interval (200 to 350 nmol/mL) or the cutoff used to indicate taurine deficiency (< 150 nmol/mL). 18 dogs with clinical or presumptive subclinical EPI with residual blood samples available for taurine concentration analysis. Dogs were classified as having clinical EPI if they had a serum trypsin-like immunoreactivity concentration of < 2.0 μg/L and presumptive subclinical EPI if they had a concentration of 2.0 to 5.0 μg/L. Archived, frozen blood samples stored in EDTA were submitted for measurement of taurine concentration with an automated high-performance liquid chromatography amino acid analyzer. Medical record data were examined for associations with blood taurine concentration. None of the 18 dogs had a blood taurine concentration < 150 nmol/mL. Two dogs had a concentration < 200 nmol/mL. No clinical signs, physical examination findings, or serum biochemical abnormalities were associated with blood taurine concentration. Eleven of the 17 dogs for which diet histories were available were not receiving a diet that met recommendations of the World Small Animal Veterinary Association Global Nutrition Committee. A low blood taurine concentration was noted in a small subset of dogs with EPI. Additional research is needed to determine whether EPI was the primary cause of this low concentration. Findings suggested the importance of obtaining complete diet histories and ensuring dietary requirements are sufficiently met in dogs with EPI. (Am J Vet Res 2020;81:958-963).


Does young adult suicide cluster geographically in Scotland?
Suicide rose dramatically among young adults in Scotland between 1980-1982 and 1999-2001, especially among those living in deprived areas. To determine whether there are statistically significant geographical clusters of suicide and undetermined deaths among those aged 15 to 44 years in Scotland, and whether these persist through time. Deaths from suicide and undetermined causes by young adults in Scotland for three periods-1980 to 1982, 1990 to 1992, and 1999 to 2001-were aggregated into 10,058 small areas for Scotland. Tests for significant (p<0.05) geographical clustering of suicide were carried out for each period separately. Methods of suicide inside the identified clusters were compared with those in the rest of Scotland. A significant geographical cluster of suicide among young adults was identified in east Glasgow in all three time periods (involving 92, 159, and 245 cases). Compared with the rest of Scotland, significantly more deaths in these clusters were caused by poisoning from liquids or solids over the entire period, but this was not the case in the most recent period (1999 to 2001). All three clusters could be explained by the concentration of socioeconomic deprivation in this part of Scotland. One interpretation of this large, persistent, and statistically significant cluster of suicides among young adults in east Glasgow is that suicide is geographically contagious, but the present results suggest that it is explained by the concentration of deprivation in this area. Suicide prevention strategies targeting at-risk populations living in east Glasgow are necessary to reduce the suicide burden in Scotland.


Contributors to Patients' Ratings of Quality of Care Among Ethnically Diverse Patients with Type 2 Diabetes.
We examined racial/ethnic differences in patients' ratings of components of interpersonal quality [participatory decision making (PDM) style, being treated as an equal partner, and feelings of trust], and evaluated the association between each of these components and patients' ratings of overall healthcare quality among non-Hispanic white (NHW), Vietnamese American, and Mexican American patients with type 2 diabetes. The findings indicated that although all three components were significantly associated with ratings of overall healthcare quality, the significant interactions between race/ethnicity and both PDM style (β = -0.09, p < 0.01) and equal partner (β = -0.06, p < 0.05) for the Vietnamese American patients suggested that the relationship between these components and patients' ratings of healthcare quality were less strong among Vietnamese American patients than among the NHW patients. Understanding racial/ethnic differences in the components of interpersonal quality that are associated with patients' ratings of overall healthcare quality is an important step for improving patients' experiences of their own care.


Endomyocardiofibrosis in the Americas Collaborative Study: The EMF-SIAC Registry.
Endomyocardiofibrosis (EMF) is a restrictive cardiomyopathy characterized by subendocardial fibrosis due to eosinophilic myocardial infiltration. EMF may commonly present with heart failure (HF) or atrial fibrillation (AF). Immunosuppression can be effective in early stages, but not in the chronic phase. Our objective was to describe the characteristics of EMF patients in the Americas. This registry is a retrospective multicenter cross-sectional study including patients ≥18 years-old with EMF diagnosed by imaging methods, according to the Mocumbi criteria. Clinical, biochemical, and imaging variables were analyzed. On the 54 patients included, 28 (52%) were male with an age of 47 years. The etiology was idiopathic in 47 (87%) patients, familial in 4 (7%), and secondary to chemotherapy in 2 (3.5%). We detected a history of HF in 41 patients (76%), AF in 19 (35%), and ischemic stroke in 8 (15%). The diagnosis was made by echocardiography in all patients, and 38% had Cardiac Resonance or Computed Tomography. Thirty-five patients (65%) presented a left ventricular ejection fraction ≥50%, 11 (21%) severe mitral regurgitation, and 18 (33%) severe tricuspid regurgitation. In 17 patients (32%) the diagnosis was confirmed by endomyocardial biopsy. Among medical therapy, 72% received beta-blockers, 63% vasodilators, 65% mineralocorticoid antagonists, 7.4% SGLT2 inhibitors, and 11% corticosteroids. Subendocardial resection was performed in 9 (16%) patients and mitral valve replacement in 11 (20%) patients. In conclusion, EMF patients had a high prevalence of HF, AF, and embolic events. The diagnosis was frequently made in an advanced stage when HF management and surgery were the only effective treatments.


Induction of inducible cAMP early repressor expression in nucleus accumbens by stress or amphetamine increases behavioral responses to emotional stimuli.
Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.


Patients' views on bedside nursing handover: creating a space to connect.
A study was undertaken to explore patients' experiences and perceptions associated with implementation of bedside nursing handover. Interviews were conducted with patients and analyzed using a directed content analysis. Three themes emerged through which patients described their experience with bedside nursing handover as follows: (1) creating a space for personal connection; (2) "bumping up to speed"; and (3) varying preferences. Health care leaders and nurses can use study findings to tailor strategies to engage patients, taking into account their preferences, in bedside nursing handover.


Obesity indexes and total mortality among elderly subjects at high cardiovascular risk: the PREDIMED study.
Different indexes of regional adiposity have been proposed for identifying persons at higher risk of death. Studies specifically assessing these indexes in large cohorts are scarce. It would also be interesting to know whether a dietary intervention may counterbalance the adverse effects of adiposity on mortality. We assessed the association of four different anthropometric indexes (waist-to-height ratio (WHtR), waist circumference (WC), body mass index (BMI) and height) with all-cause mortality in 7447 participants at high cardiovascular risk from the PREDIMED trial. Forty three percent of them were men (55 to 80 years) and 57% were women (60 to 80 years). All of them were initially free of cardiovascular disease. The recruitment took place in 11 recruiting centers between 2003 and 2009. After adjusting for age, sex, smoking, diabetes, hypertension, intervention group, family history of coronary heart disease, and leisure-time physical activity, WC and WHtR were found to be directly associated with a higher mortality after 4.8 years median follow-up. The multivariable-adjusted HRs for mortality of WHtR (cut-off points: 0.60, 0.65, 0.70) were 1.02 (0.78-1.34), 1.30 (0.97-1.75) and 1.55 (1.06-2.26). When we used WC (cut-off points: 100, 105 and 110 cm), the multivariable adjusted Hazard Ratios (HRs) for mortality were 1.18 (0.88-1.59), 1.02 (0.74-1.41) and 1.57 (1.19-2.08). In all analyses, BMI exhibited weaker associations with mortality than WC or WHtR. The direct association between WHtR and overall mortality was consistent within each of the three intervention arms of the trial. Our study adds further support to a stronger association of abdominal obesity than BMI with total mortality among elderly subjects at high risk of cardiovascular disease. We did not find evidence to support that the PREDIMED intervention was able to counterbalance the harmful effects of increased adiposity on total mortality. Controlled-Trials.com ISRCTN35739639.


TLR9 Signaling Suppresses the Canonical Plasma Cell Differentiation Program in Follicular B Cells.
The relative potency and quality of mouse B cell response to Toll-like receptors (TLRs) signaling varies significantly depending on the B cell subset and on the TLR member being engaged. Although it has been shown that marginal zone cells respond faster than follicular (FO) splenic B cells to TLR4 stimulus, FO B cells retain full capacity to proliferate and generate plasmablasts and plasma cells (PBs/PCs) with 2-3 days delayed kinetics. It is not clear whether this scenario could be extended to other members of the TLR family. Here, using quantitative cell culture conditions optimized for B cell growth and differentiation, we show that TLR9 signaling by CpG, while promoting vigorous proliferation, completely fails to induce differentiation of FO B cells into PBs/PCs. Little or absent Ig secretion following TLR9 stimulus was accompanied by lack of expression of cell surface markers and canonical transcription factors involved in PB/PC differentiation. Moreover, not only TLR9 did not induce plasmocyte differentiation, but it also strongly inhibited the massive PB/PC differentiation of FO B cells triggered by LPS/TLR4. Our study reveals unexpected opposite roles for TLR4 and TLR9 in the control of plasma cell differentiation program and disagrees with previous conclusions obtained in high-density cultures conditions on the generation of plasmocytes by TRL9 signaling. The potential implications of these findings on the role of TLR9 in controlling self-tolerance, clonal sizes and regulation of humoral responses are discussed.


Human and rhesus macaque hematopoietic stem cells cannot be purified based only on SLAM family markers.
Various combinations of antibodies directed to cell surface markers have been used to isolate human and rhesus macaque hematopoietic stem cells (HSCs). These protocols result in poor enrichment or require multiple complex steps. Recently, a simple phenotype for HSCs based on cell surface markers from the signaling lymphocyte activation molecule (SLAM) family of receptors has been reported in the mouse. We examined the possibility of using the SLAM markers to facilitate the isolation of highly enriched populations of HSCs in humans and rhesus macaques. We isolated SLAM (CD150(+)CD48(-)) and non-SLAM (not CD150(+)CD48(-)) cells from human umbilical cord blood CD34(+) cells as well as from human and rhesus macaque mobilized peripheral blood CD34(+) cells and compared their ability to form colonies in vitro and reconstitute immune-deficient (nonobese diabetic/severe combined immunodeficiency/interleukin-2 γc receptor(null), NSG) mice. We found that the CD34(+) SLAM population contributed equally or less to colony formation in vitro and to long-term reconstitution in NSG mice compared with the CD34(+) non-SLAM population. Thus, SLAM family markers do not permit the same degree of HSC enrichment in humans and rhesus macaques as in mice.


Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis.
Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.


Two-dimensional optical Hartley transforms in the presence of errors.
When the optical Hartley transform of a real, 2-D input object is constructed by the addition of two Fourier transforms with the correct relative amplitude, phase, and orientation the resulting field then encodes, in the form of amplitude only, all the information normally associated with Fourier amplitude and phase. If the transformer fails to correctly realize the desired relationship between the two Fourier transforms, the field at the transform plane no longer represents a true Hartley transform. Nevertheless knowledge of the nature of the error along with measurements in the transform plane enables the Hartley transform to be precisely recovered.


A prospective study of neonatal sepsis and meningitis in southern Israel.
To study the epidemiology of neonatal sepsis and meningitis in the Negev area of southern Israel. A prospective 8-year study conducted at the neonatal intensive care unit and pediatric wards of the Soroka University Medical Center. Two hundred twenty-nine cases of hospital and community-acquired neonatal sepsis occurred during the study period. Thirty-two patients (14%) were meningitis. During this period 70,709 births (59% Jews and 41% Bedouins) were recorded; thus the rates of neonatal sepsis and meningitis were 3.2 and 0.5/1000 live births, respectively. One hundred seventeen (4/1000 live births) cases were recorded in Bedouins and 112 (2.6/1000 live births) in Jewish neonates (P < 0.001). Twenty-six percent of all sepsis cases occurred within < 24 h from birth, 25% from Days 2 to 7 of life and 49% between Days 8 and 28. A total of 251 organisms that were considered true pathogens were isolated. Fifty-seven of all isolates were Gram-negative organisms (mainly Klebsiella pneumoniae (20%) and Escherichia coli (16%)). Gram-positive organisms were isolated in 41% of cases. Although E. coli was the most frequently recovered Gram-negative pathogen in community-acquired late onset sepsis, Klebsiella and Enterobacter spp. represented the most commonly isolated Gram-negative organisms in nosocomial late onset sepsis. All Staphylococcus aureus isolates recovered in late onset sepsis were nosocomial. The incidence of Streptococcus agalactiae was 3 times higher in early onset sepsis than in late onset sepsis. All cases of Streptococcus pneumoniae sepsis occurred in Bedouins. Neonatal sepsis and meningitis rates in southern Israel are similar to those reported in Western Europe and the United States. The incidence of neonatal sepsis is significantly higher for Bedouins than for Jewish neonates. The distribution of the main pathogens is different in southern Israel and although Gram-negative enteric organisms are predominant, S. agalactiae plays a relatively minor role in the etiology of sepsis during the first month of life. In southern Israel the etiology of community-acquired late onset sepsis is different from that of nosocomial late onset sepsis.


Decreasing polymethyl methacrylate bone cement concentration extends working and setting times in vitro.
To determine setting and temperature properties of diluted polymethyl methacrylate (PMMA) bone cement in vitro to assess utility for vocal fold augmentation in horses. 4 dilutions of PMMA equivalent to volumes of 15 mL, 20 mL, 25 mL, and 30 mL PMMA powder (PMMAp) in 10 mL solvent. For each volume PMMAp, setting times (tset), peak temperatures (Tmax), and times to peak temperature (tmax) were determined using a temperature data logger in a 4-mL volume of PMMA. Injectability was assessed in vitro by documenting the force required to inject 0.2 mL PMMA through an 18-gauge 3.5-inch spinal needle attached to a 6-mL syringe at 1-minute intervals. Working time (twork) was calculated from a linear regression of injectability. Peak temperatures increased with increasing volume of PMMAp: 56 °C, 86 °C, 99 °C, and 101 °C. Times for tset, twork, and tmax were inversely proportional to PMMA concentrations, resulting in tset of 23, 21, 17, and 14 minutes; twork of 22.75, 12.25, 7, and 4 minutes; and tmax of 28, 24, 19, and 16 minutes, respectively, for 15, 20, 25, and 30 mL PMMAp. Pairwise comparisons for all analyses were significant apart from Tmax for 25 and 30 mL PMMAp (P = .96) and twork for 20 and 25 mL PMMAp (P = .06). Decreasing the concentration of PMMA bone cement resulted in longer working times and setting times; however, peak temperatures did not differ between the 2 strongest concentrations. Further research is warranted to quantify diluted PMMA properties for in vivo use for vocal fold augmentation in horses.


Prospective study of colonic irrigation for the treatment of defaecation disorders.
Retrograde colonic irrigation is a possible treatment for defaecation disorders when conservative treatment or surgery has failed. The aim of this prospective study was to investigate its effectiveness. Patients were divided into three groups: those with faecal incontinence (A), constipation (B) or both (C). The Biotrol Irrimatic pump or the irrigation bag was used for colonic irrigation. Patients completed a questionnaire at baseline and after 3, 6 and 12 months, as well as a Short Form 36 health survey and an American Society of Colon and Rectal Surgery quality of life questionnaire at baseline and after 6 months. The study included 39 patients (26 women; mean age 58.0 years). In group A, 11 of 18 patients were pseudocontinent for faeces at 3 months (P < 0.001). Parks' incontinence scores decreased for all patients in this group at 3 months (P < 0.001), 6 months (P = 0.036) and 1 year (P = 0.005). In group B, three of ten patients reported a major improvement. The mean score for the feeling of incomplete evacuation decreased at 3 months (P = 0.007), 6 months (P = 0.013) and 1 year (P = 0.036). In group C, six of ten patients became pseudocontinent for faeces (P = 0.009) and three reported improvement in constipation. The overall quality of life scores improved (P = 0.012). Retrograde colonic irrigation is an undervalued but effective alternative treatment for intractable defaecation disorders.


Characterization of the Rapid Drop in Pulse Oximetry Reading After Intraoperative Administration of Methylene Blue in Open Thoracoabdominal Aortic Repairs.
This study evaluates the changes of oxygen saturation (SpO2) after intravenous administration of methylene blue in 103 patients undergoing open repair of thoracoabdominal aortic aneurysms. We found that SpO2 decreased by a median (interquartile range [IQR]) of 49% (37%-81%) <1 minute after methylene blue administration and recovered completely after approximately 6 minutes-median (IQR) of 270 seconds (180-510). A shorter time to nadir SpO2 was associated with a higher nadir (Spearman r [95% confidence interval {CI}], -0.32 [-0.50 to -0.13]; P = .001). Body surface area (BSA) was positively correlated with nadir SpO2 (Spearman r [95% CI], 0.36 [0.15-0.51]; P < .001).


Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.
Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.


Maternal and child cytokine relationship in early life is not altered by cytokine gene polymorphisms.
The development of immune responses is influenced by the interaction between environmental and genetic factors. Our previous study showed a close association between maternal and young infant's cytokine responses. The question is how this association evolves over time and the contribution of genetic polymorphisms to this association. Five cytokines in mitogen-stimulated whole blood culture were measured from pregnant mothers and their children aged 2, 5, 12, 24 and 48 months. Cytokine gene polymorphisms were determined in both mothers and children. High production of maternal interleukin (IL)-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) was significantly associated with higher levels of the corresponding cytokines in their children at 2 months (T2), but the association decreased over time. Maternal single-nucleotide polymorphism (SNP) in IFN-γ gene, rs3181032, was found to be associated with child's IFN-γ levels at T2 only, whereas maternal IL-10 rs4579758 and child's TNF-α rs13215091 were associated with child's corresponding cytokines at later ages but not at T2. In the final models including the gene polymorphisms, maternal cytokines were still the strongest determinant of child cytokines. Maternal cytokine during pregnancy, which could be a proxy for child's environmental factors, showed its highest impact at early age, with no or little influence from genetic factors.


Etiologies of autism in a case-series from Tanzania.
Most autism has a genetic cause although post-encephalitis cases are reported. In a case-series (N = 20) from Tanzania, 14 met research criteria for autism. Three (M:F = 1:2) had normal development to age 22, 35, and 42 months, with onset of autism upon recovery from severe malaria, attended by prolonged high fever, convulsions, and in one case prolonged loss of consciousness. In four other cases (M:F = 3:1), the temporal relationship between onset of autism and severe infection was close, but possibly spurious since malaria is common in Tanzania and there were indications of abnormal development in the child or a family member. In seven cases, (M:F = 6:1) autism onset was unrelated to malaria. The excess of non-verbal cases (N = 10) is related local diagnostic practice.


Birth weight, biological maturation and obesity in adolescents: a mediation analysis.
This study was aimed to investigate associations between birth weight and multiple adiposity indicators in youth, and to examine potential mediating effects by biological maturation. This was a school-based study involving 981 Brazilian adolescents aged between 10 and 17 years. Birth weight was reported retrospectively by mothers. Maturation was estimated by age of peak height velocity. Adiposity indicators included body mass index (BMI), waist circumference and percent body fat estimated from triceps and subscapular skinfolds. Multilevel mediation analyses were performed using the Sobel test, adjusted for chronological age, gestational age, cardiorespiratory fitness and socio-economic status. Except for body fat in girls, biological maturation partly or fully mediated (P<0.05) positive relationships between birth weight with all other obesity indicators in both sexes with their respective values of indirect effects with 95% confidence intervals: BMI [boys: 0.44 (0.06-0.82); girls: 0.38 (0.13-0.64)], waist circumference [boys: 1.14 (0.22-2.05); girls: 0.87 (0.26-1.48)] and body fat [boys: 0.60 (0.13-1.07)]. To conclude, birth weight is associated with elevated obesity risk in adolescence and biological maturation seems to at least partly mediate this relationship.


Effects of firocoxib, meloxicam, and tepoxalin administration on eicosanoid production in target tissues of healthy cats.
To evaluate the effects of firocoxib, meloxicam, and tepoxalin administration in healthy cats by measuring the ability of stimulated tissues to synthesize eicosanoids ex vivo. 8 healthy adult male cats. In a blinded, randomized, crossover study design, cats were treated with firocoxib (1 mg/kg, PO, q 24 h), meloxicam (0.05 mg/kg, PO, q 24 h), tepoxalin (5.0 mg/kg, PO, q 12 h), or a placebo for 8 days. Blood samples and gastric and duodenal mucosal biopsy specimens were collected on days 0 (baseline; immediately before treatment), 3, and 8 of each treatment period. Thromboxane B2 (TXB2) concentrations were measured in serum, and prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) concentrations were measured in plasma. Prostaglandin E1 (PGE1) synthesis, PGE2 synthesis, and LTB4 concentrations were measured in mucosal biopsy specimens. A 21-day minimum washout period was observed between treatments. Repeated-measures analyses were performed. Firocoxib and meloxicam administration resulted in a lower plasma PGE2 concentration than at baseline on days 3 and 8 of administration, whereas tepoxalin administration did not. Tepoxalin administration resulted in a lower serum TXB2 concentration and pyloric and duodenal PGE1 synthesis on both days, compared with baseline and placebo administration. Neither firocoxib nor meloxicam administration altered pyloric or duodenal PGE1 synthesis on either day, compared with placebo administration. Tepoxalin administration also resulted in lower pyloric mucosal LTB4 concentrations on both days, compared with baseline values. Firocoxib and meloxicam administration had no effect on cyclooxygenase-1 activity, whereas tepoxalin administration resulted in inhibition of cyclooxygenase-1 and 5-lipoxygenase.


Associations between social and intellectual activities with cognitive trajectories in Chinese middle-aged and older adults: a nationally representative cohort study.
Associations between the frequency of social and intellectual activities and cognitive trajectories are understudied in Chinese middle-aged and older adults. We aimed to examine this association in a nationally representative longitudinal study. The China Health and Retirement Longitudinal Study (CHARLS) is a nationally representative sample of Chinese middle-aged and older participants. The frequency of social and intellectual activities was measured at baseline. Interview-based cognitive assessments of orientation and attention, episodic memory, and visuospatial skills and the calculation of combined global scores were assessed every 2 years from 2011 to 2016. Cognitive aging trajectories over time were analyzed using group-based trajectory modeling, and the associations of the trajectory memberships with social and intellectual activities were analyzed using multinomial logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) were reported. Among 8204 participants aged 50-75 years at baseline, trajectory analysis identified three longitudinal patterns of cognitive function based on the global cognitive scores: "persistently low trajectory" (n = 1550, 18.9%), "persistently moderate trajectory" (n = 3194, 38.9%), and "persistently high trajectory" (n = 3460, 42.2%). After adjustment for sociodemographic variables, lifestyles, geriatric symptoms, and health conditions, more frequent intellectual activities (OR 0.54, 95% CI 0.38-0.77) and social activities (OR 0.79, 95% CI 0.65-0.95) were both associated with a lower likelihood of being in the "persistently low trajectory" for global cognitive function. These findings suggested that more frequent social and intellectual activities were associated with more favorable cognitive aging trajectories.


Analysis of sternotomy as treatment option for the resection of bilateral pulmonary metastases in pediatric solid tumors.
Radical surgical resection of metastases is an important prognostic factor for survival of patients suffering from solid pediatric tumors. The aim of this study is to evaluate the efficacy of median sternotomy as treatment option for the resection of multiple bilateral lung metastases in children with different tumor entities. Furthermore, the sensitivity of preoperative imaging (CT) was assessed by intraoperative findings. Between 2002 and 2007, 13 children (4 with sarcoma, 4 with nephroblastoma, 5 with hepatoblastoma) underwent median sternotomy for resection of bilateral lung metastases after R0-resection of the primary tumor. In 6/13 cases, the sternotomy was combined with the primary tumor resection. Median patient age at the first operation was 5 years (range: 11 months to 17 years). The median total number of resected metastases per operation was 9 and ranged from 0 to 65. In 13/16 operations, the intraoperative number of metastases did not agree with the preoperative radiological work-up. Median hospital stay was 14 days (range from 9 to 36 days). Ten out of 13 children are alive after a median follow-up of 13 months (range from 6 to 66 months). Median sternotomy is an adequate treatment modality for the resection of bilateral pulmonary metastases as a one-stage procedure. The combination of primary tumor resection with sternotomy should be considered as a treatment option. Complete resection of metastases of solid pediatric tumors should be aimed for in order to increase the survival of these patients.


The non-JAZ TIFY protein TIFY8 from Arabidopsis thaliana is a transcriptional repressor.
Jasmonate (JA) signalling is mediated by the JASMONATE-ZIM DOMAIN (JAZ) repressor proteins, which are degraded upon JA perception to release downstream responses. The ZIM protein domain is characteristic of the larger TIFY protein family. It is currently unknown if the atypical member TIFY8 is involved in JA signalling. Here we show that the TIFY8 ZIM domain is functional and mediated interaction with PEAPOD proteins and NINJA. TIFY8 interacted with TOPLESS through NINJA and accordingly acted as a transcriptional repressor. TIFY8 expression was inversely correlated with JAZ expression during development and after infection with Pseudomonas syringae. Nevertheless, transgenic lines with altered TIFY8 expression did not show changes in JA sensitivity. Despite the functional ZIM domain, no interaction with JAZ proteins could be found. In contrast, TIFY8 was found in protein complexes involved in regulation of dephosphorylation, deubiquitination and O-linked N-acetylglucosamine modification suggesting an important role in nuclear signal transduction.


Pregnant Sheep in a Farm Environment Did Not Develop Anaemia.
The aim of this study was to document the haematological profile of pregnant ewes throughout gestation. Sheep were divided into three groups (n = 8 per group): non-pregnant, singleton, or twin pregnancy. Blood samples were collected every 14 days from day 55 of gestation for haemoglobin concentration; packed cell volume; total protein; and albumin concentration. On days 55 and 125 of gestation blood was collected for trace element estimation: soluble copper and zinc; glutathione peroxidase (GSHPx); and methylmalonic acid (MMA). Pooled faecal samples were collected on days 55, 97, and 139 of gestation. Pasture cuts were collected on days 97 and 153 of gestation. The haematology and protein concentrations were not different between groups throughout the study. Copper concentration increased in all animals during the study (p < 0.0001). Zinc concentration was lowest in the singleton and twin pregnant sheep on day 55 of gestation (p = 0.04). GSHPx was not different between groups during the study. MMA decreased in all animals during the study (p < 0.0001), but was not different between groups. Faecal samples were consistently negative for strongyle and nematode eggs, and coccidian oocysts. The pasture was good quality. Pregnant sheep in a farm environment with normal trace element status, no parasites, and an adequate diet, did not develop anaemia (PCV < 0.27).


Embryonal carcinoma of an intraabdominal testicular tumor on an undescended testicle: a case report.
Cryptorchidism, as a singular pathology or associated with other dysgenesis syndromes, is one of the main factors of risk for the development of the testicular tumors. Although there are a great number of cases of undescended testicles that are diagnosed and treated during the first 6-12 months of life, there are rare cases of adults who are undiagnosed and untreated from this anomaly, which can present a high risk of malignancy. In this study we present the case of a 36-year-old patient, diagnosed at puberty with left cryptorchidism, untreated, who also hadevidenced a large intraabdominal tumoral mass associated with it. The tumoral mass had its origin in the undescended left testicle. Surgical excision of the tumor and retroperitoneal lymphadenectomy was performed. The histological result revealed embryonal carcinoma, without lymphnode metastasis. Adult patients with untreated cryptorchidism should be thoroughly investigated, as they have a high risk of developing testicular cancer.


Improving End-of-Life Communication and Decision Making: The Development of a Conceptual Framework and Quality Indicators.
The goal of end-of-life (EOL) communication and decision making is to create a shared understanding about a person's values and treatment preferences that will lead to a plan of care that is consistent with these values and preferences. Improvements in communication and decision making at the EOL have been identified as a high priority from a patient and family point of view. The purpose of this study was to develop quality indicators related to EOL communication and decision making. We convened a multidisciplinary panel of experts to develop definitions, a conceptual framework of EOL communication and decision making, and quality indicators using a modified Delphi method. We generated a list of potential items based on literature review and input from panel members. Panel members rated the items using a seven-point Likert scale (1 = very little importance to 7 = extremely important) over four rounds of review until consensus was achieved. About 24 of the 28 panel members participated in all four rounds of the Delphi process. The final list of quality indicators comprised 34 items, divided into the four categories of our conceptual framework: Advance care planning (eight items), Goals of care discussions (13 items), Documentation (five items), and Organization/System aspects (eight items). Eleven items were rated "extremely important" (median score). All items had a median score of five (moderately important) or greater. We have developed definitions, a conceptual framework, and quality indicators that researchers and health care decision makers can use to evaluate and improve the quality of EOL communication and decision making.


[Cardiovascular risk factors--an integrated sympathetic viewpoint].
A large body of experimental and clinical data concerning the "classical cardiovascular risk factors" may be integrated into a unifying concept in which an increase in sympathetic activity and nutritional factors play a crucial role. The enhancement of sympathetic activity (e.g. as a consequence of psychosocial stress), induces--via direct and indirect mechanisms--activation of the renin-angiotensin-aldosterone system and the insulin axis. Balanced endothelial function may also be disrupted. Subsequently, these alterations lead to cardiovascular remodelling and development of the early stages of arteriosclerosis. Mechanical forces such as pressure and strain, and also mild hyperinsulinemia with secondary elevations in the LDL/HDL ratio further amplify these processes. Wrong nutrition, characterized by an elevated salt, sugar and fat intake, further stimulates these pathological events. The chain of events finally leading to the clinical manifestation of arteriosclerosis is certainly strongly based on, and modified by, a genetic predisposition. Cigarette smoking acts as a pulsatile, exogenous amplifier of the sympathetic nervous system. Furthermore, complex interactions of the various "hormonal risk systems", namely renin-angiotensin, insulin, and LDL/HDL cholesterol, have been observed at the cellular and molecular level. These interactions are integratively influenced by environmental and sympathetic factors. Therefore, a comprehensive approach should be incorporated into prophylactic and therapeutic strategies.


Inhibition of human liver cathepsin L by alpha 2 cysteine-proteinase inhibitor and the low-Mr cysteine proteinase inhibitor from human serum.
The inhibition of human liver cathepsin L by two specific proteinase inhibitors present in human serum, namely alpha 2 cysteine-proteinase inhibitor and the low-Mr cysteine-proteinase inhibitor, was studied. Kinetic parameters, including inhibition constants (Ki) and rate constants for association and dissociation (k+1 and K-1), were determined. The values found are consistent with a possible physiological function of these inhibitors to control cathepsin L activity. Furthermore, a transfer of active proteinase from the complex with either cysteine-proteinase inhibitor species to alpha 2-macroglobulin was demonstrated in vitro. Given the rate of dissociation of both cathepsin-L-cysteine-proteinase inhibitor complexes, a function of transitory inhibitor can therefore be hypothesized for these proteins and might then provide an explanation of the clearance of lysosomal proteinases.


Modeling protected species distributions and habitats to inform siting and management of pioneering ocean industries: A case study for Gulf of Mexico aquaculture.
Marine Spatial Planning (MSP) provides a process that uses spatial data and models to evaluate environmental, social, economic, cultural, and management trade-offs when siting (i.e., strategically locating) ocean industries. Aquaculture is the fastest-growing food sector in the world. The United States (U.S.) has substantial opportunity for offshore aquaculture development given the size of its exclusive economic zone, habitat diversity, and variety of candidate species for cultivation. However, promising aquaculture areas overlap many protected species habitats. Aquaculture siting surveys, construction, operations, and decommissioning can alter protected species habitat and behavior. Additionally, aquaculture-associated vessel activity, underwater noise, and physical interactions between protected species and farms can increase the risk of injury and mortality. In 2020, the U.S. Gulf of Mexico was identified as one of the first regions to be evaluated for offshore aquaculture opportunities as directed by a Presidential Executive Order. We developed a transparent and repeatable method to identify aquaculture opportunity areas (AOAs) with the least conflict with protected species. First, we developed a generalized scoring approach for protected species that captures their vulnerability to adverse effects from anthropogenic activities using conservation status and demographic information. Next, we applied this approach to data layers for eight species listed under the Endangered Species Act, including five species of sea turtles, Rice's whale, smalltooth sawfish, and giant manta ray. Next, we evaluated four methods for mathematically combining scores (i.e., Arithmetic mean, Geometric mean, Product, Lowest Scoring layer) to generate a combined protected species data layer. The Product approach provided the most logical ordering of, and the greatest contrast in, site suitability scores. Finally, we integrated the combined protected species data layer into a multi-criteria decision-making modeling framework for MSP. This process identified AOAs with reduced potential for protected species conflict. These modeling methods are transferable to other regions, to other sensitive or protected species, and for spatial planning for other ocean-uses.


Influence of the Sea Surface Microlayer on Oceanic Iodine Emissions.
The influence of organic compounds on iodine (I2) emissions from the O3 + I- reaction at the sea surface was investigated in laboratory and modeling studies using artificial solutions, natural subsurface seawater (SSW), and, for the first time, samples of the surface microlayer (SML). Gas-phase I2 was measured directly above the surface of liquid samples using broadband cavity enhanced absorption spectroscopy. I2 emissions were consistently lower for artificial seawater (AS) than buffered potassium iodide (KI) solutions. Natural seawater samples showed the strongest reduction of I2 emissions compared to artificial solutions with equivalent [I-], and the reduction was more pronounced over SML than SSW. Emissions of volatile organic iodine (VOI) were highest from SML samples but remained a negligible fraction (<1%) of the total iodine flux. Therefore, reduced iodine emissions from natural seawater cannot be explained by chemical losses of I2 or hypoiodous acid (HOI), leading to VOI. An interfacial model explains this reduction by increased solubility of the I2 product in the organic-rich interfacial layer of seawater. Our results highlight the importance of using environmentally representative concentrations in studies of the O3 + I- reaction and demonstrate the influence the SML exerts on emissions of iodine and potentially other volatile species.


The ethanol extract from Artemisia princeps Pampanini induces p53-mediated G1 phase arrest in A172 human neuroblastoma cells.
In the present study, the antiproliferative effects of the ethanol extract of Artemisia princeps Pampanini (EAPP) and the mechanism involved were investigated. Of the various cancer cells examined, human neuroblastoma A172 cells were most sensitive to EAPP, and their proliferation was dose- and time-dependently inhibited by EAPP. DNA flow cytometry analysis indicated that EAPP notably induced the G(1) phase arrest in A172 cells. Of the G(1) phase cycle-related proteins examined, the expressions of cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 and of cyclin D(1), D(2), and D(3) were found to be markedly reduced by EAPP, whereas cyclin E was unaffected. Moreover, the protein and mRNA levels of the CDK inhibitors p16(INK4a), p21(CIP1/WAF1), and p27(KIP1) were increased, and the activities of CDK2, CDK4, and CDK6 were reduced. Furthermore, the expressions of E2F-1 and of phosphorylated pRb were also decreased, and the protein levels of p53 and pp53 (Ser15) were increased. Up-regulation of p21(CIP1/WAF1) was found to be mediated by a p53-dependent pathway in EAPP-induced G(1)-arrested A172 cells. When these data are taken together, the EAPP was found to potently inhibit the proliferation of human neuroblastoma A172 cells via G(1) phase cell cycle arrest.


Quantitative evaluation of sympathetic and parasympathetic control of iris function.
The use of quantitative measurements of pupil size as an index of autonomic nervous system (ANS) activity in normal and diabetic subjects is described. The dual innervation of the iris by the parasympathetic (PNS) and sympathetic (SNS) nervous system was demonstrated by measurement of steady-state pupil size before and after changes in ANS activity by pharmacologic agents. In the presence of total PNS blockade, dark-adapted pupil size was a reliable index of SNS activity to the iris. Latency time (time from light stimulation to initial pupil response) appeared to be a good index of PNS activity. However, increased SNS activity may also prolong the latency time. Thus, consideration of SNS activity is necessary when evaluating the latency time. In 25 diabetic subjects, there was evidence of impaired SNS activity (smaller dark-adapted pupil size during total PNS blockade) and PNS activity (prolonged latency time). In a subgroup of diabetic subjects without clinical manifestations of autonomic neuropathy and normal subjects, both dark-adapted pupil size during PNS blockade (SNS index) and latency time (PNS index) were abnormal. The coefficient of variation for these two indices was less than 5% in glycemic stable diabetic subjects. Thus, these two indices are reliable and sensitive measures of the SNS and PNS activity to the iris in normal and diabetic subjects.


The open conformation of WASP regulates its nuclear localization and gene transcription in myeloid cells.
Mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASP) are responsible for Wiskott-Aldrich syndrome and WASP is a major actin regulator in the cytoplasm. Although rare gain-of-function mutations in the WASP gene are known to result in X-linked neutropenia (XLN), the molecular pathogenesis of XLN is not fully understood. In this study, we showed that all reported constitutively activating mutants (L270P, S272P and I294T) of WASP were hyperphosphorylated by Src family tyrosine kinases and demonstrated higher actin polymerization activities compared with wild-type (WT) WASP. Further analysis showed a tendency of activating WASP mutants to localize in the nucleus compared with WT or the Y291F mutant of WASP. In addition, we found that WASP could form a complex with nuclear RNA-binding protein, 54 kDa (p54nrb) and RNA polymerase II (RNAP II). ChIP assays revealed that WASP associated with DNA, although the affinity was relatively weaker than RNAP II. To determine whether gene transcription was affected by WASP mutation in myeloid cells, we performed microarray analysis and found different expression profiles between WT and L270P WASP-transfected K562 cells. Among the genes affected, granulocyte colony-stimulating factor receptor, Runx1, and protein tyrosine phosphatase receptor c were included. ChIP on chip analysis of genomic DNA showed WT and L270P WASP had a highly similar DNA-binding pattern but differed in binding affinity at the same locus. Therefore, our results suggest that the open conformation of WASP regulates its nuclear localization and plays requisite roles in regulating gene transcription that would contribute to the outcome in the nucleus of myeloid cells.


[Effect of lithium on the central serotonin- and adrenergic processes after its chronic administration].
With its chronic administration in a dose of 100 mg/kg lithium carbonate inhibited shaking of the head induced in mice with 5-hydroxytryptophan (5-HTP). This effect did not differ from the action following a single injection of lithium, when the interval between injection of lithium and of 5-HTP was one hour. With the interval lengthened to 24 hours the frequency of shaking diminished only under the effect of chronic administration. At the 5th, 10th and 21st day of a daily administration lithium failed to produce any effect on the hypothermal action of a reserpine-like agent Po 4-1284, but would reduce the protective action of imipramine in a ptosis test. A single injection of lithium made against the background of a chronic injection of water produced an opposite effect, viz. it significantly reduced the protective action of imipramine in hypothermia, but did not affect it with reference to ptosis. Hence, chronic administration of lithium leads to potentiation in its action of the serotonin-negative and central adreno-negative componets and to extenuating the peripheral adreno-negative component.


Identification of the transcription factor ZEB1 as a central component of the adipogenic gene regulatory network.
Adipose tissue is a key determinant of whole body metabolism and energy homeostasis. Unraveling the regulatory mechanisms underlying adipogenesis is therefore highly relevant from a biomedical perspective. Our current understanding of fat cell differentiation is centered on the transcriptional cascades driven by the C/EBP protein family and the master regulator PPARγ. To elucidate further components of the adipogenic gene regulatory network, we performed a large-scale transcription factor (TF) screen overexpressing 734 TFs in mouse pre-adipocytes and probed their effect on differentiation. We identified 22 novel pro-adipogenic TFs and characterized the top ranking TF, ZEB1, as being essential for adipogenesis both in vitro and in vivo. Moreover, its expression levels correlate with fat cell differentiation potential in humans. Genomic profiling further revealed that this TF directly targets and controls the expression of most early and late adipogenic regulators, identifying ZEB1 as a central transcriptional component of fat cell differentiation.


[Shift in the content of immune cytokines in heart of mice under acoustic stress conditions and delta-sleep inducing peptide application].
Quantitative shifts in the content of interleukine-1, -2 and -6 of the myocardium of mice under the conditions of acoustic stress and delta-sleep inducing peptide action are studied. It has been shown that injection of delta-sleep inducing peptide has no effect on the level of interleukine-1 and -2 in the myocardial tissue, whereas the quantity of interleukine-6 increased. The level of interleukine-1- and -6 in the myocardium were increased and no significant changes were observed in the level of interleukine-2 under the noise action. Interleukine-1- and -2 were not detected in the hypophysis of experimental animals of all groups (intact, under acoustic stress, under delta-sleep inducing peptide application). The level of interleukine-6 in the hypothalamus decreased under conditions of acoustic stress, whereas administration of delta-sleep inducing peptide has no effect on its level. The obtained data are considered in the context of immune modulating properties of delta-sleep inducing peptide.