Antisense modulation of the coding or regulatory sequence of the folate receptor (folate binding protein-1) in mouse embryos leads to neural tube defects.
Although folic acid decreases the incidence of neural tube defects (NTDs) in humans, the mechanism for this protection is unknown. We have employed antisense technology to alter expression of the gene for the folate receptor (folate binding protein-1 [Folbp1]) in mouse embryos cultured in vitro. Embryos were explanted on day 8 of gestation and cultured for 44 hr. Several oligodeoxyribonucleotides designed to modulate the coding region or a regulatory sequence in the 5'-untranslated region of Folbp1 were microinjected into the amniotic sac of embryos at the beginning of the culture period. Two different antisense sequences to the 5' and 3' coding region in Folbp1 produced concentration-dependent increases in the number of embryos with NTDs. Coinjection of 5-methyltetrahydrofolate with these sequences decreased the frequency of abnormal embryos. A semi-quantitative RT-PCR technique used to measure the amount of Folbp1 mRNA in treated and control embryos confirmed that the mRNA level was decreased by treatment with the antisense sequences. An antisense oligodeoxyribonucleotide to a 17 base cis regulatory element also generated a concentration-dependent increase in the frequency of embryos with NTDs, and a decrease in the level of Folbp1 mRNA. These results demonstrate that alterations in expression of Folbp1 by perturbing either the coding sequence or a critical regulatory cis-element can play a role in NTDs.


Benzidine dihydrochloride: toxicological assessment in mice during chronic exposures.
Although benzidine is recognized as a bladder carcinogen in humans and a liver carcinogen in laboratory animals, its toxicological effects appear to be extended to several other endpoints. This economically important chemical is the base for over 200 dyes and is used extensively in manufacturing. In a chronic lifespan study lasting 33 months, both sexes of F1 hybrid (genetically homogeneous) and monohybrid cross (genetically heterogeneous) mice from BALB/c male and C57BL/6 female crosses were exposed to benzidine dihydrochloride in their drinking water at concentrations of 0, 20, 30, 40, 60, 80, and 120 ppm for the females, and 0, 30, 40, 60, 80, 120, and 160 ppm for males. Animals were removed from the study when they were dead or moribund. In addition to hepatocellular carcinomas, there were several other toxicological end-points identified that appeared to be related to the administration of benzidine. Dose-response trends were noted for pigmentation of the spleen, hepatic cytological alterations, hyperplasia of the bile ducts, megakaryocytosis of the bone marrow, vacuolization of the brain, adenoma of the Harderian gland, atrophy of the ovaries, and angioma of the uterus. Also, dose-related effects were noted with respect to time to lung tumor and time to mortality due to reticulum-cell sarcomas.


Neuro and intraocular cysticercosis: A clinicopathological case report.
Cysticercosis is one of the most common parasitic infestations in humans. Neurocysticercosis (NCC) is the commonest parasitosis of the central nervous system (CNS), endemic in developing countries and is also seen in developed nations with high rates of immigration from prevalent areas. Co-infection of ocular tissue is also significant and often ophthalmologists come across these lesions in their clinical practice. The mode of treatment in NCC and that of intraocular cysticercosis is somewhat different as far as antiparasitic treatment is concerned. This case report highlights the proper management of this parasitic infestation which involved both eye and brain.


Infrared warming reduced winter wheat yields and some physiological parameters, which were mitigated by irrigation and worsened by delayed sowing.
Winter wheat has a central role in ensuring the food security and welfare of 1.3 billion people in China. Extensive previous studies have concluded that winter wheat yields would decrease with higher temperatures, owing to warming-induced soil drying or shortening of phenophase. Temperature in China is predicted to increase by 1-5°C by 2100, which may greatly impact plant production and cause other negative effects. We performed a manipulative field experiment, creating diverse growth regimes for wheat by infrared radiation (IR) warming day and night, including IR warming only (DW), IR warming + delayed sowing dates (DS), IR warming + increased irrigation (IW), and a control (CK). The results show that IR warming increased daily average wheat canopy and soil temperatures by 2.0°C and 2.3°C, respectively. DW was associated with an advanced maturity of 10 days and yield reduction of 8.2%. IR-warming effects on the photosynthetic apparatus of wheat varied with season as well as significant differences were found in the booting stage. DS represented a worsened situation, lowering yield per plant by 16.4%, with a significant decline in aboveground biomass and functional leaf area. Wheat under DS showed double-peak patterns of diurnal gas exchange during booting stages and, consequently, lower photosynthetic capacity with high transpiration for cooling. Significantly lower actual water use efficiency and intrinsic water use efficiency from jointing to anthesis stages were also found under DS. However, IW had no significant difference from CK, irrespective of yield and photosynthesis. Therefore, we concluded that delayed sowing date may not be a good choice for winter wheat, whereas a thoroughly-watered wheat agroecosystem should be promoted in the context of global warming.


Type 2 innate lymphoid cells: a novel actor in anti-melanoma immunity.
Immunity to melanoma is thought to be mainly mediated by adaptive immune cells. To what extent innate immunity, particularly innate lymphoid cells, drive the immune response and impact melanoma prognosis and therapeutic responsiveness is not well understood. In a recent article published in Nature Immunology, we uncovered a critical role that ILC2 play in the control of melanoma. Using both complementary mouse models and human samples, we showed that ILC2-derived granulocyte macrophage-colony stimulating factor (GM-CSF) drives eosinophil tumor recruitment and activation. We found that ILC2 express PD-1 which inhibits ILC2 effector function and impairs anti-tumor responses. We further demonstrated that the combination of IL-33 and anti-PD-1 blocking antibodies improved anti-tumor responses through the expansion of splenic and tumor-infiltrating ILC2 and eosinophils. These findings have revealed an essential mechanism involving ILC2 and eosinophils necessary for anti-melanoma immunity and immunotherapy responses.


Swim speed, behavior, and movement of North Atlantic right whales (Eubalaena glacialis) in coastal waters of northeastern Florida, USA.
In a portion of the coastal waters of northeastern Florida, North Atlantic right whales (Eubalaena glacialis) occur close to shore from December through March. These waters are included within the designated critical habitat for right whales. Data on swim speed, behavior, and direction of movement--with photo-identification of individual whales--were gathered by a volunteer sighting network working alongside experienced scientists and supplemented by aerial observations. In seven years (2001-2007), 109 tracking periods or "follows" were conducted on right whales during 600 hours of observation from shore-based observers. The whales were categorized as mother-calf pairs, singles and non-mother-calf pairs, and groups of 3 or more individuals. Sample size and amount of information obtained was largest for mother-calf pairs. Swim speeds varied within and across observation periods, individuals, and categories. One category, singles and non mother-calf pairs, was significantly different from the other two--and had the largest variability and the fastest swim speeds. Median swim speed for all categories was 1.3 km/h (0.7 kn), with examples that suggest swim speeds differ between within-habitat movement and migration-mode travel. Within-habitat right whales often travel back-and-forth in a north-south, along-coast, direction, which may cause an individual to pass by a given point on several occasions, potentially increasing anthropogenic risk exposure (e.g., vessel collision, fishing gear entanglement, harassment). At times, mothers and calves engaged in lengthy stationary periods (up to 7.5 h) that included rest, nursing, and play. These mother-calf interactions have implications for communication, learning, and survival. Overall, these behaviors are relevant to population status, distribution, calving success, correlation to environmental parameters, survey efficacy, and human-impacts mitigation. These observations contribute important parameters to conservation biology, predictive modeling, and management. However, while we often search for predictions, patterns, and means, the message here is also about variability and the behavioral characteristics of individual whales.


The motor cortex: a network tuned to 7-14 Hz.
The neocortex or six layer cortex consists of at least 52 cytoarchitectonically distinct areas in humans, and similar areas can be distinguished in rodents. Each of these areas has a defining set of extrinsic connections, identifiable functional roles, a distinct laminar arrangement, etc. Thus, neocortex is extensively subdivided into areas of anatomical and functional specialization, but less is known about the specialization of cellular and network physiology across areas. The motor cortex appears to have a distinct propensity to oscillate in the 7-14 Hz frequency range. Augmenting responses, normal mu and beta oscillations, and abnormal oscillations or after discharges caused by enhancing excitation or suppressing inhibition are all expressed around this frequency range. The substrate for this activity may be an excitatory network that is unique to the motor cortex or that is more strongly suppressed in other areas, such as somatosensory cortex. Interestingly, augmenting responses are dependent on behavioral state. They are abolished during behavioral arousal. Here, I briefly review this evidence.


Gemigliptin Inhibits Interleukin-1β-Induced Endothelial-Mesenchymal Transition via Canonical-Bone Morphogenetic Protein Pathway.
Endothelial-to-mesenchymal transition (EndMT) contributes to inflammatory conditions inducing conversion of endothelial cells (ECs) into activated fibroblasts, promoting fibrotic diseases. Pro-inflammatory cytokine is the most potent inducer of EndMT. We investigated inhibition of interleukin-1β (IL-1β)-induced EndMT by gemigliptin, a dipeptidyl peptidase-IV inhibitor. We exposed human umbilical vein endothelial cells (HUVECs) to 10 ng/mL IL-1β/20 μM gemigliptin and analyzed the expression of endothelial, smooth muscle, mesenchymal, and osteoblastic markers, bone morphogenetic protein (BMP), Smad, and non-Smad signaling pathway proteins. Morphological changes showed gemigliptin blocked IL-1β-induced EndMT, upregulated EC markers, and downregulated smooth muscle and mesenchymal markers. IL-1β activation of HUVECs is initiated by the BMP/Smad and non-smad BMP signaling pathways. Gemigliptin inhibited IL-1β induction of BMP2 and 7, activin receptor type IA, BMP receptor type IA, and BMP receptor type II. Reversal of IL-1β-mediated inhibition of BMP-induced Smad1/5/8, Smad2, and Smad3 phosphorylation by gemigliptin suggests involvement of the Smad pathway in gemigliptin action. In the non-Smad BMP pathway, gemigliptin treatment significantly increased the deactivation of extracellular regulated protein kinase (ERK), p38, and JNK by IL-1β. Gemigliptin treatment suppressed BMP-2-induced expression of key osteoblastic markers including osterix, runt-related transcription factor 2, and hepcidin during IL-1β-induced EndMT. We demonstrated a novel protective mechanism of gemigliptin against fibrosis by suppressing IL-1β-induced EndMT.


Owning your mistakes.
Most scientists admit to their errors but, as Eve Marder explains, the scientific community as a whole needs to rethink the way it recognizes achievement.


The plant MT1 metallothioneins are stabilized by binding cadmiums and are required for cadmium tolerance and accumulation.
The small Arabidopsis genome contains nine metallothionein-like (MT) sequences with classic, cysteine-rich domains separated by spacer sequences, quite unlike the small conserved MT families found vertebrate genomes. Phylogenetic analysis revealed four ancient and divergent classes of plant MTs that predate the monocot-dicot divergence. A distinct cysteine spacing pattern suggested differential metal ion specificity for each class. The in vivo stability of representatives of the four classes of plant MT proteins and a mouse MT2 control expressed in E. coli were enhanced by cadmium (Cd). Particular MTs were also stabilized by arsenic (As), copper (Cu), and or zinc (Zn). To understand why plants have such a diversity of MT sequences, the Arabidopsis MT1 class, comprised of three genes, MT1a, MT1b, and MT1c, was characterized in more detail in plants. MT1 family transcripts were knocked down to less than 5-10% of wild-type levels in Arabidopsis by expression of a RNA interference (RNAi) construct. The MT1 knockdown plant lines were all hypersensitive to Cd and accumulated several fold lower levels of As, Cd, and Zn than wildtype, while Cu and Fe levels were unaffected. The ancient class of MT1 protein sequences may be preserved in plant genomes, because it has distinct metal-binding properties, confers tolerance to cadmium, and can assist with zinc homeostasis.


"Knowing I can be helpful makes me feel good inside, it makes me feel essential": community health care workers' experiences of conducting a home-based rehabilitation intervention for people living with HIV in KwaZulu-Natal, South Africa.
People living with HIV (PLHIV) are living longer lives on antiretroviral therapy and are prone to a wide range of disabilities. Innovative strategies are required to meet the rehabilitation needs of PLHIV, particularly in resource-poor communities where HIV is endemic and access to institution-based rehabilitation is limited. Home-based rehabilitation (HBR) is one such approach, but there is a paucity of research related to HBR programmes for PLHIV or the experiences of community care workers (CCWs) involved in these programmes. Following a four month randomised controlled trial of a HBR intervention designed specifically for PLHIV in KwaZulu-Natal, South Africa; four CCWs were interviewed. This study employed a qualitative research design, using semi-structured interviews to explore these workers' experiences of being involved in carrying out this intervention. Participants reported how their personal development, improvement in their own health and increased feelings of self-worth enabled them to successfully implement the intervention. Participants also described a number of inhibitors, including stigma and environmental challenges related to the distances between patients' homes, the steep terrain and the hot climate. Despite this, the participants felt empowered by acquiring knowledge and skills that enabled them to shift roles beyond rehabilitation provision. The findings of this study should be considered when employing a task shifting approach in the development and implementation of HBR interventions for PLHIV. By employing a less specialised cadre of community workers to conduct basic HBR interventions, both the relative lack of qualified rehabilitation professionals and the high levels of disability in HIV-epidemic communities can be simultaneously addressed.


A 219-mer CHO-expressing receptor-binding domain of SARS-CoV S protein induces potent immune responses and protective immunity.
Development of vaccines is essential for the prevention of future recurrences of severe acute respiratory syndrome (SARS), caused by the SARS coronavirus (SARS-CoV). The spike (S) protein, especially receptor-binding domain (RBD) of SARS-CoV, plays important roles in the prevention of SARS infection, and is thus an important component in SARS vaccine development. In this study, we expressed a 219-mer (residues 318-536) RBD protein in Chinese hamster ovary (CHO)-K1 cells (RBD219-CHO), and tested its immune responses and protective immunity in a mouse model. The results showed that this recombinant protein was correctly folded, being able to maintain intact conformation and authentic antigenicity. It could induce strong humoral and cellular immune responses and high titers of neutralizing antibodies in the vaccinated mice. RBD219-CHO protein elicited potent protective immunity that protected all vaccinated mice from SARS-CoV challenge. These results suggest that the recombinant RBD219-CHO protein has great potential for the development of an effective and safe SARS subunit vaccine.


Sickness absence in the private sector of Greece: comparing shipyard industry and national insurance data.
Approximately 3% of employees are absent from work due to illness daily in Europe, while in some countries sickness absence exceeds 20 days per year. Based on a limited body of reliable studies, Greek employees in the private sector seem to be absent far less frequently (<5 days/year) compared to most of the industrialized world. The aim of this study was to estimate the levels of sickness absence in the private sector in Greece, using shipyard and national insurance data. Detailed data on absenteeism of employees in a large shipyard company during the period 1999-2006 were utilized. National data on compensated days due to sickness absence concerning all employees (around 2 million) insured by the Social Insurance Institute (IKA, the largest insurance scheme in Greece) were retrieved from the Institute's annual statistical reports for the period 1987-2006. Sick-leave days per employee and sick-leave rate (%) were calculated, among other indicators. In the shipyard cohort, the employment time loss due to sick leave was 1%. The mean number of sick-leave days per employee in shipyards ranged between 4.6 and 8.7 and sick-leave rate (sickness absenteeism rate) varied among 2% and 3.7%. The corresponding indicators for IKA were estimated between 5 and 6.3 sick-leave days per insured employee (median 5.8), and 2.14-2.72% (median 2.49%), respectively. Short sick-leave spells (<4 days) may account at least for the 25% of the total number of sick-leave days, currently not recorded in national statistics. The level of sickness absence in the private sector in Greece was found to be higher than the suggested by previous reports and international comparative studies, but still remains one of the lowest in the industrialized world. In the 20-years national data, the results also showed a 7-year wave in sickness absence indexes (a decrease during the period 1991-1997 and an increase in 1998-2004) combined with a small yet significant decline as a general trend. These observations deserve detailed monitoring and could only partly be attributed to the compensation and unemployment rates in Greece so other possible reasons should be explored.


Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.
Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.


Cell adhesion ability of artificial extracellular matrix proteins containing a long repetitive Arg-Gly-Asp sequence.
We generated recombinant artificial extracellular matrix (ECM) proteins containing repetitive Arg-Gly-Asp (RGD) sequences: double (RGD2), 21 (RGD21) and 43 (RGD43) repeats of RGD. RGD43-coated glass slides promoted fibroblast NIH3T3 cell adhesion and spreading on the surface. Since actin stress fibers and focal contacts were also observed in cells adhering on RGD43-coated glass slides, it was suggested that the RGD peptides in RGD43 transmitted an adhesion signal via integrins and promoted cell adhesion. We coated recombinant ECM proteins, each containing repetitive RGD domains, on polystyrene plates and investigated the effects of RGD length on the cell adhesion ability using three different cell lines, namely, fibroblast NIH3T3, HeLa cancer and neuronal PC12 cell lines. The results indicated that RGD43 had a cell adhesion ability superior to those of natural extracellular matrix proteins, fibronectin and laminin, although the effects of RGD repeat length on the cell adhesion ability depended on the cell line. As an artificial three-dimensional scaffold for cell cultivation, we also prepared an RGD43 hydrogel by a cross-linking reaction using glutaraldehyde. On the RGD43 hydrogel scaffold, fibroblast cells also successfully adhered under serum-free conditions.


PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41-q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41-q42 region linked to SLE.


Evaluation of Maculopathy in Patients Using Hydroxychloroquine
To determine length of hydroxychloroquine use and cumulative dose and evaluate the ocular effects by 10-2 central visual field test, microperimetry (MP), color fundus photography, optical coherence tomography (OCT), and fundus autofluorescence (FAF) in hydroxychloroquine users. Patients who used hydroxychloroquine continuously for at least 2 years for various connective tissue diseases were included in the study. A total of 300 eyes of 150 patients aged 19-78 years who were followed due to risk of developing hydroxychloroquine maculopathy in the İstanbul University İstanbul Faculty of Medicine Ophthalmology Department between the years 1995-2017 were evaluated. Best corrected visual acuity (BCVA), biomicroscopic, and fundoscopic examination were performed at all visits. MP, FAF, OCT, fundus photography, and central 10-2 visual field examinations were performed 3 times at 6-month intervals. The mean age of patients was 48.9±10.8 years; 141 (94%) patients were female and 9 (6%) were male. The mean duration of hydroxychloroquine use was 10.5±6.4 (2-30) years. Fifty-six patients had been using the drug for 5 years or less. The mean cumulative drug dose was 754.7±447.2 (146-1825) g. Mean BCVA was 0.02±0.08 LogMAR at all follow-up visits (p=0.999). Mean MP values at the first, second, and third examinations were 14.07±3.24 dB, 14.18±3.35 dB, and 14.54±2.79 dB, respectively (p>0.05). Mean central macular thickness was 221.9±19.8 µm at initial examination, 221.8±19.9 µm at the second visit, and 221.8±19.8 µm at the final visit (p=0.113). There was a weak negative correlation between age and MP values at all three visits (visit 1: p=0.003, r=- 0.170; visit 2: p=0.001, r=-0.185, visit 3: p=0.011, r=-0.146). There was statistically significant relationship between MP values and hydroxychloroquine length of use and cumulative dose (p=0.027 and p=0.049, respectively). Duration of use was not associated with changes in 10/2 visual field (p=0.124). There were significant relationships between alterations in FAF and hydroxychloroquine length of use and cumulative dose (p=0.027 and p=0.049, respectively). FAF alterations were significantly associated with duration of hydroxychloroquine use and cumulative dose. As objective methods are more reliable, examinations such as FAF can be recommended as auxiliary methods in the follow-up and early detection of toxic maculopathy.


Development of a multispecies oral bacterial community in a saliva-conditioned flow cell.
Microbial communities within the human oral cavity are dynamic associations of more than 500 bacterial species that form biofilms on the soft and hard tissues of the mouth. Understanding the development and spatial organization of oral biofilms has been facilitated by the use of in vitro models. We used a saliva-conditioned flow cell, with saliva as the sole nutritional source, as a model to examine the development of multispecies biofilm communities from an inoculum containing the coaggregation partners Streptococcus gordonii, Actinomyces naeslundii, Veillonella atypica, and Fusobacterium nucleatum. Biofilms inoculated with individual species in a sequential order were compared with biofilms inoculated with coaggregates of the four species. Our results indicated that flow cells inoculated sequentially produced biofilms with larger biovolumes compared to those biofilms inoculated with coaggregates. Individual-species biovolumes within the four-species communities also differed between the two modes of inoculation. Fluorescence in situ hybridization with genus- and species-specific probes revealed that the majority of cells in both sequentially and coaggregate-inoculated biofilms were S. gordonii, regardless of the inoculation order. However, the representation of A. naeslundii and V. atypica was significantly higher in biofilms inoculated with coaggregates compared to sequentially inoculated biofilms. Thus, these results indicate that the development of multispecies biofilm communities is influenced by coaggregations preformed in planktonic phase. Coaggregating bacteria such as certain streptococci are especially adapted to primary colonization of saliva-conditioned surfaces independent of the mode of inoculation and order of addition in the multispecies inoculum. Preformed coaggregations favor other bacterial strains and may facilitate symbiotic relationships.


G-quartet-based nanostructure for mimicking light-harvesting antenna.
Artificial light-harvesting systems have received great attention for use in photosynthetic and optoelectronic devices. Herein, a system involving G-quartet-based hierarchical nanofibers generated from the self-assembly of guanosine 5'-monophosphate (GMP) and a two-step Förster resonance energy transfer (FRET) is presented that mimics natural light-harvesting antenna. This solid-state property offers advantages for future device fabrication. The generation of photocurrent under visible light shows it has potential for use as a nanoscale photoelectric device. The work will be beneficial for the development of light-harvesting systems by the self-assembly of supramolecular nanostructures.


Transient inflammation and dysfunction of the eustachian tube secondary to multiple exposures of simulated gastroesophageal refluxant.
Gastroesophageal reflux is a common problem in the newborn and preschool periods. Recent research suggests that it may be related to eustachian tube dysfunction and otitis media with effusion. The purpose of this experiment was to investigate the relationship between simulated gastroesophageal reflux and eustachian tube dysfunction. Rat middle ears were repeatedly exposed (transtympanically) to pepsin in hydrochloric acid or to phosphate-buffered saline solution. Their eustachian tube function was evaluated by assessing passive opening and passive closing pressures, and active clearance of positive and negative pressure. The passive pressure function tests showed variable results. The rats exposed to pepsin in hydrochloric acid had an impaired ability to clear positive and negative pressure from the middle ear as compared to the rats exposed only to phosphate-buffered saline solution. The results demonstrate that multiple middle ear exposures to pepsin in hydrochloric acid leads to eustachian tube dysfunction in rats.


Neutralization against Omicron subvariants after BA.5/BF.7 breakthrough infection weakened as virus evolution and aging despite repeated prototype-based vaccination1.
Omicron had swept the mainland China between December 2022 and January 2023, while SARS-CoV-2 still continued to evolve. To fully prepare for the next wave, it's urgent to evaluate the humoral immune response post BA.5/BF.7 breakthrough infection against predominant sub-lineages among existing vaccination strategies and the elders. This study enrolled a longitudinal young-adult cohort from 2/3-dose vaccination to 1 month after breakthrough infection, and an elder cohort at 1 month after breakthrough infection. Seral samples were collected and tested for humoral immune response to SARS-CoV-2 subvariants including WT, BA.2, BA.5, BF.7, BQ.1.1, CH.1.1, XBB.1.5. BA.5/BF.7 breakthrough infection induced higher neutralization activity than solely vaccination in all SARS-CoV-2 strains, while the latest Omicron subvariants, BQ.1.1, CH.1.1, XBB.1.5, exhibited the strongest neutralization evasion ability. There was a negative correlation between age and humoral immune response in WT, BA.5, BQ.1.1, and XBB.1.5. Compared to non-vaccination groups, breakthrough infection in two-dose vaccination groups had significantly higher neutralizing antibody against WT, BA.2, BA.5, BF.7 but not to BQ.1.1, CH.1.1, XBB.1.5 while booster dose against the prototype prior-breakthrough would not further significantly enhance individual's humoral responses against the latest Omicron subvariants. Newer variants manifest increasing immune evasion from neutralization and repeated prototype-based booster vaccines may not further enhance neutralizing antibody against emerging new variants. Older adults have lower levels of neutralizing antibody. Future vaccination strategies should aim to enhance effective neutralization to contemporary variants.


Daily fluctuations in teachers' well-being: a diary study using the Job Demands-Resources model.
The study tests the dynamic nature of the Job Demands-Resources model with regard to both motivational and health impairment processes. It does so by examining whether daily fluctuations in co-workers' support (i.e., a typical job resource) and daily fluctuations in work/family conflict (i.e., a typical job demand) predict day-levels of job satisfaction and mental health through work engagement and exhaustion, respectively. A total of 61 schoolteachers completed a general questionnaire and a daily survey over a period of five consecutive work days. Multilevel analyses provided evidence for both the above processes. Consistently with the hypotheses, our results showed that day-level work engagement mediated the impact of day-level co-workers' support on day-level job satisfaction and day-level mental health, after general levels of work engagement and outcome variables had been controlled for. Moreover, day-level exhaustion mediated the relationship between day-level work/family conflict and day-level job satisfaction and day-level mental health after general levels of exhaustion and outcome variables had been controlled for. These findings provide new insights into the dynamic psychological processes that determine daily fluctuations in employee well-being. Such insights may be transformed into job redesign strategies and other interventions designed to enhance work-related psychological well-being on a daily level.


No Evidence of Narrowly Defined Cognitive Penetrability in Unambiguous Vision.
The classical notion of cognitive impenetrability suggests that perceptual processing is an automatic modular system and not under conscious control. Near consensus is now emerging that this classical notion is untenable. However, as recently pointed out by Firestone and Scholl, this consensus is built on quicksand. In most studies claiming perception is cognitively penetrable, it remains unclear which actual process has been affected (perception, memory, imagery, input selection or judgment). In fact, the only available "proofs" for cognitive penetrability are proxies for perception, such as behavioral responses and neural correlates. We suggest that one can interpret cognitive penetrability in two different ways, a broad sense and a narrow sense. In the broad sense, attention and memory are not considered as "just" pre- and post-perceptual systems but as part of the mechanisms by which top-down processes influence the actual percept. Although many studies have proven top-down influences in this broader sense, it is still debatable whether cognitive penetrability remains tenable in a narrow sense. The narrow sense states that cognitive penetrability only occurs when top-down factors are flexible and cause a clear illusion from a first person perspective. So far, there is no strong evidence from a first person perspective that visual illusions can indeed be driven by high-level flexible factors. One cannot be cognitively trained to see and unsee visual illusions. We argue that this lack of convincing proof for cognitive penetrability in the narrow sense can be explained by the fact that most research focuses on foveal vision only. This type of perception may be too unambiguous for transient high-level factors to control perception. Therefore, illusions in more ambiguous perception, such as peripheral vision, can offer a unique insight into the matter. They produce a clear subjective percept based on unclear, degraded visual input: the optimal basis to study narrowly defined cognitive penetrability.


An Asymptomatic Case of Radiologically Active Neurocysticercosis.
The case describes an 82-year-old right-handed Hispanic male with multiple chronic comorbidities complaining of upper and lower extremity weakness as well as paresthesias that had been worsening over the last two weeks. He had bilateral upper and lower extremity weakness that was worse on the right and he complained of not being able to walk on his own with several falls preceding admission because of this. There were no overt signs of spinal cord compression or cauda equina syndrome. Laboratory work-up was unremarkable with exception to mildly elevated acute phase reactants. Computed tomography (CT) and magnetic resonance (MR) imaging later showed critical cervical compressive myelopathy at the C3-C4 level and multiple parenchymal and extra-axial enhancing lesions in the frontal lobes with associated calcifications suspicious for neurocysticercosis. Antihelminthic therapy was started and the patient underwent spinal fusion surgery with neurosurgery with an uncomplicated post-operative course - also lacking seizure activity of any kind.


Medical Ethics Resource Network of Michigan: development of a statewide ethics network.
The Medical Ethics Resource Network (MERN) of Michigan has, over approximately 5 years, become a viable organization for disseminating educational information and raising the general standard of ethics discussion in a variety of institutional settings. This article reviews the history of the network's development, with special emphasis upon features that may suggest useful strategies for other networks now under formation.


Role of glycemic control and protein restriction in clinical management of diabetic kidney disease.
To assess the role of control of blood glucose levels and restriction of dietary protein in the management of diabetic nephropathy. We summarize the results of pertinent published studies of glycemic control and modification of protein intake to provide information about strategies that potentially could benefit patients with diabetes and renal dysfunction. Considerable evidence is available to support the contention that improved glycemic control may have beneficial effects on the development and progression of diabetic renal disease. Maximal benefits of improved glycemia occur when instituted before the onset of macroalbuminuria. Once overt diabetic nephropathy is established, improved glycemic control may not be beneficial. Current evidence indicates that a glycosylated hemoglobin level of less than 8.1% should be the glycemic goal. At this level, the risk of developing micro-albuminuria is substantially reduced, and the risk of hypoglycemia is minimized. Most studies have been conducted in type I diabetes, and the results have been extrapolated to type II diabetes. Whether improved glycemic control will be equally beneficial in the nephropathy of type II diabetes has yet to be determined. Although some scientific evidence supports dietary protein restriction in patients with diabetic nephropathy, the extent of restriction needed for optimal benefits and minimal side effects remains to be determined. On the basis of current information, patients with both types of diabetes who have evidence of nephropathy should have protein limited to the recommended dietary allowance for adults (0.8 g/kg of body weight per day or approximately 10% of total daily caloric intake), and protein should be derived primarily from vegetable and lean animal sources. End-stage renal disease is not inevitable in patients with diabetic nephropathy. Normalization of glucose levels and modification of protein intake can favorably influence the course of diabetes-related kidney disease.


In vitro carcinogenesis of hamster pancreatic duct cells: cellular and molecular alterations.
Neoplastic transformation of Syrian golden hamster (SGH) pancreatic duct cells was induced by in vitro treatment with the direct-acting carcinogens N-methylnitrosourea (MNU) and N-(2-hydroxypropyl)nitrosourea (HPNU), with subsequent selection by sustained culture in serum- and epidermal growth factor (EGF)-deprived medium. The present study examines the efficacy of serum and EGF deprivation as a selection pressure and the effect of the carcinogen dose, frequency and interval of exposure on tumorigenesis and K-ras mutation. Selection of carcinogen-initiated duct cells by serum and EGF deprivation is highly reproducible and effective, increasing the incidence of tumors from 26 to 93% for MNU or from 0 to 100% for HPNU. SGH pancreatic duct cells exposed to 0.5 mM MNU for 13 weeks (long-treatment schedule) produced K-ras mutations at codon 12 in six of six tumors. However, when cells were exposed to 0.125, 0.25 or 0.5 mM MNU daily for 5 days (short-treatment schedule), mutations of K-ras at codon 13 were identified in four of 16 tumors, the remaining 12 showing no mutations. Duct cells exposed to 0.5 mM HPNU by the short-treatment schedule produced K-ras mutations in codon 13 in six of six tumors, as contrasted to 12 tumors that developed from cells exposed to 0.125 or 0.25 mM HPNU, which all contained K-ras codon 12 mutations. The current experiments demonstrate that K-ras mutation in pancreatic carcinogenesis in vitro by MNU or HPNU can be modified by the nature and dose of the carcinogen as well as the frequency and duration of exposure.


Transition in acquired brain injury youth (TrABI-Y): a systematic literature review protocol.
Acquired brain injury (ABI) in paediatrics refers to children born with a neurological deficit, which will lead to a chronic neurological disorder. As advances in medical paediatric health progress, we are seeing these ABI youth transitioning into adult healthcare services while also going through different life events. Despite the growing number of young adult patients, access to transition programmes to facilitate the transition process is still limited and evidence on the effectiveness of these programmes is inconclusive. The purpose of this paper is to provide the protocol for an upcoming systematic literature review on this important issue. The start of this systematic literature review is planned for 1 October 2019 and will end on 31 December 2021. According to the PICO framework developed, the Population and the Problem of interest (P) will include children, adolescents and young adults (0-18 years) diagnosed with ABI. The selected articles will have to involve an Intervention (I) relating to the healthcare of this population or life transitions from paediatric to adult-oriented care. Studies will be included if a Comparator (C) intervention was used. The expected Outcomes (O) will have to report quantitative or qualitative health-related outcomes post-transition. This comprehensive search of peer-reviewed literature will include articles published between 2010 and 2020. The databases to be searched include Medline, All EBM Reviews, Embase, PsycINFO and CINAHL. The selected articles will be appraised using the Mixed Methods Appraisal Tool. A synthesis of the findings will be drafted to identify the effectiveness of available transition programmes as well as predictors, factors and determinants involved in the transition process. This project is not associated with direct individuals. The dissemination plan includes strategies such as using this systematic literature review to develop a research project on transition that will be published.


The HANDS project: studying and refining the automated collection of a cross-setting clinical data set.
The consistent availability of a core set of clinical nursing data is essential to promote quality patient care. Although important work to improve terminology and enhance comparability of data is underway, the efforts do not address the immediate need for useful nursing data sets and valid methods of collection at the point of data entry. The Hands-on Automated Nursing Data System (HANDS) project is dedicated to refining a feasible methodology for gathering, storing, and retrieving a standardized nursing data set. To date the project team has developed and tested a prototype research tool that is automated and contains the structured terminologies (North American Nursing Diagnosis Association, Nursing Outcomes Classification, and Nursing Interventions Classification) to represent nursing diagnoses, outcomes, and interventions, respectively. The Phase I project development activities are reported in this article, along with Phase II and III plans for testing and refining the methodology under actual clinical conditions. Results and lessons learned during Phase I are reported.


[Clinical features of horizontal semicircular canal benign paroxysmal positional vertigo].
To explore the clinical features of horizontal semicircular canal benign paroxysmal positional vertigo. The clinical manifestations of 239 patients with horizontal semicircular canal benign paroxysmal positional vertigo from August 2003 to December 2010 were retrospectively analyzed. 25.7% (239/931) of all the benign paroxysmal positional vertigo patients were the horizontal semicircular canal benign paroxysmal positional vertigo was involved. One hundred and ninety-seven patients showed geotropic nystagmus in head rolling test with a mean latency period of (0.88 ± 0.72) s and a mean duration period of (26.36 ± 19.71) s. Forty-two patients showed apogeotropic nystagmus in head rolling test with a mean latency period of (2.69 ± 1.83) s and a mean duration period of (53.48 ± 43.12) s. Among all the horizontal semicircular canal benign paroxysmal positional vertigo patients, 39 (16.3%) presented horizontal nystagmus with slight upbeating component. The nystagmus latency in apogeotropic nystagmus group was longer than that in geotropic nystagmus group (t = -6.33, P < 0.001), and nystagmus duration period was also longer (t = -3.99, P < 0.001). Applied Barbecue maneuver to the patients with geotropic nystagmus, 192 patients were cured after (1.6 ± 0.8) rotations; After applied head shaking maneuver to the patients with apogeotropic nystagmus, 40 patients changed to geotropic nystagmus and cured after (1.9 ± 0.8) rotations. Incidence rate of horizontal semicircular canal benign paroxysmal positional vertigo was higher than expectation. Barbecue maneuver was applied to patients with geotropic nystagmus. While to the patients with apogeotropic nystagmus, head shaking maneuver should be performed firstly and then followed by Barbecue maneuver.


High Rates of Access to Health Care, Disclosure of Sexuality and Gender Identity to Providers Among House and Ball Community Members in New York City.
The House and Ball community is an important cultural manifestation of resiliency for Black and Latino gay and bisexual men and transgender women. Participants at the August 2013 House of Latex Ball in New York City were surveyed about insurance coverage, health care access, experiences in health care, and housing instability. The sample (n = 367) was 58% Black/African American and 20% Hispanic/Latino, with a mean age of 31. Fifty-five percent were gay and bisexual men. Although only 6% identified as transgender, nearly one half were gender nonconforming. Strong majorities had health insurance, were in regular medical care, and were "out" to their providers. Some were unstably housed and had recently exchanged sex for shelter or money. High rates of health care access and disclosure indicate resiliency and agency. Unstable housing and income insecurity may be structural drivers of vulnerability for this population to HIV infection and other health risks.


Hybrid fiber optic-fMRI for multimodal cell-specific recording and manipulation of neural activity in rodents.
Significance: Multiscale imaging holds particular relevance to neuroscience, where it helps integrate the cellular and molecular biological scale, which is most accessible to interventions, with holistic organ-level evaluations, most relevant with respect to function. Being inextricably interdisciplinary, multiscale imaging benefits substantially from incremental technology adoption, and a detailed overview of the state-of-the-art is vital to an informed application of imaging methods. Aim: In this article, we lay out the background and methodological aspects of multimodal approaches combining functional magnetic resonance imaging (fMRI) with simultaneous optical measurement or stimulation. Approach: We focus on optical techniques as these allow, in conjunction with genetically encoded proteins (e.g. calcium indicators or optical signal transducers), unprecedented read-out and control specificity for individual cell-types during fMRI experiments, while leveraging non-interfering modalities. Results: A variety of different solutions for optical/fMRI methods has been reported ranging from bulk fluorescence recordings via fiber photometry to high resolution microscopy. In particular, the plethora of optogenetic tools has enabled the transformation of stimulus-evoked fMRI into a cell biological interrogation method. We discuss the capabilities and limitations of these genetically encoded molecular tools in the study of brain phenomena of great methodological and neuropsychiatric interest-such as neurovascular coupling (NVC) and neuronal network mapping. We provide a methodological description of this interdisciplinary field of study, and focus in particular on the limitations of the widely used blood oxygen level dependent (BOLD) signal and how multimodal readouts can shed light on the contributions arising from neurons, astrocytes, or the vasculature. Conclusion: We conclude that information from multiple signaling pathways must be incorporated in future forward models of the BOLD response to prevent erroneous conclusions when using fMRI as a surrogate measure for neural activity. Further, we highlight the potential of direct neuronal stimulation via genetically defined brain networks towards advancing neurophysiological understanding and better estimating effective connectivity.


Evaluation of direct analysis in real time for the determination of highly polar pesticides in lettuce and celery using modified Quick Polar Pesticides Extraction method.
Direct analysis in real time (DART) was evaluated for the determination of a number of highly polar pesticides using the Quick Polar Pesticides Extraction (QuPPe) method. DART was hyphenated to high resolution mass spectrometry (HRMS) in order to get the required selectivity that allows the determination of these compounds in complex samples such as lettuce and celery. Experimental parameters such as desorption temperature, scanning speed, and distances between the DART ion source and MS inlet were optimized. Two different mass analyzers (Orbitrap and QTOF) and two accessories for sample introduction (Dip-it® tips and QuickStrip™ sample cards) were evaluated. An extra clean-up step using primary-secondary amine (PSA) was included in the QuPPe method to improve sensitivity. The main limitation found was in-source fragmentation, nevertheless QuPPe-DART-HRMS proved to be a fast and reliable tool with quantitative capabilities for at least seven compounds: amitrole, cyromazine, propamocarb, melamine, diethanolamine, triethanolamine and 1,2,4-triazole. The limits of detection ranged from 20 to 60μg/kg. Recoveries for fortified samples ranged from 71 to 115%, with relative standard deviations <18%.


Virus markers associated with vertical transmission of human T lymphotropic virus type 1 in Jamaica.
In a prospective study involving 150 mothers and their offspring in Jamaica, we examined maternal viral factors associated with the risk of transmission of human T lymphotropic virus type 1 (HTLV-1). Overall, the incidence of HTLV-1 infection among children was 8.3 occurrences per 1000 person-months. A higher maternal provirus level (odds ratio [OR], 1.9 per quartile) and a higher HTLV-1 antibody titer (OR, 2.2 per quartile) were independently associated with transmission to children, whereas the presence of anti-Tax antibody was not. Higher maternal antibody titers also were associated with older age at infection among children who were breast-fed for </=12 months, which suggests that passively transferred maternal antibodies confer protection against infection while they persist. These data imply that mothers who have high provirus loads should be encouraged not to breast-feed. Alternatively, the successful reduction of maternal provirus loads or maintenance of passive antibody levels in infants during breast-feeding may lower the risk of transmission.


Transcriptome Analysis of Protocatechualdehyde against Listeria monocytogenes and Its Effect on Chicken Quality Characteristics.
The development of natural antimicrobial agents offers new strategies for food preservation due to the health hazards associated with the spoilage of meat products caused by microbial contamination. In this paper, the inhibitory mechanism of protocatechualdehyde (PCA) on Listeria monocytogenes was described, and its effect on the preservation of cooked chicken breast was evaluated. The results showed that the minimal inhibitory concentration (MIC) of PCA on L. monocytogenes was 0.625 mg/mL. Secondly, PCA destroyed the integrity of the L. monocytogenes cell membrane, which was manifested as a decrease in membrane hyperpolarization, intracellular ATP level, and intracellular pH value. Field emission gun scanning electron microscopy (FEG-SEM) observed a cell membrane rupture. Transcriptome analysis showed that PCA may inhibit cell growth by affecting amino acid, nucleotide metabolism, energy metabolism, and the cell membrane of L. monocytogenes. Additionally, it was discovered that PCA enhanced the color and texture of cooked chicken breast meat while decreasing the level of thiobarbituric acid active substance (TBARS). In conclusion, PCA as a natural antibacterial agent has a certain reference value in extending the shelf life of cooked chicken breast.


Can skeletomotor action integration occur without consciousness? Evidence from unconscious action inhibition.
Morsella et al. claim that consciousness functions to integrate incompatible skeletal muscle intentions. Their primary cases of conscious skeletomotor integration involve action suppression, such as holding one's breath underwater, which requires suppressing the urge to inhale. This indicates that the authors seem to think action inhibition counts as the relevant kind of integration. I suggest that there is reason to think this kind of inhibition can occur unconsciously via unconscious inhibitory mechanisms. Unconscious inhibition therefore potentially undermines the authors' thesis. If cases of unconscious inhibition are not instances of integration, then the authors should clarify exactly what counts as integration.


Prognostic role of neoplastic markers in Takotsubo syndrome.
Takotsubo syndrome (TTS) is an acute heart failure syndrome with significant rates of in and out-of-hospital mayor cardiac adverse events (MACE). To evaluate the possible role of neoplastic biomarkers [CA-15.3, CA-19.9 and Carcinoembryonic Antigen (CEA)] as prognostic marker at short- and long-term follow-up in subjects with TTS. Ninety consecutive subjects with TTS were enrolled and followed for a median of 3 years. Circulating levels of CA-15.3, CA-19.9 and CEA were evaluated at admission, after 72 h and at discharge. Incidence of MACE during hospitalization and follow-up were recorded. Forty-three (46%) patients experienced MACE during hospitalization. These patients had increased admission levels of CEA (4.3 ± 6.2 vs. 2.2 ± 1.5 ng/mL, p = 0.03). CEA levels were higher in subjects with in-hospital MACE. At long term follow-up, CEA and CA-19.9 levels were associated with increased risk of death (log rank p < 0.01, HR = 5.3, 95% CI 1.9-14.8, HR = 7.8 95% CI 2.4-25.1, respectively, p < 0.01). At multivariable analysis levels higher than median of CEA, CA-19.9 or both were independent predictors of death at long term (Log-Rank p < 0.01). Having both CEA and CA-19.9 levels above median (> 2 ng/mL, > 8 UI/mL respectively) was associated with an increased risk of mortality of 11.8 (95% CI 2.6-52.5, p = 0.001) at follow up. Increased CEA and CA-19.9 serum levels are associated with higher risk of death at long-term follow up in patients with TTS. CEA serum levels are correlated with in-hospital MACE.


Weighted pseudolikelihood for SNP set analysis with multiple secondary outcomes in case-control genetic association studies.
We propose a weighted pseudolikelihood method for analyzing the association of a SNP set, example, SNPs in a gene or a genetic pathway or network, with multiple secondary phenotypes in case-control genetic association studies. To boost analysis power, we assume that the SNP-specific effects are shared across all secondary phenotypes using a scaled mean model. We estimate regression parameters using Inverse Probability Weighted (IPW) estimating equations obtained from the weighted pseudolikelihood, which accounts for case-control sampling to prevent potential ascertainment bias. To test the effect of a SNP set, we propose a weighted variance component pseudo-score test. We also propose a penalized IPW pseudolikelihood method for selecting a subset of SNPs that are associated with the multiple secondary phenotypes. We show that the proposed variable selection procedure has the oracle properties and is robust to misspecification of the correlation structure among secondary phenotypes. We select the tuning parameter using a weighted Bayesian Information-like Criterion (wBIC). We evaluate the finite sample performance of the proposed methods via simulations, and illustrate the methods by the analysis of the multiple secondary smoking behavior outcomes in a lung cancer case-control genetic association study.


Correlates and Consequences of Nursing Staff Job Insecurity.
The health care system, and hospitals, underwent considerable restructuring and downsizing in the early to mid-1900s in several countries as governments cut costs to reduce their budget deficits. Studies of the effects of these efforts on nursing staff and hospital functioning in various countries generally reported negative impacts with threats to job security emerging as an important outcome of these changes. Health care restructuring and hospital downsizing is again being implemented as governments struggle to reduce deficits at a time of worldwide economic recession in 2008/2010. This study examines correlates and consequences of job insecurity among Canadian nursing staff, with a focus on nurses' well-being. Data were collected from 290 nursing staff working in hospitals in Ontario, Canada. Feelings of job insecurity in the sample as a whole were relatively low. Personal demographics and work situation characteristics were generally uncorrelated with feelings of job insecurity. Consistent with previous findings, perceived job insecurity was once again associated with less favorable work and well-being outcomes. Some suggestions for more successful approaches to addressing levels of subjective job insecurity are offered.


[Evaluation of bone mineral density using digital image processing in children receiving anticonvulsants].
Bone mineral density (BMD) increases rapidly in a biphasic manner in childhood. During and after adolescence, BMD correlates more closely with bone age than chronological age. Digital image processing (DIP) allows the rapid assessment of BMD and bone age on one X-ray film. Herein, using DIP methods, the effects of various anticonvulsants on chronological and bone age were evaluated in 98 epilepsy patients (age range, 3-15 years) with no intellectual or motor disorders or diseases affecting bone metabolism. All patients were taking one or a combination of the following anticonvulsants: valproate sodium (VPA); carbamazepine (CBZ); and phenobarbital (PB). Bone maturation scores for radius-ulnar-short bones (RUS) were calculated using Tanner-Whitehouse 2 methods. Bone age was determined based on standard Japanese bone-maturation scores. In each patient, Z-scores for chronological and bone ages were calculated by subtracting standard BMD for gender and age from each BMD, then dividing the result by the standard deviation. The Z-score for each drug in relation to the administration period was analyzed using the Mann-Whitney test. For chronological age, significant differences in BMD were observed regarding the administration periods in children taking multiple drugs, but not in children on VPA, CBZ, or PB monotherapy. For bone age, no significant differences in BMD were observed regarding the administration periods for all drugs. Children taking multiple drugs showed a significant negative correlation between administration period and Z-scores for BMD calculated based on chronological age (Spearman rank correlation: - 0.457, p = 0.008), but not bone age. Among children receiving long-term VPA administration, bone age was delayed approximately 1 year, and bone maturation may have been delayed. No delay in bone age was noted among children receiving long-term administration of multiple drugs, suggesting that these anticonvulsants do not influence bone maturity. These findings indicate that bone age should be considered when assessing BMD.


Intramedullary compression osteosynthesis for fractures of the femur.
There are obvious advantages in intramedullary osteosynthesis by closed reduction as compared with open reduction and osteosynthesis using a plate and screws in non-articular fractures of the long bones. This has led to a modification of Küntscher's nail with a view to improving its effectiveness and enlarging the indications.


Aerobic adaptation in yeast. I. Changes in metabolic intermediates during a step-down anaerobic-aerobic transfer.
Early investigation into the mechanism of mitochondriogenesis in the facultative anaerobe Saccharomyces cerevisiae used anaerobic-aerobic transitions as model systems to study the in vivo assembly of these oxidative organelles. This methodology has become entrenched in the early literature and as a result a definitive study has been undertaken utilizing this protocol (high hexose, complete medium under anaerobic growth transferred to low hexose, minimal medium with aerobic environment) to study the altered distribution of various metabolites during these transitions. Measurement of all the glycolytic, and some tricarboxylic acid intermediates during such a transition has elucidated the following points. On a qualitative basis, the metabolic controls prevalent in these growing cultures are similar to those identified in yeast under less physiological conditions. Also, the effect of anaerobic catabolism, which preconditions enzyme and pool levels in the yeast, is of paramount importance in determining the events subsequent to oxygen challenge. However, this experimental approach has severe limitations and does not lend itself to a clear-cut delineation of the events that occur during the process of mitochondriogenesis.


Neutrality tests for sequences with missing data.
Missing data are common in DNA sequences obtained through high-throughput sequencing. Furthermore, samples of low quality or problems in the experimental protocol often cause a loss of data even with traditional sequencing technologies. Here we propose modified estimators of variability and neutrality tests that can be naturally applied to sequences with missing data, without the need to remove bases or individuals from the analysis. Modified statistics include the Watterson estimator θW, Tajima's D, Fay and Wu's H, and HKA. We develop a general framework to take missing data into account in frequency spectrum-based neutrality tests and we derive the exact expression for the variance of these statistics under the neutral model. The neutrality tests proposed here can also be used as summary statistics to describe the information contained in other classes of data like DNA microarrays.


The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway.
Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.


Roles of PCNA ubiquitination and TLS polymerases κ and η in the bypass of methyl methanesulfonate-induced DNA damage.
Translesion synthesis (TLS) provides a highly conserved mechanism that enables DNA synthesis on a damaged template. TLS is performed by specialized DNA polymerases of which polymerase (Pol) κ is important for the cellular response to DNA damage induced by benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), ultraviolet (UV) light and the alkylating agent methyl methanesulfonate (MMS). As TLS polymerases are intrinsically error-prone, tight regulation of their activity is required. One level of control is provided by ubiquitination of the homotrimeric DNA clamp PCNA at lysine residue 164 (PCNA-Ub). We here show that Polκ can function independently of PCNA modification and that Polη can function as a backup during TLS of MMS-induced lesions. Compared to cell lines deficient for PCNA modification (Pcna(K164R)) or Polκ, double mutant cell lines display hypersensitivity to MMS but not to BPDE or UV-C. Double mutant cells also displayed delayed post-replicative TLS, accumulate higher levels of replication stress and delayed S-phase progression. Furthermore, we show that Polη and Polκ are redundant in the DNA damage bypass of MMS-induced DNA damage. Taken together, we provide evidence for PCNA-Ub-independent activation of Polκ and establish Polη as an important backup polymerase in the absence of Polκ in response to MMS-induced DNA damage.


A study of the partitioning of the first-order reduced density matrix according to the theory of atoms in molecules.
This work describes a simple spatial decomposition of the first-order reduced density matrix corresponding to an N-electron system into first-order density matrices, each of them associated to an atomic domain defined in the theory of atoms in molecules. A study of the representability of the density matrices arisen from this decomposition is reported and analyzed. An appropriate treatment of the eigenvectors of the matrices defined over atomic domains or over unions of these domains allows one to describe satisfactorily molecular properties and chemical bondings within a determined molecule and among its fragments. Numerical determinations, performed in selected molecules, confirm the reliability of our proposal.


Lycopene, Tomato Products, and Prostate Cancer Incidence: A Review and Reassessment in the PSA Screening Era.
Lycopene has been proposed to protect against prostate cancer through various properties including decreased lipid oxidation, inhibition of cancer cell proliferation, and most notably potent antioxidant properties. Epidemiologic studies on the association between lycopene and prostate cancer incidence have yielded mixed results. Detection of an association has been complicated by unique epidemiologic considerations including the measurement of lycopene and its major source in the diet, tomato products, and assessment of prostate cancer incidence and progression. Understanding this association has been further challenging in the prostate-specific antigen (PSA) screening era. PSA screening has increased the detection of prostate cancer, including a variety of relatively indolent cancers. This paper examines the lycopene and prostate cancer association in light of epidemiologic methodologic issues with particular emphasis on the effect of PSA screening on this association.


A novel investigation of a micropolar fluid characterized by nonlinear constitutive diffusion model in boundary layer flow and heat transfer.
The rheological and heat-conduction constitutive models of micropolar fluids (MFs), which are important non-Newtonian fluids, have been, until now, characterized by simple linear expressions, and as a consequence, the non-Newtonian performance of such fluids could not be effectively captured. Here, we establish the novel nonlinear constitutive models of a micropolar fluid and apply them to boundary layer flow and heat transfer problems. The nonlinear power law function of angular velocity is represented in the new models by employing generalized "n-diffusion theory," which has successfully described the characteristics of non-Newtonian fluids, such as shear-thinning and shear-thickening fluids. These novel models may offer a new approach to the theoretical understanding of shear-thinning behavior and anomalous heat transfer caused by the collective micro-rotation effects in a MF with shear flow according to recent experiments. The nonlinear similarity equations with a power law form are derived and the approximate analytical solutions are obtained by the homotopy analysis method, which is in good agreement with the numerical solutions. The results indicate that non-Newtonian behaviors involving a MF depend substantially on the power exponent n and the modified material parameter [Formula: see text] introduced by us. Furthermore, the relations of the engineering interest parameters, including local boundary layer thickness, local skin friction, and Nusselt number are found to be fitted by a quadratic polynomial to n with high precision, which enables the extraction of the rapid predictions from a complex nonlinear boundary-layer transport system.


Gold-Catalyzed Intramolecular Cyclization of N-Propargylic β-Enaminones for the Synthesis of 1,4-Oxazepine Derivatives.
An efficient and mild one-pot, gold-catalyzed intramolecular cyclization of N-propargylic β-enaminones has been achieved for the generation of 1,4-oxazepine derivatives. This synthetic transformation tolerates a range of substituted N-propargylic β-enaminones in moderate to good yields.


[Hungarian university lecturers and professors of pathology from Arányi to the present days].
Lajos Arányi (Lostainer), who introduced pathological anatomy into Hungary, was born in Komárom in 1812. He lost his father at the age of three, and then was adopted by one of his wealthy uncles. Arányi first studied at the faculty of arts and later law at university, but after a cholera epidemic in 1831, in which he helped the infected in Pest, he changed his mind and went over to the faculty of medicine. After he had received his degree he worked as an assistant to Ferenc Bene from 1837. Two years later he spent six months at Italian clinics, and four years in Vienna. In Vienna, where he worked with Professor Rokitansky at the Allgemeines Krankenhaus, he learned the techniques of pathology, and studied the humouralpathological theory of his principal, and above all the clinicopathologic views of the Vienna medical school. Returning home he decided to introduce patholoogy into the medical curriculum. In his objectives he was helped by Ignác Stáhly, Agost Schöpf-Merei and János Balassa. His introductory lecture took place in 10 April 1844, and his regular lectures and demonstrations started from the autumn. His autopsy records were rather modern, he used clear and logical categories. ...


[Paroxysmal tachyarrhythmias in pediatrics].
The purpose of this retrospective study was to investigate the clinical characteristics in pediatric patients with supraventricular or ventricular tachycardia. Sixty-nine pediatric patients were included. Age distribution at first episode of tachyarrythmia, most indicative symptoms and signs, associated conditions and long-term prognosis were determined for the different mechanisms of tachyarrythmia. 78% of the children had supraventricular tachycardia and 22% ventricular tachycardia. At diagnosis, 57% of the children with supraventricular tachycardia were younger than 1 year. The majority of infants were detected during routine investigation without having any complaints whereas the majority of children presented with symptoms. Recurrence was rare in cases diagnosed during infancy, but was usual in cases diagnosed beyond infancy.


Use of flat panel DynaCT myelography to locate the site of CSF leak.
Spontaneous intracranial hypotension is often treated conservatively or with epidural blood patch. Patients who are resistant to these treatments require accurate imaging localisation of the site of cerebrospinal fluid (CSF) leak for surgical repair. We describe two patients where MRI, CT myelography and MRI gadolinium myelography showed evidence of a large volume of epidural CSF, but failed to identify the pressure site of leak. Subsequently, DynaCT (Siemens, Erlangen, Germany) accurately identified the site with confidence in both cases, confirmed at surgery. This technique of using a flat panel detector-based, angiographic system to produce high quality, high-contrast multiplanar CT images for detecting the source of rapid CSF leak is detailed.


Effect of atropine on the plasma cholecystokinin response to intraduodenal fat in man.
The present study was undertaken to determine whether atropine inhibits the plasma cholecystokinin (CCK) response to intraduodenal fat. Plasma CCK concentrations were measured by radioimmunoassay using two sequence-specific antibodies. Antibody 1703 bound to all COOH-terminal CCK peptides containing at least 14 amino acid residues, while antibody T204 was specific for the sulphated tyrosine region of CCK. Intraduodenal instillation of 60 ml corn oil in 6 normal subjects induced significant increases in plasma CCK. Intravenous administration of atropine (0.015 mg/kg as bolus followed by 0.005 mg/kg X h over 3 h) resulted in significant inhibition of plasma CCK concentrations at 10, 20 and 30 min (antibody 1703) and at 20 and 30 min (antibody T204 ) after instillation of fat. However, the peak increments in plasma CCK during atropine (8.6 +/- 1.9 pmol/l, antibody 1703; 5.4 +/- 1.1 pmol/l, antibody T204 ) were not different from those found without atropine (6.3 +/- 0.8 pmol/l, antibody 1703; 3.9 +/- 0.9 pmol/l, antibody T204 ). Similarly, the integrated plasma CCK secretion after intraduodenal fat was not significantly different when measured during atropine (461 +/- 119 pmol/l X 3 h, antibody 1703; 269 +/- 97 pmol/l X 3 h, antibody T204 ) and without atropine (428 +/- 62 pmol/l X 3 h, antibody 1703; 188 +/- 66 pmol/l X 3 h). It is concluded that administration of atropine delays but does not inhibit the CCK response to intraduodenal corn oil in man.


Recent Trends in Graphene-Based Sorbents for LC Analysis of Food and Environmental Water Samples.
This review provides an overview of recent advancements in applying graphene-based materials as sorbents for liquid chromatography (LC) analysis. Graphene-based materials are promising for analytical chemistry, including applications as sorbents in liquid chromatography. These sorbents can be functionalized to produce unique extraction or stationary phases. Additionally, graphene-based sorbents can be supported in various materials and have consequently been applied to produce various devices for sample preparation. Graphene-based sorbents are employed in diverse applications, including food and environmental LC analysis. This review summarizes the application of graphene-based materials in food and environmental water analysis in the last five years (2019 to 2023). Offline and online sample preparation methods, such as dispersive solid phase microextraction, stir bar sorptive extraction, pipette tip solid phase extraction, in-tube solid-phase microextraction, and others, are reviewed. The review also summarizes the application of the columns produced with graphene-based materials in separating food and water components and contaminants. Graphene-based materials have been reported as stationary phases for LC columns. Graphene-based stationary phases have been reported in packed, monolithic, and open tubular columns and have been used in LC and capillary electrochromatography modes.


Laplace-Beltrami based multi-resolution shape reconstruction on subdivision surfaces.
The eigenfunctions of the Laplace-Beltrami operator have widespread applications in a number of disciplines of engineering, computer vision/graphics, machine learning, etc. These eigenfunctions or manifold harmonics (MHs) provide the means to smoothly interpolate data on a manifold and are highly effective, specifically as it relates to geometry representation and editing; MHs form a natural basis for multi-resolution representation (and editing) of complex surfaces and functions defined therein. In this paper, we seek to develop the framework to exploit the benefits of MHs for shape reconstruction. To this end, a highly compressible, multi-resolution shape reconstruction scheme using MHs is developed. The method relies on subdivision basis sets to construct boundary element isogeometric methods for analysis and surface finite elements to construct MHs. This technique is paired with the volumetric source reconstruction method to determine an initial starting point. The examples presented highlight efficacy of the approach in the presence of noisy data, including a significant reduction in the number of degrees of freedom for complex objects, accuracy of reconstruction, and multi-resolution capabilities.


Disrupted IGF2 promoter control by silencing of promoter P1 in human hepatocellular carcinoma.
Previous investigations have supported or indicated a stimulatory role of the insulin-like growth factor II gene (IGF2) in hepatocarcinogenesis. We have studied the transcript levels, promoter usage, and imprinting status of the ICF2 gene and its relationship to H19 in human hepatocellular carcinomas (HCCs) and liver tumor cell lines. The activity of the IGF2 promoter P1 was lost in about 70% of the cases (18 of 25). This is the most prominent abnormality regarding the IGF2 regulation in this study. Total IGF2 as well as promoter P3 transcription were up-regulated in a small group of the tumors. Twenty genetically informative cases were obtained from 26 cases, thus excluding the probability of loss of heterozygosity of the IGF2 gene. Among these, nine showed abnormal monoallelic expression of IGF2. One HCC and one HCC cell line proved loss of functional imprinting of IGF2. H19 and IGF2 were regulated in parallel, and expression levels were variable. Taken together, the disruption of the IGF2 promoter regulation, particularly the loss of P1 activity, is a common feature of human HCCs. The loss of P1 activity explains the frequent loss of biallelic IGF2 expression and may potentially be used as a diagnostic or monitoring marker for human HCC.


Bee Pollen Flavonoids as a Therapeutic Agent in Allergic and Immunological Disorders.
Bee pollen grains, as the male reproductive part of seed-bearing plants contain considerable concentrations of various phytochemicals and nutrients. Since antiquity, people throughout the world used pollens to cure colds, flu, ulcers, premature aging, anemia and colitis. It is now well-documented that some bee pollen secondary metabolites (e.g. flavonoid) may have positive health effects. In recent years, the flavonoids have attracted much interest because of their wide range of biological properties and their beneficial effects on human health. The current review, points out potential therapeutic effects of bee pollen flavonoids as one of the main bee pollen bioactive compounds in allergic and immunological diseases. Due to the fact that some types of flavonoid components in bee pollen have anti-allergic, anti-oxidant and anti-inflammatory properties, bee pollen flavonoids can be excellent candidates for future studies including phytotherapy, molecular pharmacology and substitutes for chemicals used in treating allergic and immunological disorders.


Sublingual administration of warfarin: a novel form of delivery.
Current therapy for venous thromboembolism (VTE) includes the initiation of short acting parenteral agents, heparin, low-molecular-weight heparin, or fondaparinux, with subsequent conversion to oral warfarin therapy for the duration of anticoagulation. We present two patients who required long-term anticoagulation for VTE but because of gastrointestinal dysmotility issues were unable to use standard oral anticoagulation. Warfarin is water soluble and absorbed across the epithelium; therefore, we elected to administer warfarin sublingually in an effort to avoid the dysmotility issues while trying to achieve therapeutic anticoagulation. Using sublingual warfarin dosing we were able to achieve therapeutic anticoagulation without complications. Both patients required approximately 6 days to achieve a therapeutic International Normalized Ratio (INR). Neither patient reported adverse side effects related to the sublingual dosing. This unique form of warfarin delivery may be considered for patients with gastrointestinal dysmotility or other gastrointestinal issues which prevent oral use of medications.


A systematic review of economic evaluations in second and later lines of therapy for the treatment of non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) is associated with high morbidity and mortality. Surgery is generally accepted as the first-line treatment in patients with advanced/metastatic NSCLC, followed by radiotherapy and chemotherapy as second-line treatments. Docetaxel or erlotinib are generally recommended as the first-line chemotherapy option. The objective of this review was to identify previously published economic evaluations in NSCLC for second- and later-line treatments in order to (i) determine common modelling approaches and (ii) establish the relative cost effectiveness of these treatments. An overview of model critique was also produced to identify common criticisms from health technology assessment (HTA) bodies on the models submitted. MEDLINE, Embase, EconLit, MEDLINE in Process(®) and NHS Economic Evaluation Database (NHSEED) were searched (database start-October 2011), along with proceedings from eight major conferences (2007-2011). National Institute for Health and Clinical Excellence (NICE), Scottish Medicines Consortium (SMC), Pharmaceutical Benefits Advisory Committee (PBAC) and Canadian Agency for Drugs and Technologies in Health (CADTH) websites and the International Network of Agencies for Health Technology Assessment (INAHTA) database were also searched for appraisals in second- or later-line NSCLC. All published studies and HTA appraisals that reported economic evaluations of interventions used in current clinical practice as second- or later-line treatment in patients with advanced/metastatic NSCLC were included. Only studies in English were considered for inclusion. Studies which met the eligibility criteria after the screening of full-text articles were extracted by a reviewer and checked by a second party. Where multiple publications were identified describing a single study, the extracted data were compiled into one entry. A total of 29 studies were included which clearly evaluated second-line or later-line regimens. Most studies were either cost-effectiveness or cost-utility evaluations. Three-state transition Markov models were frequently used in cost-effectiveness and cost-utility evaluations. The model inputs were well reported and commonly consisted of data from pivotal trials. Sensitivity analyses were conducted in the majority of studies and covered variables such as cost, effectiveness, hospitalization and treatment duration. Therapies (docetaxel, pemetrexed and erlotinib) are for the most part cost-effective/cost-saving second-line therapies compared with best supportive care (BSC). Six erlotinib HTAs, across NICE, SMC, and PBAC, and four pemetrexed HTAs, one by NICE and three by SMC, were identified. The CADTH website did not provide sufficient detail on the appraisals and was excluded. Certain aspects of the models and model assumptions, e.g. efficacy inputs, were criticized or determined unjustifiable by the NICE, SMC and PBAC appraisal committees. Erlotinib and pemetrexed were considered to be cost effective versus docetaxel by NICE and SMC in the final submissions. PBAC considered erlotinib to be cost effective versus BSC following a price reduction in 2008. Three-state Markov models are often used to conduct economic analysis in NSCLC and are regarded as appropriate to HTA agencies. Docetaxel, erlotinib and BSC are suitable comparators that should be considered for use in the model in the UK and Australia. Further, manufacturers should carefully select underlying assumptions used in the model, for both costs and clinical inputs, where the latter is derived from direct head-to-head trial data.


[Immunopathological analysis of T and non-T cell involvement in corneal inflammation caused by HSV type-1 infection].
In herpetic keratitis, the role of T cell subsets is not clearly understood although the involvement of cell-mediated immunity has been reported. The purpose of this paper is to analyse T cell-mediated immunopathological conditions and the role of non-T cell lineage in herpetic stromal keratitis employing nude (nu/nu) and Balb/c mice. All mice were divided into three groups. Group 1: Herpes simplex virus type 1 (HSV-1)-inoculated nu/nu mice. Group 2: HSV-1-inoculated nu/nu mice with interleukin-2 (IL-2). Group 3: HSV-1-inoculated Balb/c mice. The conditions of the disease were compared in those three groups clinically and by using histological and immunopathological staining. Following antibodies were employed: anti-Asialo GMI (natural killer). anti-Thy 1 (pan-T). anti-L3T4 (helper/inducer), anti-Lyt 2 (suppressor/killer), anti-Mac 3 (macrophage), anti-Mice Immunoglobulins (monocyte. B.). Corneal lesions showed a reduced inflammatory tendency in nu/nu mice. Topical application of IL-2 in nu/nu mice induced moderate stromal inflammation compared with nu/nu mice. However, the severity of these was less than in Balb/c. Many natural killer cells (NK) were found in nu/nu mice but few in Balb/c mice. These results confirm the involvement of T-cell mediated immunity in stromal inflammation and indicate that NK cell may have an important role in suppressed T-cell immunity in nu/nu mice but are not involved in stromal inflammation.


The distinct profiles of the inhibitory effects of fluensulfone, abamectin, aldicarb and fluopyram on Globodera pallida hatching.
Fluensulfone is a nematicide with a novel mode of action against plant parasitic nematodes. Here, we utilize in vitro hatching assays to investigate fluensufone's ability to inhibit Globodera pallida hatching, relative to the efficacy of other distinct classes of nematicides. Fluensulfone, abamectin, aldicarb and fluopyram inhibit G. pallida hatching from cysts more potently than from isolated eggs. At 1 μM for cysts, the order of potency is fluensulfone> fluopyram> abamectin> aldicarb. At low concentrations of fluensulfone, inhibition of hatching is reversible, however, more than 50% of the juveniles that hatch from cysts pre-treated with fluensulfone have reduced motility. This is observed to a lesser extent with abamectin, fluopyram and aldicarb. When cysts are exposed to higher concentrations of fluensulfone (≥500 μM), abamectin (≥100 μM) and fluopyram (≥50 μM) inhibition of hatching is irreversible. This results from the loss of encysted juvenile structure giving rise to a granulated appearance consistent with necrosis, suggesting a nematicidal effect. Intriguingly, hatching initiated by root diffusate is arrested when egg populations are subsequently exposed to fluensulfone. Fluensulfone, abamectin, fluopyram and aldicarb inhibit G. pallida hatching. Fluensulfone is a potent inhibitor of hatching and impacts on the viability of the J2 s emerging from the cysts. This activity, and the previously described impaired motility and metabolism of hatched juveniles, show that fluensulfone's distinct mode of action among existing nematicides intersects at two pivotal steps of the parasitic life cycle.


[Inhibition of HBV replication and antigen expression by RNA interference against different targets].
To observe the inhibition of HBV replication and antigen expression by RNA interference aimed at different parts of the HBV genome. Following the rules of shRNA expression vector design and construction, we constructed seven kinds of sequence specific vectors and two kinds of mutant shRNA expression ones. We then cotransfected those shRNA and HBV expression vectors into HepG2 cells using lipofectamine2000. The level of HBV replication was investigated using Southern blot and the antigen expression using ELISA. The replication of HBV DNA was inhibited by many shRNAs, especially the ones against P1, S2, C2, S1 and X. The inhibition rate against P1 was as high as 95%. Results obtained with ELISA showed that the shRNAs targeting C2, C1 and S2 had high rates of inhibition to HBsAg. The replication and antigen expression of HBV could be inhibited by shRNAs aimed at four different open read frames, and higher inhibition rates of HBV replication and surface antigen expression could be obtained by P1 and C2, respectively.


Adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration.
Increased vascular endothelial cell (EC) permeability and neutrophilic leukocyte (PMN) diapedesis through paracellular gaps are cardinal features of acute inflammation. Activation of the EC contractile apparatus is necessary and sufficient to increase vascular permeability in specific models of EC barrier dysfunction. However, it is unknown whether EC contraction with subsequent paracellular gap formation is required for PMN transendothelial migration in response to chemotactic factors. To test this possibility, we assessed migration of human PMNs across confluent bovine pulmonary arterial EC monolayers. Transendothelial PMN migration in the absence of a chemotactic gradient was minimal, whereas abluminal addition of leukotriene B4 (LTB4; 5 microM) resulted in significantly increased PMN migration. Reductions in EC myosin light chain kinase (MLCK) activity by EC monolayer pretreatment with specific MLCK inhibitors (KT-5926 or ML-7) or by increases in cAMP-protein kinase A activity (cholera toxin) significantly reduced PMN transmigration (30-70% inhibition). In contrast, pretreatment with the myosin-associated phosphatase inhibitor calyculin resulted in the accumulation of phosphorylated myosin light chains, EC contraction, and significantly enhanced PMN migration. Finally, the interaction of PMNs with 32P-labeled EC monolayers was shown to directly increase EC myosin phosphorylation in a time-dependent fashion. Taken together, these results are consistent with the hypothesis that the phosphorylation status of EC myosin regulates PMN migration and further indicate that EC MLCK is activated by chemoattractant-stimulated PMNs. Neutrophil-dependent activation of the EC contractile apparatus with subsequent paracellular gap formation may be a key determinant of transendothelial PMN migration responses to chemotactic agents.


[Antioxidant vitamin supplementation in the prevention of cardiovascular disease].
Oxidative stress, in particular oxidative modification of LDL-cholesterol, appears to be of great importance in the pathogenesis of atherosclerosis. Various observational epidemiological studies have suggested that antioxidant vitamin intake is associated with reduced cardiovascular morbidity and mortality. Also, experimental studies in animals have demonstrated that antioxidant vitamins slow the progression of atherosclerosis. However, prospective controlled clinical trials have failed to demonstrate a benefit of antioxidant vitamin supplementation in primary or secondary prevention of cardiovascular disease. Thus, the use of antioxidants and vitamin supplements as a preventive or therapeutic intervention can not be recommended.


A workflow for mathematical modeling of subcellular metabolic pathways in leaf metabolism of Arabidopsis thaliana.
During the last decade genome sequencing has experienced a rapid technological development resulting in numerous sequencing projects and applications in life science. In plant molecular biology, the availability of sequence data on whole genomes has enabled the reconstruction of metabolic networks. Enzymatic reactions are predicted by the sequence information. Pathways arise due to the participation of chemical compounds as substrates and products in these reactions. Although several of these comprehensive networks have been reconstructed for the genetic model plant Arabidopsis thaliana, the integration of experimental data is still challenging. Particularly the analysis of subcellular organization of plant cells limits the understanding of regulatory instances in these metabolic networks in vivo. In this study, we develop an approach for the functional integration of experimental high-throughput data into such large-scale networks. We present a subcellular metabolic network model comprising 524 metabolic intermediates and 548 metabolic interactions derived from a total of 2769 reactions. We demonstrate how to link the metabolite covariance matrix of different Arabidopsis thaliana accessions with the subcellular metabolic network model for the inverse calculation of the biochemical Jacobian, finally resulting in the calculation of a matrix which satisfies a Lyaponov equation. In this way, different strategies of metabolite compartmentation and involved reactions were identified in the accessions when exposed to low temperature.


Highly enantioselective synthesis of atropisomeric anilide derivatives through catalytic asymmetric N-arylation: conformational analysis and application to asymmetric enolate chemistry.
In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).


Idiopathic arterial calcification of infancy-- peritoneal dialysis for treatment of hypertension.
Idiopathic infantile arterial calcification (IIAC) is a rare autosomal recessive disease usually diagnosed postmortem. The clinical presentation is not typical, but usually implies refractory hypertension and cardiorespiratory failure. We present a case of a newborn with IIAC who had fetal hydrops and refractory hypertension which normalized soon after initialization of peritoneal dialysis. With this case report, we wanted to highlight that peritoneal dialysis may be beneficial an effective therapeutic option for patients with IIAC and severe refractory hypertension. Until now, peritoneal dialysis was never performed in the treatment of patients with IIAC.


Family resources and parental health in families of children with Duchenne muscular dystrophy.
This study was based on two models, namely, the resiliency model of family stress, adjustment, and adaptation and the model for family stressors, resources, and function. Family resources, such as family hardiness and support, have previously been shown to improve family adaptation. There is little evidence for the potential buffering effects of family resources on parental health in families of children with Duchenne muscular dystrophy (DMD). This article reports on relationships among family support, family hardiness, severity of child disability, and parental perceptions of child health status variables and their influence on parental health in families of children with DMD in Taiwan. A total of 126 parents, all with children suffering from DMD, were recruited for this study. Associations between child health status, age at diagnosis, demographics, and family resource variables were examined using Pearson linear correlation, linear regression, and causal modeling. Parental employment and education, perceived child health, family hardiness, and family support were found to correlate with parental health. Age at diagnosis correlated with family hardiness but not directly with parental health. Nursing intervention to promote family hardiness and support can help maintain parental health and promote family adaptation in the face of a child's chronic disease. Caregiving programs should also promote parental health by enhancing family hardiness and support. Family members' support through health promotion, psychological and spiritual care, financial support, and convenient community services can lead to better parental health and contribute to overall family health and adaptation.