Rights, laws and tensions: A comparative analysis of the Convention on the Rights of Persons with Disabilities and the WHO Resource Book on Mental Health, Human Rights and Legislation.
Good mental health legislation is essential for ensuring high quality mental health care and protecting human rights. Many countries are attempting to bring mental health legislation in line with the UN - Convention on the Rights of Persons with Disability (UN-CRPD). The UN-CRPD requires policy-makers to rethink the 'medical model' of mental illness and existing laws. It also challenges WHO guidelines on drafting mental health law, described in the WHO Resource Book on Mental Health, Human Rights and Legislation (WHO-RB). This study examines the relationship between the UN-CRPD and the WHO-RB. It compares the documents, highlighting similarities and identifying areas of disagreement. The WHO-RB contains a checklist of human rights standards it recommends are met at national level. This study analyses each component on this checklist and identifies the relevant sections in the UN-CRPD that pertain to each. Both the UN-CRPD and WHO-RB address more than just acute exacerbations of illness, providing guidelines on, inter alia, treatment, education, occupation and housing. They are patient-centred and strongly influenced by social rights. The UN-CRPD, however, gives just superficial consideration to the management of acute illness, forensic and risk issues, and does little to identify the role of family and carers. The UN-CRPD has evolved from disability research and strong advocacy organisations. Careful consideration is needed to enable it to address the specific needs encountered in mental illness. Both the UN-CRPD and WHO-RB highlight common tensions that must be resolved by clinicians, and provide some guidance for stakeholders who commonly need to observe one principle at the expense of another.


Highly efficient capture of uranium from seawater by layered double hydroxide composite with benzamidoxime.
Through swelling/restoration reaction, benzamidoxime (BAO) is introduced into MgAl-LDH interlayers to assemble a new composite of MgAl-BAO-LDH (abbr. BAO-LDH). Wet samples of the BAO-LDH obtained by washing with diverse solvents are present in colloidal state, which facilitates the fabrication of thin film adsorbents convenient for actual application. After drying, the assembled sample exhibits floral morphology composed of thin nanosheets, much different from hexagonal morphology of NO3- intercalated MgAl-LDH precursor (NO3-LDH), demonstrating a phenomenon rarely found in swelling/restoration. The BAO-LDH depicts an extremely large maximum sorption capacity (qmU) of 327 mg·g-1 and ultra-high selectivity for U. At low U concentrations (5-10 ppm), nearly complete capture (~100%) is achieved in a wide pH range of 3-11, while at high U concentrations (110 ppm), quite high U removals (≥93.0%) are obtained at pH = 6-8, meaning perfect suitability for trapping U from seawater. For natural seawater containing trace amounts of U (3.93 ppb) coexisting with high concentration of competitive ions, the BAO-LDH displays significantly high U removal (87%). Complexation between interlayer BAO (N and O as ligands) with UO22+ and synergistic interactions of LDH layer hydroxyls with UO22+ contribute to the highly effective uranium capture. All results demonstrate the BAO-LDH is a promising adsorbent applied in seawater uranium extraction and nuclear wastewater disposal.


Visual loss as the initial manifestation of an ignored disseminated prostate cancer: A case report.
To present a rare case of advanced disseminated prostate cancer with bilateral visual loss as the initial manifestation of the disease. A 55-year-old man referring progressive visual blurring for the last 6 months and painless severe bilateral visual loss in the last 7 days prior to our consultation, associated with a bilateral optic disc swelling and leptomeningeal metastases from a previously ignored prostate carcinoma is presented. Rapid improvement of visual acuity and involution of leptomeningeal metastasis was observed after initiation of the specific oncologic treatment. Bilateral visual loss may be the initial manifestation of leptomeningeal carcinomatosis from an ignored prostate cancer. Prompt diagnosis is crucial in order to improve the quality of life of a critically ill patient with a disseminated prostate cancer.


Expression of a functional cold active β-galactosidase from Planococcus sp-L4 in Pichia pastoris.
Lactase deficiency problem discourages many adults from consuming milk as a major source of micro- and macronutrients. Enzymatic hydrolysis of lactose is an ideal solution for this problem but such processing adds significant costs. In this study, a cold active β-galactosidase from Planococcus sp-L4 (bgal) was optimized for expression of recombinant "BGalP" in Pichia pastoris. As a result of codon optimization, the codon adaptation index was improved from 0.58 to 0.85 after replacing rare codons. After transformation of two P. pastoris strains (KM71H and GS115), the activity of BGalP enzyme was measured in the culture supernatants using ortho-Nitrophenyl-β-galactoside (ONPG). Maximal activity was recorded as 3.7U/ml on day 11 in KM71H clone #2 which was 20% higher than the best GS115 clone. Activity measurements under different conditions indicated optimal activity at pH 6.5. It was active at temperatures ranging from 0 to 55°C with deactivation occurring at or above 60°C. Protein analysis of the crude ultra-filtrate showed the enzyme was ∼75kDa and was the major constituent (85%) of the sample. This enzyme have the potential to find utility for the breakdown of lactose in chilled milk and subsequently can be deactivated by pasteurization. The use of BGalP would minimize energy consumption thus decreasing cost and also help to preserve the nutritional elements of the milk.


Measuring musical abilities of autistic children.
Three normal children with reported musical ability and three autistic children were tested for the ability to imitate individual tones and series of tones delivered by voice, piano, and synthesizer. Accuracy of imitation was judged by two independent observers on the basis of pitch, rhythm, and duration. The autistic children overall performed as well as or better than the age-matched normal children. These results are discussed and their implications for future neurological and clinical research are considered.


NOGO-66 receptor deficient mice show slow acquisition of spatial memory task performance.
The Nogo-66 receptor (NgR1) is part of a co-receptor complex on neurons that transmits a signal for inhibition of neurite outgrowth. In addition, NgR1 function has also been related to other disorders such as schizophrenia and Alzheimer's disease. Here, we studied the effect of life-long deletion of NgR1 (ngr(-/-)) in tests for cognition and positive symptoms of schizophrenia. In the water maze, ngr(-/-) mice learned to locate the hidden platform as well as wild type mice, although with slower acquisition. Deletion of NgR1 did not affect amphetamine- or phencyclidine (PCP)-induced hyperactivity, two models of positive symptoms of schizophrenia. Taken together, ngr(-/-) animals show slower acquisition of a spatial learning and memory task.


Exon-level expression analyses identify MYCN and NTRK1 as major determinants of alternative exon usage and robustly predict primary neuroblastoma outcome.
Using mRNA expression-derived signatures as predictors of individual patient outcome has been a goal ever since the introduction of microarrays. Here, we addressed whether analyses of tumour mRNA at the exon level can improve on the predictive power and classification accuracy of gene-based expression profiles using neuroblastoma as a model. In a patient cohort comprising 113 primary neuroblastoma specimens expression profiling using exon-level analyses was performed to define predictive signatures using various machine-learning techniques. Alternative transcript use was calculated from relative exon expression. Validation of alternative transcripts was achieved using qPCR- and cell-based approaches. Both predictors derived from the gene or the exon levels resulted in prediction accuracies >80% for both event-free and overall survival and proved as independent prognostic markers in multivariate analyses. Alternative transcript use was most prominently linked to the amplification status of the MYCN oncogene, expression of the TrkA/NTRK1 neurotrophin receptor and survival. As exon level-based prediction yields comparable, but not significantly better, prediction accuracy than gene expression-based predictors, gene-based assays seem to be sufficiently precise for predicting outcome of neuroblastoma patients. However, exon-level analyses provide added knowledge by identifying alternative transcript use, which should deepen the understanding of neuroblastoma biology.


Progenitor Biological Bandages: An Authentic Swiss Tool for Safe Therapeutic Management of Burns, Ulcers, and Donor Site Grafts.
Clinical experience gathered over two decades around therapeutic use of primary human dermal progenitor fibroblasts in burn patient populations has been at the forefront of regenerative medicine in Switzerland. Relative technical simplicity, ease of extensive serial multitiered banking, and high stability are major advantages of such cell types, assorted to ease of safety and traceability demonstration. Stringent optimization of cell source selection and standardization of biobanking protocols enables the safe and efficient harnessing of the considerable allogenic therapeutic potential yielded by primary progenitor cells. Swiss legal and regulatory requirements have led to the procurement of fetal tissues within a devised Fetal Progenitor Cell Transplantation Program in the Lausanne University Hospital. Proprietary nonenzymatic isolation of primary musculoskeletal cell types and subsequent establishment of progeny tiered cell banks under cGMP standards have enabled safe and effective management of acute and chronic cutaneous affections in various patient populations. Direct off-the-freezer seeding of viable dermal progenitor fibroblasts on a CE marked equine collagen scaffold is the current standard for delivery of the therapeutic biological materials to patients suffering from extensive and deep burns. Diversification in the clinical indications and delivery methods for these progenitor cells has produced excellent results for treatment of persistent ulcers, autograft donor site wounds, or chronic cutaneous affections such as eczema. Herein we describe the standard operating procedures for preparation and therapeutic deployment of the progenitor biological bandages within our translational musculoskeletal regenerative medicine program, as they are routinely used as adjuvants in our Burn Center to treat critically ailing patients.


The combination of area under the curve and percentage change in estimated glomerular filtration rate predicts long-term outcome of kidney transplants.
The development of surrogate markers for long-term outcomes of kidney transplant (KT) is a focus of attention. We examined the possibility of using a combination of the area under the curve of estimated glomerular filtration rate (eGFR) for 2 years (AUCeGFR2yrs ) and percent change in eGFR between 1 and 2 years after KT (% changeeGFR1/2yr ) as a surrogate marker. We compared the predictive power of death-censored graft failure with various combinations. The combination of >2% vs ≤2% for % changeeGFR1/2yr and >1300 vs ≤1300 mL/min/month for AUCeGFR2yr had the highest Harrell C-index (0.647; 95% confidence interval [95% CI], 0.604-0.690). The death-censored graft survival rate of the group with ≤2% changeeGFR1/2yr and ≤1300 mL/min/month AUCeGFR2yr was significantly lower than those of other groups. The AUC/% change eGFR had comparable predictive power to the previously identified marker ≥30% decline in eGFR between years 1 and 3 after KT (≤-30% changeeGFR1/3yr ) (Harrell's C-index = 0.645 [95% CI 0.628-0.662] for ≤-30% changeeGFR1/3yr ). The proposed combination might be useful as a surrogate marker in KT trials because it requires a shorter surveillance period than the established marker while having comparable predictive power.


Leaf mines: their effect on leaf longevity.
The effects of a number of factors, notably leaf mining insects, on the longevity of beech and holm oak leaves have been studied. The regular monitoring of individually labelled leaves was complemented by analysis of leaf fall data. Both methods confirm that these mining insects have only a slight impact on their host trees. The presence of first generation Phyllonorycter maestingella mines on beech leaves and winter generation P. messaniella mines on holm oak leaves accelerates leaf loss. Beech leaves mined by second generation P. maestingella and Rhynchaenus fagi did not show this accelerated loss. Their patterns of leaf fall can be explained by within-tree variation in both mine distribution and the timing of leaf fall. It is argued that this premature leaf fall is a damage response, and is not an attempt by the tree to regulate miner numbers.


Adjuvant chemotherapy non-adherence, patient-centered communication, and patient-level factors in elderly breast and colon cancer patients.
We examined patient-level factors (patient characteristics, disease and treatment factors, and patient experience), patient-centered communication (PCCM), and non-adherence to adjuvant chemotherapy (AC) guidelines among breast and colon cancer patients to inform AC adherence promotion and improve clinical outcomes. Descriptive statistics for patient-level factors, PCCM, and AC non-adherence (primary non-adherence, non-persistence at 3 and 6 months) were obtained. Multiple logistic regression models were used to estimate AC non-adherence after accounting for the identified patient-level factors. The majority of the sample (n = 577) were White (87%), breast cancer patients (87%), and reported PCCM (provider communication score ≥ 90%, 73%, provider communication score = 100%, 58%). All three levels of AC nonadherence were significantly higher in breast cancer patients (69%, 81%, and 89% for primary non-adherence, and non-persistence at 3 and 6 months, respectively) than colon cancer patients (43%, 46%, and 62%, respectively). Male sex, survey assistance, and low/average ratings of a personal doctor, specialist, and healthcare were associated with lower PCCM. Older age, breast cancer diagnosis, and diagnosis group following 2007-2009 increased the likelihood of all three levels of AC non-adherence. Comorbidities and PCCM-90 were exclusively associated with non-persistence at 3 months. Adjuvant chemotherapy non-adherence varied by cancer diagnosis and treatment factors. The relationship between PCCM and AC non-adherence differed by level of PCCM, time period, and the presence of comorbidities. AC guideline adherence, communication, and value-concordant treatment should be assessed and compared simultaneously to improve our understanding of their interrelationships.


Negative calcium balance despite normal plasma ionized calcium concentrations during citrate anticoagulated continuous venovenous hemofiltration (CVVH) in ICU patients.
Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients. This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set (n = 324 in 42 patients) and a validation set (n = 441 in 42 different patients). Using mixed linear models, we developed an equation to calculate calcium excretion from routinely available parameters. We retrospectively calculated calcium balance in 788 patients treated with citrate CVVH between 2014 and 2021. Calcium excretion (mmol/24 h) was - 1.2877 + 0.646*[Ca]blood,total * ultrafiltrate (l/24 h) + 0.107*blood flow (ml/h). The mean error of the estimation was - 1.0 ± 6.7 mmol/24 h, the mean absolute error was 4.8 ± 4.8 mmol/24 h. Calculated calcium excretion was 105.8 ± 19.3 mmol/24 h. Mean daily CVVH calcium balance was - 12.0 ± 20.0 mmol/24 h. Mean cumulative calcium balance ranged from - 3687 to 448 mmol. During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH.


Sustained release of isoniazid from polylactide microspheres prepared using solid/oil drug loading method for tuberculosis treatment.
Polylactide (PLA) microspheres were prepared using the solid-in-oil (S/O) spray-drying method to achieve the sustained release of a hydrophilic drug for the treatment of tuberculosis, via intratracheal instillation. Isoniazid (IN), a low-molecular-weight hydrophilic drug, was used as a model drug. The effects of various sizes of micronized IN powder, different drug/polymer ratios, spray-drying process parameters, and drug-release characteristics were studied to optimize the manufacturing parameters. A high entrapment efficiency (87.3%) was obtained using this method; furthermore, the microspheres were spherical and smooth. They were individually and homogenously distributed, with a mean diameter of 5.6 μm; furthermore, they showed a satisfactory extended sustained-release phase. After administration of the microspheres to rats, pulmonary drug concentrations were maintained at a relatively stable level for up to 4 weeks.


Anti-CD23 monoclonal antibody inhibits germline Cepsilon transcription in B cells.
A chimeric macaque/human (PRIMATIZED) anti-CD23 antibody, p6G5G1, demonstrated a strong inhibitory effect on IL-4 and anti-CD40 antibody-stimulated IgE production by human peripheral blood mononuclear cells (PBMCs). RNA analysis by both reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot showed that p6G5G1 inhibited germline Cepsilon RNA synthesis, but had no effect on CD23 mRNA levels. These data suggest that p6G5G1 may inhibit immunoglobulin class switching to IgE through the inhibition of germline Cepsilon RNA synthesis. Early addition of p6G5G1 after stimulation by IL-4 and anti-CD40 was critical for IgE inhibition. In contrast, later addition of p6G5G1 still showed inhibition of increased levels of surface CD23, which is normally upregulated by stimulation with IL-4 and anti-CD40.


Resolution of manic symptoms following unilateral adrenalectomy in patient with primary bilateral macronodular adrenal hyperplasia.
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is often associated with symptoms of cortisol excess, which may include neuropsychological symptoms. We report a patient with PBMAH who presented with manic symptoms that resolved following unilateral adrenalectomy.


New surgical paradigm for open neural tube defects.
An open neural tube defect (ONTD) features an exposed, unclosed neural plate in the form of an expanded, flat, and frequently hefty neural placode. Traditional philosophy of ONTD repair aims at preserving function at any cost, which often means stuffing the entire thick and unwieldy but non-functional placode into a tight dural sac, increasing the likelihood of future tethering of the spinal cord. The same philosophy of attempting to save the whole perimetry of the placode also sometimes leads to inadvertent inclusion of parts of the squamous epithelial membrane surrounding the placode into the reconstructed product, only to form inclusion dermoid cyst causing further injury to the neural tissues. Lastly, defective closure of the caudal primary neural tube usually results in abolition of secondary and junctional neurulation, leaving a defective conus and sacral nerve roots, clinically presenting in most cases with neurogenic bladder and bowel dysfunction. Preserving this trapped but locally active sacral micturition center, isolated from suprasegmental inhibitory moderation, leads to a spastic, hyperactive, low compliance, and high-pressure bladder predisposing to upstream kidney damage, without benefits of normal bladder function. We report the post-natal surgical treatment of 8 newborn infants with ONTD, in which we resected the non-functional portion of the neural placode identified as such by direct spinal cord/placode and nerve root stimulation, as well as by transcortical evoked motor responses to check for suprasegmental corticospinal connectivity. Any part of the placode without local function or upstream connections was resected, and the small caudal spinal cord stump closed with pia-to-pia microsutures. The patients were followed for pre- and post-operative neuro-urological status and with serial magnetic resonance imaging (MRI) at 3 weeks, 6 months, and 2 years post-repair. Follow-up period ranged from birth to 3 years (mean of 24 months). Of the 8 patients analyzed, 7 had a terminal and one a segmental ONTD. Pre-operative neurological level ranged from L4 to S2. Applying our new surgical paradigm, we found no neurological worsening post-operatively. All patients had a neurogenic bladder and bowel dysfunction but none had a high-pressure bladder on urodynamics studies. Early and late MRIs all showed a loose and capacious neural placode to dural sac relationship. None had an inclusion dermoid cyst. We propose a new paradigm for the surgical repair of open neural tube defects with intraoperative neuromonitoring and introduce a safe and reliable technique of placode debulking.


Exosomes from hypoxic endothelial cells have increased collagen crosslinking activity through up-regulation of lysyl oxidase-like 2.
Exosomes are important mediators of intercellular communication. Additionally, they contain a variety of components capable of interacting with the extracellular matrix (ECM), including integrins, matrix metalloproteinases and members of the immunoglobin superfamily. Despite these observations, research on exosome-ECM interactions is limited. Here, we investigate whether the exosome-associated lysyl oxidase family member lysyl oxidase-like 2 (LOXL2) is involved in ECM remodelling. We found that LOXL2 is present on the exterior of endothelial cell (EC)-derived exosomes, placing it in direct vicinity of the ECM. It is up-regulated twofold in EC-derived exosomes cultured under hypoxic conditions. Intact exosomes from hypoxic EC and LOXL2 overexpressing EC show increased activity in a fluorometric lysyl oxidase enzymatic activity assay as well as in a collagen gel contraction assay. Concordantly, knockdown of LOXL2 in exosome-producing EC in both normal and hypoxic conditions reduces activity of exosomes in both assays. Our findings show for the first time that ECM crosslinking by EC-derived exosomes is mediated by LOXL2 under the regulation of hypoxia, and implicate a role for exosomes in hypoxia-regulated focal ECM remodelling, a key process in both fibrosis and wound healing.


Overcoming transport barriers to immunotherapy.
Immunotherapies are designed to treat disease by modulating the activity of immune cells. Here, we consider how anatomy and microphysiology create transport barriers to immunotherapeutic delivery and retention at diseased sites, and summarize recent developments to overcome these barriers by exploiting immunobiology to engineer molecular and cellular engineering approaches. Creating impactful and practical solutions across these diseases requires the integration of the collective expertise of pathologists, clinicians, immunologists, biophysicists, immunoengineers, and more.


Older peoples' narratives of use and misuse of alcohol and psychotropic drugs.
Studies revealed that misuse of drugs and alcohol is an increasing phenomenon among older people (aged 65 years and above), and we know that such misuse is a risk factor for mortality and morbidity. Furthermore, we do not know to what extent older people have experiences, understanding and knowledge about the use and misuse of alcohol and psychotropic drugs. To investigate older peoples' experiences with and reflections on the use and misuse of alcohol and psychotropic drugs among older people. Qualitative interviews with 16 older people were performed during 2013 and 2014. The sample included informants aged from 65 to 92 years from 11 municipalities. The data were analysed by using the phenomenological hermeneutic method. The first theme that arose from the informants' narratives was to be a part of a culture in change that details the informants' experiences with and reflections on the cultural changes regarding the use and misuse of alcohol and psychotropic drugs. This theme is divided into three subthemes: to use and attitudes toward use, to trivialise use and risks of use, and to disclaim responsibility for use and misuse. The second theme, to explain use and misuse involved reasons for the use and misuse of alcohol and psychotropic drugs. It included the subthemes: to be afraid, to be lonely, and to be informed. The study revealed that most informants had experiences with the use of alcohol and psychotropic drugs, but disclaimed any challenges with their use. The use was trivialised and seen as something older people just do. They disclaimed responsibility for their own psychotropic use as their general practitioners were defined as the responsible persons. Moreover, the study showed that the informants had poor knowledge about the risk of use and misuse of alcohol and psychotropic drugs.


[Multiple myeloma of the second cervical vertebrae with C2-C3 translocation. Case report].
A case of 40 years old female with C2 vertebrae destruction caused by multiple myeloma treated surgically has been presented. The tumor has been resected through transoral approach and posterior pharyngeal wall. Posterior fusion has been performed with the use of a bony iliac graft. Good early result has been achieved after 1 month follow-up.


The zinc finger protein NGFI-A exists in both nuclear and cytoplasmic forms in nerve growth factor-stimulated PC12 cells.
The NGFI-A gene, which encodes a zinc finger protein with a predicted molecular mass of congruent to 54 kDa, is rapidly activated in PC12 cells by nerve growth factor (NGF). As a transcription factor, NGFI-A is a potentially important mediator of the cellular response to this growth factor. To characterize this protein, antibodies to four different domains of NGFI-A were raised. Immunogens included a bacterial trpE/NGFI-A fusion protein (A310) and three peptides predicted from the NGFI-A cDNA nucleotide sequence. Three of these antisera recognize two predominant NGFI-A species in NGF-stimulated PC12 cells: a 54-kDa form and a closely spaced doublet at 84 kDa. However, one of these antisera, directed against the last 15 carboxyl terminal residues of NGFI-A, recognizes only the 84-kDa species. Both NGFI-A species are rapidly induced in PC12 cells by NGF, phorbol ester, and the calcium ionophore A23187. Pulse-chase analysis revealed no obvious precursor-product relationship between these two forms and demonstrated that both the 54- and 84-kDa species are short-lived proteins. V8 protease digestion of the 54- and 84-kDa forms resulted in the formation of several small peptides that were common to both species. The digest of each species also contained one large, relatively V8 protease-resistant fragment that was substantially larger in digests of the 84-kDa form. These two fragments contained common epitopes and were derived from the amino-terminal portion of the NGFI-A protein. When NGFI-A was incubated with alkaline phosphatase, the 84-kDa doublet resolved into a single band with slightly increased mobility, indicating that this form is phosphorylated. Cell fractionation studies demonstrated that the 84-kDa species are found exclusively in the nucleus, while the 54-kDa form resides solely in the cytoplasm. It therefore appears that the 54-kDa form lacks the signal necessary for nuclear localization and is missing a portion of the carboxyl terminal domain.


Dietary supplementation of soy germ phytoestrogens or estradiol improves spatial memory performance and increases gene expression of BDNF, TrkB receptor and synaptic factors in ovariectomized rats.
Estrogen or phytoestrogens treatment has been suggested to improve cognitive function of the brain in postmenopausal women. However, there is lack of information on the mechanism of such treatment on the central nervous system. The present study aimed to determine the effects of estradiol and soy germ phytoestrogens on spatial memory performance in ovariectomized rats and to explore the underlying mechanisms affecting the central nervous system. Ovariectomized Sprague-Dawley rats were fed a basic diet supplemented with soy germ phytoestrogens (0.4 g/kg or 1.6 g/kg) or 17β-estradiol (0.15 g/kg) for 12 weeks. At the end of the experiment, animals were evaluated for their spatial learning and memory performance by the Morris Water Maze task. The expressions of brain-derived neurotrophic factor (BDNF) and synaptic formation proteins in the hippocampal tissue were estimated using RT-PCR and ELISA. It was found that rats supplemented with soy germ phytoestrogens or estradiol performed significantly better in spatial memory acquisition and retention when compared to the rats fed on the control diet. Estradiol or the high dose of phytoestrogens treatment significantly increased BDNF concentration and the mRNA levels for BDNF and its TrkB receptors as well as the synaptic formation proteins, synaptophysin, spinophilin, synapsin 1 and PSD-95, in the hippocampal tissue of the experimental animals. It was also found that phytoestrogens, in contrast to estradiol, did not show any significant effect on the vaginal and uteri. Soy germ phytoestrogens, which may be a substitute of estradiol, improved spatial memory performance in ovariectomized rats without significant side-effects on the vaginal and uteri. The memory enhancement effect may relate to the increase in BDNF and the synaptic formation proteins expression in the hippocampus of the brain.


Separation of hemodynamic signals from GCaMP fluorescence measured with wide-field imaging.
Wide-field calcium imaging is often used to measure brain dynamics in behaving mice. With a large field of view and a high sampling rate, wide-field imaging can monitor activity from several distant cortical areas simultaneously, revealing cortical interactions. Interpretation of wide-field images is complicated, however, by the absorption of light by hemoglobin, which can substantially affect the measured fluorescence. One approach to separating hemodynamics and calcium signals is to use multiwavelength backscatter recordings to measure light absorption by hemoglobin. Following this approach, we develop a spatially detailed regression-based method to estimate hemodynamics. This Spatial Model is based on a linear form of the Beer-Lambert relationship but is fit at every pixel in the image and does not rely on the estimation of physical parameters. In awake mice of three transgenic lines, the Spatial Model offers improved separation of hemodynamics and changes in GCaMP fluorescence. The improvement is pronounced near blood vessels and, in contrast with the Beer-Lambert equations, can remove vascular artifacts along the sagittal midline and in general permits more accurate fluorescence-based determination of neuronal activity across the cortex.NEW & NOTEWORTHY This paper addresses a well-known and strong source of contamination in wide-field calcium-imaging data: hemodynamics. To guide researchers toward the best method to separate calcium signals from hemodynamics, we compare the performance of several methods in three commonly used mouse lines and present a novel regression model that outperforms the other techniques we consider.


[Gestural forms of communication in primates. II. The relation of gestures to acoustic signals and tool activities in primate phylogeny].
The connection between the frequency of acoustic signals application, contact and gestural communication and the manipulation activity of Cercopithecidea and Anthropoidea have been examined. A scheme reflecting the changes of correlational behavioural systems at different periods of primate phylogenesis is proposed. The behavioural changes in the connections of gestures, vocalisation and manipulation activity during the process of their transition into the language and labour on the way to hominization are shown. On the basis of the exact data a possible role of gestural an acoustic signals in the origin of language is given.


miR-146b-5p Enhances the Sensitivity of NSCLC to EGFR Tyrosine Kinase Inhibitors by Regulating the IRAK1/NF-κB Pathway.
Although patients with non-small cell lung cancer harboring activating mutations in the epidermal growth factor receptor (EGFR) show good clinical response to EGFR tyrosine kinase inhibitors (TKIs), patients eventually develop acquired resistance. Previous studies have shown that several microRNAs (miRNAs) are involved in EGFR TKI resistance. Here, we aimed to investigate whether miR-146b-5p sensitizes the EGFR TKI-resistant lung cancer cells. Clinical analysis showed that miR-146b-5p expression in lung cancer cells isolated from pleural effusions of treatment-naive patients was significantly higher than that after acquiring resistance to EGFR TKI treatment. Ectopic expression of miR-146b-5p in EGFR TKI-resistant cells enhanced EGFR TKI-induced apoptosis. The same results were observed in EGFR-dependent and -independent osimertinib-resistant primary cancer cells (PE3479 and PE2988). Mechanically, miR-146b-5p suppressed nuclear factor κB (NF-κB) activity and NF-κB-related IL-6 and IL-8 production by targeting IRAK1. A negative correlation was observed between miR-146b-5p and IRAK1 in clinical specimens. In rescue experiments, restoration of IRAK1 expression reversed the effects of miR-146b-5p on EGFR TKI sensitivity and recovered NF-κB-regulated IL-6 and IL-8 production. In conclusion, miR-146b-5p/IRAK1/NF-κB signaling is important in promoting EGFR TKI resistance, and miR-146b-5p may be a useful tool for overcoming EGFR TKI resistance.


Influence of social determinants of health barriers to family management of type 1 diabetes in Black single parent families: A mixed methods study.
US disparities in pediatric type 1 diabetes treatment and outcomes are increasing disproportionately among Black youth and compounded for youth from single parent homes. Despite worsened outcomes, Black youth from single parent homes and their caregivers are underrepresented in pediatric type 1 diabetes research. The purpose of this study was to understand the social determinants of health (SDOH) barriers that may contribute to health disparities and family management in Black youth with type 1 diabetes from single parent homes. A three-phase mixed methods study with self-identified Black single parents of youth with type 1 diabetes from an urban US pediatric diabetes center was conducted. Focus groups and interviews informed development of a parent-generated survey of SDOH barriers to diabetes management. Survey results are presented. A resulting 71 item parent-generated survey was administered to 105 parents. Among all items, most problematic SDOH barriers included lack of social support, managing parent/child diabetes-related stress, difficulties accessing diabetes supplies, pain management, cost of food and diabetes camp, need to take time off from work, lack of skilled school staff, school absences and unsafe neighborhoods. Structural racism related to child welfare reporting, and police targeting were also notable concerns. There is a critical need for clinical, community, and policy-related research and interventions, designed to reduce type 1 diabetes racial health disparities by addressing the impacts of SDOH as drivers of family management outcomes among Black youth from single parent families.


Isoguvacine, isonipecotic acid, muscimol and N-methyl isoguvacine on the GABA receptor in rat sympathetic ganglia.
The GABA-mimetic activities of 4 analogues muscimol, isonipecotic acid, isoguvacine and N-methyl isoguvacine have been examined at the GABA receptor in the rat isolated superior cervical ganglion. The depolarizing action of all 4 analogues could be selectively antagonized by bicuculline methochloride and isopropyl bicyclophosphate. Muscimol was the only analogue more potent than GABA (molar potency ratio = 5.08 +/- 0.707). The potency of isoguvacine was 0.23 +/- 0.026 and isonipecotic acid 0.011 +/- 0.0028. N-methyl isoguvacine was less than 0.001 GABA.


Measuring Post-training Activities Following a Veterinary Teaching Workshop in East Africa.
A teaching workshop was delivered for faculty members of East African colleges of veterinary medicine to foster teaching development and reflection. The goal was for participants to use knowledge gained to improve teaching skills. The approach was to "train the trainer" so attendees could transfer new knowledge to colleagues at their institutions. Techniques were used to increase the likelihood that participants would apply the training. A culturally responsive survey was developed to assess training transfer 1 year later. Pilot survey results suggest that participants applied what they learned and shared with colleagues largely due to peer and supervisor support. The online version contains supplementary material available at 10.1007/s40670-021-01428-2.


Reducing radiation exposure to patients from kV-CBCT imaging.
This study explores methods to reduce dose due to kV-CBCT imaging for patients undergoing radiation therapy. Doses resulting from kV-CBCT scans were calculated using Monte Carlo techniques and were analyzed using dose-volume histograms. Patients were modeled as were CBCT acquisitions using both 360° and 200° gantry rotations. The effects of using the half fan bow-tie and the full fan bow-tie filters were examined. Doses for OBI 1.3 are 15 times (head), 5 times (thorax) and 2 times (Pelvis) larger than the current OBI 1.4. When using 200° scans, the doses to eyes and cord are 0.2 (or 0.65) cGy and 0.35 (or 0.2) cGy when rotating the X-ray source underneath (or above) the patient, respectively. The 360° Pelvis scan dose is 1-2 cGy. The rectum dose is 1.1 (or 2.8) cGy when rotating the source above (or below) the patient with the 200° Pelvis scan. The dose increases up to two times as the patient size decreases. The dose can be minimized by reducing the scan length, the exposure settings, by selecting the gantry rotation angles, and by using the full fan bow-tie whenever possible.


A menagerie of promotional characters: promoting food to children through food packaging.
To determine the extent to which (1) promotional characters are used on food packaging for healthful and less-healthful food and (2) different companies use this persuasive marketing strategy. Cross-sectional supermarket audit of all food and beverages featuring promotional characters on the packaging. Three Australian supermarket chains. Frequency of observed products, package size, nutritional composition. Frequencies and bivariate analyses was conducted. Nutritional composition (healthful vs less healthful) was analyzed by character type and company type, that is, whether the company was signed to the Australian Food and Grocery Council Responsible Marketing to Children Initiative (RMCI) signatory. Products featuring promotional characters on packaging (n = 352) were predominantly less-healthful food and beverages (70%). [corrected]. Nutritional composition varied significantly by character type, with 69% of products with sportspersons, celebrities, or movie tie-ins being healthful, compared with 38% of licensed and 16% [corrected] of company-owned characters. Only 13 of the 75 companies using characters on packaging were RMCI signatory. Promotional characters are largely used on food packaging to promote less-healthful food to children. Most of these characters are company-owned characters that are not subject to any form of regulation in Australia. Further efforts to limit this form of marketing to children are required.


Accuracy of genomic selection for grain yield and agronomic traits in soft red winter wheat.
Genomic selection has the potential to increase genetic gains by using molecular markers as predictors of breeding values of individuals. This study evaluated the accuracy of predictions for grain yield, heading date, plant height, and yield components in soft red winter wheat under different prediction scenarios. Response to selection for grain yield was also compared across different selection strategies- phenotypic, marker-based, genomic, combination of phenotypic and genomic, and random selections. Genomic selection was implemented through a ridge regression best linear unbiased prediction model in two scenarios- cross-validations and independent predictions. Accuracy for cross-validations was assessed using a diverse panel under different marker number, training population size, relatedness between training and validation populations, and inclusion of fixed effect in the model. The population in the first scenario was then trained and used to predict grain yield of biparental populations for independent validations. Using subsets of significant markers from association mapping increased accuracy by 64-70% for grain yield but resulted in lower accuracy for traits with high heritability such as plant height. Increasing size of training population resulted in an increase in accuracy, with maximum values reached when ~ 60% of the lines were used as a training panel. Predictions using related subpopulations also resulted in higher accuracies. Inclusion of major growth habit genes as fixed effect in the model caused increase in grain yield accuracy under a cross-validation procedure. Independent predictions resulted in accuracy ranging between - 0.14 and 0.43, dependent on the grouping of site-year data for the training and validation populations. Genomic selection was "superior" to marker-based selection in terms of response to selection for yield. Supplementing phenotypic with genomic selection resulted in approximately 10% gain in response compared to using phenotypic selection alone. Our results showed the effects of different factors on accuracy for yield and agronomic traits. Among the factors studied, training population size and relatedness between training and validation population had the greatest impact on accuracy. Ultimately, combining phenotypic with genomic selection would be relevant for accelerating genetic gains for yield in winter wheat.


Clinical utility of 18 F-fluorodeoxyglucose/positron emission tomography in diagnosis of immunoglobulin G4-related sclerosing sialadenitis.
The aim of this study was to evaluate the utility of 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for accurately diagnosing immunoglobulin G4-related sclerosing sialadenitis (IgG4-SS). Retrospective cohort study. We reviewed the records of 64 patients with IgG4-SS (35 male and 29 female patients) and 10 patients with clinically suspected IgG4-SS. Pathological diagnoses of patients clinically suspected with IgG4-SS included four cases of malignant lymphoma, one case of multicentric Castleman disease, one case of Sjögren's syndrome, and four cases of sialadenitis. All patients underwent submandibular gland (SMG) biopsies and baseline FDG-PET/CT evaluation. Clinical, serological, pathological, and PET/CT findings were analyzed. We also investigated maximum standardized uptake values (SUVmax) in the salivary glands of 15 patients with malignant disease of the salivary glands during the same period. Increased FDG uptake in the SMG and parotid gland was found in 63 (98%) and 23 (35%) patients with IgG4-SS, respectively. FDG uptake of the bilateral SMG and unilateral SMG was recorded in 57 patients (89%) and six patients (9%), respectively. Mean SUVmax in patients with malignant disease of the salivary glands was significantly higher than that in patients with IgG4-SS (P = .035). We defined a positive test for IgG4-SS diagnosis as high SMG FDG uptake and serum IgG4 level ≥135 mg/dL, resulting in a sensitivity, specificity, and accuracy of 96.9%, 90.0%, and 86.4%, respectively. FDG-PET/CT findings in combination with serological and clinical findings may have the capacity to diagnose IgG4-SS and lead to less-invasive biopsy procedures. 4. Laryngoscope, 128:1120-1125, 2018.


Discovery of biologically active peptides in random libraries: solution-phase testing after staged orthogonal release from resin beads.
To speed drug discovery, we developed an approach for identification of individual peptides with a desired biological activity from a library containing millions of peptides. The approach uses sequential orthogonal release of chemically synthesized peptides from insoluble beads, followed by testing in solution. In this system, each bead within a library of beads has one peptide sequence, but peptide molecules are attached to the bead with three types of chemical linkers, including two linkers cleavable at different pH optima. An uncleavable linker keeps some peptide attached to the bead for sequencing positives from the solution assay. Applicability of this discovery technique was documented by identifying ligands for a monoclonal antibody and for the human platelet fibrinogen receptor, glycoprotein IIb/IIIa.


Tannic acid antagonizes atrazine exposure-induced autophagy and DNA damage crosstalk in grass carp hepatocytes via NO/iNOS/NF-κB signaling pathway to maintain stable immune function.
Atrazine (ATR) is a herbicide widely used in grass crops. The pollution of the soil and water environment is extremely harmful to aquatic animals and their offspring. iNOS/NO upregulation, DNA damage and cellular autophagy affect the immune function of fish liver cells. The effects of ATR at exposure doses on grass carp hepatocytes in terms of autophagy and DNA damage effects in genotoxicity, as well as the antagonistic effects of TAN on the above phenotypes and the internal mechanisms are not known. Therefore, we constructed control (Con group), ATR exposure (ATR group), TAN exposure (TAN group) and mixed group (ATR + TAN group) models on grass carp hepatocytes. Validation was performed by comet assay, MDC staining, qRT-PCR and protein blotting assay as well as iNOS/NO indicator levels and expression of immune factors as these experimental methods. Our data indicate that iNOS/NO assay kit measured that ATR treatment resulted in a significant increase in iNOS/NO activity and levels in grass carp hepatocytes (p < 0.05). We also found that NO/iNOS/NF-κB pathway genes were significantly activated (p < 0.05) at the exposure dose of ATR (3 μg mL-1). In addition, the proportion of cells that died due to DNA damage, autophagy, and immunotoxic effects was significantly increased at the exposure dose of ATR. Comet assay protein blotting detected increased DNA damage in cells at the ATR exposure dose (p < 0.05). MDC staining and qRT-PCR and protein blotting to detect the proportion of autophagic cells and autophagy-related genes also appeared upregulated at the exposed dose of ATR (p < 0.05). In brief, this study showed that ATR exposure caused cellular DNA damage and autophagy via the NO/iNOS/NF-κB axis, which led to immunotoxic effects and eventual death of grass carp hepatocytes. The present study facilitates the demonstration of the molecular mechanism of TAN alleviation of ATR cytotoxicity from the perspective of NO-mediated iNOS/NF-κB axis. It provides insights into the protection of farmed fish from agricultural contaminants and opens up new horizons in the use of natural plant-derived monomers for the clinical treatment of antagonistic triazine pesticide poisoning.


Intrahepatic inferior vena cava interruption with transhepatic venous continuation initially misdiagnosed as a congenital portosystemic shunt.
We report a case of intrahepatic inferior vena cava interruption with azygos and transhepatic venous continuation discovered incidentally on CT angiography for acute aortic syndrome. The lesion was initially misdiagnosed as a congenital portosystemic shunt on multiphase CT of the liver but subsequent fluoroscopic venogram revealed no evidence of portosystemic shunting. While intrahepatic IVC interruption with azygos continuation is an uncommon but well-known anatomical variant, transhepatic venous continuation is extremely rare and only a few cases have been published. Excluding portosystemic shunting is important for determining management as persistent congenital portosystemic shunts can be associated with significant morbidity.


Value-based decision-making network functional connectivity correlates with substance use and delay discounting behaviour among young adults.
Substance use disorders are characterized by reduced control over the quantity and frequency of psychoactive substance use and impairments in social and occupational functioning. They are associated with poor treatment compliance and high rates of relapse. Identification of neural susceptibility biomarkers that index risk for developing a substance use disorder can facilitate earlier identification and treatment. Here, we aimed to identify the neurobiological correlates of substance use frequency and severity amongst a sample of 1,200 (652 females) participants aged 22-37 years from the Human Connectome Project. Substance use behaviour across eight classes (alcohol, tobacco, marijuana, sedatives, hallucinogens, cocaine, stimulants, opiates) was measured using the Semi-Structured Assessment for the Genetics of Alcoholism. We explored the latent organization of substance use behaviour using a combination of exploratory structural equation modelling, latent class analysis, and factor mixture modelling to reveal a unidimensional continuum of substance use behaviour. Participants could be rank ordered along a unitary severity spectrum encompassing frequency of use of all eight substance classes, with factor score estimates generated to represent each participant's substance use severity. Factor score estimates and delay discounting scores were compared with functional connectivity in 650 participants with imaging data using the Network-based Statistic. This neuroimaging cohort excludes participants aged 31 and over. We identified brain regions and connections correlated with impulsive decision-making and poly-substance use, with the medial orbitofrontal, lateral prefrontal and posterior parietal cortices emerging as key hubs. Functional connectivity of these networks could serve as susceptibility biomarkers for substance use disorders, informing earlier identification and treatment.


Clinical and video-polygraphic features of epileptic spasms in adults with cortical migration disorder.
The International Classification of Epileptic Syndromes considers epileptic spasms to be typical seizures of West syndrome. Literature reports show that spasms are present in epileptic syndromes other than West syndrome but there are few data on their characteristics in adults. We describe ictal, clinical and video-polygraphic findings in three patients (aged 21, 32 and 57 years) with epileptic spasms and with diffuse (case 2), focal right fronto-parietal (case 1) and bi-opercular (case 3) pachygyria. Spasms had been present since the ages of 1 month, 11 and 27 years respectively. Only one patient is mentally retarded. Two of our patients (cases 2 and 3) have partial seizures. Ictal polygraphic studies showed a positive, diffuse, high amplitude slow wave activity during spasms, with superimposed fast activity, followed by a diffuse flattening in all cases with a typical muscle pattern. Epileptic spasms, as typically described in West syndrome, can maintain the same semeiological and electroencephalographic features during adulthood in certain patients with cortical dysplasia.


Modification of vacuolar proton pumps in cucumber roots under salt stress.
The time-dependent effect of 50mM NaCl on the activities of two tonoplast proton pumps was investigated in Cucumis sativus L. var. Krak root cells. Distinct activity profiles for vacuolar proton transporting ATPase (V-ATPase) (EC 22.214.171.124) and vacuolar proton transporting pyrophosphatase (V-PPase) (EC 18.104.22.168) under salinity are presented. ATP-dependent proton transport and ATP hydrolysis increased after 24h of NaCl exposure, and then decreased in roots stressed with NaCl for 4 and 8d. Both PP(i)-driven H(+) transport and PP(i) hydrolysis were clearly inhibited by NaCl at all times examined. It was demonstrated that changes in enzyme activities were not due to the salt action on the expression of encoding genes. The levels of specific transcripts for subunit A of V-ATPase (CsVHA-A), subunit c of V-ATPase (CsVHA-c) and V-PPase (CsVP) were similar in cucumber roots untreated (control) and treated with salt. Such results suggest that alterations of proton pump activities under salinity are rather due to the post-translational alterations induced by NaCl.


Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer.
A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a "triple-target" agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.


Fluorescence lifetime imaging in an optically sectioning programmable array microscope (PAM).
The programmable array microscopes (PAMs) are a family of instruments incorporating arbitrary control of the patterns of illumination and/or detection. The PAM can be used in sectioning and nonsectioning modes, thereby constituting a useful platform for fluorescence lifetime imaging. We used a PAM for acquisition of optically sectioned and widefield fluorescence lifetime images, in which contrast was increased predominantly by suppressing out-of-focus light contributions. We simulate, display, and discuss the effects of blurring and fluorophore heterogeneity on lifetime imaging in widefield and confocal configurations. Sectioning improves the quality of lifetime images of samples with multiple fluorophores or spatially varying Förster resonance energy transfer.


Imaging lysosomal enzyme activity in live cells using self-quenched substrates.
Endocytosis, the internalization and transport of extracellular cargo, is an essential cellular process. The ultimate step in endocytosis is the intracellular degradation of extracellular cargo for use by the cell. While live cell imaging and single particle tracking have been well-utilized to study the internalization and transport of cargo, the final degradation step has required separate biochemical assays. We describe the use of self-quenched endocytic cargo to image the intracellular transport and degradation of endocytic cargo directly in live cells. We first outline the fluorescent labeling and quantification of two common endocytic cargos: a protein, bovine serum albumin, and a lipid nanoparticle, low-density lipoprotein. In vitro measurements confirm that self-quenching is a function of the number of fluorophores bound to the protein or particle and that recovery of the fluorescent signal occurs in response to enzymatic degradation. We then use confocal fluorescence microscopy and flow cytometry to demonstrate the use of self-quenched bovine serum albumin with standard fluorescence techniques. Using live cell imaging and single particle tracking, we find that the degradation of bovine serum albumin occurs in an endo-lysosomal vesicle that is positive for LAMP1.


Draft Genome Sequence of Streptomyces olivochromogenes NBRC 3561, a Bioactive Peptide-Producing Actinobacterium.
Recently, we found that Streptomyces olivochromogenes NBRC 3561 produced a bioactive peptide, so we sequenced its genome to clarify its biosynthesis. We report here the draft genome sequence of S. olivochromogenes NBRC 3561, in which 40 potential secondary metabolite gene clusters were predicted by antiSMASH.


Phase Conjugated and Transparent Wavelength Conversions of Nyquist 16-QAM Signals Employing a Single-Layer Graphene Coated Fiber Device.
We fabricate a nonlinear optical device based on a fiber pigtail cross-section coated with a single-layer graphene grown by chemical vapor deposition (CVD) method. Using the fabricated graphene-assisted nonlinear optical device and employing Nyquist 16-ary quadrature amplitude modulation (16-QAM) signal, we experimentally demonstrate phase conjugated wavelength conversion by degenerate four-wave mixing (FWM) and transparent wavelength conversion by non-degenerate FWM in graphene. We study the conversion efficiency as functions of the pump power and pump wavelength and evaluate the bit-error rate (BER) performance. We also compare the time-varying symbol sequence for graphene-assisted phase conjugated and transparent wavelength conversions of Nyquist 16-QAM signal.


Characterization of the mechanism of endocytic vesicle fusion in vitro.
A cell-free assay to monitor receptor-mediated endocytic processes has been developed that uses biotinylated transferrin and avidin-linked beta-galactosidase as receptor-associated and fluid-phase probes, respectively (Wessling-Resnick, M., and Braell, W. A. (1990) J. Biol. Chem. 265, 690-699). The fusion of vesicles from heterologous sources can be detected in this assay: endocytic vesicles from K562 cells (a human cell line) will fuse with vesicles from Chinese hamster ovary cells. Fusion between endocytic vesicles is inhibited upon treatment with N-ethylmaleimide but can be restored by the addition of untreated cytosol from either cell type. The in vitro fusion reaction is also inhibited by the nonhydrolyzable nucleotide analogs guanosine 5'-(3-thiotriphosphate) (GTP gamma S) and adenosine 5'-(3-thiotriphosphate) (ATP gamma S). Other nonhydrolyzable guanine nucleotides are found to inhibit the in vitro reaction in the following order of potency: GTP gamma S greater than 5'-guanylyl imidodiphosphate (GTP-PNP) greater than alpha,beta-methylene GTP (GTP-PCP). The inhibitory effects of the nonhydrolyzable analogs of GTP and ATP are not additive. Moreover, excess GTP relieves the inhibition by GTP gamma S more than it relieves the inhibition by ATP gamma S, while excess ATP preferentially alleviates ATP gamma S (not GTP gamma S) inhibition. These properties suggest that the two nucleotides exert their effects at distinct points in the fusion process. Although micromolar levels of excess Ca2+ also inhibit vesicle fusion, the inhibition exerted by GTP gamma S appears to proceed via a pathway independent of the divalent cation. The GTP gamma S-sensitive step in endocytic vesicle fusion is found to occur at a mechanistic stage prior to and distinct from the N-ethylmaleimide-sensitive step of the reaction. This situation permits the accumulation of a membrane vesicle intermediate in the presence of GTP gamma S; subsequent incubation of these vesicles with cytosol and GTP restores their fusion competence. Characteristics of in vitro endocytic vesicle fusion suggest that similarities exist with steps of the fusion mechanism involved with membrane traffic events of the secretory pathway.


Ubiquitous anaerobic ammonium oxidation in inland waters of China: an overlooked nitrous oxide mitigation process.
Denitrification has long been regarded as the only pathway for terrestrial nitrogen (N) loss to the atmosphere. Here we demonstrate that large-scale anaerobic ammonium oxidation (anammox), an overlooked N loss process alternative to denitrification which bypasses nitrous oxide (N2O), is ubiquitous in inland waters of China and contributes significantly to N loss. Anammox rates in aquatic systems show different levels (1.0-975.9 μmol N m(-2) h(-1), n = 256) with hotspots occurring at oxic-anoxic interfaces and harboring distinct biogeochemical and biogeographical features. Extrapolation of these results to the China-national level shows that anammox could contribute about 2.0 Tg N yr(-1), which equals averagely 11.4% of the total N loss from China's inland waters. Our results indicate that a significant amount of the nitrogen lost from inland waters bypasses denitrification, which is important for constructing more accurate climate models and may significantly reduce potential N2O emission risk at a large scale.


Evaluating a digital sepsis alert in a London multisite hospital network: a natural experiment using electronic health record data.
The study sought to determine the impact of a digital sepsis alert on patient outcomes in a UK multisite hospital network. A natural experiment utilizing the phased introduction (without randomization) of a digital sepsis alert into a multisite hospital network. Sepsis alerts were either visible to clinicians (patients in the intervention group) or running silently and not visible (the control group). Inverse probability of treatment-weighted multivariable logistic regression was used to estimate the effect of the intervention on individual patient outcomes. In-hospital 30-day mortality (all inpatients), prolonged hospital stay (≥7 days) and timely antibiotics (≤60 minutes of the alert) for patients who alerted in the emergency department. The introduction of the alert was associated with lower odds of death (odds ratio, 0.76; 95% confidence interval [CI], 0.70-0.84; n = 21 183), lower odds of prolonged hospital stay ≥7 days (OR, 0.93; 95% CI, 0.88-0.99; n = 9988), and in patients who required antibiotics, an increased odds of receiving timely antibiotics (OR, 1.71; 95% CI, 1.57-1.87; n = 4622). Current evidence that digital sepsis alerts are effective is mixed. In this large UK study, a digital sepsis alert has been shown to be associated with improved outcomes, including timely antibiotics. It is not known whether the presence of alerting is responsible for improved outcomes or whether the alert acted as a useful driver for quality improvement initiatives. These findings strongly suggest that the introduction of a network-wide digital sepsis alert is associated with improvements in patient outcomes, demonstrating that digital based interventions can be successfully introduced and readily evaluated.


Response preparation and code overlap in dual tasks.
In a dual-task paradigm, a visual-encoding task with a deferred verbal report of a moving target was combined with a speeded task, in which participants prepared a precued leftward or rightward key-press response that was withheld until an auditory go signal. We manipulated the interval between the response cue and the target for the visual-encoding task, the interval between this target and the go signal, and spatial cross-task compatibility between the direction of the target movement in the visual task and the speeded manual response. The results of two experiments suggest that visual encoding interferes with response preparation and with the initiation of the prepared manual response at a short target-go interval. Also, responses were faster in compatible than in incompatible trials, indicating a cross-task compatibility effect. Experiment 2 reversed this compatibility effect by instruction, suggesting that the compatibility effect is based on response-response overlap. In both experiments, response preparation impaired accuracy in the visual task. Taken together, these results suggest that response processes and visual encoding share common codes and processes.


Organic compounds removal and toxicity reduction of landfill leachate by commercial bakers' yeast and conventional bacteria based membrane bioreactor integrated with nanofiltration.
This study aimed to compare the performance of a commercial bakers' yeast (MBRy) and conventional bacteria (MBRb) based membrane bioreactor integrated with nanofiltration (NF) in the removal of landfill leachate toxicity. Performances were evaluated using physicochemical analyses, toxicity tests and identification of organic compounds. The MBRb and MBRy were operated with a hydraulic retention time (HRT) of 48h and solids retention time (SRT) of 60 d. The MBRy demonstrated better removal efficiencies for COD (69±7%), color (54±11%) and ammoniacal nitrogen (34±7%) compared to MBRb, which showed removal efficiencies of 27±5%, 33±4% and 27±7%, for COD, color and ammoniacal nitrogen. Although the MBRy seems to be the configuration that presented the highest efficiency; it generated toxic permeate whose toxicity cannot be explained by physicochemical results. The identification of compounds shows that there is a wide range of compounds in the landfill leachate in addition to others that are produced in the biological treatment steps. The NF plays a crucial role in the polishing of the final effluents by the either complete or partial retention of compounds, that attribute toxicity to the leachate, and inorganic contaminants.


ras p21 expression in ovine pulmonary carcinoma.
We have adapted an enzyme-linked immunoblot assay (ELIBA) for the detection of a c-ras proto-oncogene and oncogene protein products in human cell lines and tumors of 21,000 daltons molecular weight (p21ras) to studies of tissues derived from sheep. In the ELIBA, a double antibody system is used in which p21ras proteins are initially immunoprecipitated from protein extracts with monoclonal antibodies, and subsequently identified using additional anti-ras antibodies. Binding is identified with a non-radioactive enzyme-linked colorimetric detection system. In the present study, the ELIBA system was used to study twenty-seven ovine lung specimens, representing normal lung, inflammatory, and neoplastic lesions. We detected p21ras protein expression in every tissue examined, but the nature and amount of the protein product varied significantly among the tissues examined. Some tissues expressed multiple ras species. Broncho-alveolar carcinoma specimens were most likely to express c-Ki-ras proteins. Mutant proteins of c-N-ras and c-Ki-ras were detected in several bronchoalveolar carcinoma specimens, based on migrational differences between mutant and normal proteins in 15% polyacrylamide gels. The results of this study demonstrate the utility of the ELIBA system for detection of c-ras expression in ovine lung tissues, and demonstrate the ability of the system to discriminate specific ras protein species. The prognostic significance of ras expression in sheep pulmonary carcinoma has yet to be determined.


Decline of instrumental activities of daily living is a risk factor for nutritional deterioration in older adults: a prospective cohort study.
The association between functional capacity and the subsequent risk of nutritional deterioration is yet to be understood. The purpose of this study was to elucidate the relationship between functional capacity, comprising instrumental activities of daily living (IADL), intellectual activity, and social function, and future decline in nutritional status. The current study is a two-year prospective cohort study. A total of 468 community-dwelling older adults without nutritional risks were enrolled. We used the Mini Nutritional Assessment Screening Form. Functional capacity, including IADL, intellectual activity, and social function, was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence at baseline. The nutritional status was reassessed at a 2-year follow-up. Risk ratios (RR) of functional capacity for the incidence of nutritional decline were estimated. Low functional capacity was significantly associated with future deterioration of nutritional status (RR 1.12, 95% confidence interval [CI] 1.02-1.25). Of the subdomains of functional capacity, IADL decline (adjusted RR 2.21, 95% CI 1.18-4.13) was an independent risk factor for the incidence of nutritional risk. Intellectual and social activities were not significant. Decline in functional capacity, especially IADL, is a risk factor for future deterioration in nutritional status. Further studies are required to elucidate the effect of interventions for IADL decline on maintaining nutritional status in older adults.


Development of two devices for high-throughput screening of ethanol-producing microorganisms by real-time CO2 production monitoring.
Bioethanol's importance as a renewable energy carrier led to the development of new devices for the high-throughput screening (HTS) of ethanol-producing microorganisms, monitoring ethanol production, and process optimization. This study developed two devices based on measuring CO2 evolution (an equimolar byproduct of microbial ethanol fermentation) to allow for a fast and robust HTS of ethanol-producing microorganisms for industrial purposes. First, a pH-based system for identifying ethanol producers (Ethanol-HTS) was established in a 96-well plate format where CO2 emission is captured by a 3D-printed silicone lid and transferred from the fermentation well to a reagent containing bromothymol blue as a pH indicator. Second, a self-made CO2 flow meter (CFM) was developed as a lab-scale tool for real-time quantification of ethanol production. This CFM contains four chambers to simultaneously apply different fermentation treatments while LCD and serial ports allow fast and easy data transfer. Applying ethanol-HTS with various yeast concentrations and yeast strains displayed different colors, from dark blue to dark and light green, based on the amount of carbonic acid formed. The results of the CFM device revealed a fermentation profile. The curve of CO2 production flow among six replications showed the same pattern in all batches. The comparison of final ethanol concentrations calculated based on CO2 flow by the CFM device with the GC analysis showed 3% difference which is not significant. Data validation of both devices demonstrated their applicability for screening novel bioethanol-producer strains, determining carbohydrate fermentation profiles, and monitoring ethanol production in real time.


Handwipes as indicators to assess organophosphate flame retardants exposure and thyroid hormone effects in e-waste dismantlers.
Dermal exposure is increasingly recognized as an important pathway for organic pollutant exposure. However, data on dermal exposure are limited, particularly with respect to the health effects. This study evaluated association between organophosphorus flame retardants (OPFRs) in handwipes and internal body burden on workers and adult residents in an electronic waste (e-waste) dismantling area. The impact of dermal exposure to OPFRs on thyroid hormones (THs) served as a biomarker for early effects. Triphenyl phosphate (TPhP) was the most detected compound in handwipes, with median levels of 1180, 200, and 24.0 ng in people identified as e-waste bakers, e-waste dismantlers, and adult residents. Among e-waste dismantlers, TPhP levels in handwipes were positively correlated with paired serum TPhP and urinary diphenyl phosphate (DPhP) levels. In multiple linear regression models controlling for sex, age and smoking, TPhP levels in handwipes of e-waste dismantlers were significantly negatively correlated with three THs used to evaluate thyroid function: serum reverse 3,3',5-triiodo-L-thyronine (rT3), 3,3'-diiodo-L-thyronine (3,3'-T2), and 3,5-diiodo-L-thyronine (3,5-T2). These findings suggest that handwipes can act as non-invasive exposure indicators to assess body burden of dermal exposure to TPhP and health effects on THs of e-waste dismantlers. This study highlights importance of OPFR effect on human THs through dermal exposure.


Developmental toxicity evaluation of three hexabromocyclododecane diastereoisomers on zebrafish embryos.
Structural dissimilarities of hexabromocyclododecane diastereoisomers could raise substantial differences in physicochemical, biological and toxicological properties. In order to fully assess the environmental safety and health risk of hexabromocyclododecanes (HBCDs), zebrafish embryos were used to evaluate the developmental toxicity of individual HBCD diastereoisomers (α-HBCD, β-HBCD and γ-HBCD). Four-hour post-fertilization (hpf) zebrafish embryos were exposed to different concentrations of HBCD diastereoisomers (0, 0.01, 0.1 and 1.0 mg/l) until 120 hpf. The results showed that exposure to HBCDs can affect the development of zebrafish embryos/larvae in a dose-dependent and diastereoselective manner. The diastereoisomers α-, β- and γ-HBCD at 0.01 mg/l had little effect on the development of zebrafish embryos except that exposure to 0.01 mg/l γ-HBCD significantly delayed hatching (P<0.05). At 0.1mg/l, α-HBCD resulted in depressed heart rate of larvae (96 hpf) and delayed hatching, whereas β- and γ-HBCD both caused significant hatching delay and growth inhibition (P<0.05). In addition, a remarkable and significant increase in mortality and malformation rate was noted at 0.1 mg/l γ-HBCD exposure groups (P<0.05). At 1.0 mg/l, α-, β- and γ-HBCD significantly affected all of the endpoints monitored (P<0.05). Additionally, HBCD diastereoisomers could induce the generation of reactive oxygen species (ROS) and the activities of caspase-3 and caspase-9 in a dose-dependent manner. The results indicated that HBCD diastereoisomers could cause developmental toxicity to zebrafish embryos through inducing apoptosis by ROS formation. The overall results showed a good agreement confirming that the order of developmental toxicity of HBCD diastereoisomers in zebrafish is γ-HBCD>β-HBCD>α-HBCD.


The classification and assessment of osteoarthritis.
Osteoarthritis is the commonest rheumatic disease, but despite its high prevalence in the elderly, associated disability and public health costs, there is little understanding of the aetiology of the disease. Questions still remain unanswered: 'what do we mean by the term osteoarthritis?; how do we define it?; how do we classify patients with the disease?; how do we differentiate between cases for population studies, and clinically relevant disease the physician wishes to treat?'. This chapter has demonstrated the considerable advances that have been made over the last thirty years in solving these issues, but we are still lacking a universal definition and classification of the disease. Defining and classifying OA is not an easy task, as it is not a single disease, but rather a spectrum of diseases that are the end result of a number of different processes. However, in order to understand the aetiology and natural course of the disease, and to devise appropriate treatment strategies, correct definition of OA at distinct sites is vital. Radiological site-specific definition of the disease is now recognized as the major tool available in defining OA. There is general consensus that the grading of osteophytes and joint space narrowing at the major sites using validated atlases is an important step forward.


[Pyoderma gangrenosum following AICD implantation: differential diagnosis to necrotizing fasciitis].
Pyoderma gangrenosum is rarely seen in the surgical disciplines. In the described case the patient was initially diagnosed with necrotizing fasciitis and admitted to the intensive care unit suffering from septic shock. The automated implantable cardioverter defibrillator (AICD), the suspected focus for infection, had already been removed. Following weeks of broad spectrum antibiotics and wound debridement without clinical improvement the alternative diagnosis of pyoderma gangrenosum was reached. Consequently the patient was treated with immunosuppressive therapy and his condition improved rapidly such that he was ultimately discharged to rehabilitation.


The relationship between sustained attention and aerobic fitness in a group of young adults.
A growing set of studies has shown a positive relationship between aerobic fitness and a broad array of cognitive functions. However, few studies have focused on sustained attention, which has been considered a fundamental cognitive process that underlies most everyday activities. The purpose of this study was to investigate the role of aerobic fitness as a key factor in sustained attention capacities in young adults. Forty-four young adults (18-23 years) were divided into two groups as a function of the level of aerobic fitness (high-fit and low-fit). Participants completed the Psychomotor Vigilance Task (PVT) and an oddball task where they had to detect infrequent targets presented among frequent non-targets. The analysis of variance (ANOVA) showed faster responses for the high-fit group than for the low-fit group in the PVT, replicating previous accounts. In the oddball task, the high-fit group maintained their accuracy (ACC) rate of target detection over time, while the low-fit group suffered a significant decline of response ACC throughout the task. Importantly, the results show that the greater sustained attention capacity of high-fit young adults is not specific to a reaction time (RT) sustained attention task like the PVT, but it is also evident in an ACC oddball task. In sum, the present findings point to the important role of aerobic fitness on sustained attention capacities in young adults.


Intensivist staffing and outcome in the ICU: daytime, nighttime, 24/7?
Many hospitals, particularly large academic centers, have begun to provide 24-h in-house intensive care attending coverage. Proposed advantages for this model include improved patient care, greater provider, nursing and patient satisfaction, better communication, and greater cost-effectiveness. This review will evaluate current evidence with respect to 24/7 coverage, including patient outcomes, cost-effectiveness, and impact on training/education. Evidence surrounding 24-h intensivist staffing has been mixed. Although a subset of studies suggest a possible benefit to 24-h intensivist coverage, recent prospective studies have shown no difference in major patient outcomes, including mortality and ICU length of stay between patients in ICUs with and those without 24-h intensivist coverage. Although some studies cite increased caregiver and patient satisfaction, outcome studies find no consistent effect on patient-centered outcomes such as mortality or length of stay. Downsides to in-house nighttime attending staffing include physician burnout, adverse effects on physician health, decreased trainee autonomy, and effects on trainee specialty choices because of undesirable lifestyle considerations. Tele-ICU and other novel approaches may allow for attending supervision without physical presence.


Subjective estimation of the quality of life in relation to neuroticism.
It is generally agreed that personality variables have a relatively consistent influence on the subjective estimation of different situations in everyday life and the way people react to them. The aim of this review was to summarise our previously published findings on the relationship between subjective estimation of one's quality of life and the personality trait neuroticism-emotional stability. We used the WHO Quality of Life--BREF or SF-36 questionnaires for the assessment of the quality of life, Cornell Index for the assessment of neuroticism, and The Social Readjustment Rating Scale for the evaluation of common stressors. Our results have shown that more emotionally stable participants (lower neuroticism) perceive their life better in quality and are more satisfied with their work environment. In addition, our results support the findings from other studies that women have higher neuroticism and lower quality of life scores than men.


Intramandibular inflammatory myofibroblastic tumor--a true neoplasm or reactive lesion?
Inflammatory myofibroblastic tumor (IMT) is an uncommon lesion reported to arise in various organs and by convention believed to be a nonneoplastic reactive inflammatory condition. Because of its radiographic and histologic similarities to malignancy, IMT can pose a considerable diagnostic dilemma. The purpose of this study is to report the first intramandibular IMT and to discuss the possible nature of this lesion. Detailed documentation of clinical, radiographic, and histologic features; literature review. This lesion showed distinct radiographic, histologic, and immunohistochemical features. The lesion recurred 14 months after initial removal with almost identical histology. This is the first documented case of an intramandibular IMT. Due to the rarity of these lesions, their clinical sequelae and prognosis are undetermined. As a result of specific immunohistochemical phenotyping and clinical behavior of this lesion, we favored a diagnosis of inflammatory myofibroblastic tumor. Wide excision with a long-term clinical follow-up is required.


The fate of prenatally diagnosed primary nonrefluxing megaureter: do we have reliable predictors for spontaneous resolution?
To compare predictive values of current morphologic parameters with congenital renal damage associated with severe megaureter. A retrospective analysis was performed using records of 37 patients (50 megaureters) referred before birth for a primary megaureter. Mean follow-up was 26 months (range, 1 to 8 years). Dilatation resolved spontaneously in 46 of 50 ureters. Only 4 of 37 patients required surgery (10.8%) after a mean follow-up of 58 months (range, 32 to 80 months). Average time to resolution was 24 months (range, 1 to 82 months) and was independent from sex, side, and bilaterality. A weak correlation was found with initial anteroposterior pelvic diameter, ureteral diameter, and separate function at renogram. A significant correlation (P <0.02) was found between megaureter type and time elapsed to spontaneous resolution. As far as differential function was concerned, mean values were significantly lower among type III megaureters, which had the lowest rate of resolution. The fate of severe megaureter seems strongly influenced by congenital renal damage secondary to a developmental abnormality of the ureteric bud. A poor resolution rate has to be expected in these cases; surgery must be reserved for symptomatic cases but has no influence on pre-existing renal damage.


A serosurvey evaluation of the school-based measles 'catch-up' immunisation campaign in Victorian school-aged children.
To determine the proportion of Victorian primary school students protected against measles infection one year after the completion of the measles 'catch-up' immunisation campaign of 1998 and to compare this with the proportion of year 9 and 10 (aged 14-16 years) students. Three-stage random cluster survey in Victorian primary and secondary schools. Proportion of primary and year 9 and 10 secondary school students protected against measles infection one year after the completion of the mass 'catch-up' immunisation campaign. the proportion of both primary and year 9 and 10 secondary school students protected against both mumps and rubella. Of 1,037 Victorian primary and 2,357 years 9 and 10 secondary school students invited to participate in this study, 403 (39%) and 752 (32%) respectively provided a blood specimen for serological testing for antibodies against measles, mumps and rubella. 94.8% (95% confidence interval, 91.5, 96.9) of primary school and 93.1% (90.9, 94.8) of year 9 and 10 students were protected against measles infection. One year after the completion of the school-based measles 'catch-up' immunisation campaign the level of protection in Victorian primary school aged students is sufficient to prevent the continuing circulation of measles virus within this age group. The proportion of year 9 and 10 secondary school students protected against measles is also probably sufficient to prevent continuing circulation of wild type virus in Victoria, even though this age group was not specifically targeted by the 'catch-up' campaign.


Switching patients from olanzapine or risperidone to a combination treatment using perphenazine plus buspirone: evaluation of antipsychotic efficacy and side-effects, including extrapyramidal effects and weight loss.
In this pilot study, we have investigated the effects of switching from olanzapine or risperidone treatment to low-dose perphenazine combined with buspirone in six schizophrenic patients who had experienced weight gain. We found no relapse as to psychotic symptoms measured by the CGI-S scale and no exacerbation of extrapyramidal side-effects as measured by the Simpson-Angus Scale. In addition, we observed a medium weight reduction of 10.5 kg (range 1-20 kg).


[Disturbance of binocular vision by wiper smears on windshields].
Sunlight or light from other sources can be scattered and refracted by the smears left on windshields by wipers. Under certain circumstances the resulting light phenomena can disturb binocular vision and distract the driver's attention.


The effects of food deprivation on protein turnover and nucleic acid concentrations of active and immobilized extensor digitorum longus muscles of the rat.
Deprivation of food caused significant changes in the weight, protein content, protein turnover and RNA concentrations of the extensor digitorum longus muscle. Simultaneous immobilization to render the muscle inactive did not make the tissue any more susceptible to the effects of starvation. In contrast, immobilization in a stretched state resulted in less muscle wasting after deprivation of food.


A candidate complex approach to study functional mitochondrial DNA changes: sequence variation and quaternary structure modeling of Drosophila simulans cytochrome c oxidase.
A problem with studying evolutionary dynamics of mitochondrial (mt) DNA is that classical population genetic techniques cannot identify selected substitutions because of genetic hitchhiking. We circumvented this problem by employing a candidate complex approach to study sequence variation in cytochrome c oxidase (COX) genes within and among three distinct Drosophila simulans mtDNA haplogroups. First, we determined sequence variation in complete coding regions for all COX mtDNA and nuclear loci and their isoforms. Second, we constructed a quaternary structure model of D. simulans COX. Third, we predicted that six of nine amino acid changes in D. simulans mtDNA are likely to be functionally important. Of these seven, genetic crosses can experimentally determine the functional significance of three. Fourth, we identified two single amino acid changes and a deletion of two consecutive amino acids in nuclear encoded COX loci that are likely to influence cytochrome c oxidase activity. These data show that linking population genetics and quaternary structure modeling can lead to functional predictions of specific mtDNA amino acid mutations and validate the candidate complex approach.


Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas.
Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.Radiation-induced meningiomas are often more aggressive than sporadic ones. In this study, the authors perform an exome, methylation and RNA-seq analysis of 31 cases of radiation-induced meningioma and show NF2 rearrangement, an observation previously unreported in the sporadic tumors.


Improving quantitation accuracy in isobaric-labeling mass spectrometry experiments with spectral library searching and feature-based peptide-spectrum match filter.
Isobaric labeling relative quantitation is one of the dominating proteomic quantitation technologies. Traditional quantitation pipelines for isobaric-labeled mass spectrometry data are based on sequence database searching. In this study, we present a novel quantitation pipeline that integrates sequence database searching, spectral library searching, and a feature-based peptide-spectrum-match (PSM) filter using various spectral features for filtering. The combined database and spectral library searching results in larger quantitation coverage, and the filter removes PSMs with larger quantitation errors, retaining those with higher quantitation accuracy. Quantitation results show that the proposed pipeline can improve the overall quantitation accuracy at the PSM and protein levels. To our knowledge, this is the first study that utilizes spectral library searching to improve isobaric labeling-based quantitation. For users to conveniently perform the proposed pipeline, we have implemented the feature-based filter being executable on both Windows and Linux platforms; its executable files, user manual, and sample data sets are freely available at https://ms.iis.sinica.edu.tw/comics/Software_FPF.html . Furthermore, with the developed filter, the proposed pipeline is fully compatible with the Trans-Proteomic Pipeline.


Repair of aortic coarctation in infants: experience with an intraluminal shunt.
From 1962 to mid-1984, 63 infants underwent coarctation repair. Cardiac defects were present in 46 (73%). Repair was by subclavian aortoplasty in 35 patients, resection and end-to-end anastomosis in 19, and other techniques in 6. Three patients died before the repair was completed. In 15 patients, an intraluminal shunt was used during subclavian aortoplasty. Prostaglandin E1 (PGE1) was infused in 9 patients. Early (thirty-day) mortality was 16% (10 patients): 4 patients who underwent end-to-end anastomosis; 3 during attempted end-to-end anastomosis; 2 who received bypass grafts; and 1 who had subclavian aortoplasty without a shunt. None of the 15 patients who had subclavian aortoplasty with a shunt died. There were no early deaths among the last 25 patients seen. One patient who underwent subclavian aortoplasty without a shunt is paraplegic. There were 10 late deaths among the 53 patients followed from 1 month to 12 years (mean, 3 years). Arm-leg pressure gradients of 20 mm Hg or greater were found in 4 of the patients who had end-to-end anastomosis but not in any of the patients who had subclavian aortoplasty. Improved results of coarctation repair in infants in this study were attributed to PGE1, subclavian aortoplasty, and use of an intraluminal shunt.


Development of an epiphyte indicator of nutrient enrichment: a critical evaluation of observational and experimental studies.
An extensive review of the literature describing epiphytes on submerged aquatic vegetation (SAV), especially seagrasses, was conducted in order to evaluate the evidence for response of epiphyte metrics to increased nutrients. Evidence from field observational studies, together with laboratory and field mesocosm experiments, was assembled from the literature and evaluated for a hypothesized positive response to nutrient addition. There was general consistency in the results to confirm that elevated nutrients tended to increase the load of epiphytes on the surface of SAV, in the absence of other limiting factors. In spite of multiple sources of uncontrolled variation, positive relationships of epiphyte load to nutrient concentration or load (either nitrogen or phosphorus) often were observed along strong anthropogenic or natural nutrient gradients in coastal regions. Such response patterns may only be evident for parts of the year. Results from both mesocosm and field experiments also generally support the increase of epiphytes with increased nutrients, although outcomes from field experiments tended to be more variable. Relatively few studies with nutrient addition in mesocosms have been done with tropical or subtropical species, and more such controlled experiments would be helpful. Experimental duration influenced results, with more positive responses of epiphytes to nutrients at shorter durations in mesocosm experiments versus more positive responses at longer durations in field experiments. In the field, response of epiphyte biomass to nutrient additions was independent of climate zone. Mesograzer activity was a critical covariate for epiphyte response under experimental nutrient elevation, but the epiphyte response was highly dependent on factors such as grazer identity and density, as well as nutrient and ambient light levels. The balance of evidence suggests that epiphytes on SAV will be a useful indicator of persistent nutrient enhancement in many situations. Careful selection of appropriate temporal and spatial constraints for data collection, and concurrent evaluation of confounding factors will help increase the signal to noise ratio for this indicator.


The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans.
The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown. Haemodynamic function, circulating renin-angiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22). AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects. The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape.


The rs7911488-T allele promotes the growth and metastasis of colorectal cancer through modulating miR-1307/PRRX1.
We previously discovered that rs7911488T>C in pre-miR-1307 was closely correlated to the risk of colorectal cancer (CRC). However, the roles of rs7911488 in CRC are still largely unknown. Here we explored the roles of rs7911488 in the growth and metastasis of CRC. We firstly generated cell lines SW480-T and SW480-C for stable expression of rs7911488 T-allelic and C-allelic pre-miR-1307, respectively. We subcutaneously grafted the cells into nude mice. We found that SW480-T tumors with high expression of miR-1307 obviously grew faster than the SW480-C tumors. Moreover, liver metastases (5/8) were observed in the mice bearing SW480-T tumors but not the SW480-C tumor-bearing mice. The results from colony formation assays, transwell assays, and wound healing assays demonstrated that the proliferative and metastatic abilities of SW480-T cells were evidently more potent than the SW480-C cells. Then we utilized gene array, real-time PCR, western blotting, and dual-luciferase reporter assays to figure out that miR-1307 directly inhibited PPRX1 expression by binding to its 3'-UTR. Thereafter, we confirmed that the proliferative and metastatic abilities of SW480 and HCT-116 cells were markedly enhanced by miR-1307, but were suppressed by PRRX1. Moreover, the regulatory roles of miR-1307 in the proliferation and metastasis of CRC cells were reversed by PRRX1. Notably, we also found that PRRX1 repressed CRC tumor growth in nude mice. In summary, our current study revealed that rs7911488-T allele led to over-expression of miR-1307, which inhibited PRRX1 and consequently promoted the proliferation and migration of CRC cells. This might offer a novel insight into the progression of CRC.