mDixon-Based Synthetic CT Generation for PET Attenuation Correction on Abdomen and Pelvis Jointly Using Transfer Fuzzy Clustering and Active Learning-Based Classification.
We propose a new method for generating synthetic CT images from modified Dixon (mDixon) MR data. The synthetic CT is used for attenuation correction (AC) when reconstructing PET data on abdomen and pelvis. While MR does not intrinsically contain any information about photon attenuation, AC is needed in PET/MR systems in order to be quantitatively accurate and to meet qualification standards required for use in many multi-center trials. Existing MR-based synthetic CT generation methods either use advanced MR sequences that have long acquisition time and limited clinical availability or use matching of the MR images from a newly scanned subject to images in a library of MR-CT pairs which has difficulty in accounting for the diversity of human anatomy especially in patients that have pathologies. To address these deficiencies, we present a five-phase interlinked method that uses mDixon MR acquisition and advanced machine learning methods for synthetic CT generation. Both transfer fuzzy clustering and active learning-based classification (TFC-ALC) are used. The significance of our efforts is fourfold: 1) TFC-ALC is capable of better synthetic CT generation than methods currently in use on the challenging abdomen using only common Dixon-based scanning. 2) TFC partitions MR voxels initially into the four groups regarding fat, bone, air, and soft tissue via transfer learning; ALC can learn insightful classifiers, using as few but informative labeled examples as possible to precisely distinguish bone, air, and soft tissue. Combining them, the TFC-ALC method successfully overcomes the inherent imperfection and potential uncertainty regarding the co-registration between CT and MR images. 3) Compared with existing methods, TFC-ALC features not only preferable synthetic CT generation but also improved parameter robustness, which facilitates its clinical practicability. Applying the proposed approach on mDixon-MR data from ten subjects, the average score of the mean absolute prediction deviation (MAPD) was 89.78±8.76 which is significantly better than the 133.17±9.67 obtained using the all-water (AW) method (p=4.11E-9) and the 104.97±10.03 obtained using the four-cluster-partitioning (FCP, i.e., external-air, internal-air, fat, and soft tissue) method (p=0.002). 4) Experiments in the PET SUV errors of these approaches show that TFC-ALC achieves the highest SUV accuracy and can generally reduce the SUV errors to 5% or less. These experimental results distinctively demonstrate the effectiveness of our proposed TFCALC method for the synthetic CT generation on abdomen and pelvis using only the commonly-available Dixon pulse sequence.


Inactivation of DNA-dependent protein kinase promotes heat-induced apoptosis independently of heat-shock protein induction in human cancer cell lines.
The inhibition of DNA damage response pathway seems to be an attractive strategy for cancer therapy. It was previously reported that in rodent cells exposed to heat stress, cell growth was promoted by the activity of DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair. The absence of a functioning DNA-PK was associated with down regulation of heat shock protein 70 (HSP70). The objective of this study is thus to investigate the role of DNA-PK inhibition in heat-induced apoptosis in human cell lines. The inhibitors of phosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser2056, such as NU7026 and NU7441, were utilized. Furthermore, knock down of DNA-PKcs was carried out using small interfering RNA (siDNA-PKcs). For heat exposure, cells were placed in water bath at 44°C for 60 min. Apoptosis was evaluated after 24 h incubation flow cytometrically. Proteins were extracted after 24 h and analyzed for HSP70 and HSP40 expression by Western blotting. Total RNA was extracted 6 h after treatment and analyzed using a GeneChip® microarray system to identify and select the up-regulated genes (≥1.5 fold). The results showed an enhancement in heat-induced apoptosis in absence of functioning DNA-PKcs. Interestingly, the expression levels of HSP70 and HSP40 were elevated in the absence of DNA-PKcs under heat stress. The results of genetic network analysis showed that HSPs and JUN genes were up-regulated independently of DNA-PKcs in exposed parent and knock out cells. In the presence of functioning DNA-PKcs, there was an observed up-regulation of anti-apoptotic genes, such as NR1D1, whereas in the absence of DNA-PKcs the pro-apoptotic genes, such as EGR2, were preferentially up-regulated. From these findings, we concluded that in human cells, the inactivation of DNA-PKcs can promote heat-induced apoptosis independently of heat-shock proteins.


Novel metallo-therapeutics of the NSAID naproxen. Interaction with intracellular components that leads the cells to apoptosis.
Two new mixed ligand-silver(I) complexes of the anti-inflammatory drug naproxen (naprH) and triphenylphosphine (tpp) or tri(p-tolyl)phosphine (tptp) of formulae {[Ag(tpp)3(napr)](H2O)} (1) and [Ag(tptp)2(napr)] (2) have been synthesized and characterized by m.p., vibrational spectroscopy (mid-FT-IR), Raman, (1)H-NMR, UV-Vis, ESI-MS spectroscopic techniques and X-ray crystallography. The complexes show high photo-sensitivity to UVC light. Photolysis of 1-2 was studied and the results showed monotonic degradation of the complexes with simultaneous triarylphosphine oxide formation. The complexes 1-2 were tested for their antiproliferative activity against human breast adenocarcinoma (MCF-7) cells. Complexes 1-2 were more active than cisplatin against cells. UVC light increases the effectiveness of complexes 1-2 on MCF-7 cells by 13% and 38% respectively. Due to the morphology of the MCF-7 cells, which were incubated with the complexes 1-2, the cell death was ascribed to apoptosis. Electrophoresis to genomic DNA of MCF-7 cells confirmed the apoptosis through DNA fragmentation. The binding affinity of 1-2 towards the intracellular molecules CT-DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of cell death. Thus, the binding constants (K(b)) of 1-2 towards CT-DNA calculated by UV-Vis spectra are 32.8 ± 8.5 × 10(4) (1) and 4.7 ± 1.8 × 10(4) (2) M(-1), respectively. Changes in fluorescent emission light of ethidium bromide (EB) in the presence of DNA suggest intercalation or electrostatic interactions into DNA of both complexes 1-2 in the minor groove. The corresponding apparent binding constants (K(app)) of 1-2 towards CT-DNA calculated through fluorescence spectra are 2.9 ± 0.3 × 10(4) (1) and 1.6 ± 0.4 × 10(4) (2) M(-1) respectively. Docking studies on DNA-complexes interactions show the binding of 1 in the major groove and the corresponding one of 2 in the minor one. Moreover, the influence of complexes 1-2 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. Only 1 inhibits lipoxygenase activity (IC50 = 5.1 (1), >30 (2) μM).


Galectin-3 expression is ubiquitous in tumors of the sellar region, nervous system, and mimics: an immunohistochemical and RT-PCR study.
Galectin-3 expression has been reported in spindle cell oncocytoma, certain pituitary adenoma subtypes, astrocytomas, oligodendrogliomas, and meningiomas. We evaluated galectin-3 protein expression by immunohistochemistry in 201 cases of a variety of nervous system and sellar tumors, as well as mRNA expression by reverse transcription-polymerase chain reaction in formalin-fixed paraffin-embedded tissue in a subset (20 cases). Immunohistochemical results were evaluated in a semiquantitative fashion on a 4-tiered scale (0 to 3). Strong (3+) immunoreactivity was seen in most of the cases (61%), followed by 2+(22%), and 1+(13%) staining. Only 4% of the lesions studied were immunonegative. Galectin-3 mRNA was present in 15 of the 18 cases (83%) in which reverse transcription-polymerase chain reaction was successful. Significant differences in protein expression were noted in the following 2 settings: specific meningioma subtypes (P=0.004, Fisher exact test) wherein clear cell meningioma demonstrated weak protein expression when compared with other meningioma variants. No significant difference was noted with respect to World Health Organization grade. Galectin-3 was also strongly expressed in benign nerve sheath tumors but only moderately expressed in malignant peripheral nerve sheath tumors (P=0.0009, Fisher exact test). Although galectin-3 positivity is a key feature of the immunophenotype of spindle cell oncocytoma, its consistent expression in other morphologically similar tumors (meningioma, pituicytoma, nerve sheath tumors, granular cell tumor, metastases) makes it of little use in the differential diagnosis of sellar region tumors, a setting in which it should be discouraged. Diagnostic uses of this marker may be limited to specific settings, including some meningioma subtypes and nerve sheath tumors.


Glomerular C4d deposition indicates in situ classic complement pathway activation, but is not a marker for lupus nephritis activity.
This study was designed to evaluate whether glomerular C4d deposition may be a useful marker of lupus nephritis activity. Twenty-one patients diagnosed as having lupus nephritis (WHO class III: 4 cases; IV: 12 cases; V: 5 cases) were included. Mean patient age was 29.3 +/- 13.5 years (range: 7-55 years). The presence and intensity of glomerular C4d deposition were compared with the corresponding histologic activity index for each case. Immunofluorescence for C4d showed diffusely granular staining along glomerular capillary loops, in all cases examined (1+, in 8 cases; 2+, in 7 cases; 3+, in 6 cases). In eight cases, C4d deposition was found in the absence of capillary or mesangial C4 deposits. Moreover, the intensity of C4d deposits correlated with those of capillary IgG, IgA, C4, C1q, and fibrinogen deposits. However, C4d staining intensity did not correlate with the lupus nephritis activity index. Although glomerular capillary C4d deposition is a sensitive marker of classic complement pathway activation, it is not a sensitive marker for active lupus nephritis.


Alleviation of thermally induced phase mismatch in CsLiB6O10 crystal by means of temperature-profile compensation.
A new mechanism was found to alleviate the thermally induced phase mismatch of nonlinear optical crystals. By cooling CsLiB>(6)O(10) at an elevated crystal temperature with gas, we improved laser conversion efficiency from green (532 nm) to UV (266 nm) 2.3 times compared with that without cooling. In situ observation of the temperature profile on the output surface revealed that such cooling initiates a negative temperature profile that compensates for the positive profile generated from laser absorption. A 10.6-W UV output with excellent stability was generated. The optimum crystal length was substantially extended.


Improving management of patients with acute cough by C-reactive protein point of care testing and communication training (IMPAC3T): study protocol of a cluster randomised controlled trial.
Most antibiotic prescriptions for acute cough due to lower respiratory tract infections (LRTI) in primary care are not warranted. Diagnostic uncertainty and patient expectations and worries are major drivers of unnecessary antibiotic prescribing. A C-reactive protein (CRP) point of care test may help GPs to better guide antibiotic treatment by ruling out pneumonia in cases of low test results. Alternatively, enhanced communication skills training to help clinicians address patients' expectations and worries could lead to a decrease in antibiotic prescribing, without compromising clinical recovery, while enhancing patient enablement. The aim of this paper is to describe the design and methods of a study to assess two interventions for improving LRTI management in general practice. This cluster randomised controlled, factorial trial will introduce two interventions in general practice; point of care CRP testing and enhanced communication skills training for LRTI. Twenty general practices with two participating GPs per practice will recruit 400 patients with LRTI during two winter periods. Patients will be followed up for at least 28 days. The primary outcome measure is the antibiotic prescribing rate. Secondary outcomes are clinical recovery, cost-effectiveness, use of other diagnostic tests and medical services (including reconsultation), and patient enablement. This trial is the first cluster randomised trial to evaluate the influence of point of care CRP testing in the hands of the general practitioner and enhanced communication skills, on the management of LRTI in primary care. The pragmatic nature of the study, which leaves treatment decisions up to the responsible clinicians, will enhance the applicability and generalisability of findings. The factorial design will allow conclusion to be made about the value of CRP testing on its own, communication skills training on its own, and the two combined. Evaluating a biomedical and communication based intervention ('hard' and 'soft' technologies) together in this way makes this trial unique in its field.


Chemical components of bleached eucalypt kraft pulp effluent COD and treatment removal efficiency during normal mill operation and maintenance shutdowns.
In order to meet increasingly strict Brazilian COD emissions limits, mills must understand the components that contribute to effluent COD, how these vary between normal mill operation and maintenance shutdowns, and how this variation affects treatment efficiency. To this end, primary and secondary effluents from a Brazilian bleached eucalypt kraft pulp mill activated sludge system were analyzed for COD, lignin, extractives, carbohydrates and AOX over a sixth month period that included two general maintenance shutdowns and four months of normal operation. Primary effluent presented significantly different compositions during periods of normal operation and mill shutdowns. During normal operation, the main components of effluent COD (909 mg/l average) were carbohydrates, followed by lignin. However, the lignin fraction was the main component of secondary effluent COD during both normal operation and mill shutdowns. Higher removal efficiencies for COD carbohydrates and AOX were observed during normal operation compared to shutdowns, while no difference in removal efficiencies of lignin and extractives was observed. Carbohydrate removal efficiency was significantly lower in one of the parallel treatment lines. The different removal efficiencies reflect not only variations in effluent composition, but possibly differences in system operational control which should be explored in greater detail.


Long-term outcome of patients who receive ketamine during research.
To comprehend the pathophysiology of schizophrenia and to facilitate drug discovery, animal and human models of schizophrenia are necessary. Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has been used to probe glutamatergic function in normal and schizophrenic volunteers. These studies and others have provided data consistent with a putative involvement of a glutamatergic dysfunction in the pathophysiology of schizophrenia; however, these studies have also raised concerns about the distress inflicted on patients, the potential for adverse events, and the serious long-term effects that could possibly be induced by symptom-simulating action. For all patient volunteers (n = 30) who participated in these studies, we reviewed the acute safety during and in the immediate postketamine administration. Patients available for long-term follow-up (n = 25) were matched to a group of patients (n = 25) who participated in research but did not receive ketamine. We compared their long-term outcome in terms of psychopathology, the need for psychiatric care, and the amount of antipsychotic medication required for optimal therapeutic response. There were no serious adverse events in more than 90 ketamine interviews. Distress to patients was minimal, which is shown by the lack of anxiety ratings. Over a mean follow-up period of 8 months, we found no differences between patients who did and did not receive ketamine on any measures of psychopathology, psychiatric care, or the amount of antipsychotic medication. In a controlled environment and paying close attention to subject safety features, administering subanesthetic doses of ketamine causes no adverse events and little distress to schizophrenic volunteers. This study strongly indicates that administering ketamine does not change any aspect of the course of schizophrenic illness.


The 2017 hormone therapy position statement of The North American Menopause Society.
The 2017 Hormone Therapy Position Statement of The North American Menopause Society (NAMS) updates the 2012 Hormone Therapy Position Statement of The North American Menopause Society and identifies future research needs. An Advisory Panel of clinicians and researchers expert in the field of women's health and menopause was recruited by NAMS to review the 2012 Position Statement, evaluate new literature, assess the evidence, and reach consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees.Hormone therapy (HT) remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) and has been shown to prevent bone loss and fracture. The risks of HT differ depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. Treatment should be individualized to identify the most appropriate HT type, dose, formulation, route of administration, and duration of use, using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of the benefits and risks of continuing or discontinuing HT.For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture. For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia. Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.This NAMS position statement has been endorsed by Academy of Women's Health, American Association of Clinical Endocrinologists, American Association of Nurse Practitioners, American Medical Women's Association, American Society for Reproductive Medicine, Asociación Mexicana para el Estudio del Climaterio, Association of Reproductive Health Professionals, Australasian Menopause Society, Chinese Menopause Society, Colegio Mexicano de Especialistas en Ginecologia y Obstetricia, Czech Menopause and Andropause Society, Dominican Menopause Society, European Menopause and Andropause Society, German Menopause Society, Groupe d'études de la ménopause et du vieillissement Hormonal, HealthyWomen, Indian Menopause Society, International Menopause Society, International Osteoporosis Foundation, International Society for the Study of Women's Sexual Health, Israeli Menopause Society, Japan Society of Menopause and Women's Health, Korean Society of Menopause, Menopause Research Society of Singapore, National Association of Nurse Practitioners in Women's Health, SOBRAC and FEBRASGO, SIGMA Canadian Menopause Society, Società Italiana della Menopausa, Society of Obstetricians and Gynaecologists of Canada, South African Menopause Society, Taiwanese Menopause Society, and the Thai Menopause Society. The American College of Obstetricians and Gynecologists supports the value of this clinical document as an educational tool, June 2017. The British Menopause Society supports this Position Statement.


Dose-dependent Nodal/Smad signals pattern the early mouse embryo.
Nodal signals in the early post-implantation stage embryo are essential to establish initial proximal-distal (P-D) polarity and generate the final anterior-posterior (A-P) body axis. Nodal signaling in the epiblast results in the phosphorylation of Smad2 in the overlying visceral endoderm necessary to induce the AVE, in part via Smad2-dependent activation of the T-box gene Eomesodermin. Slightly later following mesoderm induction a continuum of dose-dependent Nodal signaling during the process of gastrulation underlies specification of mesodermal and definitive endoderm progenitors. Dynamic Nodal expression during the critical 72 h time window immediately following implantation, accomplished by a series of feed-back and feed-forward mechanisms serves to provide key positional cues required for establishment of the body plan and controls cell fate decisions in the early mammalian embryo.


DNA adenine methyltransferase influences the virulence of Aeromonas hydrophila.
Among the various virulence factors produced by Aeromonas hydrophila, a type II secretion system (T2SS)-secreted cytotoxic enterotoxin (Act) and the T3SS are crucial in the pathogenesis of Aeromonas-associated infections. Our laboratory molecularly characterized both Act and the T3SS from a diarrheal isolate, SSU of A. hydrophila, and defined the role of some regulatory genes in modulating the biological effects of Act. In this study, we cloned, sequenced, and expressed the DNA adenine methyltransferase gene of A. hydrophila SSU (dam(AhSSU)) in a T7 promoter-based vector system using Escherichia coli ER2566 as a host strain, which could alter the virulence potential of A. hydrophila. Recombinant Dam, designated as M.AhySSUDam, was produced as a histidine-tagged fusion protein and purified from an E. coli cell lysate using nickel affinity chromatography. The purified Dam had methyltransferase activity, based on its ability to transfer a methyl group from S-adenosyl-l-methionine to N(6)-methyladenine-free lambda DNA and to protect methylated lambda DNA from digestion with DpnII but not against the DpnI restriction enzyme. The dam gene was essential for the viability of the bacterium, and overproduction of Dam in A. hydrophila SSU, using an arabinose-inducible, P(BAD) promoter-based system, reduced the virulence of this pathogen. Specifically, overproduction of M.AhySSUDam decreased the motility of the bacterium by 58%. Likewise, the T3SS-associated cytotoxicity, as measured by the release of lactate dehydrogenase enzyme in murine macrophages infected with the Dam-overproducing strain, was diminished by 55% compared to that of a control A. hydrophila SSU strain harboring the pBAD vector alone. On the contrary, cytotoxic and hemolytic activities associated with Act as well as the protease activity in the culture supernatant of a Dam-overproducing strain were increased by 10-, 3-, and 2.4-fold, respectively, compared to those of the control A. hydrophila SSU strain. The Dam-overproducing strain was not lethal to mice (100% survival) when given by the intraperitoneal route at a dose twice that of the 50% lethal dose, which within 2 to 3 days killed 100% of the animals inoculated with the A. hydrophila control strain. Taken together, our data indicated alteration of A. hydrophila virulence by overproduction of Dam.


Identifying an early treatment window for predicting breast cancer response to neoadjuvant chemotherapy using immunohistopathology and hemoglobin parameters.
Breast cancer pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) varies with tumor subtype. The purpose of this study was to identify an early treatment window for predicting pCR based on tumor subtype, pretreatment total hemoglobin (tHb) level, and early changes in tHb following NAC. Twenty-two patients (mean age 56 years, range 34-74 years) were assessed using a near-infrared imager coupled with an Ultrasound system prior to treatment, 7 days after the first treatment, at the end of each of the first three cycles, and before their definitive surgery. Pathologic responses were dichotomized by the Miller-Payne system. Tumor vascularity was assessed from tHb; vascularity changes during NAC were assessed from a percentage tHb normalized to the pretreatment level (%tHb). After training the logistic prediction models using the previous study data, we assessed the early treatment window for predicting pathological response according to their tumor subtype (human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), triple-negative (TN)) based on tHb, and %tHb measured at different cycles and evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). In the new study cohort, maximum pretreatment tHb and %tHb changes after cycles 1, 2, and 3 were significantly higher in responder Miller-Payne 4-5 tumors (n = 13) than non-or partial responder Miller-Payne 1-3 tumors (n = 9). However, no significance was found at day 7. The AUC of the predictive power of pretreatment tHb in the cohort was 0.75, which was similar to the performance of the HER2 subtype as a single predictor (AUC of 0.78). A greater predictive power of pretreatment tHb was found within each subtype, with AUCs of 0.88, 0.69, and 0.72, in the HER2, ER, and TN subtypes, respectively. Using pretreatment tHb and cycle 1 %tHb, AUC reached 0.96, 0.91, and 0.90 in HER2, ER, and TN subtypes, respectively, and 0.95 regardless of subtype. Additional cycle 2 %tHb measurements moderately improved prediction for the HER2 subtype but did not improve prediction for the ER and TN subtypes. By combining tumor subtypes with tHb, we predicted the pCR of breast cancer to NAC before treatment. Prediction accuracy can be significantly improved by incorporating cycle 1 and 2 %tHb for the HER2 subtype and cycle 1 %tHb for the ER and TN subtypes. ClinicalTrials.gov, NCT02092636 . Registered in March 2014.


Improving hydrogels' toughness by increasing the dissipative properties of their network.
The weak mechanical performance and fragility of hydrogels limit their application as biomaterials for load bearing applications. The origin of this weakness has been explained by the low resistance to chains breakage composing the hydrogel and to the cracks propagation in the hydrogel submitted to loading conditions. These low resistance and crack propagation were in turn related to an insufficient energy dissipation mechanism in the hydrogel structure. The goal of this study is to evaluate the dissipation mechanism in covalently bonded hydrogels so that tougher hydrogels can be developed while keeping for the hydrogel a relatively high mechanical stiffness. By varying parameters such as cross-linker type or concentration as well as water ratio, the dissipative properties of HEMA-based hydrogels were investigated at large deformations. Different mechanisms such as special friction-like phenomena, nanoporosity, and hydrophobicity were proposed to explain the dissipative behavior of the tested hydrogels. Based on this analysis, it was possible to develop hydrogels with increased toughness properties.


Enhancement of synthesis of extracellular matrix proteins on retinoic acid loaded electrospun scaffolds.
Electrospinning is a renowned technique for the generation of ultrafine, micro- and nanoscale fibres due to its simplicity, versatility and tunability. Owing to its adaptability to a wide selection of materials and scaffold architectures, electrospun meshes have been developed as biocompatible scaffolds and drug delivery systems for tissue engineering. Here, we developed a drug delivery scaffold by electrospinning poly(ε-caprolactone) (PCL) directly blended with a therapeutic agent, retinoic acid (RA), at different concentrations. The release profile, DNA, and elastin analysis of direct and transwell seeded RA-loaded PCL electrospun scaffolds showed desirable controlled release at 15 kV fabrication, with 0.01% RA as the optimum concentration. The selected 0.01% (w/v) RA-loaded PCL meshes were further analysed using five different seeding cultures to investigate and extensively distinguish the effects of RA release with or without cell contact to the PCL electrospun meshes for cell morphology, proliferation and extracellular matrix (ECM) protein secretion of collagen and elastin. Upon exposure to RA-loaded PCL scaffolds, an increase of human dermal fibroblast (HDF) proliferation was observed. In contrast, human mesenchymal stromal cell (hMSC) cultures showed a decrease in cell proliferation. For both hMSC and HDF cultures, exposure to RA-loaded PCL scaffolds provided a significant increase in elastin production per cell. For collagen expression, a slight increase was measured and was outperformed by the 3D geometry stimulation from PCL scaffolds. In contrast to hMSCs, HDFs showed enhanced stress actin fibres in cultures with RA-loaded PCL scaffolds. Both cell types exhibited more vinculin expression when seeded to RA-loaded PCL scaffolds. Hence, electrospun scaffolds releasing RA in a controlled manner were able to regulate cell proliferation, morphology and ECM secretion, and present an attractive approach for optimizing tissue regeneration.


Spinel Co3O4 nanomaterials for efficient and stable large area carbon-based printed perovskite solar cells.
Carbon based perovskite solar cells (PSCs) are fabricated through easily scalable screen printing techniques, using abundant and cheap carbon to replace the hole transport material (HTM) and the gold electrode further reduces costs, and carbon acts as a moisture repellent that helps in maintaining the stability of the underlying perovskite active layer. An inorganic interlayer of spinel cobaltite oxides (Co3O4) can greatly enhance the carbon based PSC performance by suppressing charge recombination and extracting holes efficiently. The main focus of this research work is to investigate the effectiveness of Co3O4 spinel oxide as the hole transporting interlayer for carbon based perovskite solar cells (PSCs). In these types of PSCs, the power conversion efficiency (PCE) is restricted by the charge carrier transport and recombination processes at the carbon-perovskite interface. The spinel Co3O4 nanoparticles are synthesized using the chemical precipitation method, and characterized by X-ray diffraction (XRD), X-ray absorption spectroscopy (XAS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and UV-Vis spectroscopy. A screen printed thin layer of p-type inorganic spinel Co3O4 in carbon PSCs provides a better-energy level matching, superior efficiency, and stability. Compared to standard carbon PSCs (PCE of 11.25%) an improved PCE of 13.27% with long-term stability, up to 2500 hours under ambient conditions, is achieved. Finally, the fabrication of a monolithic perovskite module is demonstrated, having an active area of 70 cm2 and showing a power conversion efficiency of >11% with virtually no hysteresis. This indicates that Co3O4 is a promising interlayer for efficient and stable large area carbon PSCs.


Radiologic review of acquired pulmonary vein stenosis in adults.
Acquired pulmonary vein stenosis (PVS) is an uncommon occurrence in adults, but one that carries significant morbidity/mortality. PVS can be secondary to neoplastic infiltration/extrinsic compression, non-neoplastic infiltration/extrinsic compression, or iatrogenic intervention. This article: (I) reviews the common causes of acquired PVS; (II) illustrates direct and indirect cross-sectional imaging findings in acquired PVS (in order to avoid misinterpretation of these imaging findings); and (III) details the role of imaging before and after the treatment of acquired PVS.


Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control.
Chronic orthostatic intolerance (COI) is a debilitating autonomic condition in young adults. Its neurohumoral and hemodynamic profiles suggest possible alterations of postural sympathetic function and of baroreflex control of heart rate (HR). In 16 COI patients and 16 healthy volunteers, intra-arterial blood pressure (BP), ECG, central venous pressure (CVP), and muscle sympathetic nerve activity (MSNA) were recorded at rest and during 75 degrees tilt. Spectral analysis of RR interval and systolic arterial pressure (SAP) variabilities provided indices of sympathovagal modulation of the sinoatrial node (ratio of low-frequency to high-frequency components, LF/HF) and of sympathetic vasomotor control (LFSAP). Baroreflex mechanisms were assessed (1) by the slope of the regression line obtained from changes of RR interval and MSNA evoked by pharmacologically induced alterations in BP and (2) by the index alpha, obtained from cross-spectral analysis of RR and SAP variabilities. At rest, HR, MSNA, LF/HF, and LFSAP were higher in COI patients, whereas BP and CVP were similar in the two groups. During tilt, BP did not change and CVP fell by the same extent in the 2 groups; the increase of HR and LF/HF was more pronounced in COI patients. Conversely, the increase of MSNA was lower in COI than in control subjects. Baroreflex sensitivity was similar in COI and control subjects at rest; tilt reduced alpha similarly in both groups. COI is characterized by an overall enhancement of noradrenergic tone at rest and by a blunted postganglionic sympathetic response to standing, with a compensatory cardiac sympathetic overactivity. Baroreflex mechanisms maintain their functional responsiveness. These data suggest that in COI, the functional distribution of central sympathetic tone to the heart and vasculature is abnormal.


Maize: A Paramount Staple Crop in the Context of Global Nutrition.
The maize plant (Zea mays), characterized by an erect green stalk, is one of the 3 great grain crops of the world. Its kernels, like other seeds, are storage organs that contain essential components for plant growth and reproduction. Many of these kernel constituents, including starch, protein, and some micronutrients, are also required for human health. For this reason, and others, maize has become highly integrated into global agriculture, human diet, and cultural traditions. The nutritional quality and integrity of maize kernels are influenced by many factors including genetic background, environment, and kernel processing. Cooking procedures, including nixtamalization and fermentation, can increase accessibility of micronutrients such as niacin. However, man cannot live on maize alone. For one-third of the world's population, namely in sub-Saharan Africa, Southeast Asia, and Latin America, humans subsist on maize as a staple food but malnutrition pervades. Strategies to further improve kernel macronutrient and micronutrient quality and quantities are under intense investigation. The 2 most common routes to enhance grain nutritional value are exogenous and endogenous fortification. Although exogenous fortification, such as addition of multivitamin premixes to maize flour, has been successful, endogenous fortification, also known as "biofortification," may provide a more sustainable and practical solution for chronically undernourished communities. Recent accomplishments, such as low-phytate, high-lysine, and multivitamin maize varieties, have been created using novel genetic and agronomic approaches. Investigational studies related to biofortified maize are currently underway to determine nutrient absorption and efficacy related to human health improvement.


Absorption and emission line shapes in the O(2) atmospheric bands: Theoretical model and limb viewing simulations.
A multiple scattering radiative transfer model has been developed to carry out a line by line calculation of the absorption and emission limb measurements that will be made by the High Resolution Doppler Imager to be flown on the Upper Atmosphere Research Satellite. The multiple scattering model uses the doubling and adding methods to solve the radiative transfer equation, modified to take into account a spherical inhomogeneous atmosphere. Representative absorption and emission line shapes in the O(2)((1)Sigma(+)(g)-(3)Sigma(-)(g)) atmospheric bands (A, B, and gamma) and their variation with altitude are presented. The effects of solar zenith angle, aerosol loading, surface albedo, and cloud height on the line shapes are also discussed.


Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation.
Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets.


Standard practice and controversial issues in front-line therapy of acute promyelocytic leukemia.
In addition to choosing a state-of-the-art regimen including all-transretinoic and anthracycline chemotherapy, modern management of acute promyelocytic leukemia (APL) implies the adoption of appropriate supportive measures, rapid establishment of an accurate genetic diagnosis, correct assessment of response to therapy and evaluation of the risk of disease recurrence by molecular monitoring. However, the general consensus about this overall strategy for APL treatment still leaves room for a number of controversial issues. In the present article, we review the current standard practice and controversial issues in the treatment of patients with newly diagnosed APL, including the management of special situations such as elderly patients, children and pregnant women.


Genetic Analysis of Substrain Divergence in Non-Obese Diabetic (NOD) Mice.
The non-obese diabetic (NOD) mouse is a polygenic model for type 1 diabetes that is characterized by insulitis, a leukocytic infiltration of the pancreatic islets. During ~35 years since the original inbred strain was developed in Japan, NOD substrains have been established at different laboratories around the world. Although environmental differences among NOD colonies capable of impacting diabetes incidence have been recognized, differences arising from genetic divergence have not been analyzed previously. We use both mouse diversity array and whole-exome capture sequencing platforms to identify genetic differences distinguishing five NOD substrains. We describe 64 single-nucleotide polymorphisms, and two short indels that differ in coding regions of the five NOD substrains. A 100-kb deletion on Chromosome 3 distinguishes NOD/ShiLtJ and NOD/ShiLtDvs from three other substrains, whereas a 111-kb deletion in the Icam2 gene on Chromosome 11 is unique to the NOD/ShiLtDvs genome. The extent of genetic divergence for NOD substrains is compared with similar studies for C57BL6 and BALB/c substrains. As mutations are fixed to homozygosity by continued inbreeding, significant differences in substrain phenotypes are to be expected. These results emphasize the importance of using embryo freezing methods to minimize genetic drift within substrains and of applying appropriate genetic nomenclature to permit substrain recognition when one is used.


Soft selective sweeps in complex demographic scenarios.
Adaptation from de novo mutation can produce so-called soft selective sweeps, where adaptive alleles of independent mutational origin sweep through the population at the same time. Population genetic theory predicts that such soft sweeps should be likely if the product of the population size and the mutation rate toward the adaptive allele is sufficiently large, such that multiple adaptive mutations can establish before one has reached fixation; however, it remains unclear how demographic processes affect the probability of observing soft sweeps. Here we extend the theory of soft selective sweeps to realistic demographic scenarios that allow for changes in population size over time. We first show that population bottlenecks can lead to the removal of all but one adaptive lineage from an initially soft selective sweep. The parameter regime under which such "hardening" of soft selective sweeps is likely is determined by a simple heuristic condition. We further develop a generalized analytical framework, based on an extension of the coalescent process, for calculating the probability of soft sweeps under arbitrary demographic scenarios. Two important limits emerge within this analytical framework: In the limit where population-size fluctuations are fast compared to the duration of the sweep, the likelihood of soft sweeps is determined by the harmonic mean of the variance effective population size estimated over the duration of the sweep; in the opposing slow fluctuation limit, the likelihood of soft sweeps is determined by the instantaneous variance effective population size at the onset of the sweep. We show that as a consequence of this finding the probability of observing soft sweeps becomes a function of the strength of selection. Specifically, in species with sharply fluctuating population size, strong selection is more likely to produce soft sweeps than weak selection. Our results highlight the importance of accurate demographic estimates over short evolutionary timescales for understanding the population genetics of adaptation from de novo mutation.


Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy.
Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce. To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C. In this cohort study, first- and last-available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression. The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression. Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate -3.3% per 5 years; IQR, -8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, -0.2% per 5 years; IQR, -6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by ±2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC. Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C.


Combining brain stimulation and video game to promote long-term transfer of learning and cognitive enhancement.
Cognitive training offers the potential for individualised learning, prevention of cognitive decline, and rehabilitation. However, key research challenges include ecological validity (training design), transfer of learning and long-term effects. Given that cognitive training and neuromodulation affect neuroplasticity, their combination could promote greater, synergistic effects. We investigated whether combining transcranial direct current stimulation (tDCS) with cognitive training could further enhance cognitive performance compared to training alone, and promote transfer within a short period of time. Healthy adults received real or sham tDCS over their dorsolateral prefrontal cortices during two 30-minute mathematics training sessions involving body movements. To examine the role of training, an active control group received tDCS during a non-mathematical task. Those who received real tDCS performed significantly better in the game than the sham group, and showed transfer effects to working memory, a related but non-numerical cognitive domain. This transfer effect was absent in active and sham control groups. Furthermore, training gains were more pronounced amongst those with lower baseline cognitive abilities, suggesting the potential for reducing cognitive inequalities. All effects associated with real tDCS remained 2 months post-training. Our study demonstrates the potential benefit of this approach for long-term enhancement of human learning and cognition.


Use of all cause mortality to quantify the consequences of covid-19 in Nembro, Lombardy: descriptive study.
To quantify the impact of coronavirus disease 2019 (covid-19) on all cause mortality in Nembro, an Italian city severely affected by the covid-19 pandemic. Descriptive study. Nembro, in the Bergamo province of Lombardy, northern Italy. Residents of Nembro. Monthly all cause mortality between January 2012 and April 2020 (data to 11 April), number of confirmed deaths from covid-19 to 11 April 2020, and weekly absolute number of deaths between 1 January and 4 April across recent years by age group and sex. Nembro had 11 505 residents as of 1 January 2020. Monthly all cause mortality between January 2012 and February 2020 fluctuated around 10 per 1000 person years, with a maximum of 21.5 per 1000 person years. In March 2020, monthly all cause mortality reached a peak of 154.4 per 1000 person years. For the first 11 days in April, this rate decreased to 23.0 per 1000 person years. The observed increase in mortality was driven by the number of deaths among older people (≥65 years), especially men. From the outbreak onset until 11 April 2020, only 85 confirmed deaths from covid-19 in Nembro were recorded, corresponding to about half of the 166 deaths from all causes observed in that period. The study findings show how covid-19 can have a considerable impact on the health of a small community. Furthermore, the results suggest that the full implications of the covid-19 pandemic can only be completely understood if, in addition to confirmed deaths related to covid-19, consideration is also given to all cause mortality in a given region and time frame.


THE ROLE OF POROUS MEDIA IN MODELING FLUID FLOW WITHIN HOLLOW FIBER MEMBRANES OF THE TOTAL ARTIFICIAL LUNG.
A numerical study was conducted to analyze fluid flow within hollow fiber membranes of the artificial lungs. The hollow fiber bundle was approximated using a porous media model. In addition, the transport equations were solved using the finite-element formulation based on the Galerkin method of weighted residuals. Comparisons with previously published work on the basis of special cases were performed and found to be in excellent agreement. A Newtonian viscous fluid model for the blood was used. Different flow models for porous media, such as the Brinkman-extended Darcy model, Darcy's law model, and the generalized flow model, were considered. Results were obtained in terms of streamlines, velocity vectors, and pressure distribution for various Reynolds numbers and Darcy numbers. The results from this investigation showed that the pressure drop across the artificial lung device increased with an increase in the Reynolds number. In addition, the pressure drop was found to increase significantly for small Darcy numbers.


Suprasegmental and segmental timing models in Mandarin Chinese and American English.
This paper formalizes and tests two key assumptions of the concept of suprasegmental timing: segmental independence and suprasegmental mediation. Segmental independence holds that the duration of a suprasegmental unit such as a syllable or foot is only minimally dependent on its segments. Suprasegmental mediation states that the duration of a segment is determined by the duration of its suprasegmental unit and its identity, but not directly by the specific prosodic context responsible for suprasegmental unit duration. Both assumptions are made by various versions of the isochrony hypothesis [I. Lehiste, J. Phonetics 5, 253-263 (1977)], and by the syllable timing hypothesis [W. Campbell, Speech Commun. 9, 57-62 (1990)]. The validity of these assumptions was studied using the syllable as suprasegmental unit in American English and Mandarin Chinese. To avoid unnatural timing patterns that might be induced when reading carrier phrase material, meaningful, nonrepetitive sentences were used with a wide range of lengths. Segmental independence was tested by measuring how the average duration of a syllable in a fixed prosodic context depends on its segmental composition. A strong association was found; in many cases the increase in average syllabic duration when one segment was substituted for another (e.g., bin versus pin) was the same as the difference in average duration between the two segments (i.e., [b] versus [p]). Thus, the [i] and [n] were not compressed to make room for the longer [p], which is inconsistent with segmental independence. Syllabic mediation was tested by measuring which locations in a syllable are most strongly affected by various contextual factors, including phrasal position, within-word position, tone, and lexical stress. Systematic differences were found between these factors in terms of the intrasyllabic locus of maximal effect. These and earlier results obtained by van Son and van Santen [R. J. J. H van Son and J. P. H. van Santen, "Modeling the interaction between factors affecting consonant duration," Proceedings Eurospeech-97, 1997, pp. 319-322] showing a three-way interaction between consonantal identity (coronals vs labials), within-word position of the syllable, and stress of surrounding vowels, imply that segmental duration cannot be predicted by compressing or elongating segments to fit into a predetermined syllabic time interval. In conclusion, while there is little doubt that suprasegmental units play important predictive and explanatory roles as phonological units, the concept of suprasegmental timing is less promising.


Sodium and potassium intake and blood pressure change in childhood.
To assess the association between sodium and potassium intake and the rise in blood pressure in childhood. Longitudinal study of a cohort of children with annual measurements during an average follow up period of seven years. Epidemiological survey of the population of a suburban town in western Netherlands. Cohort of 233 children aged 5-17 drawn at random from participants in the population survey. At least six annual timed overnight urine samples were obtained. The mean 24 hour sodium and potassium excretion during the follow up period was estimated for each participant and the sodium to potassium ratio calculated. Individual slopes of blood pressure over time were calculated by linear regression analysis. No significant association was observed between sodium excretion and the change in blood pressure over time. The mean systolic blood pressure slopes, however, were lower when potassium intake was higher (coefficient of linear regression -0.045 mm Hg/year/mmol; 95% confidence interval -0.069 to -0.020), and the change in systolic pressure was greater when the urinary sodium to potassium ratio was higher (0.356 mm Hg/year/unit; 95% confidence interval 0.069 to 0.642). In relation to potassium this was interpreted as a rise in blood pressure that was on average 1.0 mm Hg (95% confidence interval -1.65 to -0.35) lower in children in the upper part of the distribution of intake compared with those in the lower part. The mean yearly rise in systolic blood pressure for the group as a whole was 1.95 mm Hg. Urinary electrolyte excretion was not associated with diastolic blood pressure. Dietary potassium and the dietary sodium to potassium ratio are related to the rise in blood pressure in childhood and may be important in the early pathogenesis of primary hypertension.


Current challenges in handling genetic data.
In no other field of biomedicine has such revolutionary change taken place in recent decades as it has in molecular genetics. The accumulated knowledge in this field will not only enable clinicians to make new treatment decisions in future, but will also help to save on healthcare costs. A positive test result will be the prerequisite for carrying out targeted drug treatment (companion diagnostics). Specific molecular diagnostics provide doctors with additional information that was not previously available, enabling them to optimise treatment accordingly. At the same time, prognostic tests mean that targeted preventive measures can be taken. Highly informative non-invasive tests will enable early detection and prevention to play a greater role. Technological breakthroughs, such as high-throughput sequencing, will lead to a flood of data in the future. The challenge lies in the quality of interpretation, which means extracting useful information for doctor and patient. Unlike data collection, interpretation is complex and expensive: it requires a high degree of expertise and a lot of resources. At the same time, experts stress that - as well as improvements in the accuracy and speed of data analysis - defined quality criteria must be generated for reliable interpretation of results. These challenges need to be tackled so that the population can benefit to the utmost from the opportunities offered by these developments: rapidly available and informative tests for targeted therapies based on high-quality data.


C-H bond functionalization based on metal carbene migratory insertion.
Cross-coupling reactions involving metal carbene migratory insertion have been established as a new type of coupling reaction with diazo compounds as the reaction partners. Since 2011, an interesting development has been made in which the carbene migratory insertion process is successfully merged into C-H bond activations. Along this line, a series of investigations have been documented in the past few years. This feature article summarizes the developments in this area.


Prevention of microsomal production of hydroxyl radicals, but not lipid peroxidation, by the glutathione-glutathione peroxidase system.
The glutathione-glutathione peroxidase system is an important defense against oxidative stress. The ability of this system to protect against iron-catalyzed microsomal production of hydroxyl radicals [oxidation of 4-methylmercapto-2-oxo-butyrate (KMBA)] and lipid peroxidation was evaluated. When rat liver cytosol was added to microsomes, strong inhibition against KMBA oxidation was observed. No protection was found when the cytosol was boiled or dialyzed. In the latter case, the addition of 0.5 mM glutathione restored almost complete protection, whereas in the former case protection could be restored by the addition of both glutathione and glutathione peroxidase. Cysteine could not replace glutathione, nor could glutathione S-transferase replace glutathione peroxidase. The glutathione-glutathione peroxidase system was also very effective in decreasing production of hydroxyl radicals stimulated by the addition of menadione or paraquat to microsomes. In the absence of cytosol, the addition of glutathione plus glutathione peroxidase was also effective; however, 5 mM glutathione was necessary to protect against KMBA oxidation. The effective concentration of glutathione required for protection was lowered when glutathione reductase was added to the system, to regenerate reduced glutathione. These results indicate that low concentrations of glutathione in conjunction with glutathione peroxidase plus reductase can be very effective in preventing microsomal formation of hydroxyl radicals catalyzed by iron and other toxic compounds. Microsomal lipid peroxidation was decreased 40% by glutathione alone, and this decrease was potentiated in the presence of glutathione reductase. In contrast to KMBA oxidation, the combination of glutathione plus glutathione peroxidase was not any more effective than glutathione alone in preventing lipid peroxidation. The differences in sensitivities of microsomal lipid peroxidation and KMBA oxidation to glutathione peroxidase suggest that these two processes can be distinguished from each other, and that free H2O2 and hydroxyl radicals are involved in KMBA oxidation, but not lipid peroxidation.


Nicephor[e]: a web-based solution for teaching forensic and scientific photography.
Nicephor[e] is a project funded by "Swiss Virtual Campus" and aims at creating a distant or mixed web-based learning system in forensic and scientific photography and microscopy. The practical goal is to organize series of on-line modular courses corresponding to the educational requirements of undergraduate academic programs. Additionally, this program could be used in the context of continuing educational programs. The architecture of the project is designed to guarantee a high level of knowledge in forensic and scientific photographic techniques, and to have an easy content production and the ability to create a number of different courses sharing the same content. The e-learning system Nicephor[e] consists of three different parts. The first one is a repository of learning objects that gathers all theoretical subject matter of the project such as texts, animations, images, and films. This repository is a web content management system (Typo3) that permits creating, publishing, and administrating dynamic content via a web browser as well as storing it into a database. The flexibility of the system's architecture allows for an easy updating of the content to follow the development of photographic technology. The instructor of a course can decide which modular contents need to be included in the course, and in which order they will be accessed by students. All the modular courses are developed in a learning management system (WebCT or Moodle) that can deal with complex learning scenarios, content distribution, students, tests, and interaction with instructor. Each course has its own learning scenario based on the goals of the course and the student's profile. The content of each course is taken from the content management system. It is then structured in the learning management system according to the pedagogical goals defined by the instructor. The modular courses are created in a highly interactive setting and offer autoevaluating tests to the students. The last part of the system is a digital assets management system (Extensis Portfolio). The practical portion of each course is to produce images of different marks or objects. The collection of all this material produced, indexed by the students and corrected by the instructor is essential to the development of a knowledge base of photographic techniques applied to a specific forensic subject. It represents also an extensible collection of different marks from known sources obtained under various conditions. It allows to reuse these images for creating image-based case files.


Monte carlo simulation of the Leksell Gamma Knife: II. Effects of heterogeneous versus homogeneous media for stereotactic radiosurgery.
The absence of electronic equilibrium in the vicinity of bone-tissue or air-tissue heterogeneity in the head can misrepresent deposited dose with treatment planning algorithms that assume all treatment volume as homogeneous media. In this paper, Monte Carlo simulation (PENELOPE) and measurements with a specially designed heterogeneous phantom were applied to investigate the effect of air-tissue and bone-tissue heterogeneity on dose perturbation with the Leksell Gamma Knife. The dose fall-off near the air-tissue interface caused by secondary electron disequilibrium leads to overestimation of dose by the vendor supplied treatment planning software (GammaPlan) at up to 4 mm from an interface. The dose delivered to the target area away from an air-tissue interface may be underestimated by up to 7% by GammaPlan due to overestimation of attenuation of photon beams passing through air cavities. While the underdosing near the air-tissue interface cannot be eliminated with any plug pattern, the overdosage due to under-attenuation of the photon beams in air cavities can be eliminated by plugging the sources whose beams intersect the air cavity. Little perturbation was observed next to bone-tissue interfaces. Monte Carlo results were confirmed by measurements. This study shows that the employed Monte Carlo treatment planning is more accurate for precise dosimetry of stereotactic radiosurgery with the Leksell Gamma Knife for targets in the vicinity of air-filled cavities.


BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case-control study.
Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.


Common pattern of cortical pathology in childhood-onset and adult-onset schizophrenia as identified by proton magnetic resonance spectroscopic imaging.
Multislice proton magnetic resonance spectroscopic imaging (1H-MRSI) permits simultaneous acquisition and mapping of signal intensities of N-acetyl-containing compounds (mainly N-acetylaspartate, NAA), choline-containing compounds (CHO), and creatine plus phosphocreatine (CRE) from multiple whole-brain slices consisting of small single-volume elements. Previous 1H-MRSI studies of adult patients with schizophrenia showed small NAA relative signals in the hippocampal area and in the dorsolateral prefrontal cortex in comparison with healthy subjects. As part of a program to address the pathophysiological continuity between childhood-onset and adult-onset schizophrenia, the authors performed 1H-MRSI of patients with childhood-onset schizophrenia to specifically test whether the hippocampal area and dorsolateral prefrontal cortex show the same abnormalities as seen in adult-onset schizophrenia. A 1.5-T nuclear magnetic resonance machine was used to test 14 patients (mean age, 16.4 years) and 14 comparison subjects. Ratios of areas under the metabolite peaks of the proton spectra were determined (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions. The patients showed significantly lower NAA/CRE ratios bilaterally in the hippocampal area and the dorsolateral prefrontal cortex than the comparison subjects. There were no significant differences in CHO/CRE or in NAA ratios in any other area sampled. The present study shows that patients with childhood-onset schizophrenia have smaller than normal regional NAA relative signals, suggesting neuronal damage or malfunction in the hippocampal area and dorsolateral prefrontal cortex. These differences were similar in magnitude to those found in patients with adult-onset schizophrenia. The present data extend other evidence of a biological continuum between childhood- and adult-onset schizophrenia.


Protein kinase C and NF-κB-dependent CD4 downregulation in macrophages induced by T cell-derived soluble factors: consequences for HIV-1 infection.
Upon activation, CD4(+) T cells release cytokines, chemokines, and other soluble factors that influence the kinetics of HIV-1 replication in macrophages (M). In this article, we show that activation of human primary T cells suppresses the early stages of HIV-1 replication in human primary Mφ by downregulating the main cellular receptor for the virus CD4. The secreted factors responsible for this effect have a molecular mass greater than conventional cytokines, are independent of Th1 or Th2 polarization, and are not IFN-γ, IL-16, RANTES, or macrophage inhibitory factor, as revealed by cytokine array analysis and neutralization assays. CD4 downregulation is entirely posttranslational and involves serine phosphorylation of CD4 and its targeting to an intracellular compartment destined for acidification and degradation. CD4 downregulation is dependent on the activities of both protein kinase C and NF-κB as well as the proteasomes. Using high-resolution liquid chromatography-tandem mass spectrometry analysis in conjugation with label-free protein quantitation software, we found that proteins that promote Mφ adherence and spreading, such as attractin, fibronectin, and galectin-3-binding protein, were significantly overrepresented in the activated T cell supernatant fractions. These results reveal the existence of previously unreported anti-HIV-1 proteins, released by activated T cells that downregulate CD4 expression, and are of fundamental importance to understand the kinetics of HIV infection in vivo.


Co-ordination of the discharge planning process in critical care.
This article reports on the current discharge planning beliefs in relation to the co-ordination of the discharge planning process in the critical care environment in the health care system in the state of Victoria, Australia. As there is a paucity of previous studies examining discharge planning in critical care nursing knowledge about the phenomena is consequently limited. The study reported here is part of a larger study exploring critical care nurses' perceptions and understanding of the discharge planning process in the health care system in the state of Victoria, Australia. While a number of different discharge planning models are reported in the literature there is no agreement on the most effective or the most efficient model. An exploratory descriptive research design was used for this study. A total of 502 Victorian critical care nurses were approached to take part in the study. A total of 218 participants completed the survey, which represented a nett response rate of 43.4%. The data from the questionnaire were entered into the Statistical Package for Social Sciences (SPSS) Base 10.0. This allowed calculation of descriptive statistics and statistical analysis using chi-square test for goodness-of-fit. While just over half the participants reported that the discharge planning process in their unit was co-ordinated by a combination of personnel that included a nurse, just under half the participants believed that this was an appropriate model. Another key finding was of those participants who worked in critical care units using primary nursing, just over half responded that the bedside nurse/primary nurse co-ordinated the discharge planning process while just under half responded that a combination of health care team members, including a nurse, co-ordinated the process. Overall there was little support for the designated discharge planning nurse to co-ordinate the process. The findings presented here suggest critical care nurses need to examine who has the ultimate responsibility of co-ordinating the critical care patient's discharge plan irrespective of the nursing model employed within the critical care ward. There is the need to ensure that when discharge planning becomes everybody's responsibility it ultimately does not become no-one's responsibility. If discharge planning practices are to be changed with the introduction of new discharge planning models in the critical care environment then it is important not only to know current practice but also the perceptions of critical care nurses in terms of who they believe should co-ordinate the discharge planning process.


Mesenchymal Stem Cell-Derived Interleukin 1 Receptor Antagonist Promotes Macrophage Polarization and Inhibits B Cell Differentiation.
The role of interleukin 1 receptor antagonist (IL1RA) in mediating the immunosuppressive effect of mesenchymal stem/stromal cells (MSCs) has been reported in several studies. However, how MSC-derived IL1RA influences the host response has not been clearly investigated. We therefore derived MSCs from the bone marrow of IL1RA knockout mice and evaluated their immunosuppressive effect on different immune cell subsets. IL1RA deficient (IL1RA(-/-) ) or wild type (wt) MSCs inhibited to the same extend the proliferation of T lymphocytes. On the contrary, IL1RA(-/-) MSCs were less effective than wt MSCs to induce in vitro the macrophage polarization from M1 to M2 phenotype secreting IL10 and exerting a suppressive effect on CD4(+) T cells. Moreover compared with wt MSCs, IL1RA(-/-) MSCs did not efficiently support the survival of quiescent B lymphocytes and block their differentiation toward CD19(+) CD138(+) plasmablasts secreting IgG antibodies. The effectiveness of IL1RA secreted by MSCs in controlling inflammation was further shown in vivo using the collagen-induced arthritis murine model. MSCs lacking IL1RA expression were unable to protect mice from arthritic progression and even worsened clinical signs, as shown by higher arthritic score and incidence than control arthritic mice. IL1RA(-/-) MSCs were not able to decrease the percentage of Th17 lymphocytes and increase the percentage of Treg cells as well as decreasing the differentiation of B cells toward plasmablasts. Altogether, our results provide evidence of the key role of IL1RA secreted by MSCs to both control the polarization of macrophages toward a M2 phenotype and inhibit B cell differentiation in vivo.


Using National Drug Codes and drug knowledge bases to organize prescription records from multiple sources.
The utility of National Drug Codes (NDCs) and drug knowledge bases (DKBs) in the organization of prescription records from multiple sources was studied. The master files of most pharmacy systems include NDCs and local codes to identify the products they dispense. We obtained a large sample of prescription records from seven different sources. These records carried a national product code or a local code that could be translated into a national product code via their formulary master. We obtained mapping tables from five DKBs. We measured the degree to which the DKB mapping tables covered the national product codes carried in or associated with the sample of prescription records. Considering the total prescription volume, DKBs covered 93.0-99.8% of the product codes from three outpatient sources and 77.4-97.0% of the product codes from four inpatient sources. Among the in-patient sources, invented codes explained 36-94% of the noncoverage. Outpatient pharmacy sources rarely invented codes, which comprised only 0.11-0.21% of their total prescription volume, compared with inpatient pharmacy sources for which invented codes comprised 1.7-7.4% of their prescription volume. The distribution of prescribed products was highly skewed, with 1.4-4.4% of codes accounting for 50% of the message volume and 10.7-34.5% accounting for 90% of the message volume. DKBs cover the product codes used by outpatient sources sufficiently well to permit automatic mapping. Changes in policies and standards could increase coverage of product codes used by inpatient sources.


Pathology findings and correlation with body condition index in stranded killer whales (Orcinus orca) in the northeastern Pacific and Hawaii from 2004 to 2013.
Understanding health and mortality in killer whales (Orcinus orca) is crucial for management and conservation actions. We reviewed pathology reports from 53 animals that stranded in the eastern Pacific Ocean and Hawaii between 2004 and 2013 and used data from 35 animals that stranded from 2001 to 2017 to assess association with morphometrics, blubber thickness, body condition and cause of death. Of the 53 cases, cause of death was determined for 22 (42%) and nine additional animals demonstrated findings of significant importance for population health. Causes of calf mortalities included infectious disease, nutritional, and congenital malformations. Mortalities in sub-adults were due to trauma, malnutrition, and infectious disease and in adults due to bacterial infections, emaciation and blunt force trauma. Death related to human interaction was found in every age class. Important incidental findings included concurrent sarcocystosis and toxoplasmosis, uterine leiomyoma, vertebral periosteal proliferations, cookiecutter shark (Isistius sp.) bite wounds, excessive tooth wear and an ingested fish hook. Blubber thickness increased significantly with body length (all p < 0.001). In contrast, there was no relationship between body length and an index of body condition (BCI). BCI was higher in animals that died from trauma. This study establishes a baseline for understanding health, nutritional status and causes of mortality in stranded killer whales. Given the evidence of direct human interactions on all age classes, in order to be most successful recovery efforts should address the threat of human interactions, especially for small endangered groups of killer whales that occur in close proximity to large human populations, interact with recreational and commercial fishers and transit established shipping lanes.


The oldest haplogyne spider (Araneae: Plectreuridae), from the Middle Jurassic of China.
New fossil spiders (Arachnida: Araneae) from Middle Jurassic (ca. 165 Ma) strata of Daohugou, Inner Mongolia, China are described as Eoplectreurys gertschi gen. et sp. nov. and referred to the modern haplogyne family Plectreuridae. This small family is restricted to southwestern USA, Mexico, and the adjacent Caribbean area today and hitherto has only a sparse Cenozoic fossil record. The morphology of Eoplectreurys is remarkably similar to modern forms and thus demonstrates great evolutionary conservatism. This new discovery not only extends the fossil record of the family by at least 120 Ma to the Middle Jurassic but also supports the hypothesis of a different distribution of the family in the past than today and subsequent extinction over much of its former range.


Influence of Thin Slice Reconstruction on CT Brain Perfusion Analysis.
Although CT scanners generally allow dynamic acquisition of thin slices (1 mm), thick slice (≥5 mm) reconstruction is commonly used for stroke imaging to reduce data, processing time, and noise level. Thin slice CT perfusion (CTP) reconstruction may suffer less from partial volume effects, and thus yield more accurate quantitative results with increased resolution. Before thin slice protocols are to be introduced clinically, it needs to be ensured that this does not affect overall CTP constancy. We studied the influence of thin slice reconstruction on average perfusion values by comparing it with standard thick slice reconstruction. From 50 patient studies, absolute and relative hemisphere averaged estimates of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and permeability-surface area product (PS) were analyzed using 0.8, 2.4, 4.8, and 9.6 mm slice reconstructions. Specifically, the influence of Gaussian and bilateral filtering, the arterial input function (AIF), and motion correction on the perfusion values was investigated. Bilateral filtering gave noise levels comparable to isotropic Gaussian filtering, with less partial volume effects. Absolute CBF, CBV and PS were 22%, 14% and 46% lower with 0.8 mm than with 4.8 mm slices. If the AIF and motion correction were based on thin slices prior to reconstruction of thicker slices, these differences reduced to 3%, 4% and 3%. The effect of slice thickness on relative values was very small. This study shows that thin slice reconstruction for CTP with unaltered acquisition protocol gives relative perfusion values without clinically relevant bias. It does however affect absolute perfusion values, of which CBF and CBV are most sensitive. Partial volume effects in large arteries and veins lead to overestimation of these values. The effects of reconstruction slice thickness should be taken into account when absolute perfusion values are used for clinical decision making.


Long-term acclimation to near-future ocean acidification has negligible effects on energetic attributes in a juvenile coral reef fish.
Increased levels of dissolved carbon dioxide (CO2) drive ocean acidification and have been predicted to increase the energy use of marine fishes via physiological and behavioural mechanisms. This notion is based on a theoretical framework suggesting that detrimental effects on energy use are caused by plasma acid-base disruption in response to hypercapnic acidosis, potentially in combination with a malfunction of the gamma aminobutyric acid type A (GABAA) receptors in the brain. However, the existing empirical evidence testing these effects primarily stems from studies that exposed fish to elevated CO2 for a few days and measured a small number of traits. We investigated a range of energetic traits in juvenile spiny chromis damselfish (Acanthochromis polyacanthus) over 3 months of acclimation to projected end-of-century CO2 levels (~ 1000 µatm). Somatic growth and otolith size and shape were unaffected by the CO2 treatment across 3 months of development in comparison with control fish (~ 420 µatm). Swimming activity during behavioural assays was initially higher in the elevated CO2 group, but this effect dissipated within ~ 25 min following handling. The transient higher activity of fish under elevated CO2 was not associated with a detectable difference in the rate of oxygen uptake nor was it mediated by GABAA neurotransmitter interference because treatment with a GABAA antagonist (gabazine) did not abolish the CO2 treatment effect. These findings contrast with several short-term studies by suggesting that end-of-century levels of CO2 may have negligible direct effects on the energetics of at least some species of fish.


Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly.
Recent studies indicate that splicing of pre-messenger RNA and export of mRNA are normally coupled in vivo. During splicing, the conserved mRNA export factor Aly is recruited to the spliced mRNA-protein complex (mRNP), which targets the mRNA for export. At present, it is not known how Aly is recruited to the spliced mRNP. Here we show that the conserved DEAD-box helicase UAP56, which functions during spliceosome assembly, interacts directly and highly specifically with Aly. Moreover, UAP56 is present together with Aly in the spliced mRNP. Significantly, excess UAP56 is a potent dominant negative inhibitor of mRNA export. Excess UAP56 also inhibits the recruitment of Aly to the spliced mRNP. Furthermore, a mutation in Aly that blocks its interaction with UAP56 prevents recruitment of Aly to the spliced mRNP. These data suggest that the splicing factor UAP56 functions in coupling the splicing and export machineries by recruiting Aly to the spliced mRNP.


Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity.
The Rho GTPase proteins Rac1, RhoA and Cdc42 have a central role in regulating the actin cytoskeleton in dendritic spines, thereby exerting control over the structural and functional plasticity of spines and, ultimately, learning and memory. Although previous work has shown that precise spatiotemporal coordination of these GTPases is crucial for some forms of cell morphogenesis, the nature of such coordination during structural spine plasticity is unclear. Here we describe a three-molecule model of structural long-term potentiation (sLTP) of murine dendritic spines, implicating the localized, coincident activation of Rac1, RhoA and Cdc42 as a causal signal of sLTP. This model posits that complete tripartite signal overlap in spines confers sLTP, but that partial overlap primes spines for structural plasticity. By monitoring the spatiotemporal activation patterns of these GTPases during sLTP, we find that such spatiotemporal signal complementation simultaneously explains three integral features of plasticity: the facilitation of plasticity by brain-derived neurotrophic factor (BDNF), the postsynaptic source of which activates Cdc42 and Rac1, but not RhoA; heterosynaptic facilitation of sLTP, which is conveyed by diffusive Rac1 and RhoA activity; and input specificity, which is afforded by spine-restricted Cdc42 activity. Thus, we present a form of biochemical computation in dendrites involving the controlled complementation of three molecules that simultaneously ensures signal specificity and primes the system for plasticity.


Dynamic tracking line: feasible tracking region of a robot in conveyor systems.
The concept of dynamic tracking line is proposed as the feasible tracking region for a robot in a robot-conveyor system, which takes the conveyor speed into consideration. This paper presents an effective method to find the dynamic tracking line in a robotic workcell. The maximum permissible line-speed which is a quantitative measure of the robot capability for conveyor tracking, is defined on the basis of the relation between the end-effector speed and the bounds on the joint velocities, accelerations, and torques. This measure is derived in an analytic form using the parameterized dynamics and kinematics of the manipulator, and some of its properties are established mathematically. The problem of finding the dynamic tracking line is then formulated as a root-solving problem for a single-variable equation, and solved by the use of a simple numerical technique. Finally, numerical examples are presented to demonstrate the methodology and its applications in workspace specification.


Repeated injections of cocaine inhibit the serotonergic regulation of prolactin and renin secretion in rats.
Alterations in serotonergic function following repeated cocaine injections were examined using neuroendocrine responses to a serotonin (5-HT) releaser and 5-HT agonists. Forty-two hours following administration of cocaine (1-15 mg/kg i.p.) twice daily for 7 or 30 days, male Sprague-Dawley rats were injected with the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg i.p.) and blood samples were collected 1 h later for radioimmunoassays of plasma prolactin, plasma renin activity (PRA) and plasma renin concentration (PRC). PCA significantly increased secretion of prolactin and renin. These responses were attenuated in rats pretreated with cocaine for 30 days. In rats receiving cocaine for 7 days, the attenuation of PCA-induced secretion of prolactin and renin was less consistently observed. To determine whether these alterations were due to pre- or postsynaptic effects, rats were injected with cocaine (15 mg/kg i.p.) twice daily for 7 days, and the neuroendocrine responses to the direct 5-HT agonists RU 24969 and m-CPP were examined, 42 h after the last cocaine injection. Pretreatment with cocaine potentiated RU 24969-induced stimulation of plasma prolactin concentration. However, cocaine did not alter the ability of m-CPP to increase plasma prolactin concentrations. The stimulation of renin secretion in response to both 5-HT agonists was not altered by cocaine pretreatment. The data suggest that repeated cocaine impairs the function of serotonergic nerve terminals that regulate these endocrine responses. Furthermore, the 5-HT receptors that mediate prolactin secretion may exhibit supersensitivity.


The effects of Nigella sativa (Ns), Anthemis hyalina (Ah) and Citrus sinensis (Cs) extracts on the replication of coronavirus and the expression of TRP genes family.
Extracts of Anthemis hyalina (Ah), Nigella sativa (Ns) and peels of Citrus sinensis (Cs) have been used as folk medicine to fight antimicrobial diseases. To evaluate the effect of extracts of Ah, Ns and Cs on the replication of coronavirus (CoV) and on the expression of TRP genes during coronavirus infection, HeLa-CEACAM1a (HeLa-epithelial carcinoembryonic antigen-related cell adhesion molecule 1a) cells were inoculated with MHV-A59 (mouse hepatitis virus-A59) at moi of 30. 1/50 dilution of the extracts was found to be the safe active dose. ELISA kits were used to detect the human IL-8 levels. Total RNA was isolated from the infected cells and cDNA was synthesized. Fluidigm Dynamic Array nanofluidic chip 96.96 was used to analyze the mRNA expression of 21 TRP genes and two control genes. Data was analyzed using the BioMark digital array software. Determinations of relative gene expression values were carried out by using the 2(-∆∆Ct) method (normalized threshold cycle (Ct) value of sample minus normalized Ct value of control). TCID50/ml (tissue culture infectious dose that will produce cytopathic effect in 50% of the inoculated tissue culture cells) was found for treatments to determine the viral loads. The inflammatory cytokine IL-8 level was found to increase for both 24 and 48 h time points following Ns extract treatment. TRPA1, TRPC4, TRPM6, TRPM7, TRPM8 and TRPV4 were the genes which expression levels changed significantly after Ah, Ns or Cs extract treatments. The virus load decreased when any of the Ah, Ns or Cs extracts was added to the CoV infected cells with Ah extract treatment leading to undetectable virus load for both 6 and 8 hpi. Although all the extract treatments had an effect on IL-8 secretion, TRP gene expression and virus load after CoV infection, it was the Ah extract treatment that showed the biggest difference in virus load. Therefore Ah extract is the best candidate in our hands that contains potential treatment molecule(s).


Are Americans more successful at building intercultural relations than Japanese? A comparison and analysis of acculturation outcomes in Japan.
Various Western and Japanese sources in the literature have concluded that Japanese people, who live in a nation with comparatively less ethnocultural diversity than the U.S., lag behind Americans in their capabilities to develop positive intercultural relations. To test these assumptions, this study compared the quality of acculturation outcomes between Japanese and Americans in Japan. Japanese and American scores were calculated for five dependent measures used to operationalize quality of intercultural relations. Four dependent variables revealed no significant differences. For the variable of organizational investiture, Japanese had significantly higher scores, so data were analyzed to discern why.


Community structure explains antibiotic resistance gene dynamics over a temperature gradient in soil.
Soils are reservoirs of antibiotic resistance genes (ARGs), but environmental dynamics of ARGs are largely unknown. Long-term disturbances offer opportunities to examine microbiome responses at scales relevant for both ecological and evolutionary processes and can be insightful for studying ARGs. We examined ARGs in soils overlying the underground coal seam fire in Centralia, PA, which has been burning since 1962. As the fire progresses, previously hot soils can recover to ambient temperatures, which creates a gradient of fire impact. We examined metagenomes from surface soils along this gradient to examine ARGs using a gene-targeted assembler. We targeted 35 clinically relevant ARGs and two horizontal gene transfer-related genes (intI and repA). We detected 17 ARGs in Centralia: AAC6-Ia, adeB, bla_A, bla_B, bla_C, cmlA, dfra12, intI, sul2, tetA, tetW, tetX, tolC, vanA, vanH, vanX and vanZ. The diversity and abundance of bla_A, bla_B, dfra12 and tolC decreased with soil temperature, and changes in ARGs were largely explained by changes in community structure. We observed sequence-specific biogeography along the temperature gradient and observed compositional shifts in bla_A, dfra12 and intI. These results suggest that increased temperatures can reduce soil ARGs but that this is largely due to a concomitant reduction in community-level diversity.


When nurses are also patients: Intimate partner violence and the health system as an enabler of women's health and agency in Johannesburg.
While violence against women is a recognised global health problem, women's agency in marginalised settings is poorly understood, particularly in relation to health systems. We explored agency as a practical and theoretical construct through qualitative research among 20 nurses with direct or indirect experiences of intimate partner violence (IPV) in Johannesburg. Interviews conducted from August 2013 to March 2014 generated rich descriptions from respondents in five health facilities. Nurses' self-reported IPV matched national prevalence of 24-31%. Findings revealed the way in which agency is enacted by nurses, allowing them the economic means to leave abusive partnerships, yet disabling them from agency and health promotion in their workplace. At the same time, nurses expanded agentic possibilities for patients by enabling a national response to IPV within South African health clinics - one that is largely undocumented. We posit that nurses can serve as important agentic actors in public health systems in low- and middle-income country settings by assisting patients to address IPV, even in the absence of targeted training and guidelines. To ensure the health and well-being of women experiencing IPV, nurses should be supported by the health sector to respond skilfully to patients and to safely process their own experiences of violence.


Infectious but nonpathogenic isolate of Borrelia burgdorferi.
We document for the first time an infectious but nonarthritogenic variant of Borrelia burgdorferi. Strain 25015, previously isolated from an Ixodes dammini larva collected in upstate New York, was infectious but failed to produce arthritis or carditis in laboratory rats and mice. By contrast, pathogenic strain N40 invariably caused arthritis. This nonarthritogenic variant, with proteins with molecular weights different from those of the standard B31 strain, was frequently isolated from normal joint tissues of experimentally infected rats. Outer surface proteins A and B of strain 25015 have molecular weights of about 32,500 and 35,500, respectively, in contrast to molecular weights of approximately 31,000 and 34,000, respectively, for outer surface proteins A and B of strains B31 and N40. A prominent low-molecular-weight protein of about 23,500 also characterizes strain 25015. Test animals infected for 30 to 60 days had relatively high antibody titers (greater than or equal to 1:1,280). The nonarthritogenic variant will be useful, along with pathogenic strains, in providing comparative insight into the pathogenesis of Lyme borreliosis. Homologous immunoblotting of sera from rats and mice inoculated with both the arthritogenic and nonarthritogenic strains revealed antibody reactivities to proteins of B. burgdorferi different from those revealed in the heterologous tests.


Pre-reconstruction rigid body registration for positron emission tomography: an initial validation against ground truth.
Our recent adaptation to PET of the method of Fitchard et al. [1], [2], [3] for rigid body registration of CT sinograms enables motion between two temporal frames of PET data to be estimated and corrected prior to reconstruction. This avoids both the computation required by multiple reconstructions and the need to make choices regarding reconstruction methods that influence the images produced, and potentially change the estimated motion. Using realistic, simulated data with known ground truth, we report an initial investigation into the performance of the method as the number of counts and the accuracy with which the scan is divided into frames, corresponding to different positions, varies.


Policy Evaluation Network (PEN): Protocol for systematic literature reviews examining the evidence for impact of policies on physical activity across seven different policy domains.
Introduction: Over 40 million deaths annually are due to noncommunicable diseases, 15 million of these are premature deaths and physical inactivity contributes an estimated 9% to this figure. Global responses have included the Sustainable Development Goals (SDGs) and the Global Action Plan on Physical Activity (GAPPA). Both point to policy action on physical activity (PA) to address change, yet the impact of policy on PA outcomes is unknown. The protocol described outlines the methodology for systematic literature reviews that will be undertaken by the Policy Evaluation Network (PEN) to address this knowledge gap. Methods: The seven best investments for promotion of population PA identified in the Toronto Charter highlighted seven policy domains (schools, transport, urban design, primary health care systems, public education, community-wide programmes and sport) which will form the basis of these PEN reviews. Seven individual scientific literature searches across six electronic databases will be conducted. Each will use the key concepts of policy, PA, evaluation and a distinct concept for each of the seven policy domains. This will be supplemented with a search of the reference list of included articles. Methodological quality will be assessed and overall effectiveness for each included study will be described according to pre-determined criteria. Conclusions: Each review will provide policy makers with a list of policy statements and corresponding actions which the evidence has determined impact on PA directly or indirectly. By collating the evidence, and demonstrating the depth of the science base which informs these policy recommendations, each review will provide guidance to policymakers to use evidence-based or evidence-informed policies to achieve the 15% relative reduction in physical inactivity as defined by GAPPA. Registration: PROSPERO CRD42020156630 (10/07/2020).