A new structural class of proteasome inhibitors that prevent NF-kappa B activation.
The multicatalytic proteinase or proteasome is a highly conserved cellular structure that is responsible for the ATP-dependent proteolysis of many proteins involved in important regulatory cellular processes. We have identified a novel class of inhibitors of the chymotrypsin-like proteolytic activity of the 20S proteasome that exhibit IC50 values ranging from 0.1 to 0.5 microgram/mL (0.1 to 1 microM). In cell proliferation assays, these compounds inhibit growth with an IC50 ranging from 5 to 10 micrograms/mL (10-20 microM). A representative member of this class of inhibitors was tested in other biological assays. CVT-634 (5-methoxy-1-indanone-3-acetyl-leu-D-leu-1-indanylamide) prevented lipopolysaccharide (LPS), tumor necrosis factor (TNF)-, and phorbol ester-induced activation of nuclear factor kappa B (NF-kappa B) in vitro by preventing signal-induced degradation of I kappa B-alpha. In these studies, the I kappa B-alpha that accumulated was hyperphosphorylated, indicating that CVT-634 did not inhibit I kappa B-alpha kinase, the enzyme responsible for signal-induced phosphorylation of I kappa B-alpha. In vivo studies indicated that CVT-634 prevented LPS-induced TNF synthesis in a murine macrophage cell line. In addition, in mice pretreated with CVT-634 at 25 and 50 mg/kg and subsequently treated with LPS, serum TNF levels were significantly lower (225 +/- 59 and 83 +/- 41 pg/mL, respectively) than in those mice that were treated only with LPS (865 +/- 282 pg/mL). These studies suggest that specific inhibition of the chymotrypsin-like activity of the proteasome is sufficient to prevent signal-induced NF-kappa B activation and that the proteasome is a novel target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent upon the activation of NF-kappa B.


Mutagenesis of asp-569 of glucosyltransferase I glucansucrase modulates glucan and oligosaccharide synthesis.
Glucansucrases of oral streptococci and Leuconostoc mesenteroides are enzymes of medical and biotechnological interest that synthesize alpha-glucans. They can also synthesize oligosaccharides in the presence of a sugar acceptor. Previous reports have identified an amino acid residue that may affect the structure of the glucan product; therefore, random mutagenesis of the corresponding Asp-569 of Streptococcus downei glucosyltransferase I (GTF-I) was used to further understanding of its involvement in the catalytic mechanism and to evaluate how different amino acids can modulate glucan and oligosaccharide synthesis. GTF-I variants were obtained where Asp-569 was replaced by each of the different possible classes of amino acids. These were expressed in Escherichia coli and purified by means of a His(6) tag. The results showed that the amino acid in position 569 influences the structure of the glucan and the size of the oligosaccharides produced by GTF-I. The results suggest that the amino acid occupying this position is more likely to interact with the acceptor molecules (oligosaccharides or elongating glucan chain) than to be directly involved in glucosyl transfer from sucrose. Engineering of the equivalent position in glucansucrases thus appears to be a good target to expand the range of oligosaccharides synthesized.


A promoter with an internal regulatory domain is part of the origin of replication in BPV-1.
Extrachromosomal elements that are stably maintained at a constant copy number through cell doublings are a good model system for the study of the regulation of DNA replication in higher eukaryotes. Previous studies have defined both cis and trans functions required for the regulated plasmid replication of the bovine papilloma virus in stably transformed cells. Here, a sequence known to be a cis-dominant element of the replication origin of the plasmid is shown to contain a promoter for transcription. Both in vitro and in vivo assays have been used to define this promoter and show that a sequence located just 3' to the transcriptional start site is required for activity. This DNA sequence element, which has been defined through deletions, coincides with a binding site for a cellular factor and is also required for a functional origin of replication. Possible models for how a transcription factor may play a role in the regulation of DNA replication are discussed.


Ancient DNA from 8400 Year-Old Çatalhöyük Wheat: Implications for the Origin of Neolithic Agriculture.
Human history was transformed with the advent of agriculture in the Fertile Crescent with wheat as one of the founding crops. Although the Fertile Crescent is renowned as the center of wheat domestication, archaeological studies have shown the crucial involvement of Çatalhöyük in this process. This site first gained attention during the 1961-65 excavations due to the recovery of primitive hexaploid wheat. However, despite the seeds being well preserved, a detailed archaeobotanical description of the samples is missing. In this article, we report on the DNA isolation, amplification and sequencing of ancient DNA of charred wheat grains from Çatalhöyük and other Turkish archaeological sites and the comparison of these wheat grains with contemporary wheat species including T. monococcum, T. dicoccum, T. dicoccoides, T. durum and T. aestivum at HMW glutenin protein loci. These ancient samples represent the oldest wheat sample sequenced to date and the first ancient wheat sample from the Middle East. Remarkably, the sequence analysis of the short DNA fragments preserved in seeds that are approximately 8400 years old showed that the Çatalhöyük wheat stock contained hexaploid wheat, which is similar to contemporary hexaploid wheat species including both naked (T. aestivum) and hulled (T. spelta) wheat. This suggests an early transitory state of hexaploid wheat agriculture from the Fertile Crescent towards Europe spanning present-day Turkey.


Preparation and lithium storage performances of mesoporous Fe₃O₄@C microcapsules.
Fe(3)O(4)@C microcapsules were prepared using carbon-coated α-FeOOH nanorods as precursors, which were synthesized via two-step hydrothermal reactions. During the subsequent sintering procedure, α-FeOOH was reduced to Fe(3)O(4) by carbon, accompanied by the formation of mesopores. In Fe(3)O(4)@C microcapsules, mesoporous Fe(3)O(4) nanorods are coated with amorphorous carbon layers. The Fe(3)O(4)/C composites with such special structures demonstrate high specific capacity and good cyclic stability as anode materials in Li test cells.


Electrohydrodynamic Nanopatterning: A Novel Solvent-Assisted Technique for Unconventional Substrates.
Electrohydrodynamic (EHD)-driven patterning is a pioneering lithographic technique capable of replicating and modifying micro/nanostructures efficiently. However, this process is currently restricted to conventional substrates, as it necessitates a uniform and robust electric field over a large area. Consequently, the use of nontraditional substrates, such as those that are flexible, nonflat, or have high insulation, has been notably limited. In our study, we extend the applicability of EHD-driven patterning by introducing a solvent-assisted capillary peel-and-transfer method that allows the successful removal of diverse EHD-induced structures from their original substrates. Compared with the traditional route, our process boasts a success rate close to 100%. The detached structures can then be efficiently transferred to nonconventional substrates, overcoming the limitations of the traditional EHD process. Our method exhibits significant versatility, as evidenced by successful transfer of structures with engineered wettability and patterned structures composed of metals and metal oxides onto nonconventional substrates.


Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.
To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.


Studies of the recognition sequence of phi X174 gene A protein. Cleavage site of phi X gene A protein in St-1 RFI DNA.
It is already known that phi X gene A protein converts besides phi X RFI DNA also the RFI DNAs of the single-stranded bacteriophages G4, St-1, alpha 3 and phi K into RFII DNA. We have extended this observations for bacteriophages G14 and U3. Restriction enzyme analysis placed the phi X gene A protein cleavage site in St-1 RF DNA in the HinfI restriction DNA fragment F10 and in the overlapping HaeIII restriction DNA fragment Z7. The exact position and the nucleotide sequence at the 3'-OH end of the nick were determined by DNA sequence analysis of the single-stranded DNA subfragment of the nicked DNA fragment F10 obtained by gelelectrophoresis in denaturing conditions. A stretch of 85 nucleotides of St-1 DNA around the position of the phi X gene A protein cleavage site was established by DNA sequence analysis of the restriction DNA fragment Z7F1. Comparison of this nucleotide sequence with the previously determined nucleotide sequence around the cleavage site of phi X gene A protein in phi X174 RF DNA and G4 RF DNA revealed an identical sequence of only 10 nucleotides. The results suggest that the recognition sequence of the phi X174 gene A protein lies within these 10 nucleotides.


Pathogenesis of abdominal aortic aneurysms: microRNAs, proteases, genetic associations.
Abdominal aortic aneurysm (AAA) disease is a common, morbid, and highly lethal pathology. Extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of AAAs. Although surgery is highly effective in preventing death by rupture for larger AAAs, no guidance or preventive therapy is currently available for the >90% of patients whose aneurysms are below the surgical threshold. Predictive animal models of AAA as well as human pathological samples have revealed a complex circuit of AAA formation and progression. The proteolytic destruction of matrix components of the aorta by different proteases has been extensively studied over many years. Recently, a novel class of small noncoding RNAs, called microRNAs, was identified as "fine-tuners" of the translational output of target genes; they act by promoting mRNA degradation. Their therapeutic potential in limiting AAA development appears very intriguing. Further, current studies assessing genetic and heritable associations for AAA disease have provided great insight into its pathogenesis, potentially enabling us to better clinically manage affected patients.


Strategies to enhance the distribution of nanotherapeutics in the brain.
Convection enhanced delivery (CED) provides a powerful means to bypass the blood-brain barrier and drive widespread distribution of therapeutics in brain parenchyma away from the point of local administration. However, recent studies have detailed that the overall distribution of therapeutic nanoparticles (NP) following CED remains poor due to tissue inhomogeneity and anatomical barriers present in the brain, which has limited its translational applicability. Using probe NP, we first demonstrate that a significantly improved brain distribution is achieved by infusing small, non-adhesive NP via CED in a hyperosmolar infusate solution. This multimodal delivery strategy minimizes the hindrance of NP diffusion imposed by the brain extracellular matrix and reduces NP confinement within the perivascular spaces. We further recapitulate the distributions achieved by CED of this probe NP using a most widely explored biodegradable polymer-based drug delivery NP. These findings provide a strategy to overcome several key limitations of CED that have been previously observed in clinical trials.


Optimizing antimicrobial therapy of sepsis and septic shock: focus on antibiotic combination therapy.
There has been little improvement in septic shock mortality in the past 70 years, despite ever more broad-spectrum and potent antimicrobials. In the past, resuscitative elements have been the primary area of clinical septic shock management and research. The question of the optimal use of antimicrobial therapy was relatively ignored in recent decades. This review explores the pathophysiology of sepsis in an attempt to produce a better understanding and define key determinants of antimicrobial therapy response in septic shock. Optimizing existing antimicrobials delivery can drive significant improvements in the outcome of sepsis and septic shock. Inappropriate antimicrobial selection and dosing or delays in the administration substantially increase mortality and morbidity in life-threatening infections. Definitive combination therapy (where a pathogen known to be susceptible to a given agent is additionally covered by another agent) remains controversial. Although some in vitro studies, animal models, and clinical studies of infection including endocarditis, gram-negative bacteremia, and neutropenic infections have supported combination therapy, the potential clinical benefit in other severe infections has been questioned. Several meta-analyses have failed to demonstrate improvement of outcome with combination therapy in immunocompetent patients with sepsis and/or gram-negative bacteremia. These meta-analyses did not undertake subgroup analyses of the septic shock population. This article reviews the existing evidence supporting combination therapy for severe infections, sepsis, and septic shock.


SEXINFO: a sexual health text messaging service for San Francisco youth.
In response to rising gonorrhea rates among African American youth in San Francisco, Calif, Internet Sexuality Information Services, Inc, in partnership with the San Francisco Department of Public Health, developed SEXINFO, a sexual health text messaging service. SEXINFO is an information and referral service that can be accessed by texting "SEXINFO" to a 5-digit number from any wireless phone. A consortium of community organizations, religious groups, and health agencies assisted with identifying culturally appropriate local referral services. We conducted focus group sessions among youth aged 15 to 19 years to discuss the viability of the service. Usage of the service has been greater than expected, and an initial evaluation to assess the impact of SEXINFO on increasing access to sexual health services among at-risk adolescents has had promising results.


Changes in Brain Volume Resulting from Cognitive Intervention by Means of the Feuerstein Instrumental Enrichment Program in Older Adults with Mild Cognitive Impairment (MCI): A Pilot Study.
There is increasing interest in identifying biological and imaging markers for the early detection of neurocognitive decline. In addition, non-pharmacological strategies, including physical exercise and cognitive interventions, may be beneficial for those developing cognitive impairment. The Feuerstein Instrumental Enrichment (FIE) Program is a cognitive intervention based on structural cognitive modifiability and the mediated learning experience (MLE) and aims to promote problem-solving strategies and metacognitive abilities. The FIE program uses a variety of instruments to enhance the cognitive capacity of the individual as a result of mediation. A specific version of the FIE program was developed for the cognitive enhancement of older adults, focusing on strengthening orientation skills, categorization skills, deductive reasoning, and memory. We performed a prospective interventional pilot observational study on older subjects with MCI who participated in 30 mediated FIE sessions (two sessions weekly for 15 weeks). Of the 23 subjects who completed the study, there was a significant improvement in memory on the NeuroTrax cognitive assessment battery. Complete sets of anatomical MRI data for voxel-based morphometry, taken at the beginning and the end of the study, were obtained from 16 participants (mean age 83.5 years). Voxel-based morphometry showed an interesting and unexpected increase in grey matter (GM) in the anterolateral occipital border and the middle cingulate cortex. These initial findings of our pilot study support the design of randomized trials to evaluate the effect of cognitive training using the FIE program on brain volumes and cognitive function.


Endoscopic sinus surgery for juvenile nasopharyngeal angiofibroma.
Juvenile nasopharyngeal angiofibroma is a rare tumour of the head and neck with very specific characteristics: adolescent males, choana-nasopharynx, pterygomaxillary fossa widening, specific and intense vascularisation. Staging is very important in the decision of the surgical approach. Endoscopic management of juvenile nasopharyngeal angiofibroma is technically possible after preoperative embolisation. Up to now 13 angiofibroma have been treated using the endonasal endoscopic sinus surgery approach in Belgium (Leuven 8; Mont-Godinne 2; Ghent 1; Liege 1; Woluwe 1). In smaller tumors endoscopic resection has been successful in four cases without any recurrence. Five larger tumors, extending in the pterygomaxillary fossa, were also successfully resected. Extension into the infratemporal fossa or the cavernous sinus can be endoscopically removed, but recurrences may occur as they do after classical, external approaches. In conclusion, the endoscopic approach is an acceptable alternative in small to middle sized juvenile nasopharyngeal angiofibroma.


Is the arginine-nitric oxide pathway involved in the pathogenesis of schizophrenia?
The reciprocal regulation of arginase and nitric oxide synthase (NOS) in L-arginine-metabolizing pathways has been demonstrated. There are various evidences of the role of the nitric oxide (NO) in several neuropsychiatric disorders including schizophrenia. However, there is no study which has investigated the role of arginase as an important part of the arginine regulatory system affecting NOS activity in schizophrenia. This study aims to investigate arginase, manganese (Mn) and total nitrite levels (a metabolite of NO) and their relationship to the arginine-NO pathway in patients with schizophrenia. Arginase activities, Mn and total nitrite levels were measured in plasma from 46 patients with schizophrenia and 32 healthy control subjects. Plasma arginase activities and Mn were found to be significantly lower and total nitrite level higher in patients with schizophrenia compared with controls. Our results suggest that the arginine-NO pathway is involved in the pathogenesis of schizophrenia.


Role of myeloperoxidase in the killing of Naegleria fowleri by lymphokine-altered human neutrophils.
Previously we have shown that human neutrophils treated with conditioned medium from phytohemagglutinin-stimulated mononuclear leukocytes (sCM) in the presence of antisera have amoebicidal properties for Naegleria fowleri, a pathogenic free-living amoeba. The data now presented show that neutrophils which lack myeloperoxidase (MPO) but have a normal oxygen-dependent respiratory burst could not be altered by sCM to express the amoebicidal activity. Catalase inhibited this amoebicidal activity of sCM-treated neutrophils. Various components and products of the neutrophils were examined for effects on naegleriae. A granule extract was found to have no effect at concentrations up to 100-fold that which killed Salmonella minnesota R595. Hydrogen peroxide appeared to have little effect even at 100 microM. However, in the presence of MPO, H2O2 was amoebicidal at 2.5 microM. The generation of amoebicidal activity required the presence of chloride ions. Azide inhibited the effects of the MPO-H2O2-Cl- system. Arginine, a scavenger of hypochlorite, significantly depressed the ability of sCM-treated neutrophils to kill amoebae and also prevented the amoebicidal properties of the MPO-H2O2-halide system. These results suggest that the MPO-H2O2-halide system is important in the killing of naegleriae by sCM-treated neutrophils and that hypochlorite may be the amoebicidal agent.


Quasi-experimental evidence on short- and long-term consequences of bullying victimization: A meta-analysis.
Exposure to bullying victimization is associated with a wide-range of short and long-term adverse outcomes. However, the extent to which these associations reflect a causal influence of bullying victimization remains disputed. Here, we aimed to provide the most stringent evidence regarding the consequences of bullying victimization by meta-analyzing all relevant quasi-experimental (QE) studies. Multilevel random effects models and metaregression were employed to (a) estimate the pooled QE-adjusted effect size (Cohen d) for bullying victimization on outcomes and to (b) evaluate potential sources of heterogeneity. A total of 16 studies were included. We derived 101 QE-estimates from three different methods (twin design, fixed effects analysis, and propensity score matching) for three pools of outcomes (internalizing symptoms, externalizing symptoms, academic difficulties). QE-adjusted effects were small for internalizing symptoms (dadjusted = 0.27, 95% CI [0.05, 0.49]), and smaller for externalizing symptoms (dadjusted = 0.15, 95% CI [0.10, 0.21]) and academic difficulties (dadjusted = 0.10, 95% CI [0.06, 0.13]). Accounting for a shared rater effect between the exposure and the outcome further reduced the effect for internalizing (dnonshared rater = 0.14, 95% CI [0.05, 0.23]) and externalizing symptoms (dnonshared rater = 0.06, 95% CI [0.01, 0.11]). Finally, the adverse effects declined in the long-term, most markedly for internalizing symptoms (dlong-term = 0.06, 95% CI [-0.01, 0.13]). Based on the most stringent evidence available to date, findings indicate that bullying victimization may causally impact children's wellbeing in the short-term, especially anxiety and depression levels. The reduction of adverse effects over time highlights the potential for resilience in individuals who have experienced bullying. Secondary preventive interventions in bullied children should therefore focus on resilience and address children's preexisting vulnerabilities. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Temporal and Spatial Analysis of Neural Tube Defects and Detection of Geographical Factors in Shanxi Province, China.
Neural tube defects (NTDs) are congenital birth defects that occur in the central nervous system, and they have the highest incidence among all birth defects. Shanxi Province in China has the world's highest rate of NTDs. Since the 1990s, China's government has worked on many birth defect prevention programs to reduce the occurrence of NTDs, such as pregnancy planning, health education, genetic counseling, antenatal ultrasonography and serological screening. However, the rate of NTDs in Shanxi Province is still higher than the world's average morbidity rate after intervention. In addition, Shanxi Province has abundant coal reserves, and is the largest coal production province in China. The objectives of this study are to determine the temporal and spatial variation of the NTD rate in rural areas of Shanxi Province, China, and identify geographical environmental factors that were associated with NTDs in the risk area. In this study, Heshun County and Yuanping County in Shanxi Province, which have high incidence of NTDs, were selected as the study areas. Two paired sample T test was used to analyze the changes in the risk of NTDs from the time dimension. Ripley's k function and spatial filtering were combined with geographic information system (GIS) software to study the changes in the risk of NTDs from the spatial dimension. In addition, geographical detectors were used to identify the risk geographical environmental factors of NTDs in the study areas, especially the areas close to the coal sites and main roads. In both Heshun County and Yuanping County, the incidence of NTDs was significantly (P<0.05) reduced after intervention. The results from spatial analysis showed that significant spatial heterogeneity existed in both counties. NTD clusters were still identified in areas close to coal sites and main roads after interventions. This study also revealed that the elevation, fault and soil types always had a larger influence on the incidence of NTDs in our study areas. In addition, distance to the river was a risk factor of NTDs in areas close to the coal sites and main roads. The existing interventions may have played an important role to reduce the incidence of NTDs. However, there is still spatial heterogeneity in both counties after using the traditional intervention methods. The government needs to take more measures to strengthen the environmental restoration to prevent the occurrence of NTDs, especially those areas close to coal sites and main roads. The outcome of this research provides an important theoretical basis and technical support for the government to prevent the occurrence of NTDs.


The amelioration of T2DM rat femoral bone achieved by anti-osteoporosis of caprine CSN1S2 protein through bone morphogenetic protein signaling pathway.
We investigated the potential anti-glycation and anti-osteoporosis properties of Caprine milk CSN1S2 protein on the serum AGEs and sRAGE level, osteogenic factors expressions, femoral bone mesostructure, histomorphometry, and hydroxyapatite crystals changes in T2DM rats. Varying doses of Caprine milk CSN1S2 protein (0, 375, 750, and 1500 mg/kg BW) were used to treat the control and T2DM rats. We measured AGEs and sRAGE level; RUNX2, OSX, BMP2, and Caspase-3 expressions in rats using ELISA and immunohistochemistry, respectively. The mesostructure and histomorphometry of femoral bone was analyzed using SEM Microscope and BoneJ software, then hydroxyapatite crystal size was determined using SEM-XRD. T2DM rats showed a high level of AGEs and a low level of sRAGE, the RUNX2, OSX, and BMP2 expression was down regulated, BV, BV.TV, Tb.Th, Tb.Sp, increased and SMI levels declined, respectively. Vice versa, after administration of the CSN1S2 protein to T2DM rats, improvement in all levels of molecular and cellular markers was achieved. In the CSN1S2 highest dose, AGEs level declined and sRAGE level elevated in T2DM rats. The 375 and 750 mg/kgBW of CSN1S2 protein was able to upregulate the RUNX2, OSX, and BMP2 expression in T2DM rats, thus improving the normalization of osteoclasts and osteoblasts number. The whole dose of CSN1S2 triggered the thickening of trabecular bone wall, granule formation, and normalized the trabecular thickness (Tb.Th) parameter of T2DM rats. The hydroxyapatite crystal size was increased in the highest dose of CSN1S2-treated T2DM rats. This study indicated that CSN1S2 protein had a protective effect against osteoporosis in the T2DM rat bones by means of glycation pathway inhibition, bone histomorphometry and mesostructure improvement via bone morphometric protein signaling.


ADL ORVIS: an air-delay-leg, line-imaging optically recording velocity interferometer system.
An interferometry system that enables acquisition of spatially resolved velocity-time profiles with very high velocity sensitivity has been designed and applied to two diverse, instructive experimental problems: (1) measurement of low-amplitude reverberations in laser-driven flyer plates and (2) measurement of ramp-wave profiles in symmetric impact studies of fused silica. The delay leg in this version of a line-imaging optically recording velocity interferometer system (ORVIS) consists of a long air path that includes relay optics to transmit the optical signal through the interferometer cavity. Target image quality from the delay path at the image recombination plane is preserved by means of a compact and flexible optical design utilizing two parabolic reflectors (serving as the relay optics) in a folded path. With an instrument tuned to a velocity per fringe constant of 22.4 m s(-1) fringe(-1), differences of 1-2 m s(-1) across the probe line segment can be readily distinguished. Measurements that capture small spatial variations in flyer velocity are presented and briefly discussed. In the fused silica impact experiments, the ramp-wave profile observed by this air-delay instrument compares favorably to the profile recorded simultaneously by a conventional line-imaging ORVIS.


Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: understanding weight loss and improvements in type 2 diabetes after bariatric surgery.
Obesity increases the likelihood of diseases like type 2 diabetes (T2D), heart disease, and cancer, and is one of the most serious public health problems of this century. In contrast to ineffectual prevention strategies, lifestyle modifications, and pharmacological therapies, bariatric surgery is a very effective treatment for morbid obesity and also markedly improves associated comorbidities like T2D. However, weight loss and resolution of T2D after bariatric surgery is heterogeneous and specific to type of bariatric procedure performed. Conventional mechanisms like intestinal malabsorption and gastric restriction do not fully explain this, and potent changes in appetite and the enteroinsular axis, as a result of anatomical reorganization and altered hormonal, neuronal, and nutrient signaling, are the portended cause. Uniquely these signaling changes appear to override vigorous homeostatic defenses of stable body weight and compelling self-gratifying motivations to eat and to reverse defects in beta-cell function and insulin sensitivity. Here we review mechanisms of weight loss and T2D resolution after Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy bariatric surgery, two markedly different procedures with robust clinical outcomes.


Systematic Determination of TCR-Antigen and Peptide-MHC Binding Kinetics among Field Variants of a Theileria parva Polymorphic CTL Epitope.
CTLs are known to contribute to immunity toward Theileria parva, the causative agent of East Coast fever. The Tp967-75 CTL epitope from the Muguga strain of T. parva is polymorphic in other parasite strains. Identifying the amino acids important for MHC class I binding, as well as TCR recognition of epitopes, can allow the strategic selection of Ags to induce cellular immunity toward T. parva In this study, we characterized the amino acids important for MHC class I binding and TCR recognition in the Tp967-75 epitope using alanine scanning and a series of variant peptide sequences to probe these interactions. In a peptide-MHC class I binding assay, we found that the amino acids at positions 1, 2, and 3 were critical for binding to its restricting MHC class I molecule BoLA-1*023:01. With IFN-γ ELISPOT and peptide-MHC class I Tet staining assays on two parasite-specific bovine CTL lines, we showed that amino acids at positions 5-8 in the epitope were required for TCR recognition. Only two of eight naturally occurring polymorphic Tp9 epitopes were recognized by both CTLs. Finally, using a TCR avidity assay, we found that a higher TCR avidity was associated with a stronger functional response toward one of two variants recognized by the CTL. These data add to the growing knowledge on the cross-reactivity of epitope-specific CTLs and specificities that may be required in the selection of Ags in the design of a wide-spectrum vaccine for East Coast fever.


Patient experience of a psychiatric Mother Baby Unit.
Mothers with severe mental illness are vulnerable and engage with services cautiously due to fears of stigma and custody loss. To develop best practice standards and patient-centred services, the subjective experience of those who use it must inform service improvement and policy. This study utilised exploratory concurrent mixed methods design with primarily qualitative data. Women admitted between April 2015 and December 2016 to a newly developed psychiatric Mother Baby Unit (MBU) in New Zealand were invited to participate in this study. Qualitative data were collected in three ways: (i) semi-structured interviews incorporating Māori concepts of health and wellness by research assistants near discharge; (ii) invitation to provide anonymous feedback in writing using an open format; (iii) unsolicited verbal feedback provided during a home visit three months after discharge. Thematic analysis was undertaken. Demographic and clinical information was collected prospectively for mother-infant pairs during the course of admission and three months post-discharge. Forty-five people participated in the study. High rates of satisfaction were described. Strengths of the service-as perceived by mothers-included co-admission of mother and infant, staff warmth and availability, transparent practice, inclusion of families, and having a comfortable environment. Mothers described intense distress and confusion, as well as negative self-perceptions when acutely unwell. Infant co-admission and the inclusion of partners and other family members alleviated mothers' distress. Personal attributes of staff, practical support with caregiving, a range of therapeutic approaches and holistic care were all valued. Feedback collected three months after discharge was the most reflective. Significant inter-ethnic differences were not apparent. The experience of inpatient care can have lasting influence on recovery and wellbeing. Employing a Māori model of health broadened the holistic nature of enquiry. The approach and timing taken in seeking the views of participants' yielded different information, all of which is of value to service evaluation and refinement. The findings suggest that keeping mothers and infants together during health service utilisation such as MBUs should be a priority for policy makers and service designers. This approach is consistent with Māori values, combining the importance of whānau relationships (kinship), wairua (spiritual connectivity), hinengaro (the mind) and tinana (physical health). These findings suggest that 'holistic care'-in this case following a Māori holistic health model-is important in mental health settings.


Assignment of the multifunctional NS3 protein of bovine viral diarrhea virus during RNA replication: an in vivo and in vitro study.
Studies on the replication of the pestivirus bovine viral diarrhea virus (BVDV) were considerably facilitated by the recent discovery of an autonomous subgenomic BVDV RNA replicon (DI9c). DI9c comprises mainly the untranslated regions of the viral genome and the coding region of the nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. To assess the significance of the NS3-associated nucleoside triphosphatase/helicase activity during RNA replication and to explore other functional features of NS3, we generated a repertoire of DI9c derivatives bearing in-frame mutations in different parts of the NS3 coding unit. Most alterations resulted in deficient replicons, several of which encoded an NS3 protein with an inhibited protease function. Three lesions permitted replication, though at a lower level than that of the wild-type RNA, i.e., replacement of the third position of the DEYH helicase motif II by either T or F and an insertion of four amino acid residues in the C-terminal part of NS3. While polyprotein proteolysis was found to be almost unaffected in these latter replicons, in vitro studies with the purified mutant NS3 proteins revealed a significantly impaired helicase activity for the motif II substitutions. NS3 with a DEFH motif, moreover, showed a significantly lower ATPase activity. In contrast, the C-terminal insertion had no negative impact on the ATPase/RNA helicase activity of NS3. All three mutations affected the synthesis of both replication products-negative-strand intermediate and progeny positive-strand RNA-in a symmetric manner. Unexpectedly, various attempts to rescue or enhance the replication capability of nonfunctional or less functional DI9c NS3 derivatives, respectively, by providing intact NS3 in trans failed. Our experimental data thus demonstrate that the diverse enzymatic activities of the NS3 protein-in particular the ATPase/RNA helicase-play a pivotal role even during early steps of the viral replication pathway. They may further indicate the C-terminal part of NS3 to be an important functional determinant of the RNA replication process.


Predicting short-term mortality and long-term survival for hospitalized US patients with alcoholic hepatitis.
No study has evaluated current scoring systems for their accuracy in predicting short and long-term outcome of alcoholic hepatitis in a US population. We reviewed electronic records for patients with alcoholic liver disease (ALD) admitted to Parkland Memorial Hospital between January 2002 and August 2005. Data and outcomes for 148 of 1,761 admissions meeting pre-defined criteria were collected. The discriminant function (DF) was revised (INRdf) to account for changes in prothrombin time reagents that could potentially affect identification of risk using the previous DF threshold of >32. Admission and theoretical peak scores were calculated by use of the Model for End-stage Liver Disease (MELD). Analysis models compared five different scoring systems. INRdf was closely correlated with the old DF (r (2) = 0.95). Multivariate analysis of the data showed that survival for 28 days was significantly associated with a scoring system using a combination of age, bilirubin, coagulation status, and creatinine (p < 0.001), and an elevated ammonia result within two days of admission (p = 0.012). When peak values for MELD were included, they were the most significant predictor of short-term mortality (p < 0.001), followed by INRdf (p = 0.006). On admission, two scoring systems that identify a subset of patients with severe alcoholic liver disease are able to predict >50 % mortality at four weeks and >80 % mortality at six months without specific treatment.


[Chest pain in children and adolescents].
Chest pain is a frequent complaint in children and adolescents. True organic disease is rare, especially cardiac disease is infrequently found as the underlying cause. Organic disease is associated with acute onset, fever, chest pain exclusively with physical activity and with abnormal physical findings in the patient. In the majority the symptom is not caused by organic disease, in these cases longer duration of symptoms is typically found as well as higher patient age, typically teenagers. Stress factors such as troubles in school and family need to be asked for. Detailed history and a meticulous physical examination usually allow for a clear delineation of the problem, making additional diagnostic work-up unnecessary in most instances. Laboratory tests remain indicated only upon suspicious clinical or anamnestic signs and are not efficient as widely used screening tools.


Genetic risk factors for the development of allergic disease identified by genome-wide association.
An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities.


On-line learning of dynamical systems in the presence of model mismatch and disturbances.
This paper is concerned with the on-line learning of unknown dynamical systems using a recurrent neural network. The unknown dynamic systems to be learned are subject to disturbances and possibly unstable. The neural-network model used has a simple architecture with one layer of adaptive connection weights. Four learning rules are proposed for the cases where the system state is measurable in continuous or discrete time. Some of these learning rules extend the sigma-modification of the standard gradient learning rule. Convergence properties are given to show that the weight parameters of the recurrent neural network are bounded and the state estimation error converges exponentially to a bounded set, which depends on the modeling error and the disturbance bound. The effectiveness of the proposed learning rules for the recurrent neural network is demonstrated using an illustrative example of tracking a Brownian motion.


Angle-independent plasmonic substrates for multi-mode vibrational strong coupling with molecular thin films.
Vibrational strong coupling of molecules to optical cavities based on plasmonic resonances has been explored recently because plasmonic near-fields can provide strong coupling in sub-diffraction limited volumes. Such field localization maximizes coupling strength, which is crucial for modifying the vibrational response of molecules and, thereby, manipulating chemical reactions. Here, we demonstrate an angle-independent plasmonic nanodisk substrate that overcomes limitations of traditional Fabry-Pérot optical cavities because the design can strongly couple with all molecules on the surface of the substrate regardless of molecular orientation. We demonstrate that the plasmonic substrate provides strong coupling with the C=O vibrational stretch of deposited films of PMMA. We also show that the large linewidths of the plasmon resonance allow for simultaneous strong coupling to two, orthogonal water symmetric and asymmetric vibrational modes in a thin film of copper sulfate monohydrate deposited on the substrate surface. A three-coupled-oscillator model is developed to analyze the coupling strength of the plasmon resonance with these two water modes. With precise control over the nanodisk diameter, the plasmon resonance is tuned systematically through the modes, with the Rabi splitting from both modes varying as a function of the plasmon frequency and with strong coupling to both modes achieved simultaneously for a range of diameters. This work may aid further studies into manipulation of the ground-state chemical landscape of molecules by perturbing multiple vibrational modes simultaneously and increasing the coupling strength in sub-diffraction limited volumes.


sPLINK: a hybrid federated tool as a robust alternative to meta-analysis in genome-wide association studies.
Meta-analysis has been established as an effective approach to combining summary statistics of several genome-wide association studies (GWAS). However, the accuracy of meta-analysis can be attenuated in the presence of cross-study heterogeneity. We present sPLINK, a hybrid federated and user-friendly tool, which performs privacy-aware GWAS on distributed datasets while preserving the accuracy of the results. sPLINK is robust against heterogeneous distributions of data across cohorts while meta-analysis considerably loses accuracy in such scenarios. sPLINK achieves practical runtime and acceptable network usage for chi-square and linear/logistic regression tests. sPLINK is available at https://exbio.wzw.tum.de/splink .


Specific ion effects at protein surfaces: a molecular dynamics study of bovine pancreatic trypsin inhibitor and horseradish peroxidase in selected salt solutions.
The distribution of sodium, choline, sulfate, and chloride ions around two proteins, horseradish peroxidase (HRP) and bovine pancreatic trypsin inhibitor (BPTI), is investigated by means of molecular dynamics simulations with the aim to elucidate ion adsorption at the protein surface. Although the two proteins under investigation are very different from each other, the ion distributions around them are remarkably similar. Sulfate is always strongly attached to the proteins, choline shows a significant, but unspecific, propensity for the protein surfaces, and sodium ions have a weak surface affinity, while chloride has virtually no preference for the protein surface. In mixtures of all four ion species in protein solutions, the resulting distributions are almost a superposition of the distributions of sodium sulfate and choline chloride, except that sodium partially replaces choline close to the proteins. The present simulations support a picture of ions interacting with individual ionic and polar amino acid groups rather than with an averaged protein surface. The results thus show how subtle the so-called Hofmeister and electroselectivity effects are in salt solution of proteins, making all simplified interaction models questionable.


RNA-Seq Analyses Reveal That Endothelial Activation and Fibrosis Are Induced Early and Progressively by Besnoitia besnoiti Host Cell Invasion and Proliferation.
The pathogenesis of bovine besnoitiosis and the molecular bases that govern disease progression remain to be elucidated. Thus, we have employed an in vitro model of infection based on primary bovine aortic endothelial cells (BAEC), target cells during the acute infection. Host-parasite interactions were investigated by RNA-Seq at two post-infection (pi) time points: 12 hpi, when tachyzoites have already invaded host cells, and 32 hpi, when tachyzoites have replicated for at least two generations. Additionally, the gene expression profile of B. besnoiti tachyzoites was studied at both pi time points. Up to 446 differentially expressed B. taurus genes (DEGs) were found in BAEC between both pi time points: 249 DEGs were up-regulated and 197 DEGs were down-regulated at 32 hpi. Upregulation of different genes encoding cytokines, chemokines, leukocyte adhesion molecules predominantly at 12 hpi implies an activation of endothelial cells, whilst upregulation of genes involved in angiogenesis and extracellular matrix organization was detected at both time points. NF-κB and TNF-α signaling pathways appeared to be mainly modulated upon infection, coordinating the expression of several effector proteins with proinflammatory and pro-fibrotic phenotypes. These mediators are thought to be responsible for macrophage recruitment setting the basis for chronic inflammation and fibrosis characteristic of chronic besnoitiosis. Angiogenesis regulation also predominated, and this multistep process was evidenced by the upregulation of markers involved in both early (e.g., growth factors and matrix metalloproteinases) and late steps (e.g., integrins and vasohibin). Besnoitia besnoiti ortholog genes present in other Toxoplasmatinae members and involved in the lytic cycle have shown to be differentially expressed among the two time points studied, with a higher expression at 32 hpi (e.g., ROP40, ROP5B, MIC1, MIC10). This study gives molecular clues on B. besnoiti- BAECs interaction and shows the progression of type II endothelial cell activation upon parasite invasion and proliferation.


Proteoglycans secreted by packaging cell lines inhibit retrovirus infection.
Using a model recombinant retrovirus encoding the Escherichia coli lacZ gene, we have found that medium conditioned with NIH 3T3 cells and packaging cell lines derived from NIH 3T3 cells inhibits infection. Most of the inhibitory activity was greater than 100 kDa and was sensitive to chondroitinase ABC digestion, which is consistent with the inhibitor being a chondroitin sulfate proteoglycan. Proteoglycans secreted by NIH 3T3 cells and purified by anion-exchange chromatography inhibited amphotropic retrovirus infection. Pretreatment of amphotropic retrovirus stocks with chondroitinase ABC boosted the level of transduction efficiency by more than twofold. The implications of these findings with respect to retrovirus-cell interactions and the production of high-titer retroviral stocks are discussed.


Involvement of DNA polymerase alpha in host cell reactivation of UV-irradiated herpes simplex virus.
Aphidicolin is a potent inhibitor of both host cell DNA polymerase alpha and herpes simplex virus (HSV)-induced DNA polymerase but has no effect on DNA polymerases beta and gamma of host cells. By using an aphidicolin-resistant mutant (Aphr) of HSV, a possible involvement of DNA polymerase alpha in host cell reactivation of UV-damaged HSV was studied. Plaque formation by UV-irradiated Aphr was markedly inhibited by 1 microgram of aphidicolin per ml, which did not affect the plating efficiency of nonirradiated Aphr. Aphidicolin added before 12 h postinfection inhibited plaque formation by irradiated Aphr, which became aphidicolin insensitive after 36 h postinfection. The results strongly suggest that host cell DNA polymerase alpha is involved in the repair of UV-irradiated HSV DNA.


The importance of lipase determinations in the detection of pancreaticoduodenal allograft rejection.
In canine pancreaticoduodenal allografts, the exocrine pancreas is rejected earlier that endocrine islets. Lipase levels prove to be a good parameter of the rejection onset, occurring before other parameters showed any changes. Moreover there is a good correlation between the lipasemia and the functional condition of the exocrine pancreas in periods before and after the rejection crisis. Variations in other parameters which occur during rejection and consequently can sustain the diagnosis of rejection, are an amylase rise, a leucocytosis, a fasting insulin decrease and glucose increase. These changes however are less striking than lipase variations; besides they do not occur constantly and can also be seen in other circumstances. In this way they not only lack rejection specificity but likewise do not allow the functional evolution during and after the rejection crisis. The insulinemia, after glucose loading, is the only one of the mentioned parameters which gives an adequate idea of the endocrine graft function and which consequently has a prognostic value after the rejection crisis, with regard to the function and the survival of the graft. Cool storage preservation of the grafts using a Largiadèr solution proved to have no detrimental effects on the pancreas, as judged by the graft function, the postoperative survival time of the dogs and the rejection pattern of the transplants.


Lipid A structural diversity among members of the genus Leptospira.
Lipid A is the hydrophobic component of bacterial lipopolysaccharide and an activator of the host immune system. Bacteria modify their lipid A structure to adapt to the surrounding environment and, in some cases, to evade recognition by host immune cells. In this study, lipid A structural diversity within the Leptospira genus was explored. The individual Leptospira species have dramatically different pathogenic potential that ranges from non-infectious to life-threatening disease (leptospirosis). Ten distinct lipid A profiles, denoted L1-L10, were discovered across 31 Leptospira reference species, laying a foundation for lipid A-based molecular typing. Tandem MS analysis revealed structural features of Leptospira membrane lipids that might alter recognition of its lipid A by the host innate immune receptors. Results of this study will aid development of strategies to improve diagnosis and surveillance of leptospirosis, as well as guide functional studies on Leptospira lipid A activity.


The validity of the total myocardial blood flow determination by means of 133Xe in regional ischemia.
Regional MBF in the ischemic and healthy left ventricular myocardium was measured in 21 mongrel dogs by means of locally injected 133Xe and its washout one week after ligation of the left anterior descending coronary. Simultaneously the total MBF was calculated from the precordial washout determination of 133Xe injected into the left coronary artery. The 133Xe measurements were compared with the regional 86Rb uptake. The values of total MBF determination after left coronary artery injection did not diminish adequately to the size of the ischemic area; these values were usually higher as compared with the calculated mean MBF evaluated from the regional left ventricular blood flow and did not agree with regional MBF in the intact left ventricular myocardium. The difference of perfusion between the necrotic and the healthy left ventricular myocardium determined from the local 133Xe washout was higher in comparison to 86Rb uptake. The method of total MBF determination by means of precordially determined 133Xe washout injected into the coronary artery yields artificially higher values in cases with greater ischemic areas. This may be accounted for by a low initial radioactivity of the hypoperfused areas and their negligible contribution to the total radioactivity changes produced predominantly by the well perfused areas. The relatively low 86Rb uptake difference in the healthy and the necrotic left ventricular myocardium may be caused by affected extraction coefficients of 86Rb in the necrotic tissue.


Topological Proximity-Induced Dirac Fermion in Two-Dimensional Antimonene.
Antimonene is a promising two-dimensional (2D) material that is calculated to have a significant fundamental bandgap usable for advanced applications such as field-effect transistors, photoelectric devices, and the quantum-spin Hall (QSH) state. Herein, we demonstrate a phenomenon termed topological proximity effect, which occurs between a 2D material and a three-dimensional (3D) topological insulator (TI). We provide strong evidence derived from hydrogen etching on Sb2Te3 that large-area and well-ordered antimonene presents a 2D topological state. Delicate analysis with a scanning tunneling microscope of the evolutionary intermediates reveals that hydrogen etching on Sb2Te3 resulted in the formation of a large area of antimonene with a buckled structure. A topological state formed in the antimonene/Sb2Te3 heterostructure was confirmed with angle-resolved photoemission spectra and density-functional theory calculations; in particular, the Dirac point was located almost at the Fermi level. The results reveal that Dirac fermions are indeed realized at the interface of a 2D normal insulator (NI) and a 3D TI as a result of strong hybridization between antimonene and Sb2Te3. Our work demonstrates that the position of the Dirac point and the shape of the Dirac surface state can be tuned by varying the energy position of the NI valence band, which modifies the direction of the spin texture of Sb-BL/Sb2Te3 via varying the Fermi level. This topological phase in 2D-material engineering has generated a paradigm in that the topological proximity effect at the NI/TI interface has been realized, which demonstrates a way to create QSH systems in 2D-material TI heterostructures.


Mortality and recurrence risk in relation to the use of lipid-lowering drugs in a prospective breast cancer patient cohort.
Lipid-lowering drugs are used for the prevention of cardiovascular diseases. Statins are the most commonly used lipid-lowering drugs. Evidence from preclinical and observational studies suggests that statins might improve the prognosis of breast cancer patients. We analyzed data from the German MARIEplus study, a large prospective population-based cohort of patients aged 50 and older, who were diagnosed with breast cancer between 2001 and 2005. For overall mortality, breast-cancer specific mortality, and non-breast-cancer mortality, we included 3189 patients with invasive breast cancer stage I-IV, and for recurrence risk 3024 patients with breast cancer stage I-III. We used Cox proportional hazards models to assess the association with self-reported lipid-lowering drug use at recruitment. We stratified by study region, tumor grade, and estrogen/progesterone receptor status, and adjusted for age, tumor size, nodal status, metastases (stage I-IV only), menopausal hormone treatment, mode of detection, radiotherapy, and smoking. Mortality analyses were additionally adjusted for cardiovascular disease, diabetes mellitus and body-mass index. During a median follow-up of 5.3 years, 404 of 3189 stage I-IV patients died, and 286 deaths were attributed to breast cancer. Self-reported use of lipid-lowering drugs was non-significantly associated with increased non-breast cancer mortality (Hazard ratio (HR) 1.49, 95% confidence interval (CI) 0.88-2.52) and increased overall mortality (HR 1.21, 95% CI 0.87-1.69) whereas no association with breast cancer-specific mortality was found (HR 1.04, 0.67-1.60). Restricted to stage I-III breast cancer patients, 387 recurrences occurred during a median follow-up of 5.4 years. We found lipid-lowering drug use to be non-significantly associated with a reduced risk of recurrence (HR 0.83, 95% CI 0.54-1.24) and of breast cancer-specific mortality (HR 0.89, 95% CI 0.52-1.49). Although compatible with previous findings of an improved prognosis associated with statin use, our results do not provide clear supportive evidence for an association with lipid-lowering drug use due to imprecise estimates.


Probing excited-state dynamics and intramolecular proton transfer in 1-acylaminoanthraquinones via the intermolecular solvent response.
The dynamics of a series of 1-acylaminoanthraquinones with varying degrees of excited-state intramolecular proton transfer are studied in acetonitrile and dichloromethane. Events are followed via changes in the third-order intermolecular Raman response as a function of time after resonant excitation of the chromophore. Compared to electronically resonant probes of the solute, measuring the ultrafast dynamics using the nonresonant solvent response offers a new and complementary perspective on the events that accompany excitation and proton transfer. Experimentally observed changes in the nuclear polarizability of the solvent follow dynamic changes in the solvent-solute interactions. Reorganization of the solvent in response to the significant changes in the intermolecular interactions upon proton transfer is found to play an important role in the reaction dynamics. With transfer of the proton taking place rapidly, the solvent controls the dynamics via the time-dependent evolution of the free energy surface, even on subpicosecond time scales. In addition, the solvent response probes the effects of intermolecular energy transfer as energy released during the reactive event is rapidly transferred to the local solvent environment and then dissipates to the bulk solvent on about a 10 ps time scale. A brief initial account of a portion of this work has appeared previously, J. Am. Chem. Soc. 2004, 126, 8620-8621.


Prospective study of early discharge after acute myocardial infarction (SHORT)
To identify, without additional investigation, a large group of myocardial infarction patients at low risk who would qualify for early discharge. The decision rule was developed in 647 unselected patients with consecutively admitted myocardial infarction, and validated in 825 others. Daily event-rates were calculated for major (death, ventricular fibrillation, recurrent infarction, heart failure, advanced AV-block) and minor (unstable angina and rhythm-abnormalities) cardiac complications. Patients free from major complications until day 7 (44% of all patients) were found to constitute a very low risk group and thus would qualify for discharge at day 7. Of the 39% of patients with an uncomplicated infarction (low risk) in the validation group, 31% were discharged at day 7, while 8% stayed longer because of non-cardiac co-morbidity, for social reasons or logistic problems. No major adverse event occurred within 7 days after hospital discharge and only 1.8% developed complications within 1 month. The median duration of hospital stay for all in-hospital survivors was 7 days compared to 10 days in the control group. Prospective application of the early discharge decision rule, based upon simple clinical variables and without the need for additional non-invasive and/or invasive tests, resulted in a significant reduction of hospital stay. The decision rule correctly classified patients into high and low risk groups and appeared feasible and safe. Its efficacy was demonstrated by its ability to identify a large group of post infarction survivors at low risk for complications during follow-up.


[Progressive character of embryogenesis in placental animals].
The article presents evidence of the placental animals being isolated from the rest of higher vertebrates according to many peculiarities of their structure and the embryonic development. The most important of these signs are the following: female genital tracts are disposed to the inside from the urinary tracts (in embryos the Müller's canals are on the inner side of the wolffian ducts); in placental animals there are no tertiary egg sheaths which are physiologically substituted for the trophoblast; the provisory organs reveal great variability; the allantoid placenta performs not only metabolic but also endocrinous functions. The evolution of peculiarities of the structure and development characteristic of placental animals was performed by a series of successive aromorphous phenomena. Theri mighty adaptive radiation is the result of greater perfectness of placental animals.


Metabolic response of skeletal muscle to ischemia.
To evaluate the temporal relationship and potential correlation between intramuscular phosphagen levels, lipid oxidation, and extent of muscle injury, a canine gracilis muscle model was used to study the consequences of a global ischemic episode for up to 7 h duration with reperfusion for 4 h. In this model the contralateral gracilis muscle was prepared identically to the test side but was not subjected to ischemia and thus served as a control. Blood flow, oxygen consumption, and lactate and glycerol release were measured before and after 2- and 7-h ischemic stress periods. The intramuscular metabolites, glycogen, lactate, phosphocreatine, and ATP, as well as free fatty acid conjugated dienes, were measured before, during, and after the ischemic insult. A 2-h ischemic insult resulted in minimal ultrastructural damage and complete regeneration of intramuscular phosphagens and glycogen on reperfusion with complete normalization of lipid oxidation products. In contrast, a 7-h ischemic insult resulted in profound injury at the ultrastructural level with an inability to restore intramuscular phosphagens and glycogen on reperfusion. This severe muscle injury correlated with a 2.5-fold increase in lipid oxidation products (free fatty acid conjugated dienes) and a decline in ATP levels below 5 mumol/g dry wt on reperfusion. Our results emphasize the prolonged glycolytic activity of skeletal muscle during global ischemia and document the increased production of oxygen free radical-mediated lipid oxidation products in irreversibly injured muscle.


Activation of PI3K/Akt/HIF-1α Signaling is Involved in Lung Protection of Dexmedetomidine in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Pilot Study.
Lung resection and one lung ventilation (OLV) during video-assisted thoracoscopic surgery (VATS) may lead to acute lung injury. Dexmedetomidine (DEX), a highly selective α2 adrenergic receptor agonist, improves arterial oxygenation in adult patients undergoing thoracic surgery. The aim of this pilot study was to explore possible mechanism related to lung protection of DEX in patients undergoing VATS. Seventy-four patients scheduled for VATS were enrolled in this study. Three timepoints (before anesthesia induction (T0), 40 min after OLV (T1), and 10 min after two-lung ventilation (T2)) of arterial blood gas were obtained. Meanwhile, lung histopathologic examination, immunohistochemistry analysis (occludin and ZO-1), levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in lung tissue and plasma, and activation of phosphoinositide-3-kinase (PI3K)/AKT/hypoxia-inducible factor (HIF)-1α signaling were detected. Postoperative outcomes including duration of withdrawing the pleural drainage tube, length of hospital stay, hospitalization expenses, and postoperative pulmonary complications (PPCs) were also recorded. Sixty-seven patients were randomly divided into DEX group (group D, n=33) and control group (group N, n=34). DEX improved oxygenation at T1 and T2 (group D vs group N; T1: 191.8 ± 49.8 mmHg vs 159.6 ± 48.1 mmHg, P = 0.009; T2: 406.0 mmHg [392.2-423.7] vs 374.5 mmHg [340.2-378.2], P = 0.001). DEX alleviated the alveolar capillary epithelial structure damage, increased protein expression of ZO-1 and occludin, inhibited elevation of the expression of TNF-α and IL-6 in lung tissue and plasma, and increased protein expression of p-PI3K, p-AKT and HIF-1α. Dex administered had better postoperative outcomes with less risk of PPCs and hospitalization expenses as well as shorter duration of withdrawing the pleural drainage tube and length of hospital stay. Activation of PI3K/Akt/HIF-1α signaling might be involved in lung protection of DEX in patients undergoing VATS.


Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes.
Neutral nucleotide substitutions occur at varying rates along genomes, and it remains a major issue to unravel the mechanisms that cause these variations and to analyze their evolutionary consequences. Here, we study the role of replication in the neutral substitution pattern. We obtained a high-resolution replication timing profile of the whole human genome by massively parallel sequencing of nascent BrdU-labeled replicating DNA. These data were compared to the neutral substitution rates along the human genome, obtained by aligning human and chimpanzee genomes using macaque and orangutan as outgroups. All substitution rates increase monotonously with replication timing even after controlling for local or regional nucleotide composition, crossover rate, distance to telomeres, and chromatin compaction. The increase in non-CpG substitution rates might result from several mechanisms including the increase in mutation-prone activities or the decrease in efficiency of DNA repair during the S phase. In contrast, the rate of C --> T transitions in CpG dinucleotides increases in later-replicating regions due to increasing DNA methylation level that reflects a negative correlation between timing and gene expression. Similar results are observed in the mouse, which indicates that replication timing is a main factor affecting nucleotide substitution dynamics at non-CpG sites and constitutes a major neutral process driving mammalian genome evolution.


Development and validation of a clinical scale for rating the severity of blepharospasm.
Existing scales for rating the severity of blepharospasm (BSP) are limited by a number of potential drawbacks. We therefore developed and validated a novel scale for rating the severity of BSP. The development of the scale started with careful examination of the clinical spectrum of the condition by a panel of experts who selected phenomenological aspects thought to be relevant to disease severity. Thereafter, selected items were first checked for reliability, then reliable items were combined to generate the scale, and clinimetric properties of the scale were evaluated. Finally, the confidence with which the scale could be used by people without high levels of movement disorders skill was assessed. The new scale, based on objective criteria, yielded moderate to almost perfect reliability, acceptable internal consistency, satisfactory scaling assumptions, lack of floor and ceiling effects, partial correlations with a prior severity scale and with a quality of life scale, and good sensitivity to change. Despite a few limitations, the foregoing features make the novel scale more suitable than existing scales to assess the severity of BSP in natural history and pathophysiologic studies as well as in clinical trials.


Effects of biodegradation and sorption by humic acid on the estrogenicity of 17β-estradiol.
The removal of 17β-estradiol (E2) by biodegradation and sorption onto humic acid (HA) was examined at various HA concentrations. Subsequently, estrogenicity associated with E2 removal was estimated using E-screen bioassay. Results showed that E2 biodegradation and its subsequent transformation to estrone (E1) were significantly reduced with increasing HA concentration. In addition, the presence of nutrients enhanced the biodegradation of E2. Overall, E2 biodegradation was the dominating contributor to its removal, which demonstrated a significantly negative correlation with E2 sorption at various HA concentrations. The sorption of E2 by HA was significantly enhanced with increasing HA concentration. Estrogenicity associated with residual E2 showed that there existed a significant difference among various HA concentrations, with the lowest value in the absence of HA. The findings suggest that the presence of HA and nutrients in natural waters should be considered in assessing estrogenicity of environmental samples due to complex sorption and biodegradation processes.


Contextual strategies to support social inclusion for children with and without disabilities in recreation.
Integrating children with and without disabilities in recreation programs is assumed to promote inclusion. How social inclusion is facilitated in recreation settings, however, is not fully known. This study aimed to explore how social inclusion is supported in a recreation program. A generic qualitative methodology was adopted. Seventeen children with and without disabilities registered for the same program were recruited. This sample included eight children with disabilities and nine typically developing children between the age of eight and 17. Two semi-structured interviews and three, two-hour observation periods were conducted with each participant. Inductive thematic analysis was used to analyze interview and observation data. This study revealed five themes that support meaningful aspects of social inclusion from participants' perspectives: (a) creating opportunities for children to communicate their interests and desires; (b) providing opportunities to choose self-directed activities; (c) strategically selecting and placing objects to support interactions between children with and without disabilities; (d) directly encouraging interactions between children with and without disabilities, and; (e) Having relatively equal numbers of children with and without disabilities. This study facilitates a better understanding of how meaningful inclusion experiences can be facilitated in recreation settings.Implications for rehabilitationParticipation in recreation programs that implement inclusive strategies could mitigate social isolation and loneliness for children with disabilities.Children with and without disabilities may experience greater sense of inclusion when recreation programs adopt a process-oriented and child-driven approach.Staff play a critical role in implementing inclusive strategies such as establishing group communication competency between children with and without disabilities, which could be supported by staff training.


Role of alpha L beta 2 integrin avidity in transendothelial chemotaxis of mononuclear cells.
The leukocyte integrin alpha L beta 2 (LFA-1) is important in transendothelial migration. Since it is not fully understood how LFA-1 mediates transmigration, we studied the effects of alpha L and beta 2 cytoplasmic domain mutants that alter LFA-1 adhesiveness for intercellular adhesion molecule-1. Monocyte chemotactic protein-1 (MCP-1) induced LFA-1-dependent transendothelial migration of Jurkat and J-beta 2.7 transfectants coexpressing the MCP-1 receptor CCR2B and wild-type alpha L. No transendothelial chemotaxis was observed with truncation mutants of the alpha L cytoplasmic tail, which rendered LFA-1 constitutively active or locked LFA-1 in a low avidity state unresponsive to cellular activation. Moreover, transendothelial chemotaxis of lymphoblastoid SLA transfectants was abolished by truncation of the beta 2 cytoplasmic domain, but not by mutation of its TTT motif, which is important in phorbol ester-induced adhesion. These data indicate that transmigration may require both alpha L and beta 2 cytoplasmic domains. We further show that MCP-1-induced transendothelial chemotaxis of PBMC was inhibited by sustained activation of LFA-1 with Mn2+ or a stimulatory mAb to beta 2. Dimeric soluble intercellular adhesion molecule-1 also reduced transendothelial chemotaxis of PBMC. Taken together, our data suggest that transendothelial chemotaxis of mononuclear cells may involve dynamic changes in LFA-1 avidity.


Regorafenib therapy in metastatic colorectal cancer patients: markers and outcome in an actual clinical setting.
The oral multikinase inhibitor regorafenib had beneficial effects in randomized clinical phase III trials compared to the placebo in patients with metastatic colorectal cancer (mCRC) who progressed on standard therapies. The factors which influence regorafenib response and therapy sequence during treatment history are still highly discussed, and herein we analyzed the therapy algorithm, outcome and clinical markers following regorafenib application in a single center register study. Clinical data for 48 metastatic colorectal cancer patients were collected from 01.01.2013 to 31.12.2016. Treatment effects according to various patient and tumor characteristics were evaluated using univariate and multivariate Cox proportional hazard regression models. The 48 patients comprised 14 (29%) females and 34 (71%) males, with mean age 64.2±9 and ECOG 0-1. Progression free survival under regorafenib therapy was 2.9 months (quartiles 2.2; 4.4) and the overall response rate was 2 (4%) and disease control rate was 19 (40%). Overall survival (OS) and progression free survival (PFS) were investigated under regorafenib in the chemotherapy regimen given immediately before and afterthis treatment. Variables including tumor localization, Ras status, CEA and CA 19-9 plasma levels were analyzed for their impact on PFS, and the regorafenib-related adverse events were also observed. Our study confirms the efficacy of regorafenib in a real-life setting. We established that response rate and PFS in regorafenib treatment are independent of tumor localization, Ras status or biomarkers such as CEA and CA 19-9. Trifluridin/tripacil application or re-induction of chemotherapy +/- target therapy was effective following regorafenib therapy.


Supervised consumption sites and crime: scrutinizing the methodological weaknesses and aberrant results of a government report in Alberta, Canada.
To date, peer-reviewed research has found no evidence linking supervised consumptions sites (SCSs) to increased crime. Yet, in March 2020, a government Report released in the province of Alberta, Canada, presented the results of a review that reached a different conclusion. This commentary highlights the Report's major methodological limitations with respect to its criminological components, including that crime was poorly operationalized and measured, change in crime was inadequately assessed, and the effect of SCSs on crime was not ascertained. It is argued that the magnitude of methodological flaws in the Report undermine the validity of its criminological claims and raise significant issues with the soundness of its conclusions.


Remarks on metacommunity synchronization with application to prey-predator systems.
The problem of synchronization of metacommunities is investigated in this article with reference to a rather general model composed of a chaotic environmental compartment driving a biological compartment. Synchronization in the absence of dispersal (i.e., the so-called Moran effect) is first discussed and shown to occur only when there is no biochaos. In other words, if the biological compartment is reinforcing environmental chaos, dispersal must be strictly above a specified threshold in order to synchronize population dynamics. Moreover, this threshold can be easily determined from the model by computing a special Lyapunov exponent. The application to prey-predator metacommunities points out the influence of frequency and coherence of the environmental noise on synchronization and agrees with all experimental studies performed on the subject.


Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder.
Recently, the translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR) and both the starting point and an important rate-limiting step in neurosteroidogenesis, has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD) because it affects the production of neurosteroids, reinforcing the hypothesis that selective TSPO ligands could potentially be used as anti-PTSD drugs. As expected, we showed that chronic treatment with YL-IPA08 [N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl)-7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, caused significant suppression of enhanced anxiety and contextual fear induced in the inescapable electric foot-shock-induced mouse model of PTSD and the time-dependent sensitization (TDS) procedure. These effects were completely blocked by the TSPO antagonist PK11195. Furthermore, YL-IPA08 could increase the level of allopregnanolone in the prefrontal cortex and serum of post-TDS rats, and these effects were antagonized by PK11195. In summary, the findings from the current study showed that YL-IPA08, a potent and selective TSPO ligand, had a clear anti-PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.


Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition.
Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae. High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre-empt the emergence of inhibitor resistant KPC-2 variants.


The role of interstitial potassium in the generation of low-calcium hippocampal seizures.
The explosive nature of a focal cortical seizure suggests the operation of strong positive feedback in the neuronal network. It was previously proposed that in the hippocampus this may be provided by the regenerative accumulation of potassium in the interstitium. This hypothesis was severely criticized in the past. However, it gained new impetus with the recent discovery that focal seizures can arise in mammalian hippocampal slices perfused with low calcium solutions despite the block of chemical synaptic transmission. Here, we examine the relationship of interstitial potassium concentration to the electrogenesis of these low-calcium seizures. Both the experimental data and the behavior of a simplified mathematical model describing neuronal discharge in low calcium, support the contention that interstitial potassium accumulation may play an important role in the buildup of hippocampal seizures.


Osteomyelitis: clinical update for practical guidelines.
Bone infections represent a diagnostic or therapeutic challenge for the infectivologist, orthopaedic surgeon, radiologist and nuclear medicine physician. Staphylococcus aureus is the major bacterium responsible for bone infections although Mycobacterium tuberculosis is emerging as an infectious agent in Italy because of immigration from Africa and Asia. Osteomyelitis requires long and expensive antibiotic treatment, including rifampicin administered parenterally for several weeks and the use of antimicrobial-impregnated cement in prosthesis substitution. Sometimes it is necessary to carry out surgical debridement of a necrotic bone or the consolidation of compromised bones and joint prosthesis implants. Radiographs and bone cultures are mainstays for the diagnosis of bone infections but are often useless in the lengthy management of these patients. Diagnosis of skeletal infections still includes conventional radiography but magnetic resonance imaging is essential in haematogenous and spinal infections. Bone scans are still useful in acute osteomyelitis whereas scintigraphy using labelled white blood cells is preferred in infections of peripheral bone segments or joint prosthesis. In the axial skeleton a combination of an agent for detecting inflammation ((67)Ga citrate) and a metabolic agent ((99m)Tc-methylene diphosphonate) enables an infection and an area of increased metabolic activity to be distinguished. [(18)F]Fluorodeoxyglucose positron emission tomography, where available, has a significant impact in the study of infections using radionuclides: high-resolution tomographic images represent an effective alternative to gallium in the assessment of inflammation of spine lesions but a comparison with morphological examinations (computed tomography or magnetic resonance imaging) is essential.


Experimental observation of the polarization coherence theorem.
For light fields, the manifestation of correlations between fluctuating electric field components at different space-time points is referred to as coherence, whereas these correlations appearing between orthogonal electric field components at a single space-time point are referred to as polarization. In this context, a natural question is as follows: how are coherence and polarization interconnected? Very recently, a tight equality P2=V2+D2, namely, the "polarization coherence theorem" (PCT) connecting polarization P with interference visibility V (measure of coherence) and distinguishability D (measure of which-path information) has been proposed [Optica4, 1113 (2017)OPTIC82334-253610.1364/OPTICA.4.001113]. We here report a direct observation of the PCT for classical light fields using a Mach-Zehnder interferometer along with a synthesized source producing a complete gamut of degrees of polarizations. Our experimental demonstration could motivate ongoing experimental efforts toward probing the hidden coherences and complementarity features.


Brain Angiotensin II Involvement in Chronic Mental Disorders.
The functioning of the central nervous system is complex and it implies tight and coordinated interactions among multiple components. Neurotransmitters systems imbalance is a hallmark in the central nervous system (CNS) disorders. These pathologies profoundly impact the social, cultural, and economic perspective worldwide. The etiopathology of CNS illnesses is still poorly understood, making their treatment difficult. Brain angiotensin II (Ang II), through its AT1 receptors, modulates dopaminergic, glutamatergic and GABAergic neurotransmission, which are responsible for movement control, cognition, emotions and stress responses. Alterations of these functions, concomitant with modified brain reninangiotensin system (RAS) components, have been described in CNS pathologies like depression, Parkinson, Alzheimer, and schizophrenia. In this sense, altered functionality of angiotensin I converting enzyme and AT1 receptors, is associated with augmented susceptibility to the occurrence of these pathologies. Moreover, some epidemiological data showed lower incidence of Alzheimer disease in hypertensive patients under treatment targeting RAS; meanwhile preclinical studies relate RAS with Parkinson and depression. Little is known about schizophrenia and RAS; however, Ang II is closely related to dopamine and glutamate pathways, which are mainly altered in this pathology. The available evidences, together with the results obtained by our group, open the possibility to postulate brain Ang II as a possible therapeutic target to treat the above-mentioned CNS disorders.


Effect of Community Support Agents on Retention of People Living With HIV in Pre-antiretroviral Care: A Randomized Controlled Trial in Eastern Uganda.
Over 50% of people living with HIV (PLHIV) in sub-Saharan Africa are lost to follow-up between diagnosis and initiation of antiretroviral treatment during pre-antiretroviral (pre-ARV) care. The effect of providing home counseling visits by community support agents on 2-year retention in pre-ARV care was evaluated through a randomized controlled trial in eastern Uganda. Four hundred newly screened HIV-positive patients were randomly assigned to receive posttest counseling alone (routine arm) or posttest counseling and monthly home counseling visits by community support agents to encourage them go back for routine pre-ARV care (intervention arm). The outcome measure was the proportion of new PLHIV in either arm who attended their scheduled pre-ARV care visits for at least 6 of the anticipated 8 visits in the first 24 months after HIV diagnosis. The difference between the 2 study arms was assessed using the χ and T tests. Mantel-Haenszel Risk Ratios and multivariate logistic models were used to assess the adjusted effect of the intervention on the outcome. In all models generated, participants receiving monthly home counseling visits were 2.5 times more likely to be retained in pre-ARV compared with those in standard care over a period of 24 months (adjusted risk ratio, 2.5; 95% confidence interval: 2.0 to 3.0). Monthly follow-up home visits by community workers more than doubled the retention of PLHIV in pre-ARV care in rural Uganda and can be applicable in similar resource-poor settings.


The Prevalence of Culture Change Practice in US Nursing Homes: Findings From a 2016/2017 Nationwide Survey.
Given the dynamic nursing home (NH) industry and evolving regulatory environment, depiction of contemporary NH culture-change (person/resident-centered) care practice is of interest. Thus, we aimed to portray the 2016/2017 prevalence of NH culture change-related processes and structures and to identify factors associated with greater practice prevalence. We administered a nationwide survey to 2142 NH Administrators at NHs previously responding to a 2009/2010 survey. Seventy-four percent of administrators (1583) responded (with no detectable nonresponse bias) enabling us to generalize (weighted) findings to US NHs. From responses, we created index scores for practice domains of resident-centered care, staff empowerment, physical environment, leadership, and family and community engagement. Facility-level covariate data came from the survey and the Certification and Survey Provider Enhanced Reporting system. Ordered logistic regression identified the factors associated with higher index scores. Eighty-eight percent of administrators reported some facility-level involvement in NH culture change, with higher reported involvement consistently associated with higher domain index scores. NHs performed the best (82.6/100 weighted points) on the standardized resident-centered care practices index, and had the lowest scores (54.8) on the family and community engagement index. Multivariable results indicate higher index scores in NHs with higher leadership scores and in states having Medicaid pay-for-performance with culture change-related quality measures. The relatively higher resident-centered care scores (compared with other domain scores) suggest an emphasis on person-centered care in many US NHs. Findings also support pay-for-performance as a potential mechanism to incentivize preferred NH practice.


Conscientious objection to abortion: Zambian healthcare practitioners' beliefs and practices.
The potential health consequences of limiting access to safe abortion make it imperative to understand how conscience-based refusal to provide legally permitted services is understood and carried out by healthcare practitioners. This in-depth study of conscientious objection to abortion provision in Zambia is based on qualitative interviews (N = 51) with practitioners working across the health system who object and do not object to providing abortion services in accordance with their cadre. Interviews were conducted in September 2015. Regardless of whether practitioners self-identified as providers or non-providers of abortion services, they presented similar religiously-informed understandings of abortion as a morally-challenging practice that is, or is not, shifted from iniquity to acceptability based on the reasons for which it has been requested or the likelihood of unsafe abortion if services are not provided. These contextual factors presented a series of tipping points for participants, rather than a single justification for providing abortion. Subsequently both groups reported that their decisions about providing services were complex and changeable, rather than clear one-time resolutions. This shaped their practices, both in terms of whether or not they provided services, and when and how they delivered them. Practitioners self-identifying as non-providers, and those self-identifying as providers, reported provision, counselling, and referral practices likely to lessen women's access to safe legal abortion. In this way, conscientious objection in practice could be understood as a continuum of behaviours rather than a binary position. Our results suggest that data on prevalence of claims to conscientious objector status may underestimate the impact of practitioners' religious, moral and ethical beliefs on abortion accessibility. In Zambia, eliminating practitioners' right to conscientious objection alone or conducting rights-based advocacy may therefore not significantly increase access to safe abortion.


Interrogating the Role of the Two Distinct Fructose-Bisphosphate Aldolases of Bacillus methanolicus by Site-Directed Mutagenesis of Key Amino Acids and Gene Repression by CRISPR Interference.
The Gram-positive Bacillus methanolicus shows plasmid-dependent methylotrophy. This facultative ribulose monophosphate (RuMP) cycle methylotroph possesses two fructose bisphosphate aldolases (FBA) with distinct kinetic properties. The chromosomally encoded FBAC is the major glycolytic aldolase. The gene for the major gluconeogenic aldolase FBAP is found on the natural plasmid pBM19 and is induced during methylotrophic growth. The crystal structures of both enzymes were solved at 2.2 Å and 2.0 Å, respectively, and they suggested amino acid residue 51 to be crucial for binding fructose-1,6-bisphosphate (FBP) as substrate and amino acid residue 140 for active site zinc atom coordination. As FBAC and FBAP differed at these positions, site-directed mutagenesis (SDM) was performed to exchange one or both amino acid residues of the respective proteins. The aldol cleavage reaction was negatively affected by the amino acid exchanges that led to a complete loss of glycolytic activity of FBAP. However, both FBAC and FBAP maintained gluconeogenic aldol condensation activity, and the amino acid exchanges improved the catalytic efficiency of the major glycolytic aldolase FBAC in gluconeogenic direction at least 3-fold. These results confirmed the importance of the structural differences between FBAC and FBAP concerning their distinct enzymatic properties. In order to investigate the physiological roles of both aldolases, the expression of their genes was repressed individually by CRISPR interference (CRISPRi). The fba C RNA levels were reduced by CRISPRi, but concomitantly the fba P RNA levels were increased. Vice versa, a similar compensatory increase of the fba C RNA levels was observed when fba P was repressed by CRISPRi. In addition, targeting fba P decreased tkt P RNA levels since both genes are cotranscribed in a bicistronic operon. However, reduced tkt P RNA levels were not compensated for by increased RNA levels of the chromosomal transketolase gene tkt C.


Examining the link between dose-dependent dietary iron intake and Alzheimer's disease through oxidative stress in the rat cortex.
Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by the progressive deterioration of the structure and function of the nervous system. A number of environmental risk factors including potentially toxic elements such as iron, lead to negative effects on many metabolic reactions as well as neuroprotection. The aim of this study is to reveal whether long-term iron overload is one of the underlying factors in the pathogenesis of Alzheimer's disease (AD). 15 young-adult male rats were randomly divided into 5 groups treated with iron through drinking water for 4 months. Following feeding, the iron content, reduced glutathione (GSH), and hydrogen peroxide (H2O2) levels of cortex tissues were measured. Specific enzyme activities were determined spectrophotometrically. mRNA expression profiles were measured using real-time PCR (qPCR). Iron levels were elevated in case of non-toxic (0.87 and 3 μg/mL) iron administration. However, no changes were observed in toxic (30 and 300 μg/mL) iron administration. GSH and H2O2 levels altered with long-term iron overload. Glutathione peroxidase (GPx) enzyme activities significantly increased in all groups, while glutathione S-transferase (GST) activity increased only in case of 0.87 and 30 μg/mL iron administration. Expression levels of neuroprotective and AD-related genes were altered by 3 μg/mL iron overload in a dose-dependent manner. The expression and activity of acetylcholinesterase (AChE) were elevated at 3 μg/mL iron concentration. The findings of the present study allow us to conclude that long-term dietary iron intake, especially at a dose of 3 μg/mL demonstrates negative effects on the rat cortex by provoking antioxidant metabolism and AD pathology in a dose-dependently.


Quasi-Ab initio molecular dynamic study of Fe melting
We have investigated the melting of hcp Fe at high pressure by employing molecular dynamics simulations in conjunction with the full potential linear muffin tin orbital method. Apart from being of fundamental value, the melting of iron at high pressure is also important for our understanding of the Earth. The subject of iron melting at high pressures is controversial. The experimental data for the iron melting temperature can be separated into two regions, "low" and "high." Here we present an ab initio simulated iron melting curve which is in agreement with the low temperatures at lower pressures, but is in excellent agreement with the high-mostly shockwave-temperatures at high pressures. A comparison with available data lends support to the presented iron melting curve.