Focusing on new monoamine oxidase inhibitors: differently substituted coumarins as an interesting scaffold.
It is commonly accepted that monoamine oxidase (MAO) may play a critical role in the regulation of the central nervous system activity and contribute to the pathogenesis of human neurodegenerative and depressive disorders. This has encouraged an active research in the development of new drugs, MAO inhibitors, since they may represent an important advance in the treatment of complex diseases such as Alzheimer and Parkinson, which are becoming prevalent pathologies due to the increase of aging population of developed countries societies. Different research groups are intensively working in this area with the aim of finding new MAO selective inhibitors. Differently substituted coumarins have been synthesized and evaluated as MAO-A and MAO-B inhibitors. The purpose of this review is to summarize the findings reported in this area, particularly focuses on the coumarin scaffold.


The E3 ubiquitin ligase MID1/TRIM18 promotes atypical ubiquitination of the BRCA2-associated factor 35, BRAF35.
MID1/TRIM18 is a member of the TRIM family of ubiquitin E3 ligases characterized by the presence of a conserved RING-containing N-terminal tripartite motif. Mutations in the MID1 gene have been associated with the X-linked form of Opitz Syndrome, a developmental disorder characterized by midline defects and intellectual disability. The effect of MID1 E3 ligase activity within the cell and the role in the pathogenesis of the disease is still not completely unraveled. Here, we report BRAF35, a non-canonical HMG nuclear factor, as a novel MID1 substrate. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We observed a partial co-localization of the two proteins within cytoplasmic bodies. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance. Our data reveal a novel role for MID1 and for atypical ubiquitination in balancing BRAF35 presence, and likely its activity, within nuclear and cytoplasmic compartments.


Air leaks in COVID-19 pneumonia.
The novel coronavirus infection 2019 (COVID-19), which was first identified in Wuhan, China in December 2019 and caused a pandemic, is mostly survived with mild symptoms, while invasive and non-invasive mechanical ventilation support is required in some patients. Pneumothorax, pneumomediastinum, and subcutaneous emphysema may develop in COVID-19 patients. In this study, cases of pneumothorax, pneumomediastinum, and subcutaneous emphysema in patients who were followed in the intensive care unit with the diagnosis of COVID-19 were evaluated. In conclusion, although rare, these complications can be fatal and increase the severity of the disease, which already has a high mortality rate in the intensive care unit. Early detection and management of these complications can reduce morbidity and mortality.


Bioscaffold-mediated mucosal remodeling following short-segment colonic mucosal resection.
Precancerous or cancerous lesions of the gastrointestinal tract often require surgical resection via endomucosal resection. Although excision of the colonic mucosa is an effective cancer treatment, removal of large lesions is associated with high morbidity and complications including bleeding, perforation, fistula formation, and/or stricture, contributing to high clinical and economic costs and negatively impacting patient quality of life. The present study investigates the use of a biologic scaffold derived from extracellular matrix (ECM) to promote restoration of the colonic mucosa following short segment mucosal resection. Six healthy dogs were assigned to ECM-treated (tubular ECM scaffold) and mucosectomy only control groups following transanal full circumferential mucosal resection (4 cm in length). The temporal remodeling response was monitored using colonoscopy and biopsy collection. Animals were sacrificed at 6 and 10 wk, and explants were stained with hematoxylin and eosin (H&E), Alcian blue, and proliferating cell nuclear antigen (PCNA) to determine the temporal remodeling response. Both control animals developed stricture and bowel obstruction with no signs of neomucosal coverage after resection. ECM-treated animals showed an early mononuclear cell infiltrate (2 weeks post-surgery) which progressed to columnar epithelium and complex crypt structures nearly indistinguishable from normal colonic architecture by 6 weeks after surgery. ECM scaffold treatment restored colonic mucosa with appropriately located PCNA+ cells and goblet cells. The study shows that ECM scaffolds may represent a viable clinical option to prevent complications associated with endomucosal resection of cancerous lesions in the colon.


Distinct evolutionary rate in the eye field transcription factors found by estimation of ancestral protein structure.
Eye-field transcription factors (EFTFs) are a set of genes that compose a regulatory network for eye development in animals, which are highly conserved among various animal phyla. To investigate the processes of conservation and diversification of the transcription factors for eye development, we examined the structural changes in the EFTF proteins by estimating the ancestral sequences with the available genome information. Among the different types of EFTFs, we selected otx2, tbx3, rx1, pax6, six3/6, lhx2 and nr2e1 because they are highly conserved in bilaterian animals. We searched the genome sequences of representative animal phyla for EFTF protein sequences. With deduced ancestral sequences and three-dimensional structures of EFTFs, we traced the evolutionary changes in amino acid residues and found that the DNA-binding domains were always more conserved than other regions, and that the other regions showed distinct evolutionary rates. The EFTF rx1, which resides at the pivotal part of the EFTF network, had a faster evolutionary rate than the others. These results indicated that the evolutionary rates of each protein in the EFTF network, which were expected to be consistent with each other to maintain the interactions in the network, were not constant among or within the factors, but rather, varied to a significant extent.


Age-related changes in p56lck protein levels and phenotypic distribution of T lymphocytes in young rats.
p56lck is involved in the maturation of T-cells from double negative (DN) into double positive (DP) T-cells. The objective of this experiment was to determine changes in the levels of thymic and splenic T-cell p56lck using Western immunoblotting, along with the proportion and number ofT-cell subsets in thymus, spleen and blood using flow cytometry in growing Sprague-Dawley rats. Thymic p56lck levels were negatively correlated with age (r = - 0.42, p = 0.04) and positively correlated with age in the spleen (r = 0.50, p = 0.01). Nine-week-old rats had a higher percentage of thymic DN and CD8 cells with fewer DP cells compared to younger rats. There were minor differences in the proportions of T-cell subsets in the spleen and blood. T-cell numbers remained proportional to body weight in the lymphoid organs; however, the lower absolute number of T-cells in the younger rats might indicate that they are less able to respond to antigens.


Delayed Development of Hemolytic Anemia with Fragmented Red Blood Cells and Cardiac and Renal Impairments after High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoma.
Among 42 consecutive patients with malignant lymphoma who underwent high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (AHSCT), 5 developed hemolytic anemia with fragmented red blood cells (HA-FrRBCs) on days 87-125 (median 107) of AHSCT. Nadir Hb levels ranged between 5.0 and 6.4 g/dL with 2.2-5.6% FrRBCs. All patients developed grade ≥3 hypoxia and heart failure, and 4 developed grade ≥3 hypertension. The ejection fraction of the left ventricle assessed by echocardiography was significantly reduced in 3 patients. Peak creatinine levels were >4 times above the baseline and estimated glomerular filtration rates were reduced to <30 mL/min/1.73 m2. One patient received plasma exchange, while the remaining 4 responded to treatment with diuretics and cardiovascular agents. Hematological parameters normalized within a median duration of 91 days after the development of HA-FrRBCs. Renal and cardiac functions gradually improved, even though renal function did not return to the baseline. HA-FrRBCs associated with cardiac and renal impairments may represent a thrombotic microangiopathy syndrome and are a delayed complication of HDC/AHSCT. The close monitoring of laboratory abnormalities and persistent treatment with cardiovascular agents and diuretics are the mainstay for the management of this condition.


Vitamin C ameliorates fluoride-induced embryotoxicity in pregnant rats.
Oral administration of sodium fluoride (40 mg/kg body weight) from day 6 to 19 of gestation caused, as compared to control, significant reductions in body weight, feed consumption, absolute uterine weight and number of implantations. Significantly higher incidence of skeletal (wavy ribs, 14th rib, <6 sternal centre, dumbell-shaped second and fifth sternebrae, incomplete ossification of skull and thickening of tibia) and visceral (subcutaneous haemorrhage) abnormalities were also observed in NaF-treated dams than that of control. Oral administration of vitamin C (50 mg/kg body weight) and vitamin E (2 mg/0.2 ml olive oil/animal/day) from day 6 to 19 of gestation along with NaF significantly ameliorates NaF-induced reductions in body weight, feed consumption, absolute uterine weight (only with vitamin E treatment) and number of implantations. As compared with NaF-treated alone, the total percentage of skeletal and visceral abnormalities were significantly lowered in fluoride plus vitamin C-treated animals. Vitamin E was less effective. These findings suggest that vitamin C significantly reduced the severity and incidence of fluoride-induced embryotoxicity in rats.


Social representations of masculinities in the short film "Aids, choose your form of prevention".
This article aims to understand the social representations of masculinities in the campaign by the Ministry of Health on Combined Prevention/2016, from the short film "AIDS, choose your form of prevention". An exploratory, qualitative approach was conducted at the AIDS Portal, Sexually Transmitted Infections and Viral Hepatitis, Department of Sexually Transmitted Infections, AIDS and Viral Hepatitis. The results pointed out five organizing categories of social representations about masculinities. It was concluded that the social representations of masculinity in the short film reproduced hegemonic values of the masculine social role.


Assessing Regional-Scale Impacts of Short Rotation Coppices on Ecosystem Services by Modeling Land-Use Decisions.
Meeting the world's growing energy demand through bioenergy production involves extensive land-use change which could have severe environmental and social impacts. Second generation bioenergy feedstocks offer a possible solution to this problem. They have the potential to reduce land-use conflicts between food and bioenergy production as they can be grown on low quality land not suitable for food production. However, a comprehensive impact assessment that considers multiple ecosystem services (ESS) and biodiversity is needed to identify the environmentally best feedstock option, as trade-offs are inherent. In this study, we simulate the spatial distribution of short rotation coppices (SRCs) in the landscape of the Mulde watershed in Central Germany by modeling profit-maximizing farmers under different economic and policy-driven scenarios using a spatially explicit economic simulation model. This allows to derive general insights and a mechanistic understanding of regional-scale impacts on multiple ESS in the absence of large-scale implementation. The modeled distribution of SRCs, required to meet the regional demand of combined heat and power (CHP) plants for solid biomass, had little or no effect on the provided ESS. In the policy-driven scenario, placing SRCs on low or high quality soils to provide ecological focus areas, as required within the Common Agricultural Policy in the EU, had little effect on ESS. Only a substantial increase in the SRC production area, beyond the regional demand of CHP plants, had a relevant effect, namely a negative impact on food production as well as a positive impact on biodiversity and regulating ESS. Beneficial impacts occurred for single ESS. However, the number of sites with balanced ESS supply hardly increased due to larger shares of SRCs in the landscape. Regression analyses showed that the occurrence of sites with balanced ESS supply was more strongly driven by biophysical factors than by the SRC share in the landscape. This indicates that SRCs negligibly affect trade-offs between individual ESS. Coupling spatially explicit economic simulation models with environmental and ESS assessment models can contribute to a comprehensive impact assessment of bioenergy feedstocks that have not yet been planted.


Influence of cognition and symptoms of schizophrenia on IADL performance.
People with schizophrenia experience difficulties with instrumental activities of daily living (IADL), which are required for independent living. Yet, factors that influence IADL performance are still poorly understood. Identification of such factors will contribute to the rehabilitation process and recovery. The present study aimed to examine the influence of cognitive abilities, schizophrenia symptoms, and demographic variables on IADL functioning during acute hospital admission. The participants were 81 adults with DSM-IV chronic schizophrenia. They were assessed on the Revised Observed Tasks of Daily Living (OTDL-R), the Positive and Negative Syndrome Scale (PANSS), the Neurobehavioral Cognitive Status Examination (Cognistat), and the Kitchen Task Assessment (KTA) at acute hospitalization. The prediction model of IADL performance at this time consists of executive functioning (explained 21% of variance), memory and abstract thinking (explained 13.5%), negative symptoms (explained 13%), age of illness onset and years of education (explained 8%). The total explained variance is 53.5%. These results provide evidence-based guidelines for the evaluation process in inpatient settings. Such guidelines are important since planning of intervention processes and appropriate community integration programs often occurs during acute hospitalization, while the structured nature of inpatient settings limits natural variability in occupational performance.


Therapeutic potential of recombinant granulocyte-macrophage colony-stimulating factor and interleukin-3 in murine B-cell leukemia.
The antileukemic activity of murine recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) and a combination of rGM-CSF and recombinant interleukin-3 (rIL-3) was examined by using a murine model of spontaneous B-cell leukemia (BCL1) in BALB/c mice. All untreated mice inoculated with 2 x 10(2) BCL1 cells developed leukemia within 4 weeks, with extreme lymphocytosis and a massive increase in both spleen weight and cell number while the number of myeloid progenitors (CFU-C) per spleen was decreased. In contrast, rGM-CSF-or rGM-CSF- and rIL-3-treated recipients did not show any evidence of leukemia or splenomegaly at 4 weeks and showed a significant increase in CFU-C per spleen. Hematologic parameters in the peripheral blood of untreated mice showed anemia and thrombocytopenia. Significant elevations in these parameters were recorded in mice treated with either protocol of CSF. Treatment of recipient mice with either rGM-CSF or rGM-CSF and rIL-3 prolonged their median survival from 6 weeks in untreated controls (range, 5 to 9 weeks) up to the time they were killed at 105 days. Adoptive transfer of spleen cells obtained from mice treated with rGM-CSF, mice treated with a combination of rGM-CSF and rIL-3, and untreated controls, into normal secondary recipients indicated improved survival in recipients inoculated with rGM-CSF. These data indicate that CSFs may inhibit in vivo expansion of leukemic cells of lymphoid origin.


[Relationship between eating disorders, physical symptoms, depression and health locus of control among elementary school girls in South Korea].
The purpose of this study was to identify the relationship between eating disorders, physical symptoms, depression and health locus of control. The research design was a descriptive study done by using a constructive self-report questionnaire. A total of 464 elementary school girls were measured. The instrument was a constructive questionnaire that consisted 136 items. The subjects were divided into 4 groups according to the Body Mass Index (BMI). Data analysis was done by SPSS/WIN Programs using frequency, percentage, mean, SD, ANOVA, Pearson correlation coefficient, and stepwise multiple regression. The score of eating disorders differed significantly by BMI : the score was highest in the group of obese students(F=4.208, P=.015). Stepwise multiple regression analysis revealed that the most powerful predictor of eating disorders was BMI. These results indicate that Korean elementary school girls need more education and counseling on diet. Also, we should take systematic efforts to reestablish the social standard of beauty to promote normal growth development.


Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.
Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene ( GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies.


Specification and spatial arrangement of cells in the germline stem cell niche of the Drosophila ovary depend on the Maf transcription factor Traffic jam.
Germline stem cells in the Drosophila ovary are maintained by a somatic niche. The niche is structurally and functionally complex and contains four cell types, the escort, cap, and terminal filament cells and the newly identified transition cell. We find that the large Maf transcription factor Traffic jam (Tj) is essential for determining niche cell fates and architecture, enabling each niche in the ovary to support a normal complement of 2-3 germline stem cells. In particular, we focused on the question of how cap cells form. Cap cells express Tj and are considered the key component of a mature germline stem cell niche. We conclude that Tj controls the specification of cap cells, as the complete loss of Tj function caused the development of additional terminal filament cells at the expense of cap cells, and terminal filament cells developed cap cell characteristics when induced to express Tj. Further, we propose that Tj controls the morphogenetic behavior of cap cells as they adopted the shape and spatial organization of terminal filament cells but otherwise appeared to retain their fate when Tj expression was only partially reduced. Our data indicate that Tj contributes to the establishment of germline stem cells by promoting the cap cell fate, and controls the stem cell-carrying capacity of the niche by regulating niche architecture. Analysis of the interactions between Tj and the Notch (N) pathway indicates that Tj and N have distinct functions in the cap cell specification program. We propose that formation of cap cells depends on the combined activities of Tj and the N pathway, with Tj promoting the cap cell fate by blocking the terminal filament cell fate, and N supporting cap cells by preventing the escort cell fate and/or controlling the number of cap cell precursors.


Deposition of size-selected metal clusters generated by magnetron sputtering and gas condensation: a progress review.
This paper presents a topical review of the production and deposition of size-selected metal clusters generated by magnetron sputtering and gas condensation. Clusters with up to 75,000 atoms can be obtained by controlling the gas pressure in the sputtering source, prior to size selection with a novel (time-of-flight) mass filter. The clusters are deposited on the model graphite substrate to study the cluster-surface interaction. Two regimes for cluster deposition have been identified at elevated impact energies: (i) 'pinning' (ca. 10 eV per atom) and (ii) implantation (ca. 100 eV per atom). Of particular importance is the pinning regime, since this allows the fabrication of monodispersed cluster arrays, which are stable against diffusion at room temperature (and above). The deposition of size-selected metal clusters represents a novel method of preparing surface nanostructures, with potential applications including model catalyst studies and the immobilization of biological molecules.


[Comparison of the efficacy of ivermectin in injectable form and as a paste in horses].
A comparison was made of the efficacy of Ivermectin administered as an injection and as a paste. Fourteen horses which were naturally infected with small strongyles were divided into three groups. Animals of group 1 received an injection of 5 ml Ivermectin, equivalent to 500 kg bodyweight, horses of group 2 received one injector with Ivermectin as a paste (for 500 kg body weight), a third group remained untreated as a control. Faecal examinations and larval cultures on the day of treatment and 14, 28 and 42 days later showed that both injection and paste had a 100 percent efficacy against mature and immature small strongyles in these horses.


Predictors of engagement in adolescent drug abuse treatment.
To identify key demographic, parent, and adolescent characteristics that influence engagement in outpatient drug abuse treatment. Youths aged 12 to 17 years (N = 224; 81% male and 72% African American) referred for drug treatment and their parents participated in this study. Marijuana was the primary substance of abuse. Data were gathered prior to treatment on demographic variables as well as on both parent and youth perspectives on youth, parent, and family functioning. A discriminant function analysis revealed that engagement in treatment was related to, in order of weighting, more positive parental expectations for their adolescent's educational achievement (standardized discriminant function coefficient [SDF] = 0.68), higher parental reports of youth externalizing symptoms (SDF = 0.59), and higher levels of family conflict perceived by the youth (SDF = 0.36). Family income, gender, juvenile justice status, minority group status, family structure, parental age and psychopathology, and treatment characteristics did not distinguish treatment-engaged from unengaged adolescents. The results suggest that both parent and youth perceptions are pivotal to whether or not adolescents are engaged in psychotherapy. These findings lead the authors to recommend adolescent engagement interventions focusing on both the youth and his or her parents and suggest a content focus for adolescent engagement interventions.


New Application of cycloSaligenyl Prodrugs Approach for the Delivery of Fosfoxacin Derivatives in Mycobacteria.
In this work, we implemented for the first time the cycloSaligenyl prodrug strategy to increase the bioavailability of fosmidomycin phosphate analogs in bacteria. Here, we report the synthesis of 34 cycloSaligenyl prodrugs of fosfoxacin and its derivatives. Among them, fifteen double prodrugs efficiently prevented the growth of the non-pathogenic, fast-growing Mycobacterium smegmatis.


Anti-asthmatic effect of nitric oxide metallo-donor FOR811A [cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3] in the respiratory mechanics of Swiss mice.
We aimed at evaluating the anti-asthmatic effect of cis-[Ru(bpy)2(2-MIM)(NO)](PF6)3 (FOR811A), a nitrosyl-ruthenium compound, in a murine model of allergic asthma. The anti-asthmatic effects were analyzed by measuring the mechanical lung and morphometrical parameters in female Swiss mice allocated in the following groups: untreated control (Ctl+Sal) and control treated with FOR811A (Ctl+FOR), along asthmatic groups untreated (Ast+Sal) and treated with FOR811A (Ast+FOR). The drug-protein interaction was evaluated by in-silico assay using molecular docking. The results showed that the use of FOR811A in experimental asthma (Ast+FOR) decreased the pressure-volume curve, hysteresis, tissue elastance, tissue resistance, and airway resistance, similar to the control groups (Ctl+Sal; Ctl+FOR). However, it differed from the untreated asthmatic group (Ast+Sal, p<0.05), indicating that FOR811A corrected the lung parenchyma and relaxed the smooth muscles of the bronchi. Similar to control groups (Ctl+Sal; Ctl+FOR), FOR811A increased the inspiratory capacity and static compliance in asthmatic animals (Ast+Sal, p<0.05), showing that this metallodrug improved the capacity of inspiration during asthma. The morphometric parameters showed that FOR811A decreased the alveolar collapse and kept the bronchoconstriction during asthma. Beyond that, the molecular docking using FOR811A showed a strong interaction in the distal portion of the heme group of the soluble guanylate cyclase, particularly with cysteine residue (Cys141). In summary, FOR811A relaxed bronchial smooth muscles and improved respiratory mechanics during asthma, providing a protective effect and promising use for the development of an anti-asthmatic drug.


Do Parents Foster Self-Esteem? Testing the Prospective Impact of Parent Closeness on Adolescent Self-Esteem.
Close parent-child relationships are viewed as important for the development of global self-esteem. Cross-sectional research supports this hypothesis, but longitudinal studies provide inconsistent prospective effects. The current study uses data from Germany (N = 982) and the United States (N = 451) to test longitudinal relations between parent-child closeness and adolescent self-esteem. The authors used self-, parent-, and observer-reported parent-child closeness and self-reported self-esteem from ages 12 to 16. Results replicated concurrent correlations found in the literature, but six longitudinal models failed to show prospective relations. Thus, the longitudinal effect of parent-child closeness and self-esteem is difficult to detect with adolescent samples. These findings suggest the need for additional theorizing about influences on adolescent self-esteem development and longitudinal research with younger samples.


Repairable-conditionally repairable damage model based on dual Poisson processes.
The advent of intensity-modulated radiation therapy makes it increasingly important to model the response accurately when large volumes of normal tissues are irradiated by controlled graded dose distributions aimed at maximizing tumor cure and minimizing normal tissue toxicity. The cell survival model proposed here is very useful and flexible for accurate description of the response of healthy tissues as well as tumors in classical and truly radiobiologically optimized radiation therapy. The repairable-conditionally repairable (RCR) model distinguishes between two different types of damage, namely the potentially repairable, which may also be lethal, i.e. if unrepaired or misrepaired, and the conditionally repairable, which may be repaired or may lead to apoptosis if it has not been repaired correctly. When potentially repairable damage is being repaired, for example by nonhomologous end joining, conditionally repairable damage may require in addition a high-fidelity correction by homologous repair. The induction of both types of damage is assumed to be described by Poisson statistics. The resultant cell survival expression has the unique ability to fit most experimental data well at low doses (the initial hypersensitive range), intermediate doses (on the shoulder of the survival curve), and high doses (on the quasi-exponential region of the survival curve). The complete Poisson expression can be approximated well by a simple bi-exponential cell survival expression, S(D) = e(-aD) + bDe(-cD), where the first term describes the survival of undamaged cells and the last term represents survival after complete repair of sublethal damage. The bi-exponential expression makes it easy to derive D(0), D(q), n and alpha, beta values to facilitate comparison with classical cell survival models.


Genetic analysis reveals Finnish Formica fennica populations do not form a separate genetic entity from F. exsecta.
Coptoformica Müller, 1923 is a subgenus of Formica Linnaeus, 1758 that consists of c. a dozen species of ants that typically inhabit open grassy habitats and build small nest mounds. The most recent addition to the group is Formica fennica Seifert, 2000. The description was based on morphological characters, but the species status has not been confirmed by molecular methods. In this study, we use thirteen DNA microsatellite markers and a partial mitochondrial COI gene sequence to assess the species status of F. fennica, by comparing the genetic variation among samples identified as F. fennica and six other boreal Formica (Coptoformica) species. Most of the species studied form separate, discontinuous clusters in phylogenetic and spatial analyses with only little intraspecific genetic variation. However, both nuclear and mitochondrial markers fail to separate the species pair F. exsecta Nylander, 1846 and F. fennica despite established morphological differences. The genetic variation within the F. exsecta/fennica group is extensive, but reflects spatial rather than morphological differences. Finnish F. fennica populations studied so far should not be considered a separate species, but merely a morph of F. exsecta.


Influence of Adhesion Force on icaA and cidA Gene Expression and Production of Matrix Components in Staphylococcus aureus Biofilms.
The majority of human infections are caused by biofilms. The biofilm mode of growth enhances the pathogenicity of Staphylococcus spp. considerably, because once they adhere, staphylococci embed themselves in a protective, self-produced matrix of extracellular polymeric substances (EPSs). The aim of this study was to investigate the influence of forces of staphylococcal adhesion to different biomaterials on icaA (which regulates the production of EPS matrix components) and cidA (which is associated with cell lysis and extracellular DNA [eDNA] release) gene expression in Staphylococcus aureus biofilms. Experiments were performed with S. aureus ATCC 12600 and its isogenic mutant, S. aureus ATCC 12600 Δpbp4, deficient in peptidoglycan cross-linking. Deletion of pbp4 was associated with greater cell wall deformability, while it did not affect the planktonic growth rate, biofilm formation, cell surface hydrophobicity, or zeta potential of the strains. The adhesion forces of S. aureus ATCC 12600 were the strongest on polyethylene (4.9 ± 0.5 nN), intermediate on polymethylmethacrylate (3.1 ± 0.7 nN), and the weakest on stainless steel (1.3 ± 0.2 nN). The production of poly-N-acetylglucosamine, eDNA presence, and expression of icaA genes decreased with increasing adhesion forces. However, no relation between adhesion forces and cidA expression was observed. The adhesion forces of the isogenic mutant S. aureus ATCC 12600 Δpbp4 (deficient in peptidoglycan cross-linking) were much weaker than those of the parent strain and did not show any correlation with the production of poly-N-acetylglucosamine, eDNA presence, or expression of the icaA and cidA genes. This suggests that adhesion forces modulate the production of the matrix molecule poly-N-acetylglucosamine, eDNA presence, and icaA gene expression by inducing nanoscale cell wall deformation, with cross-linked peptidoglycan layers playing a pivotal role in this adhesion force sensing.


Pediatric neurosurgery during the COVID-19 pandemic: update and recommendations from the Brazilian Society of Pediatric Neurosurgery.
Coronavirus disease (COVID-19) is a potentially severe respiratory illness that has threatened humanity globally. The pediatric neurosurgery practice differs from that of adults in that it treats children in various stages of physical and psychological development and contemplates diseases that do not exist in other areas. The aim of this study was to identify the level of knowledge and readiness of the healthcare providers, as well as to evaluate new preventive practices that have been introduced, psychological concerns, and the impact of the COVID-19 pandemic on pediatric neurosurgical units in Brazil. Pediatric neurosurgeons were given an online questionnaire developed by the Brazilian Society of Pediatric Neurosurgery to evaluate the impact of the COVID-19 pandemic on their clinical practice. Of a cohort of 110 active members of the Brazilian Society of Pediatric Neurosurgery, 76 completed the survey (69%). Ninety-six percent were aware of the correct use of and indication for the types of personal protective equipment in clinical and surgical practices, but only 73.7% of them had unrestricted access to this equipment. Ninety-eight percent of participants agreed or strongly agreed that the pandemic had affected their pediatric neurosurgical practice. The COVID-19 pandemic interfered with outpatient care in 88% of the centers, it affected neurosurgical activity in 90.7%, and it led to the cancellation of elective neurosurgical procedures in 57.3%. Concerning the impact of COVID-19 on surgical activity, 9.2% of the centers had less than 25% of the clinical practice affected, 46.1% had 26%-50% of their activity reduced, 35.5% had a 51%-75% reduction, and 9.2% had more than 75% of their surgical work cancelled or postponed. Sixty-three percent affirmed that patients had been tested for COVID-19 before surgery. Regarding the impact of the COVID-19 pandemic on the mental health of those interviewed, 3.9% reported fear and anxiety with panic episodes, 7.9% had worsening of previous anxiety symptoms, 60.5% reported occasional fear, 10.5% had sadness and some depressive symptoms, and 2.6% reported depressive symptoms. The COVID-19 pandemic has posed unprecedented challenges to healthcare services worldwide, including neurosurgical units. Medical workers, pediatric neurosurgeons included, should be aware of safety measures and follow the recommendations of local healthcare organizations, preventing and controlling the disease. Attention should be given to the psychological burden of exposure to SARS-CoV-2 in healthcare workers, which carries a high risk of anxiety and depression.


The urgent need to implement point-of-care RNA testing for hepatitis C virus to support elimination.
Hepatitis C virus (HCV) elimination is an important global public health goal. However, the United States (US) is not on track to meet the World Health Organization's 2030 targets for HCV elimination. Recently, the White House proposed an HCV elimination plan that includes point-of-care (POC) HCV RNA testing, which is currently in use in many countries, but is not approved in the US. POC HCV RNA testing is crucial for implementing community-based testing, and for enabling test-and-treat programs, assessing cure, and monitoring for reinfection.. In this commentary, we review the status of POC HCV RNA testing in the US, discuss factors that are needed for successful implementation, and issue specific public health and policy recommendations that would allow for the use of POC HCV RNA testing to support HCV elimination.


The Impact of an Academy of Medical Educators on the Culture of an American Health Sciences Campus.
During the last two decades in the United States, academies of medical educators (AMEs) have proliferated as formal organizations within faculties of health professions education to recognize teaching excellence, support faculty development, and encourage scholarly activity. AMEs have been effective at rewarding faculty for educational excellence and providing faculty development. However, the impact of an AME on campus culture remains unclear. A qualitative case study asked, How has an AME shaped organizational culture? The authors investigated the University of Colorado health sciences campus AME given its clear mandate to impact organizational culture. The authors interviewed a purposeful sample of 26 AME members and non-AME campus faculty and educational leaders during the 2014-2015 academic year. Two reviewers employed content analysis to code the transcripts. The AME has positively impacted organizational culture by being a symbol of institutional commitment to the educational mission, and by asserting education as an evidence-based practice. At the faculty member level, the AME's impact includes creating a home and community for educators to network. Individual faculty influence departments and programs across campus through teaching and interpersonal connections. However, the AME has not impacted all of campus, due to only reaching self-identified educators, and the siloed nature of departments on campus. Although limited to a single campus and an early established AME, this study contributes significant insight by describing how an AME as a structural unit impacts individual faculty members, who in turn impact organizational campus culture regarding the educational mission.


Choline Sulfate in Higher Plants.
Choline sulfate, the sulfate ester of choline, is widely distributed in plant species and tissues. It constitutes up to one-third of the labeled metabolic products of radiosulfate uptake by roots of sulfur-deficient corn, barley, and sunflower plants. This neutral, nonabsorbed zwitterion appears to be a useful reservoir for sulfur in plants.


Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review.
Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals colloquially known as "forever chemicals" because of their high persistence. PFAS have been detected in the blood, liver, kidney, heart, muscle and brain of various species. Although brain is not a dominant tissue for PFAS accumulation compared to blood and liver, adverse effects of PFAS on brain functions have been identified. Here, we review studies related to the absorption, accumulation, distribution and toxicity of PFAS in the brain. We summarize evidence on two potential mechanisms of PFAS entering the brain: initiating blood-brain barrier (BBB) disassembly through disrupting tight junctions and relying on transporters located at the BBB. PFAS with diverse structures and properties enter and accumulate in the brain with varying efficiencies. Compared to long-chain PFAS, short-chain PFAS may not cross cerebral barriers effectively. According to biomonitoring studies and PFAS exposure experiments, PFAS can accumulate in the brain of humans and wildlife species. With respect to the distribution of PFAS in specific brain regions, the brain stem, hippocampus, hypothalamus, pons/medulla and thalamus are dominant for PFAS accumulation. The accumulation and distribution of PFAS in the brain may lead to toxic effects in the central nervous system (CNS), including PFAS-induced behavioral and cognitive disorders. The specific mechanisms underlying such PFAS-induced neurotoxicity remain to be explored, but two major potential mechanisms based on current understanding are PFAS effects on calcium homeostasis and neurotransmitter alterations in neurons. Based on the information available about PFAS uptake, accumulation, distribution and impacts on the brain, PFAS have the potential to enter and accumulate in the brain at varying levels. The balance of existing studies shows there is some indication of risk in animals, while the human evidence is mixed and warrants further scrutiny.


Indolo-quinoline boron difluoride dyes: synthesis and spectroscopic properties.
Novel indolo-quinoline compounds were efficiently prepared via a Povarov-type reaction, and the structures were further modified by a Suzuki coupling reaction. The corresponding BF2-rigidified complexes were prepared and their spectroscopic properties were characterized with large Stokes shifts (up to 211 nm) and up to near-infrared (NIR) wavelength (667 nm). The synthetic complexes could be used as new fluorescent dyes.


Medical information on the Internet: a study of an electronic bulletin board.
To assess medical information provided in a medically oriented Internet discussion group, in terms of the professional status of the individuals providing information, the consistency of the information with standard medical practice, and the nature of the evidence cited in support of specific claims or recommendations. Standardized review of 1,658 consecutive messages on a particular online discussion group during a 5-month period. An online discussion group for sufferers of painful hand and arm conditions. All participants in this discussion group during the study period. Professional training of those offering medical information, consistency of the advice and recommendations offered with conventional medical practice, and nature of evidence cited in support of medical claims were determined. Of all messages, 55.9% (927) addressed a medical topic. Of these, 79% (732) provided medical information, of which 89.3% (654) were authored by persons without professional medical training, and 5.1% (37) were authored by trained health professionals. Approximately one third of the medical information provided was classified as unconventional. Personal experience was the basis of information provided in 61% of the nonprofessionals' messages and 13.5% of the professionals' messages, while no source was given as the basis of information provided in 29.8% of the nonprofessionals' messages and 67.6% of the professionals' messages. A published source was cited in 9.2% of the nonprofessionals' and 18.9% of the professionals' messages. These findings suggest that medical information available on Internet discussion groups may come from nonprofessionals and may be unconventional, based on limited evidence, and/or inappropriate.


Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium.
Pituitary adenomas are very common neoplasms, constituting between 10 and 20% of all primary brain tumors. Historically, the treatment armamentarium for pituitary adenomas has included medical management, microsurgery, and fractionated radiotherapy. More recently, radiosurgery has emerged as a viable treatment option. The goal of this research was to define more fully the efficacy, safety, and role of radiosurgery in the treatment of pituitary adenomas. Medical literature databases were searched for articles pertaining to pituitary adenomas and stereotactic radiosurgery. Each study was examined to determine the number of patients, radiosurgical parameters (for example, maximal dose and tumor margin dose), duration of follow-up review, tumor growth control rate, complications, and rate of hormone normalization in the case of functioning adenomas. A total of 35 peer-reviewed studies involving 1621 patients were examined. Radiosurgery resulted in the control of tumor size in approximately 90% of treated patients. The reported rates of hormone normalization for functioning adenomas varied substantially. This was due in part to widespread differences in endocrinological criteria used for the postradiosurgical assessment. The risks of hypopituitarism, radiation-induced neoplasia, and cerebral vasculopathy associated with radiosurgery appeared lower than those for fractionated radiation therapy. Nevertheless, further observation will be required to understand the true probabilities. The incidence of other serious complications following radiosurgery was quite low. Although microsurgery remains the primary treatment modality in most cases, stereotactic radiosurgery offers both safe and effective treatment for recurrent or residual pituitary adenomas. In rare instances, radiosurgery may be the best initial treatment for patients with pituitary adenomas. Further refinements in the radiosurgical technique will likely lead to improved outcomes.


What determines mpox vaccination uptake? Assessing the effect of intent-to-vaccinate versus other determinants among men who have sex with men.
In response to the mpox outbreak, vaccination was offered in the Netherlands to men who have sex with men (MSM) at increased risk for mpox. Successful vaccination campaigns are leveraged by high intent-to-vaccinate, yet intent might not always lead to uptake. Therefore, we assessed the impact of intent-to-vaccinate and other factors on vaccination uptake among participants of the Amsterdam Cohort Studies (ACS). In July 2022, prior to the mpox vaccination campaign, we distributed an online survey regarding mpox intent-to-vaccinate, as well as e.g. beliefs, attitude, subjective norms, and perception of risk among ACS participants (all MSM). Vaccination uptake was self-reported during study visits after August 2022. The association between vaccination intent and uptake, and determinants of intent, was jointly assessed using a structural equation model (SEM) based on components of the Theory of Planned Behavior (TPB). In a second SEM, determinants of intent were allowed to have a direct effect on vaccination uptake. 492 MSM (median age = 46 years) were included in analyses. 380 (77%) had high intent-to-vaccinate and 238 (48%) received at least one vaccine dose. In the first model with a direct relation between intent and uptake only, TBP components predicted intent as expected, and high intent-to-vaccinate was significantly associated with getting vaccinated (β = 1.1, 95%CI = 0.6-1.5). However, 175/380 (46%) participants with high intent-to-vaccinate did not get vaccinated. The second model had an improved model fit compared to the first model. The effect of intent on uptake was non-significant, and only perceiving to be at higher risk of infection significantly increased vaccination uptake later on (β = 0.42, 95%CI = 0.26-0.59). Having a steady relationship decreased the probability of vaccination (β = -0.59, 95%CI = -1.0- -0.18). While intent-to-vaccinate for mpox was high among MSM, high intent did not necessarily result in vaccine uptake. Mpox risk perception might have played a more pivotal role in getting vaccinated, which may be related to the evolution of vaccination eligibility criteria and accessibility to the vaccine.


Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy.
Uterine serous carcinoma (USC) is an aggressive type 2 endometrial cancer. Data on prognostic factors for patients with early-stage USC without adjuvant therapy are limited. This study aims to assess the baseline recurrence risk of early-stage USC patients without adjuvant treatment and to identify prognostic factors and patients who need adjuvant therapy. Sixty-eight patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-II USC between 1997 and 2016 were included. All the cases did not undergo adjuvant treatment as institutional practice. Clinicopathological features, recurrence patterns, and survival outcomes were analyzed to determine prognostic factors. FIGO stages IA, IB, and II were observed in 42, 7, and 19 cases, respectively. Median follow-up time was 60 months. Five-year disease-free survival (DFS) and overall survival (OS) rates for all cases were 73.9% and 78.0%, respectively. On multivariate analysis, cervical stromal involvement and positive pelvic cytology were significant predictors of DFS and OS, and ≥1/2 myometrial invasion was also a significant predictor of OS. Of 68 patients, 38 patients had no cervical stromal invasion or positive pelvic cytology and showed 88.8% 5-year DFS and 93.6% 5-year OS. Cervical stromal invasion and positive pelvic cytology are prognostic factors for stage I-II USC. Patients with stage IA or IB USC showing negative pelvic cytology may have an extremely favorable prognosis and need not receive any adjuvant therapies.


Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels.
The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion-induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents. A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca(2+) levels. The lead compound SAR7334 was further characterized by whole-cell patch-clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated. SAR7334 inhibited TRPC6, TRPC3 and TRPC7-mediated Ca(2+) influx into cells with IC50 s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5-mediated Ca(2+) entry was not affected. Patch-clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6-dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short-term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR). Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.


Fatty acid compositions of red blood cell phospholipids in children with autism.
We compared the compositions of fatty acids including n-3, n-6 polyunsaturated fatty acids, trans- and cis-monounsaturated fatty acids, and saturated fatty acids in the red blood cell membranes of 40 children with autism (20 with early onset autism and 20 with developmental regression) and age-matched, 20 typically developing controls and 20 subjects with non-autistic developmental disabilities. The main findings include increased levels of eicosenoic acid (20:1n9) and erucic acid (22:1n9) in autistic subjects with developmental regression when compared with typically developing controls. In addition, an increase in 20:2n6 and a decrease in 16:1n7t were observed in children with clinical regression compared to those with early onset autism. Our results do not provide strong evidence for the hypothesis that abnormal fatty acid metabolism plays a role in the pathogenesis of autism spectrum disorder, although they suggest some metabolic or dietary abnormalities in the regressive form of autism.


Holistic optical-digital hybrid-imaging design: wide-field reflective imaging.
Reflective imaging systems are typically limited to small field angles in order to avoid overly large obscurations or off-axis aberrations. Reflective optics are often preferred in astronomy due to the associated lower weight and cost, as well as the absence of chromatic aberrations. Although these advantages are compelling, off-axis aberrations typically limit the field of view to a few degrees, while many imaging applications require a considerably larger useful field of view. A hybrid optical-digital design could alleviate the issues associated with wide-field reflective optics by exploiting the larger design freedom inherent in such systems. In this paper we demonstrate how a holistic design approach can enable reflective imaging systems with a consistently sharp image across a wide field of view.


Conditional and Unconditional Tests (and Sample Size) Based on Multiple Comparisons for Stratified 2 × 2 Tables.
The Mantel-Haenszel test is the most frequent asymptotic test used for analyzing stratified 2 × 2 tables. Its exact alternative is the test of Birch, which has recently been reconsidered by Jung. Both tests have a conditional origin: Pearson's chi-squared test and Fisher's exact test, respectively. But both tests have the same drawback that the result of global test (the stratified test) may not be compatible with the result of individual tests (the test for each stratum). In this paper, we propose to carry out the global test using a multiple comparisons method (MC method) which does not have this disadvantage. By refining the method (MCB method) an alternative to the Mantel-Haenszel and Birch tests may be obtained. The new MC and MCB methods have the advantage that they may be applied from an unconditional view, a methodology which until now has not been applied to this problem. We also propose some sample size calculation methods.


142Nd evidence for early (>4.53 Ga) global differentiation of the silicate Earth.
New high-precision samarium-neodymium isotopic data for chondritic meteorites show that their 142Nd/144Nd ratio is 20 parts per million lower than that of most terrestrial rocks. This difference indicates that most (70 to 95%) of Earth's mantle is compositionally similar to the incompatible element-depleted source of mid-ocean ridge basalts, possibly as a result of a global differentiation 4.53 billion years ago (Ga), within 30 million years of Earth's formation. The complementary enriched reservoir has never been sampled and is probably located at the base of the mantle. These data influence models of Earth's compositional structure and require revision of the timing of global differentiation on Earth's Moon and Mars.


Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up.
Concern has been expressed that calcium supplementation, a key intervention for preventing osteoporotic fracture in older women, may increase the risk of atherosclerotic vascular disease. To evaluate the risk further, an examination of complete verified atherosclerotic vascular hospitalization and mortality data from a 5-year randomized, controlled trial (RCT) of calcium carbonate and 4.5 years of posttrial follow-up was undertaken. This study used data from a published 5-year randomized, double-blinded, placebo-controlled trial [Calcium Intake Fracture Outcome Study (CAIFOS)]. The participants were 1460 women aged 75.1 ± 2.7 years at baseline (1998) recruited from the general population and randomized to receive 1200 mg of calcium carbonate daily or an identical placebo. All hospital admission and deaths during the 5-year study and the 4.5-year follow-up were derived from the Western Australian Data Linkage Service (WADLS). Hazard ratios (HRs) for the combined endpoint of atherosclerotic vascular mortality or first hospitalization were calculated using prespecified intention-to-treat and per-protocol models. The intervention group that received calcium supplementation did not have a higher risk of death or first-time hospitalization from atherosclerotic vascular disease in either the 5-year RCT [multivariate-adjusted HR = 0.938, 95% confidence interval (CI) 0.690-1.275] or during the 9.5 years of observational study (multivariate-adjusted HR = 0.919, 95% CI 0.737-1.146). Further analysis suggested that calcium supplementation may reduce the risk of hospitalization and mortality in patients with preexisting atherosclerotic cardiovascular disease. This trial provides compelling evidence that calcium supplementation of 1200 mg daily does not significantly increase the risk of atherosclerotic vascular disease in elderly women.


Perceived Discrimination During Prenatal Care at a Community Health Center.
Discrimination in healthcare is associated with fetal growth restriction, preterm birth, and postpartum depression. A community-based participatory research study was designed to measure perceived discrimination and healthcare quality during prenatal care and delivery by a community health center, where the majority of patients served belong to historically marginalized ethnic and racial groups. A 34-question phone survey was administered to women 18 years and older who received prenatal care at the study site during 2020-2021. The primary outcome was perceived discrimination during obstetric care, measured by the 7-question Discrimination in the Medical Setting (DMS) survey. Secondary outcomes included the association of race with perceived discrimination, quality of care, trust of healthcare providers, and perceived control over medical choices. Ninety-seven women completed the survey, 95 of whom were women of color. The sample was dichotomized into Black (n = 49) and non-Black (n = 46). Perceived discrimination for all participants was 21% (20/95), with 31% (15/49) of Black women reporting any discrimination during prenatal care and delivery. Compared to other women of color, Black women reported higher rates of perceived discrimination (31% vs 11%, aOR 3.9 [1.2-12.1], p < 0.05), lower control over health choices (84% vs 98%, aOR 0.1 [0.0-0.8], p < 0.05), and were more likely to perceive lack of respect (12% vs 2%, p = 0.045). Although perceived discrimination at this community health center was low compared to prior studies, Black women experienced higher rates of discrimination than other women of color.


Escherichia coli heat-labile enterotoxin promotes protective Th17 responses against infection by driving innate IL-1 and IL-23 production.
Escherichia coli heat-labile enterotoxin (LT) is a powerful mucosal adjuvant; however, it is associated with toxic effects when delivered intranasally, and its mechanism of action is poorly understood. In this article, we demonstrate that LT acts as a highly effective adjuvant when administered parenterally, promoting Ag-specific IL-17, as well as IFN-γ, IL-4, and IL-10 production in response to coadministered Ags. We found that the adjuvant activity of LT was mediated in part by inducing dendritic cell (DC) activation; LT promoted CD80 and CD86 expression by DCs and enhanced IL-1α, IL-1β, and IL-23 production. An LT mutant, LTK63, that lacks enzyme activity was less effective than the wild-type toxin in promoting DC maturation and the development of Ag-specific Th17 cells. LT enhanced IL-23 and IL-1α production from DCs via activation of ERK MAPK and IL-1β secretion through activation of caspase-1 and the NLRP3 inflammasome. These cytokines played a major role in promoting Th17 responses by LT and LTK63. The induction of Th17 cells in vivo in response to LT and LTK63 as adjuvants was significantly reduced in IL-1RI-deficient mice. Finally, using a murine respiratory infection model, we demonstrated that LT can act as a highly effective adjuvant for a pertussis vaccine, promoting Ag-specific Th17 cells and protection against Bordetella pertussis challenge, which was significantly reduced in IL-17-defective mice. Our findings provide clear evidence that LT can promote protective immune responses in part through induction of innate IL-1 and, consequently, Th17 cells.


Understanding variability in hospital-specific costs of coronary artery bypass grafting represents an opportunity for standardizing care and improving resource use.
This study was undertaken to examine interhospital variability in inpatient costs of coronary artery bypass grafting (CABG). The Nationwide Inpatient Sample was used to identify isolated CABGs performed between 2005 and 2008 in the United States. Charges for inpatient care were supplied by the data set, and hospital charge-to-cost ratios were used to derive inpatient costs for each patient and aggregated at the hospital level. Mixed-effect linear regression models were created to evaluate variability in costs between hospitals adjusting for 34 patient, operative, complication, and hospital-related variables. A total of 633 hospitals performed isolated CABG in 183,973 patients. In unadjusted analysis, there was significant baseline variability in average inpatient costs of CABG between hospitals (SD, $12,130; P < .001). This variability represented 30% of the overall unadjusted average cost of performing CABG per hospital ($40,424). After risk adjustment, significant variability in average costs between hospitals persisted (P < .001). Of the 34 additional variables included in the model, only hospital region, postoperative sepsis, in-hospital mortality, and need for ventricular assist device, extracorporeal membrane oxygenation, permanent pacemaker, or implantable cardioverter-defibrillator were stronger predictors of increased costs compared with the hospital effect. There is a wide variation in the cost of performing CABG in the United States. We determined that individual hospital centers, independent of multiple patient- and outcome-specific factors, are drivers of these differences. Comparison of hospital-specific behavior with identification of the causes of cost discrepancies represents an opportunity for standardization of care and improvement in resource use.


Maternally induced transplantation immunity, tolerance, and runt disease in rats.
A previous report that the offspring of outbred Sprague-Dawley rats, born of mothers presensitized or tolerant with respect to tissue antigens of the Lewis strain, and reinoculated with Lewis cells during their pregnancy, reject test grafts of Lewis skin in an accelerated manner has been confirmed. This "maternally induced" alteration in reactivity of the progeny has been found to be long lasting, immunologically specific, and probably not due to transfer of humoral antibody. It has been established that the reexposure of the mothers to donor cellular antigen during pregnancy augmented the influence of the prior states of tolerance or sensitivity. To obviate the complications inherent in working with the outbred Sprague-Dawley rats, the key experiments summarized above were repeated with isogenic Fischer rats as parents and Lewis rats as the tissue donors as before. With this combination it was found that a state of prior sensitization or tolerance in the mothers resulted in the apparent induction of tolerance in some of their progeny. Reinoculation of either the tolerant or sensitized mothers during pregnancy slightly increased the incidence and degree of impairment of their offsprings' capacity to reject Lewis skin grafts. A single intraperitoneal injection of 100 x 10(6) million Lewis lymphoid cells into normal Fischer rats in the 14th-16th day of pregnancy also weakened the reactivity of their progeny to Lewis test grafts. Further to test the premise that this weakened reactivity might be due to maternal induction of tolerance, by antenatal transmission of alien cells, the lymphohematopoietic tissue system of adult Fischer females was replaced by that from Lewis donors with the aid of cyclophosphamide. It was anticipated that when these animals were mated with Fischer males, sufficient Lewis leukocytes might cross the placentas to induce high degrees of tolerance. Although normal sized healthy litters were born, about 50% of the infants succumbed to graft-versus-host (GVH) or runt disease within 40 days, many of them giving evidence of being tolerant of Lewis grafts. The mothers, too, developed chronic GVH disease. The offspring of Fischer females made chimeric with cells from (Fischer x Lewis)F(1) hybrid donors, as well as their mothers, remained healthy. Intraperitoneal injection of normal Fischer females, in the 15th-17th day of pregnancy, with 100 million lymphoid cells from specifically sensitized Lewis rats, also caused fatal runt disease to develop in about 50% of their offspring, but left the mothers unscathed. Taken together, these various findings indicate that in some genetic contexts at least the extent of the natural surreptitious transplacental cellular traffic can be considerably augmented experimentally, though how this comes about and why lymphocytic cells that are foreign to the mother can apparently gain access to fetuses more readily than her own cells remain to be determined.


Closure of an open drug scene--a case register-based analysis of the impact on the demand for methadone maintenance treatment.
To assess the impact of the closure of an open drug scene on the demand for methadone maintenance treatment (MMT). Interrupted time series analysis of case register-based data of all MMTs performed in the canton of Zurich (Switzerland) between June 16 1992 and July 7 1997. Five private and 14 state-controlled institutions as well as 330 general practitioners, 35 psychiatrists, and 79 other specialists offering outpatient MMT. 5210 opiate users with 9042 MMT episodes. Monthly number of entries into MMT before, during and after the closure of the Letten scene in February 1995, MMT retention rates, participants' socio-demographic and drug-related data. ARIMA modelling revealed 68 (95% CI = 31-105; p < 0.001) additional MMT admissions due to the dispersion of the open drug scene without a decrease in MMT retention rates. Socio-demographic and drug-related characteristics of patients entering MMT in the month of the closure did not significantly differ from other admissions. Law enforcement strategies to eliminate open drug scenes may increase the demand for MMT. Sufficient treatment facilities for opioid dependence should be provided when law enforcement activities against open drug scenes are planned.


Purification of alginate oligosaccharides with root growth-promoting activity toward lettuce.
Sodium alginate was degraded by alginate lyase from Corynebacterium sp., and the product was purified by an ultrafiltration (UF) membrane module. The UF treatment was carried out at a transmembrane pressure of 0.15 MPa and a flow velocity of 0.6 m/s in the cross-flow mode, and non-degraded alginate was almost completely removed. The alginate oligosaccharide obtained was a mixture of di- to octasaccharides and had promoting activity toward lettuce root elongation (about 2-fold compared with the control) in the concentration range of 200-3000 microg/ml. The effect of the degree of polymerization on this activity was examined by using each oligosaccharide fractionated by gel chromatography. The tri-, tetra-, penta- and hexasaccharides were each found to have root growth-promoting activity in a lettuce bioassay.


Determination of growth of Sphaerotilus discophorus in the presence of manganese.
Manganese interferes strongly with most chemical methods of biomass determination. However, the biomass of manganese-encrusted Sphaerotilus discophorus can be determined after removal of the MnO2 with trichloroacetic acid and oxalic acid. Evidence which indicates that manganese inhibits the heterotrophic growth of S. discophorus and that the cells only oxidize manganese late in the growth curve is presented.


Association between glucose-to-lymphocyte ratio and in-hospital mortality in acute myocardial infarction patients.
Inflammation is involved in the development and progression of atherosclerosis. Recent studies indicated that glucose-to-lymphocyte ratio (GLR) level were significantly associated with the risk of mortality from inflammatory diseases, and showed a specific prognostic value. Herein, this study intended to explore the association between GLR level and in-hospital mortality in patients with acute myocardial infarction (AMI), and evaluate the predictive value of GLR on AMI prognosis. Data of patients with AMI were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database in 2012-2019 in this retrospective cohort study. Univariate COX proportional hazard model was used to screen covariates. The associations between GLR and in-hospital mortality were evaluated using univariate and multivariate COX proportional hazard models. Subgroup analysis of age, gender, vasopressor use, SOFA scores, renal replacement therapy, coronary artery bypass graft, and β blockers use were performed. The evaluated index was hazard ratios (HRs) and 95% confidence intervals (CIs). In addition, the predictive performance of GLR, glucose, and lymphocytes on in-hospital mortality was assessed respectively. Among eligible patients, 248 (13.74%) died in the hospital. After adjusting for covariates, we found that a higher GLR level was associated with an increased risk of in-hospital mortality [HR = 1.70, 95%CI: (1.24-2.34)]. This relationship was also found in patients who were male, aged ≥65 years old, did not have renal replacement therapy, coronary artery bypass graft, or β blockers, used vasopressor or not, and whatever the SOFA scores (all P<0.05). Moreover, the predictive performance of GLR on in-hospital mortality seemed superior to that of glucose or lymphocytes. GLR may be a potential predictor for AMI prognosis, which provided some references for identifying and managing high-risk populations early in clinical.


Relationship between marrow perfusion and bone mineral density: a pharmacokinetic study of DCE-MRI.
A reduced bone perfusion has been found for osteoporotic subjects in previous studies. However, the physiological changes underlying the varied perfusion function is not well known yet. Tofts model is one of the most frequently used pharmacokinetic models in analyzing perfusion process. This study modified the Tofts model by replacing the arterial input function (AIF) by a new algorithm. The modified model was then employed to analyze vertebral bone marrow perfusion in subjects with different bone mineral density (BMD). Eighty-two male subjects were involved in this study and classified into three groups (normal, osteopenia, and osteoporosis) according to T-score. BMD was measured by dual-energy X-ray absorptiometry (DXA). The quantitative parameters derived from the pharmacokinetic model, K(trans) (extravasation transfer efficiency for blood perfusion) and v(e) (extravascular extracellular space for blood perfusion), showed a significant reduction in subjects with lower BMD, respectively. The results suggested that with the bone mineral content lost, the vascular wall properties as well as the bone marrow content may also vary. The resultant perfusion change may also influence the bone nutrition supply in reverse.


Combining liquid chromatography with ozone-induced dissociation for the separation and identification of phosphatidylcholine double bond isomers.
Revealing the inherent molecular diversity of lipid biology requires advanced analytical technologies. Distinguishing phospholipids that differ in the position(s) of carbon-carbon double bonds within their acyl chains presents a particular challenge because of their similar chromatographic and mass spectral behaviours. Here-for the first time-we combine reversed-phase liquid chromatography for separation of isomeric phospholipids with on-line mass spectral analysis by ozone-induced dissociation (OzID) for unambiguous double bond position assignment. The customised tandem linear ion-trap mass spectrometer used in our study is capable of acquiring OzID scans on a chromatographic timescale. Resolving the contributions of isomeric lipids that are indistinguishable based on conventional mass spectral analysis is achieved using the combination of liquid chromatography and OzID. Application of this method to the analysis of simple (egg yolk) and more complex (sheep brain) extracts reveals significant populations of the phosphatidylcholine PC 16:0_18:1(n-7) alongside the expected PC 16:0_18:1(n-9) isomer.


Design and Analysis of a Rotational Mixer to produce 3D Bioprinting Gyroid-Helical-Patterned Scaffolds for Tissue Engineering Applications.
Tissue engineering scaffolds require complex networks for nutrient diffusion and cell attachment. They must have specific surface area and curvature, and often need a multimaterial composition, demanding advanced micro-fabrication methods. 3D extrusion bioprinting offers versatility to manufacture different scaffold, and strategies for multimaterial printing have been introduced. We propose a method to fabricate scaffolds based on gyroid-helical-patterned microfibers, providing a platform to study the effect of the gyroid minimum curvature on cellular processes, since the geometry wont be layer-by-layer approximated. The pattern is obtained by mixing inks using a gyroid-helix shaped rotational mixer, modifying the extruder of a conventional 3D printer. The mixer was simulated using computational fluid dynamics tools, varying the volumetric flow to obtain different gyroid-thickness. Due to its surface area minimization, it shows lower energy requirements than state-of-art fluid mixers, with a pressure drop of 1.7%, a power number of 39, and a rotation-induced shear stress of ∼400 Pa, enabling the use of cell-embedded bioinks.


Cross-Modal Distillation to Improve MRI-Based Brain Tumor Segmentation With Missing MRI Sequences.
Convolutional neural networks (CNNs) for brain tumor segmentation are generally developed using complete sets of magnetic resonance imaging (MRI) sequences for both training and inference. As such, these algorithms are not trained for realistic, clinical scenarios where parts of the MRI sequences which were used for training, are missing during inference. To increase clinical applicability, we proposed a cross-modal distillation approach to leverage the availability of multi-sequence MRI data for training and generate an enriched CNN model which uses only single-sequence MRI data for inference but outperforms a single-sequence CNN model. We assessed the performance of the proposed method for whole tumor and tumor core segmentation with multi-sequence MRI data available for training but only T1-weighted ([Formula: see text]) sequence data available for inference, using BraTS 2018, and in-house datasets. Results showed that cross-modal distillation significantly improved the Dice score for both whole tumor and tumor core segmentation when only [Formula: see text] sequence data were available for inference. For the evaluation using the in-house dataset, cross-modal distillation achieved an average Dice score of 79.04% and 69.39% for whole tumor and tumor core segmentation, respectively, while a single-sequence U-Net model using [Formula: see text] sequence data for both training and inference achieved an average Dice score of 73.60% and 62.62%, respectively. These findings confirmed cross-modal distillation as an effective method to increase the potential of single-sequence CNN models such that segmentation performance is less compromised by missing MRI sequences or having only one MRI sequence available for segmentation.


Differentiation of foot-and-mouth disease-infected pigs from vaccinated pigs using antibody-detecting sandwich ELISA.
The presence of serum antibodies for nonstructural proteins of the foot-and-mouth disease virus (FMDV) can differentiate FMDV-infected animals from vaccinated animals. In this study, a sandwich ELISA was developed for rapid detection of the foot-and-mouth disease (FMD) antibodies; it was based on an Escherichia coli-expressed, highly conserved region of the 3ABC nonstructural protein of the FMDV O/TW/99 strain and a monoclonal antibody derived from the expressed protein. The diagnostic sensitivity of the assay was 98.4%, and the diagnostic specificity was 100% for naïve and vaccinated pigs; the detection ability of the assay was comparable those of the PrioCHECK and UBI kits. There was 97.5, 93.4 and 66.6% agreement between the results obtained from our ELISA and those obtained from the PrioCHECK, UBI and CHEKIT kits, respectively. The kappa statistics were 0.95, 0.87 and 0.37, respectively. Moreover, antibodies for nonstructural proteins of the serotypes A, C, Asia 1, SAT 1, SAT 2 and SAT 3 were also detected in bovine sera. Furthermore, the absence of cross-reactions generated by different antibody titers against the swine vesicular disease virus and vesicular stomatitis virus (VSV) was also highlighted in this assay's specificity.


Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial.
Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia. In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 μmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing. Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64. Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. Ultragenyx Pharmaceutical and Kyowa Kirin International.


Printed Large-Area Single-Mode Photonic Crystal Bandedge Surface-Emitting Lasers on Silicon.
We report here an optically pumped hybrid III-V/Si photoic crystal surface emitting laser (PCSEL), consisting of a heterogeneously integrated III-V InGaAsP quantum well heterostructure gain medium, printed on a patterned defect-free Si photonic crystal (PC) bandedge cavity. Single mode lasing was achieved for a large area laser, with a side-mode suppression ratio of 28 dB, for lasing operation temperature ~ 200 K. Two types of lasers were demonstrated operating at different temperatures. Detailed modal analysis reveals the lasing mode matches with the estimated lasing gain threshold conditions. Our demonstration promises a hybrid laser sources on Si towards three-dimensional (3D) integrated Si photonics for on-chip wavelength-division multiplex (3D WDM) systems for a wide range of volume photonic/electronic applications in computing, communication, sensing, imaging, etc.


Golgi sulfation of the oligosaccharide chain of P0 occurs in the presence of myelin assembly but not in its absence.
To decipher the intracellular targeting mechanism by which the major glycoprotein of peripheral nerve myelin, P0, is delivered to myelin after crush injury, as well as to the lysosome after permanent transection injury of the sciatic nerve--experimental paradigms characterized by the presence and absence of axonal regeneration and subsequent myelin assembly, respectively--the role of sulfation of P0 was investigated. P0 sulfation is shown to occur within the Golgi apparatus as a post-translational modification of the oligosaccharide chain which is dependent on processing beyond the action of mannosidase I. It is associated with myelination as observed during development and after crush injury, but does not occur after transection injury, even in the presence of the mannosidase II inhibitor, swainsonine, or the lysosomotrophic agent, L-methionine methyl ester. Although P0 accumulation can be demonstrated with both agents when other precursors are used (e.g. fucose, mannose, amino acids) and indicates lysosomal targeting and delivery of P0 after the action of GlcNAc transferase I, the absence of P0 sulfation after transection suggests that the lack of this modification may result in a default mechanism for lysosomal targeting after nerve transection. Lysosomal degradation of P0 was evaluated after crush injury by pulse-chase analyses with 35SO4 and [3H] mannose in the presence and absence of chlorate, an inhibitor of ATP-sulfarylase. Although P0 sulfation of the oligosaccharide chain is a stable modification whose labeling is dramatically inhibited by chlorate, no decrease in mannose-labeled P0 was seen with chlorate even with prolonged chase times. Because of this lack of degradation of mannose-labeled P0 in the presence of chlorate in the crushed nerve, it is concluded that the absence of P0 sulfation does not result in a default mechanism for lysosomal delivery.


Vitamin D deficiency, interleukin 17, and vascular function in rheumatoid arthritis.
Vitamin D deficiency is associated with increased cardiovascular (CV) disease risk in the general population. We examined the association between vitamin D deficiency and CV risk in rheumatoid arthritis (RA). We measured large artery compliance by pulse wave velocity and microvascular function by the reactive hyperemia index in patients with stable RA (n = 87). We quantified CV risk factors, serum 25-hydroxyvitamin D [25(OH)D], and interleukin 17 (IL-17), and RA disease activity by Disease Activity Score of 28 joints. We used linear regression to test associations between serum 25(OH)D and CV risk factors. The mean serum 25(OH)D level in the cohort was 27.1 ± SD 13.6 ng/ml. Fifty-nine patients (68%) were vitamin D-insufficient (25(OH)D < 30 ng/ml; mean 20.2 ± 5.9 ng/ml) and of these, 25 (29%) were vitamin D-deficient (25(OH)D < 20 ng/ml; mean 14.4 ± 3.4 ng/ml). In the whole cohort and the vitamin D-insufficient group, serum 25(OH)D was inversely associated with IL-17 (log IL-17; β = -0.83, p = 0.04; β = -0.63, p = 0.004, respectively) by univariate analysis, which persisted after adjustment for season, and in multivariate analysis after adjustment for confounders (log IL-17; β = -0.74, p = 0.04; β = -0.53, p = 0.02). In vitamin D-deficient patients, serum 25(OH)D was positively associated with microvascular function by univariate and multivariate analysis after adjustment for confounders (β = 2.1, p = 0.04; β = 2.7, p = 0.04). Vitamin D deficiency in RA may affect Th17 responses and microvascular function. Maintaining normal serum vitamin D levels may protect against IL-17-mediated inflammation and vascular dysfunction in RA.


Commentary: Important design features to consider in observational research on the long-term outcomes of ADHD - reflections on Sibley et al. (2017) and Swanson et al. (2017).
In this issue of the Journal, Sibley et al. (2017) presented some important insights into how different assessment approaches influence the apparent persistence of ADHD into adulthood, while Swanson et al. (2017) presented interesting results regarding the long-term benefits (adult symptom reduction) and costs (adult height suppression) associated with the treatment of ADHD with stimulant medication. This commentary highlights that (a) future studies that attempt to explore the occurrence and predictors of persisting and remitting developmental trajectories of ADHD, as well as late-onset ADHD, need to be based on thorough assessment of ADHD in adulthood using a combination of self-ratings and other informants (parents), and that (b) observational studies of the long-term benefits and risk associated with ADHD medications will play an important role in future research and clinical guidelines.


The Toll/IL-1 receptor binding protein MyD88 is required for Xenopus axis formation.
The Toll/Dorsal pathway regulates dorsoventral axis formation in the Drosophila embryo. We had previously obtained evidence that a homologous pathway exists in Xenopus, however, its role during normal frog development had not been established. Here we report the cloning of Xenopus MyD88 (XMyD88), whose mammalian homologs are adaptor proteins linking Toll/IL-1 receptors and IRAK kinases. We show that in the frog embryo overexpression of a dominant-negative form of XMyD88 blocked Toll receptor activity, specifically inhibited axis formation and reduced expression of pivotal organizer genes. The observed stage-dependency of interference suggests a function for maternal XMyD88 soon after fertilization. We conclude that XMyD88 activity is required for normal Spemann organizer formation, implying an essential role for maternal Toll/IL-1 receptors in Xenopus axis formation.


Scale-up and intensification of (S)-1-(2-chlorophenyl)ethanol bioproduction: economic evaluation of whole cell-catalyzed reduction of o-chloroacetophenone.
Escherichia coli cells co-expressing genes coding for Candida tenuis xylose reductase and Candida boidinii formate dehydrogenase were used for the bioreduction of o-chloroacetophenone with in situ coenzyme recycling. The product, (S)-1-(2-chlorophenyl)ethanol, is a key chiral intermediate in the synthesis of polo-like kinase 1 inhibitors, a new class of chemotherapeutic drugs. Production of the alcohol in multi-gram scale requires intensification and scale-up of the biocatalyst production, biotransformation, and downstream processing. Cell cultivation in a 6.9-L bioreactor led to a more than tenfold increase in cell concentration compared to shaken flask cultivation. The resultant cells were used in conversions of 300 mM substrate to (S)-1-(2-chlorophenyl)ethanol (e.e. >99.9%) in high yield (96%). Results obtained in a reaction volume of 500 mL were identical to biotransformations carried out in 1 mL (analytical) and 15 mL (preparative) scale. Optimization of product isolation based on hexane extraction yielded 86% isolated product. Biotransformation and extraction were accomplished in a stirred tank reactor equipped with pH and temperature control. The developed process lowered production costs by 80% and enabled (S)-1-(2-chlorophenyl)ethanol production within previously defined economic boundaries. A simple and efficient way to synthesize (S)-1-(2-chlorophenyl)ethanol in an isolated amount of 20 g product per reaction batch was demonstrated.


Cyclic-AMP-dependent proliferation of a human osteoblast cell line (HOS cells) induced by hydroxyapatite: effect of exogenous nitric oxide.
BACKGROUND AND AIMS OF THE WORK: Nitric oxide (NO) has been reported to enhance the production of cAMP by hydroxyapatite (HA)-induced a human osteoblast cell line (HOS cells). The aim of the present study was to test the hypothesis that exogenous NO may up-regulate the proliferation of hydroxyapatite (HA)-induced HOS cells via the cyclic-AMP-protein kinase A (PKA) pathway. HOS cells were pre-incubated with ODQ (guanylyl cyclase inhibitor), SQ22536 (adenylyl cyclase inhibitor), forskolin (adenylyl cyclase activator), IBMX [phosphodiesterase (PDE) inhibitor], siguazodan (PDE3 inhibitor), rolipram (PDE4 inhibitor), or KT5720 (PKA inhibitor), and then, cultured on the surface of HA with or without the presence of SNAP (NO donor). The HOS cell cultures on the HA surface were added with br-cGMP (cGMP analogue), db-cAMP (cAMP analogue) with or without SNAP. The cell proliferation was assessed by a colorimetric assay. The up-regulatory effect of SNAP on HA-induced HOS cell proliferation was suppressed by SQ22536 and KT5720, but enhanced by db-cAMP, IBMX, and rolipram. The HA-induced HOS cell proliferation with or without the presence of SNAP was unaltered by ODQ br-cGMP and siguazodan. These results suggest, therefore, that HA-induced HOS cell proliferation may be mediated by the cAMP-PKA pathway regulated by PDE4 and that exogenous NO may amplify this cyclic nucleotide pathway, thereby augmenting HA-induced HOS cell proliferation.


A simple microfluidic method to select, isolate, and manipulate single-cells in mechanical and biochemical assays.
This article describes a simple and low-tech microfluidic method for single-cell experimentation, which permits cell selection without stress, cell manipulation with fine control, and passive self-exclusion of all undesired super-micronic particles. The method requires only conventional soft lithography microfabrication techniques and is applicable to any microfluidic single-cell circuitry. The principle relies on a bypass plugged in parallel with a single-cell assay device and collecting 97% of the flow rate. Cell selection into the single cell device is performed by moving the cell of interest back and forth in the vicinity of the junction between the bypass and the analysis circuitry. Cell navigation is finely controlled by hydrostatic pressure via centimetre-scale actuation of external macroscopic reservoirs connected to the device. We provide successful examples of biomechanical and biochemical assays on living human leukocytes passing through 4 mum wide capillaries. The blebbing process dynamics are monitored by conventional 24 fps videomicroscopy and subcellular cytoskeleton organization is imaged by on-chip immunostaining.


Understanding and Preventing Attacks on Health Facilities During Armed Conflict in Syria.
Despite healthcare facilities being deemed untouchable in times of conflict, the war in Syria has seen its government as well as opposition forces, target their people and infrastructure as a strategy of war. Violations of medical neutrality and International Humanitarian Law has led to the loss of countless medical personnel, civilians and health care facilities; setting the country back to health levels last seen thirty years ago. It is evident through the strategy of the Syrian and Russian government that healthcare facilities are being deliberately targeted with humanitarian organisations condemning all parties involved for violating the Geneva Conventions. The report examines the impact of the conflict in Syria on its health facilities and looks at the reasons why these services are under attack and the international response to the conflict. The report concludes by looking into plans currently implemented to protect our healthcare infrastructure during times of war whilst comparing it to past strategies. A literature review was conducted for the study with information and data collected through several search engines including Google Scholar, PubMed, MEDLINE, OVID and searches through Google. The keywords mapped to find relevant literature includes "Syria", "healthcare", "health care worker", "humanitarian aid", and "volunteer", "International Humanitarian Law", "Geneva Convention". The majority of the data used was adapted from Physicians for Human Rights (PHR) and the World Health Organisation (WHO). Limitations included using sources written in English due to limited resources to translate literature in Arabic. The conflict in Syria and deliberate targeting of healthcare facilities has left services decimated with an estimated 782 medical personnel killed during this time; doctors accounting for 32% of total deaths in the five years. Several facilities are also operating at 1% or less functionality. The results and review highlight the need for protection of health facilities from humanitarian violations as health care continues to be targeted as a strategy of war. The number of attacks has steadily remained constant throughout the years and nothing seems to be done in bringing perpetrators to justice for violations of International Humanitarian Law. The paper calls for more public attention to shed light on the atrocities being committed and further inquiries like the preliminary carried out by The Lancet - American University of Beirut.


Inequalities in hip fracture incidence are greatest in the North of England: regional analysis of the effects of social deprivation on hip fracture incidence across England.
Hip fracture risk varies by geography and by levels of deprivation. We examined the effect of local area-level deprivation on hip fracture incidence across nine regions in England, using 14 years of hospital data, to determine whether inequalities in hip fracture incidence rates vary across geographic regions in England. Sequential annual cross-sectional studies over 14 years. We used English Hospital Episodes Statistics (2001/02-2014/15) to identify hip fractures in adults aged 50+ years and mid-year population estimates (2001-2014) from the Office for National Statistics. The Index of Multiple Deprivation was used to measure local area deprivation. We calculated age-standardised hip fracture incidence rates per 100,000 population, stratified by gender, geographic region, deprivation quintiles and time-period, using the 2001 English population as the reference population. Using Poisson regression, we calculated age-adjusted incidence rate ratios (IRRs) for hip fracture, stratified as above. Over 14 years, we identified 747,369 hospital admissions with an index hip fracture. Age-standardised hip fracture incidence was highest in the North East for both men and women. In North England (North East, North West and Yorkshire and the Humber), hip fracture incidence was relatively higher in more deprived areas, particularly among men: IRR most vs least deprived quintile 2.06 (95% confidence interval [CI] = 2.00-2.12) in men, 1.62 (95% CI 1.60-1.65) in women. A relationship, albeit less marked, between deprivation and hip fracture incidence was observed among men in the Midlands and South, but with no clear pattern among women. Regional variation in hip fracture incidence exists across England, with the greatest absolute burden of incident hip fractures observed in the North East for both men and women. Across local areas in North England, absolute and relative inequalities in hip fracture incidence were greater than in other regions. Our findings highlight the need for improved fracture prevention programmes that aim to reduce regional and social inequalities in hip fracture incidence.


Targeted genome regulation via synthetic programmable transcriptional regulators.
Regulation of gene transcription controls cellular functions and coordinates responses to developmental, physiological and environmental cues. Precise and efficient molecular tools are needed to characterize the functions of single and multiple genes in linear and interacting pathways in a native context. Modular DNA-binding domains from zinc fingers (ZFs) and transcriptional activator-like proteins (TALE) are amenable to bioengineering to bind DNA target sequences of interest. As a result, ZF and TALE proteins were used to develop synthetic programmable transcription factors. However, these systems are limited by the requirement to re-engineer proteins for each new target sequence. The clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR associated 9 (Cas9) genome editing tool was recently repurposed for targeted transcriptional regulation by inactivation of the nuclease activity of Cas9. Due to the facile engineering, simplicity, precision and amenability to library construction, the CRISPR/Cas9 system is poised to revolutionize the functional genomics field across diverse eukaryotic species. In this review, we discuss the development of synthetic customizable transcriptional regulators and provide insights into their current and potential applications, with special emphasis on plant systems, in characterization of gene functions, elucidation of molecular mechanisms and their biotechnological applications.