Steady-state kinetics of horse-liver alcohol dehydrogenase with a covalently bound coenzyme analogue.
The steady-state kinetics of the enzyme modified by affinity labelling with NAD analogue, nicotinamide-N6-[N-(6-aminohexyl)carbamoylmethyl]-adenine dinucleotide, has been investigated using a recycling reaction with p-nitrosodimethylaniline and n-butanol as substrates and compared to the kinetics of native alcohol dehydrogenase. The modified enzyme obeys a ping-pong mechanism involving two inactive enzyme forms (enzyme-NAD and enzyme-NADH complexes in the 'open' conformations, the nicotinamide moieties of the coenzymes being out of the active center). The rate of p-nitrosodimethylaniline reduction in the reaction catalyzed by the modified enzyme is comparable to that observed in the presence of the native enzyme. On the other hand, the oxidation of butanol by the modified enzyme is essentially slower under our experimental conditions (pH 8.5). The measurements in the presence of specific alcohol dehydrogenase inhibitors competing with substrates and coenzymes (isobutyramide, pyrazole and AMP) revealed that the relative portion of the inactive 'open' form of the enzyme-NADH complex is negligible, whereas the 'open' form of the enzyme-NAD complex seems to represent a more significant portion (about 30%) under the conditions used.


Staphylococcus aureus-induced proteomic changes in the mammary tissue of rats: A TMT-based study.
Staphylococcus aureus is one of the most important pathogens causing mastitis in dairy cows. The objective of this study was to establish a rat model of mastitis induced by S. aureus infection and to explore changes in the proteomes of mammary tissue in different udder states, providing a better understanding of the host immune response to S. aureus mastitis. On day 3 post-partum, 6 rats were randomly divided into two groups (n = 3), with either 100 μL of PBS (blank group) or a S. aureus suspension containing 2×107 CFU·mL-1 (challenge group) infused into the mammary gland duct. After 24 h of infection, the rats were sacrificed, and mammary gland tissue was collected. Tandem mass tag (TMT)-based technology was applied to compare the proteomes of healthy and mastitic mammary tissues. Compared with the control group, the challenge group had 555 proteins with significant differences in expression, of which 428 were significantly upregulated (FC>1.2 and p<0.05) and 127 were downregulated (FC>0.83 and p<0.05 or p<0.01). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that upregulated differentially significant expressed proteins (DSEPs) were associated with mainly immune responses, including integrin alpha M, inter-α-trypsin inhibitor heavy chain 4, and alpha-2-macroglobulin. This study is the first in which a rat model of S. aureus-induced mastitis was used to explore the proteins related to mastitis in dairy cows by TMT technology, providing a model for replication of dairy cow S. aureus-induced mastitis experiments.


Turner syndrome: evaluation of prenatal diagnosis in 19 European registries.
This study evaluated the prenatal diagnosis of Turner syndrome by ultrasound examination in an unselected population from all over Europe. Data from 19 congenital malformation registries from 11 European countries were analyzed. Turner syndrome was diagnosed in 125 cases (7.2%) in a total of 1,738 chromosome abnormalities. Sixty-seven percent of cases were detected prenatally by ultrasound examination due to the presence of congenital defects. The most frequent anomalies were cystic hygroma (59.5%) and hydrops fetalis (19%). The most frequent karyotype was 45,X (81.6%) followed by different types of mosaicism (16.8%). Significant differences in congenital defects (P = 0.0003) were observed between 45,X karyotypes and 45,X mosaicism cases. Prenatal counseling for 45,X mosaicism should take into account the expectation of a milder phenotype. In 78.6% of cases diagnosed by ultrasound examination due to congenital anomalies, the pregnancy was terminated. Prenatal detection of Turner syndrome by ultrasound examination was high in this unselected population.


CAD/CAM and rapid prototyped titanium for reconstruction of ramus defect and condylar fracture caused by mandibular reduction.
Fracture or defect of the mandible is a serious complication of mandibular angleplasty, and precise reconstruction for such defect is still a huge challenge. This case report provides a new method based on CAD/CAM and rapid prototyped titanium for individual design, fabrication, and implantation of a mandibular ramus and angle. A 25-year-old woman with a square-shaped face, who had undergone mandibular outer cortex split ostectomy (MOCSO) 3 months earlier, was afflicted by a series of symptoms: asymmetric face, collapse of the right face, masticatory problems, deviation during mouth opening, malocclusion, and TMJ clicks. These symptoms were caused by unintentional removal of the fractured ramus during MOCSO. By means of CT scan data, rapid prototyping, reverse engineering, 3D display, and CAD/CAM, the individualized titanium implant was designed and fabricated. The 3D demo system of operative scheme demonstrated the operative procedure, and determined the position of the implant so as to obtain a perfect fit. Postoperatively, the patient regained satisfactory morphologic symmetry, facial appearance, occlusion, and TMJ functions.


Is the survival of melanoma patients receiving polyvalent melanoma cell vaccine linked to the human leukocyte antigen phenotype of patients?
An allogeneic polyvalent melanoma cell vaccine (PMCV) has been shown to be efficacious in improving overall survival of patients with malignant melanoma in a phase II clinical setting. The PMCV consists of three allogeneic melanoma cell lines. The objectives of the study were to determine (1) whether the survival of melanoma patients who received PMCV was related to the patient's human leukocyte antigen (HLA) class I phenotype matching the HLA class I phenotype of the PMCV, and (2) whether PMCV clinical efficacy was correlated to melanoma patients with a particular HLA phenotype(s). PMCV was given to 69 melanoma patients with American Joint Committee on Cancer (AJCC) stage I to IV disease status. The PMCV and patients lymphocytes were typed for HLA-A and -B. A correlation was made between the HLA expression of PMCV lines and the HLA of patients to their survival status. A second correlation was made between the HLA of patients and survival independent of the PMCV HLA phenotype. Patients whose HLA phenotype (A3/11 and B7/44) matched the PMCV lines had a better overall survival (P < .029). Analysis of HLA expression of patients independent of PMCV HLA to survival showed that HLA-A25 phenotype patients had a significantly better overall survival (P = .006). HLA-B35 patients had a poorer survival outcome (P = .019). The studies indicate that overall survival following PMCV treatment in melanoma patients significantly correlates with their HLA phenotypes. These correlations may be related to the host immune response to the PMCV or due to differences in the clinical course of melanoma in patients with different HLA types.


Statics and dynamics of the wormlike bundle model.
Bundles of filamentous polymers are primary structural components of a broad range of cytoskeletal structures, and their mechanical properties play key roles in cellular functions ranging from locomotion to mechanotransduction and fertilization. We give a detailed derivation of a wormlike bundle model as a generic description for the statics and dynamics of polymer bundles consisting of semiflexible polymers interconnected by crosslinking agents. The elastic degrees of freedom include bending as well as twist deformations of the filaments and shear deformation of the crosslinks. We show that a competition between the elastic properties of the filaments and those of the crosslinks leads to renormalized effective bend and twist rigidities that become mode-number dependent. The strength and character of this dependence is found to vary with bundle architecture, such as the arrangement of filaments in the cross section and pretwist. We discuss two paradigmatic cases of bundle architecture, a uniform arrangement of filaments as found in F -actin bundles and a shell-like architecture as characteristic for microtubules. Each architecture is found to have its own universal ratio of maximal to minimal bending rigidity, independent of the specific type of crosslink-induced filament coupling; our predictions are in reasonable agreement with available experimental data for microtubules. Moreover, we analyze the predictions of the wormlike bundle model for experimental observables such as the tangent-tangent correlation function and dynamic response and correlation functions. Finally, we analyze the effect of pretwist (helicity) on the mechanical properties of bundles. We predict that microtubules with different number of protofilaments should have distinct variations in their effective bending rigidity.


Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients.
Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain. Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period. Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001). OTFC appears effective in the treatment of cancer-related breakthrough pain.


CD169-dependent cell-associated HIV-1 transmission: a driver of virus dissemination.
Sexual transmission of human immunodeficiency virus type 1 (HIV-1) occurs across mucosal surfaces of the genital and gastrointestinal tracts and accounts for the vast majority of newly acquired infections worldwide. In the absence of an effective vaccine, interventional strategies such as microbicides that target viral attachment and entry into mucosa-resident target cells are particularly attractive and might have the greatest impact on reducing the HIV-1 pandemic. Rational development of microbicides would be greatly aided with a better understanding of several key questions of mucosal HIV-1 transmission, including the molecular mechanism(s) of how HIV-1 traverses mucosal barriers, the type of cells that it initially infects to gain a foothold in the naive host, and how it is disseminated from local sites of infection to draining lymph nodes. In this review, we discuss the role of myeloid dendritic cells (DCs) in cell-associated HIV-1 transmission and in facilitating systemic HIV-1 dissemination. We will evaluate the role of CD169 as a DC-associated HIV-1 attachment factor, investigate the molecular mechanisms by which HIV-1 particles are transferred from DCs to CD4(+) T cells across virological synapses, and provide arguments for inclusion of molecules in microbicides that can effectively target HIV-1 attachment to DCs and DC-mediated virus transfer.


Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation.
Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.


Effect of transesophageal echocardiography probe on tracheal perfusion pressure and ventilatory parameters in pediatric patients undergoing cardiac surgery using cardiopulmonary bypass: A prospective observational study.
Overinflation of cuffed endotracheal tubes and transesophageal echocardiography (TEE) probe causes increased intracuff pressure (CP) compromising tracheal perfusion pressure (TPP). Primary objective of the study was to assess CP, TPP on TEE probe insertion and examination during pediatric cardiac surgeries. Secondary objectives were to evaluate the effect of the probe on peak airway pressures (Ppeak), mean airway pressures (Pmean) and to monitor CP, TPP on cardiopulmonary bypass (CPB). This prospective observational study included fifty patients, aged 1-5 years undergoing cardiac surgeries using CPB. Following induction, TEE probe was introduced. CP, TPP, Ppeak, Pmean were measured before insertion of TEE probe (T1), during probe insertion (T2) and examination at mid-esophageal (T3), transgastric level (T4), and on removing probe (T6). CP, TPP were monitored on CPB (T5). Statistical analysis was done using paired t-test. CP, Ppeak and Pmean increased significantly, while TPP decreased significantly from T1 to T2, T3, T4 (P < 0.001). CP, TPP decreased significantly at T5 in comparison to T6 (P < 0.001). In 48% of the patients CP increased above 30 cm H2O at T2. TEE probe causes an increase in CP and decreases TPP. Constant monitoring and maintaining CP, TPP in optimum range is recommended.


The roles of soluble osteopontin using osteopontin-transgenic mice in vivo: proliferation of CD4+ T lymphocytes and the enhancement of cell-mediated immune responses.
We generated transgenic mice expressing osteopontin (OPN) under the control of the alpha(1)-antitrypsin promoter. These mice (OPN-T mice) expressed OPN mRNA in liver and kidney, and released a large amount of plasma OPN, which increased after stimulation with turpentine oil. Before sensitization, the number of CD4+ T cells in lymph nodes was significantly higher in OPN-T than nontransgenic mice, and that in spleen was slightly higher, whereas that of CD8+ T cells was no different between OPN-T and nontransgenic mice. After sensitization, the CD4+ T cell numbers in spleen increased significantly, while there were almost no changes in the CD8+ T cells in lymph nodes and spleen. The intensity of contact hypersensitivity responses to 2,4-dinitrofluorobenzene (DNFB) was obviously enhanced in OPN-T mice. In the delayed-type hypersensitivity (DTH) model elicited by DNFB, the number of CD8+ T cells among DNFB-2,4,6-trinitrobenzenesulfonic acid (TNBS)-peritoneal exudate cells was significantly higher in OPN-T than nontransgenic mice, while there was almost no difference in that of CD4+ T cells. Adoptive transfer experiments revealed that the enhanced reactivity is carried by CD4+ and CD8+ T cells, respectively, although the ability of transferring DTH was significantly lower in CD8+ than in CD4+ T cells. The enhancement of CD8+ T cell migration was observed in OPN-T mice. These results suggest that OPN induces a proliferation of effector CD4+ and CD8+ cells in cell-mediated reactions and plays a role in the migration of CD8+ T cells.


Cognitive-Motivational Influences on Health Behavior Change in Adults with Chronic Pain.
The primary aim was to assess the psychological factors that influence engagement in health behaviors in individuals with chronic pain using a new measure, the Behavioral Engagement Test for Chronic Pain (BET-CP). A secondary aim was to determine preliminary psychometric properties of the BET-CP. Participants were 86 adults with chronic musculoskeletal pain recruited from University of Florida pain clinics and the community. Participants completed a battery of self-report instruments online, including the BET-CP and measures of related constructs. Items on the BET-CP assessed motivation, self-efficacy, outcome expectations, and the symptom benefit required to engage across four health behaviors: exercise, diet, sleep, and pain self-management (e.g., relaxation and activity pacing). Participants reported modest expectations of pain-related symptom improvement if they practiced the health behaviors (22-26% improvement), but they required twice that (47-54% improvement) to make it worth their while to commit to practicing them. Participants expected to get the most symptom relief from relaxation and activity pacing, but they were most confident and motivated to eat a healthy diet. In a subsample of participants who provided data for psychometric analysis, the BET-CP demonstrated strong test-retest reliability across 7 days and adequate convergent validity. While patients with musculoskeletal pain have outcome expectancies that are nearly in line with research on behavioral pain treatments, their stringent requirements for symptom benefit may impede engagement in the health behaviors recommended for their pain-related symptoms. Additional psychometric study with larger sample sizes is needed to further validate the BET-CP.


The reduction of heat production in exercising pigeons after L-carnitine supplementation.
Four groups (CS,CR,PS,PR) of nine trained male racing pigeons were deprived of feed for 1 d and then subjected to a respiration chamber test in order to study the effect of oral 1-carnitine supplementation on the energy metabolism during flight. One week before, groups CS and CR were orally supplemented with 90 mg of 1-carnitine daily, whereas PS and PR were given a placebo. Groups CS and PS underwent flight simulation by electrostimulation of the breast muscles. Flight simulation increased heat production, kept respiratory quotient from decreasing, decreased thyroxine levels, and increased weight loss. L-Carnitine decreased the rise in heat production during electrostimulation but did not influence respiratory quotient, weight loss, or thyroid hormones. L-Carnitine supplementation in pigeons improves fatty acid combustion efficiency during heavy exercise.


Hypnotherapy to Reduce Hot Flashes: Examination of Response Expectancies as a Mediator of Outcomes.
The mechanism of action responsible for hypnotherapy's effect in reducing hot flashes is not yet known. The purpose of this study was to examine the role of response expectancies as a potential mediator. Hypnotizability was also tested as an effect moderator. Data were collected from a sample of 172 postmenopausal women, who had been randomized to receive either a 5-week hypnosis intervention or structured attention counseling. Measures of response expectancies were analyzed to determine if the relationship between group assignment and hot flashes frequency was mediated by expectancies for treatment efficacy. A series of simple mediation and conditional process analyses did not support mediation of the relationship between treatment condition and hot flash frequency through response expectancy. The effect of hypnotherapy in reducing hot flashes does not appear to be due to placebo effects as determined by response expectancies. Implications for clinical practice and future research are discussed.


Introduction of a population-based vascular registry: validity of data and limitations of registration. The Finnvasc Study Group.
A study was performed to assess the validity of the data in a nationwide vascular registry, Finnvasc, initiated in 1991. Data recorded during the first year were of 3507 procedures (immediate reoperations were excluded); 2436 (69 per cent) were surgical and 1071 (31 per cent) endovascular in nature. The Finnvasc data were compared with 2325 hospital records and re-registration of a random sample of 233 patients treated during October 1991 in nine centres was also carried out. In all, 21 per cent of patients from hospitals participating in Finnvasc were not registered and so it was calculated that about 4500 vascular procedures, 3125 surgical and 1375 endovascular, were performed in Finland in 1991. This represents an average of 900,625 and 275 procedures per million population per year respectively. The non-registration rate in October was 17 per cent. Apart from operation classification, and function and patency at 1 month, all simple binary and code data at re-registration were in agreement in at least 92 per cent of cases; checklist and numerical data did not show such good conformity. During the first year of the registry many data were either missing or inadequately recorded, emphasizing the need for cross-validation and re-registration of a random sample of cases. Furthermore, the non-uniformity of coding between hospital records and the Finnvasc registry illustrated deficiencies in the current coding system.


A Synthetically Generated LFeIVOH n Complex.
High-valent Fe-OH species are important intermediates in hydroxylation chemistry. Such complexes have been implicated in mechanisms of oxygen-activating enzymes and have thus far been observed in Compound II of sulfur-ligated heme enzymes like cytochrome P450. Attempts to synthetically model such species have thus far seen relatively little success. Here, the first synthetic FeIVOH n complex has been generated and spectroscopically characterized as either [LFeIVOH]- or [LFeIVOH2]0, where H4L = Me4C2(NHCOCMe2NHCO)2CMe2 is a variant of a tetra-amido macrocyclic ligand (TAML). The steric bulk provided by the replacement of the aryl group with the -CMe2CMe2- unit in this TAML variant prevents dimerization in all oxidation states over a wide pH range, thus allowing the generation of FeIVOH n in near quantitative yield from oxidation of the [LFeIIIOH2]- precursor.


Successful treatment of stage III hidradenitis suppurativa with botulinum toxin A.
A 41-year-old obese Native American woman presented with hidradenitis suppurativa (HS) after failing all available treatment options. Her HS was more pronounced in the axillary and groin regions (Hurley stage III) and was a major source of her pain and a barrier for home exercise and aquatic therapy. She received a botulinum toxin A injection every 3 months (four times thus far), which has significantly helped alleviate her pain and curb the progress of her HS by resolving abscesses and healing draining sinuses.


Carcinogenic Liver Fluke and Others Contaminated in Pickled Fish of Northeastern Thailand
Twenty provinces in northeastern Thailand were investigated for fluke metacercariae contamination in pickled fish, or pla-som, during January –June 2016. A total of 129 pickled fish shops were randomly chosen. Samples were digested with acid-pepsin and those found to be infected with metacercariae were fed to hamsters to test for metacercariae infectivity. The results demonstrated that only 20.2% of the pla-som samples were infected with fluke metacercariae (mc), at various levels (1 to 268 mc/kg). All recovered fluke metacercariae were inactive, degenerated and could not develop to adults in the animal model. In conclusion, the fluke mc infection status in pla-som was correlated with the prevalence of fluke infection in this region known for high O.viverrini and cholangiocarcinoma development. Clearly, systematic control of the fluke life cycle is needed. Whether pickling is an effective preventive measure needs further assessment.


Effects of rumen-undegradable protein and feed intake on nitrogen balance and milk protein production in dairy cows.
An experiment was designed to determine the response of milk protein production and N utilization in dairy cows to supplementation of a predominantly rumen-undegradable protein (RUP) mixture with a fixed amino acid (AA) pattern and the response to the amount of feed intake. The experiment was designed as a 6 x 6 Latin square with a 3 x 2 factorial arrangement of treatments. The factors were three concentrations of RUP supplement (4.5, 14.9, and 29.1% of dry matter intake) and two levels of feed intake restriction (10 and 20%) of the basal diet. The supplement was designed to approximate a postruminal AA pattern that was similar to bovine caseins for Met, Lys, Phe, His, and Thr. Measurements were made during the last 5 d of each 21-d period. Milk protein production responded linearly as the concentration of RUP supplement in the treatment diet increased within the given range. The difference in feed intake restriction did not affect milk protein production. Efficiency of N utilization for milk production exceeded 30% for cows fed the lowest RUP supplement. Results indicated that there is an opportunity to increase milk protein production by using RUP formulations that are balanced for AA while minimizing waste N excretion.


Body mass index and distribution of body fat can influence sensory detection and pain sensitivity.
The aim of this study was to investigate the influence of body fat percentage and its distribution on sensory detection and pain sensitivity responses to experimentally induced noxious stimuli in otherwise pain-free individuals. Seventy-two participants were divided into three equal groups according to their body mass index (BMI: normal, overweight and obese). Percentage body fat was estimated using a four-site skinfold method. Measurements of cold pressor pain threshold, tolerance and intensity; contact thermal sensory detection and heat pain threshold and tolerance (TSA-II - NeuroSensory Analyzer, Medoc); and blunt pressure pain threshold (algometer, Somedic SenseLab AB) were taken at the waist and thenar eminence. Mean ± SD pressure pain threshold of the obese group (620.72 ± 423.81 kPa) was significantly lower than normal (1154.70 ± 847.18 kPa) and overweight (1285.14 ± 998.89 kPa) groups. Repeated measures ANOVA found significant effects for site for cold detection threshold (F1,68 = 8.3, p = 0.005) and warm detection threshold (F1,68 = 38.69, p = 0.001) with waist having lower sensory detection thresholds than thenar eminence. For heat pain threshold, there were significant effects for site (F1,68 = 4.868, p = 0.031) which was lower for waist compared with thenar eminence (mean difference = 0.89 °C). Obese individuals were more sensitive than non-obese individuals to pressure pain but not to thermal pain. Body sites may vary in their response to different types and intensities of stimuli. The inconsistency of findings within and between research studies should catalyse further research in this field. This study provided evidence that body mass index and distribution of body fat can influence sensory detection and pain sensitivity. Obese individuals were more sensitive than normal range body mass index individuals to pressure pain but not to thermal pain. Pain response varied according to subcutaneous body fat at different body sites. These findings strengthen arguments that weight loss should be a significant aspect of a pain management programme for obese pain patients.


Metastatic State of Cancer Cells May Be Indicated by Adhesion Strength.
Cancer cells within a tumor are heterogeneous and only a small fraction are able to form secondary tumors. Universal biological markers that clearly identify potentially metastatic cells are limited, which complicates isolation and further study. However, using physical rather than biological characteristics, we have identified Mg2+- and Ca2+-mediated differences in adhesion strength between metastatic and nonmetastatic mammary epithelial cell lines, which occur over concentration ranges similar to those found in tumor stroma. Metastatic cells exhibit remarkable heterogeneity in their adhesion strength under stromal-like conditions, unlike their nonmetastatic counterparts, which exhibit Mg2+- and Ca2+-insensitive adhesion. This heterogeneity is the result of increased sensitivity to Mg2+- and Ca2+-mediated focal adhesion disassembly in metastatic cells, rather than changes in integrin expression or focal adhesion phosphorylation. Strongly adherent metastatic cells exhibit less migratory behavior, similar to nonmetastatic cell lines but contrary to the unselected metastatic cell population. Adhesion strength heterogeneity was observed across multiple cancer cell lines as well as isogenically, suggesting that adhesion strength may serve as a general marker of metastatic cells.


A Review of the Genetics of Hypertension with a Focus on Gene-Environment Interactions.
Here, we discuss the interpretation and modeling of gene-environment interactions in hypertension-related phenotypes, with a focus on the necessary assumptions and possible challenges. Recently, small cohort studies have discovered several novel genetic variants associated with hypertension-related phenotypes through modeling gene-environment interactions. Several consortia-based meta-analytic efforts have uncovered many novel genetic variants in hypertension without modeling interaction terms, giving promise to future meta-analytic efforts that incorporate gene-environment interactions. Heritability studies and genome-wide association studies have established that hypertension, a prevalent cardiovascular disease, has a genetic component that may be modulated by the environment (such as lifestyle factors). This review includes a discussion of known genetic associations for hypertension/blood pressure, including those resulting from the incorporation of gene-environmental interaction modeling.


Toward accurate prediction of pKa values for internal protein residues: the importance of conformational relaxation and desolvation energy.
Proton uptake or release controls many important biological processes, such as energy transduction, virus replication, and catalysis. Accurate pK(a) prediction informs about proton pathways, thereby revealing detailed acid-base mechanisms. Physics-based methods in the framework of molecular dynamics simulations not only offer pK(a) predictions but also inform about the physical origins of pK(a) shifts and provide details of ionization-induced conformational relaxation and large-scale transitions. One such method is the recently developed continuous constant pH molecular dynamics (CPHMD) method, which has been shown to be an accurate and robust pK(a) prediction tool for naturally occurring titratable residues. To further examine the accuracy and limitations of CPHMD, we blindly predicted the pK(a) values for 87 titratable residues introduced in various hydrophobic regions of staphylococcal nuclease and variants. The predictions gave a root-mean-square deviation of 1.69 pK units from experiment, and there were only two pK(a)'s with errors greater than 3.5 pK units. Analysis of the conformational fluctuation of titrating side-chains in the context of the errors of calculated pK(a) values indicate that explicit treatment of conformational flexibility and the associated dielectric relaxation gives CPHMD a distinct advantage. Analysis of the sources of errors suggests that more accurate pK(a) predictions can be obtained for the most deeply buried residues by improving the accuracy in calculating desolvation energies. Furthermore, it is found that the generalized Born implicit-solvent model underlying the current CPHMD implementation slightly distorts the local conformational environment such that the inclusion of an explicit-solvent representation may offer improvement of accuracy.


Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels.
Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of < or = 30 pg/ml and for sCT of < or = 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of < or = 30 pg/ml or sCT < or = 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.


Benefit of a contralateral routing of signal device for unilateral cochlear implant users.
To investigate objective and subjective effects of an adjunctive contralateral routing of signal (CROS) device at the untreated ear in patients with a unilateral cochlear implant (CI). Prospective study of 10 adult experienced unilateral CI users with bilateral severe-to-profound hearing loss. Speech in noise reception (SNR) and sound localization were measured with and without the additional CROS device. SNR was measured by applying speech signals at the untreated/CROS side while noise signals came from the front (S90N0). For S0N90, signal sources were switched. Sound localization was measured in a 12-loudspeaker full circle setup. To evaluate the subjective benefit, patients tried the device for 2 weeks at home, then filled out the abbreviated Speech, Spatial and Qualities of Hearing Scale as well as the Bern benefit in single-sided deafness questionnaires. In the setting S90N0, all patients showed a highly significant SNR improvement when wearing the additional CROS device (mean 6.4 dB, p < 0.001). In the unfavorable setting S0N90, only a minor deterioration of speech understanding was noted (mean -0.66 dB, p = 0.54). Sound localization did not improve substantially with CROS. In the two questionnaires, 12 of 14 items showed an improvement in mean values, but none of them was statistically significant. Patients with unilateral CI benefit from a contralateral CROS device, particularly in a noisy environment, when speech comes from the CROS ear side.


[Infantile acute lobar nephritis].
Acute lobar nephronia is a focal interstitial inflammation of the kidney healing well on conservative therapy. Authors call attention on this rare pathological entity and emphasize the role of the imaging modalities in making the diagnosis. Short literature review is also given. An 11 months old babyboy presented with febrile seizure and palpable right flank mass. Abdominal sonography and CT were done. Urine analysis gave evidence of upper urinary tract infection. Hyperechogenic solid mass in the right kidney was seen on sonography. Diagnosis of infection suspected on sonography has been confirmed by abdominal CT scan and possibility of tumor has been ruled out. Acute lobar nephronia was diagnosed and the patient has been treated successfully with antibiotics. Acute lobar nephronia may mimic both abscess and tumor. Differential diagnosis is very important because treatment of acute lobar nephronia is nonsurgical.


Hearing metaphor: an approach to working with family-generated metaphor.
This article presents a step-by-step approach to working with family-generated metaphor in family therapy. Although the use of therapist-generated "therapeutic metaphors" has been widely advocated and practiced for many years now, less attention has been paid to the metaphors used by family members. We argue that the family's metaphors are a neglected linguistic resource in family therapy. Highlighting and validating these metaphors produces a therapeutic conversation in which the voices of family members are heard more clearly by the therapist, and the families' own imaginative energies are engaged in defining and pursuing the goals of therapy. Several case examples illustrate the use of this approach with children of various ages.


Characterization of Genetic Mutations in Multi-Drug-Resistant Isolates of Mycobacterium tuberculosis Bacilli Conferring Resistance to a Second-Line Anti-tuberculosis Drug.
Multi-drug-resistant tuberculosis (MDR-TB) has become a major public health concern globally. Mutations in first- and second-line drug targets such as katG, inhA, rpoB, rrs, eis, gyrA, and gyrB have been associated with drug resistance. Monitoring predominant mutations in the MDR-TB patient population is essential to monitor and devise future therapeutic regimes. The present study is aimed to characterize genetic mutations in MDR isolates of Mycobacterium tuberculosis (MTB) bacilli conferring resistance to a second-line anti-tuberculosis drug in the Eastern Indian population. This cross-sectional study was conducted in the Department of Microbiology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, and in the Tuberculosis Demonstration & Training Centre, Agamkuan, Patna. A total of 3270 patients suspected to have MDR-TB were recruited in the study. Two sputum samples, one on the spot, and the other in the morning were collected from each patient and the diagnosis of rifampicin-sensitive (RS)/rifampicin-resistant (RR/MDR) TB was done by Gene-Xpert test. One hundred fifty RS-TB samples and 150 RR/MDR-TB samples were considered for line probe assay (LPA). RS samples were subjected to first-line LPA using Genotype® MTBDR Plus ver 2.0 and RR/MDR samples were considered for second-line LPA using Genotype® MTBDRsl ver 2.0. All sputum samples were subjected to sputum smear microscopy using the Ziehl-Neelsen staining method. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 26.0 (IBM Corp. Armonk, NY) and R (version 4.1; R Core Team 2021). In the present study, out of 3270 patients, we detected RR/MDR-TB in 235 patients (7.19%), RS-TB in 812 patients (24.83%), the rest of the patients negative for MTB (2223, 67.98%). Out of 150 RR/MDR-TB sputum samples tested, resistance to fluoroquinolone (FQ) was observed in 41 samples. The selected patients had predominantly FQ resistance due to the gyrA gene mutations (97.56%, n=40) compared to the gyrB gene mutations (2.44%, n=1). We observed >60% of the mutations in the gyrA gene in codon 94 (MUT3C (D94G), MUT3A (D94A), and MUT3D (D94H). In addition, we found the mutations MUT1 (A90V) and MUT2 (S91P) in the codons 90 and 91 of the gyrA gene in the considered MTB patient population. The identified genes can be further validated to be considered as therapeutic targets, but more therapeutics and advanced strategies should be applied in the management of MTB.


Calibrated-orifice nipples for measurement of infant nutritive sucking.
To measure infant nutritive sucking reproducibly, nipple flow resistance must be controlled. Previous investigators have accomplished this with flow-limiting venturis, which has two limitations: flow resistance is highly dependent on fluid viscosity and older infants often reject the venturi nipple. This report describes the validation of calibrated-orifice nipples for the measurement of infant nutritive sucking. The flow characteristics of two infant formulas and water through these nipples were not different; those through venturi nipples were (analysis of variance; p < 0.0001). Flow characteristics did not differ among calibrated-orifice nipples constructed from three commercial nipple styles, indicating that the calibrated-orifice design is applicable to different types of baby bottle nipples. Among 3-month-old infants using calibrated-orifice nipples, acceptability was high, and sucking accounted for 85% of the variance in fluid intake during a feeding. We conclude that calibrated-orifice nipples are a valid and acceptable tool for the measurement of infant nutritive sucking.


Presence of B7-2+ dendritic cells and expression of Th1 cytokines in the early development of sialodacryoadenitis in the IqI/Jic mouse model of primary Sjörgren's syndrome.
Subpopulations of infiltrating lymphocytes, professional antigen-presenting cells (APCs), and Th1/Th2 cytokines that could initiate an autoimmune sialodacryoadenitis were studied in the IQI/Jic mouse model of primary Sjögren's syndrome. Although lymphocytic infiltrations were first seen in submandibular glands (SMGs) of females and in lacrimal glands (LGs) of males at 8 weeks of age, clusters of MHC class II+, CD11c+, B7-2+ dendritic cells (DCs) were already localized in these tissues at 4 weeks. At 8 weeks, the infiltrating lymphocytes consisted of almost equal numbers of B cells and CD4+ T cells. In the inflammatory foci, MHC class II+, CD11c+, B7-2+ DCs formed network-like structures. Duct cells in the lesions showed immunoreactivities for MHC class II and ALCAM (a costimulatory adhesion molecule). IL-12 and IFN-gamma transcripts were detected by RT-PCR in SMGs of females and in LGs of males at 8-12 weeks. These results suggest that the clustered DCs might play an important role in the initiation of the adenitis, and further suggest that the DCs and epithelial cells may participate in the activation of CD4+ T cells. It is also likely that Th1 cytokines mediate the functional interactions between the APCs and CD4+ T cells in the early lesions.


NATURAL GENETIC VARIATION OF LIFE SPAN, REPRODUCTION, AND JUVENILE GROWTH IN DAPHNIA.
The evolutionary theory of senescence predicts that high extrinsic mortality in natural populations should select for accelerated reproductive investment and shortened life span. Here, we test the theory with natural populations of the Daphnia pulex-pulicaria species complex, a group of freshwater zooplankton that spans an environmental gradient of habitat permanence. We document substantial genetic variation in demographic life-history traits among parent and hybrid populations of this complex. Populations from temporary ponds have shorter life spans, earlier and faster increases of intrinsic mortality risk, and earlier and steeper declines in fecundity than populations from permanent lakes. We also examine the age-specific contribution to fitness, measured by reproductive value, and to expected lifetime reproduction; these traits decline faster in populations from temporary ponds. Despite having more rapid senescence, pond Daphnia exhibit faster juvenile growth and higher early fitness, measured as population growth rate (r). Among populations within this species complex we observed negative genetic correlations between r and indices of life-history timing, suggesting trade-offs between early- and late-life performance. Our results cannot be explained by a trade-off between survival and fecundity or by nonevolutionary theories of senescence. Instead, our data are consistent with the evolutionary theory of senescence because the genetic variation in life histories we observed is roughly congruent with the temporal scale of environmental change in the field.


Properties of Red Mud Neutralized with Sulfuric Acid and Effects on Cement Mortar.
The purpose of this study was to recycle red mud, an industrial byproduct that generates 300,000 tons per year, into the construction industry. Red mud was prepared as a liquid, neutralized with sulfuric acid, and replaced with cement mortar. The properties of liquefied red mud (LRM) neutralized with sulfuric acid (LRM + S) were investigated as well as its effect on cement mortar's mechanical and hydration characteristics. The pH of LRM + S stabilized at 7.6; its SO3 content was ~4.19% higher than that of LRM. Sulfites were contributed by calcium and sodium sulfate. The flows and setting times of the mortars containing LRM and LRM + S decreased as the substitution rate increased. The compressive strength of mortar that replaced 5% of cement with LRM + S was similar to that of the plain cement mortar. Scanning electron microscopy and X-ray diffraction revealed that the hydration products of LRM + S-containing cement mortar were similar to those of the plain cement mortar. Thus, LRM + S can be used as a cement substitute.


[An epidemiological study of outbreaks of Salmonella enterica serovar paratyphi A occurred in two Chinese families after traveled to different areas of China].
We reported two familial clusters of paratyphoid fever after travel to China occurring in the same Yokohama ward from September to October 2002. Six Salmonella enterica serovar Paratyphi A (S. Paratyphi A) strains, 3 each from 2 clusters, were isolated and their characteristics analyzed using phage typing, susceptibility to antibiotics, and patterns of restriction endonuclease-digested DNA fragments in agarose gel following pulsed-field gel electrophoresis (PFGE). Mutations in genes for gyrA and parC, which determine sensitivity to fluoroquinolones, were also investigated. All isolates showed the same characteristics, i.e. "untypable", employing bacteriophages, resistant to antibiotics nalidixic acid and fosfomysin, and decreased susceptibility to fluoroquinolones. No difference was observed in PFGE patterns after digesting with 4 restriction enzymes, Xba I, Bin I, Spe I, and Xho I. We also found that the gyrA gene, which is one of the quinolone-resistance-determining regions (QRDR), was mutated at position 83 from serine to phenylalanine (from TTC to TCC) in all 6 strains. Other QRDR's, parC were not mutated commonly in them. Hearing from patients and family members, it was apparent that these 2 families had been contacted neither in Japan nor in China during ill or incubation period of paratyphoid fever, although a member of one cluster had a familial relationship with one of another family. It was also reported by them that typhoid fever is endemic in both of the areas of their visits. From these results, it was suggested that these 2 cluster cases were infected separately in China with the progeny of the same clone which is endemic in these regions.


Transcription of a human transposon-like sequence is usually directed by other promoters.
The transcriptional activity of a human transposon-like family of repeats, called the THE-1 family, has been studied in cell culture and in human tissue. Both strands of THE-1 are present in several discrete length poly A plus RNAs. Primer extension studies and the structures of cDNA clones show that these THE-1 transcripts are usually the product of other transcription units. The THE-1 LTR provides the polyadenylation processing site for two transcripts, which result from upstream non THE-1 promoters. Yet another transcript, containing an internal THE-1 element in the probable sense orientation, is greatly enriched in a polysomal size fraction.


Hepatitis C prevalence studied by polymerase chain reaction and serological methods in haemodialysis patients in Mazandaran, Iran.
Patients on maintenance haemodialysis are known to have an elevated risk of acquiring hepatitis C virus (HCV) infection. The reported prevalence among haemodialysis patients in the United States ranges from eight percent to ten percent, and is considerably higher in many European and Middle Eastern countries. Therefore, a reliable diagnosis of HCV infection is essential in order to prevent the spread of the disease in dialysis units. All haemodialysis patients were interviewed in two dialysis units in Sari and Ghaemshahr, Iran, in 2006. Blood samples were collected and serum samples screened for anti-HCV antibodies by enzyme-linked immunosorbent assay (ELISA). All samples were retested for confirmation with polymerase chain reaction (PCR). A total of 186 haemodialysis patients (mean age 58.86 +/- 16.9 years) were studied. Mean duration of haemodialysis was 3.07 +/- 0.3 years. Mean of SGOT and SGPT were 30.64 +/- 6 and 32.01 +/- 8, respectively. Among the 186 patients, 39 (21 percent) were seropositive by ELISA and 21 (11.3 percent) were PCR positive. All PCR positive patients also had positive ELISA. Association between the duration of haemodialysis and HCV seropositivity was statistically significant (p-value is 0.0001), but there was no significant correlation between number of transfusions and HCV seropositivity. Despite the growing demand for cost-effectiveness in the health system, tight control of HCV infection by PCR and ELISA examination must remain an essential part of the routine screening in haemodialysis patients.


Neural control of motor output: can training change it?
Henneman's size principle of motor unit recruitment and rate coding reduces fatigue, minimizes error in transfer of information from the nervous system, and produces smooth force output. Plasticity present at various sites of the motor system may change endurance, force, speed, or precision with training, but not the recruitment order.


Elevated basal levels of cytosolic calcium of thymocytes in chronic renal failure.
The basal levels of cytosolic calcium ([Ca2+]i) in rats and/or humans with chronic renal failure (CRF) are elevated in many cells including brain synaptosomes, pancreatic islets, polymorphonuclear leukocytes, platelets and B and T cells. This rise in [Ca2+]i has been attributed to the state of secondary hyperparathyroidism of CRF. These observations have led to the proposition that CRF is a state of cellular calcium intoxication mediated by excess parathyroid hormone (PTH). The documentation of a high basal level of [Ca2+]i in other cells is needed to provide further support for this postulate. The present study evaluated the basal levels of [Ca2+]i of thymocyte, which are targets for PTH action, in normal, CRF, and CRF parathyroidectomized (CRF-PTX) rats. We also examined whether CRF affects the phenotype expression (Thy-1, CD4 and CD8) in thymocytes. The results showed that the basal levels of [Ca2+]i in thymocytes from CRF rats (81 +/- 3.7 nM) are significantly (p < 0.01) higher than those in normal animals (60 +/- 2.9 nM). PTX of CRF animals prevented the elevation in the basal levels of [Ca2+]i of thymocytes; in these animals, the levels were 59 +/- 2.8 nM. Neither CRF nor the elevation in [Ca2+]i of thymocytes affected their phenotype expression.


Interactions of D2O with methane and fluoromethane surfaces.
TOF-SIMS is used to investigate the interactions between D2O and hydrophobic molecules, such as CH4, CH3F, CH2F2, CHF3, and CF4, at cryogenic temperatures (15 K). By irradiation with a 1.5-keV He+ beam, the D(+)(D2O)n ions are ejected efficiently from the D2O nanoclusters physisorbed on the CF4 layer due to Coulomb explosion: the ion yields are by about two orders of magnitude higher than those from a thick D2O layer via the kinetic sputtering. The D(+)(D2O)n yields decrease on the CHnF(4-n) layer with increasing the number of the C-H group. This is because the Coulombic fission is quenched due to the delocalization of valence holes through the C-H...H-C and C-H...D2O contacts. A pure D2O film is hardly grown on the CH4 layer as a consequence of intermixing whereas the D2O molecules basically adsorb on the surfaces of fluoromethanes, suggesting the attractive (water-repellent) interactions in the C-H...D2O (C-F...D2O) contacts. The C-H...O bond behaves like a conventional O-H...O hydrogen bond as far as the collision-induced proton transfer reaction is concerned.


Gender and degree of tendon healing are independent predictive factors for clinical outcome in successfully healed rotator cuff tears.
Arthroscopic rotator cuff repair (aRCR) is a commonly performed procedure and has been reported to be a successful treatment. Successful healing has traditionally been considered to be associated with good outcome; however, knowledge on predictive factors affecting final outcome other than tendon healing is limited. This study aims to investigate predictive factors influencing clinical outcome following aRCR in patients with successfully healed tears. This retrospective case-control study was conducted in a single center with 135 patients who had successfully healed tendons based on Sugaya classification (grades I-III) on postoperative magnetic resonance imaging (MRI) scans following aRCR. Clinical outcome measures included Constant-Murley score (CMS), range of motion (ROM), pain score. Various preoperative, intraoperative factors and degree of postoperative tendon healing were assessed to identify independent predictive factors for final clinical outcome. Mean age of patients was 55.9 ± 9.0 years and mean follow-up duration was 46.8 ± 14.9 months. There were 50 (37%) male and 85 (63.0%) female patients. At final follow-up, mean CMS was 85.7 ± 12.0. Considering mean postoperative CMS and the minimal clinically important difference (MCID) of 10 points for CMS, a cutoff level of 75 points for CMS was set (85-10 = 75) and study population was divided into two study groups (group I, poor outcome, CMS ≤ ;75, and group II, good outcome, CMS > 75). There were 24 (17.8%) patients in group I and 111 (82.2%) patients in group II. Univariate analysis revealed that gender, body mass index (BMI) and degree of tendon healing (Sugaya classification) differed significantly between two groups (p < 0.05). Multivariate logistic regression analysis which was conducted with these variables showed that female gender (odds ratio 3.65) and Sugaya grade III (odds ratio 8.19) were independent predictive factors which were significantly associated with poor outcome (p < 0.05). This study showed that despite achieving a successful healing, considerable amount of patients (17.8%) have ended up with poor outcome. Female gender and degree of tendon healing were identified as independent predictive factors for poor outcome. These data would help surgeons during decision-making, risk assessment and patient counseling. III.


Isomerization of N-Allyl Amides To Form Geometrically Defined Di-, Tri-, and Tetrasubstituted Enamides.
Enamides represent bioactive pharmacophores in various natural products, and have become increasingly common reagents for asymmetric incorporation of nitrogen functionality. Yet the synthesis of the requisite geometrically defined enamides remains problematic, especially for highly substituted and Z-enamides. Herein we wish to report a general atom economic method for the isomerization of a broad range of N-allyl amides to form Z-di-, tri-, and tetrasubstituted enamides with exceptional geometric selectivity. This report represents the first examples of a catalytic isomerization of N-allyl amides to form nonpropenyl disubstituted, tri- and tetrasubstituted enamides with excellent geometric control. Applications of these geometrically defined enamides toward the synthesis of cis vicinal amino alcohols and tetrasubstituted α-borylamido complexes are discussed.


A Mamdani Adaptive Neural Fuzzy Inference System for Improvement of Groundwater Vulnerability.
Assessing groundwater vulnerability is an important procedure for sustainable water management. Various methods have been developed for effective assessment of groundwater vulnerability and protection. However, each method has its own conditions of use and, in practice; it is difficult to return the same results for the same site. The research conceptualized and developed an improved DRASTIC method using Mamdani Adaptive Neural Fuzzy Inference System (M-ANFIS-DRASTIC). DRASTIC and M-ANFIS-DRASTIC were applied in the Jorf aquifer, southeastern Tunisia, and results were compared. Results confirm that M-ANFIS-DRASTIC combined with geostatistical tools is more powerful, generated more precise vulnerability classes with very low estimation variance. Fuzzy logic has a power to produce more realistic aquifer vulnerability assessments and introduces new ways of modeling in hydrogeology using natural human language expressed by logic rules.


Causality of Opportunistic Pathogen Klebsiella pneumoniae to Hypertension Development.
Previous studies have reported a strong association between gut microbiome and hypertension; yet, the exact bacterial species associated with the disease development and progression have not yet been detected. This study aimed to investigate whether opportunistic pathogen Klebsiella pneumoniae is a causal factor for hypertension pathogenesis, and explore the potential mechanisms. The enrichment of Klebsiella pneumoniae in the gut of patients with hypertension was validated by meta-analysis based on 3 independent cohorts. Klebsiella pneumoniae was inoculated into germ-free mice, antibiotic pretreated and conventional mice. Klebsiella pneumoniae led to higher blood pressure, slight cardiac hypertrophy, and enhanced contractility of resistant arteries in recipient mice. Moreover, Klebsiella pneumoniae induced pathological damages, deficiency of tight junction proteins and transcriptional shifts. Metabolic alterations, especially the depletion of stearoylethanolamide, were observed upon Klebsiella pneumoniae administration. In addition, renal transcriptome dysfunction with significant upregulation of genes related to hypertension pathogenesis was observed in Klebsiella pneumoniae treated mice. These results provide evidence that the enrichment of Klebsiella pneumoniae acts as a direct contributor to blood pressure elevation and hypertension pathogenesis, and Klebsiella pneumoniae induced intestinal damages, fecal metabolic changes, and renal shifts may be integrated mediators.


Evaluation of functional capacity after stroke with special emphasis on motor function and activities of daily living.
In a multidisciplinary study comprising 280 patients with acute cerebrovascular disease (median age 76, range 30-96 years), instruments for functional assessment in stroke care were developed. The improvements of motor function and activities of daily living were investigated during a period of up to one year after a stroke. A new chart for motor capacity assessment, which includes both the paretic and the non-paretic side, modified after that of Fugl-Meyer et al, was tested for its reliability and validity. At the same time the Activity Index of Hamrin & Wohlin was further tested. The internal consistency reliability measured with the standardized item alpha method confirmed that the two instruments have high homogeneity. Construct validity was investigated by factor analysis and showed a logical structure. The predictive validity of the scores on admission was significant and the two tools had a satisfactory predictive capacity for survival and later functional outcome. The improvements in different motor functions were followed up for up to one year after the stroke among the 183 one-year survivors. In patients with minor impairment, the improvement occurred mostly during the first week. Patients with moderate or moderately severe impairment improved more continuously for up to three months, while the few surviving patients with very severe impairment continued to recover to some extent even after three months. Older patients with severe functional loss seemed to improve more slowly and not as well as younger patients with equivalent impairment. The patterns of instrumental activities of daily living (I-ADL), such as household work, locomotion, psychosocial functions and intellectual activities, were investigated in the 207 three-month survivors and the 183 one-year survivors. At both the three-month and the one-year follow-ups the scores had decreased considerably, compared with before the stroke, for all activities except locomotion, and many patients were dependent on somebody else for help. The same group of patients was also examined by a Standardized Practical Equipment (SPE) test constructed by Tömquist three months and one year after the stroke. The construct validity of the SPE test was estimated through factor analysis. Three factors emerged, one concerning mainly cognitive factors and co-ordination, one concerning hand function and one concerning mainly mobility and balance. The instruments developed in the course of this study have proved to be reliable and valid, and useful in assessing functional losses and following progress. The tools are well suited for any clinical settings and for home care examinations as well as research.


A close structural analog of 2-methyl-6-(phenylethynyl)-pyridine acts as a neutral allosteric site ligand on metabotropic glutamate receptor subtype 5 and blocks the effects of multiple allosteric modulators.
The metabotropic glutamate receptor subtype 5 (mGlu5) activates calcium mobilization via binding of glutamate, the major excitatory neurotransmitter in the central nervous system. Allosteric modulation of the receptor has recently emerged as a promising alternative method of regulation to traditional regulation through orthosteric ligands. We now report three novel compounds that bind to the allosteric 2-methyl-6-(phenylethynyl)-pyridine (MPEP) site on mGlu5 but have only partial inhibition or no functional effects on the mGlu5 response. Two of these compounds, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP) and 2-(2-(5-bromopyridin-3-yl)ethynyl)-5-methylpyridine (Br-5MPEPy), act as partial antagonists of mGlu5 in that they only partially inhibit the response of this receptor to glutamate. The third compound, 5-methyl-6-(phenylethynyl)-pyridine (5MPEP), acts as a neutral allosteric site ligand that binds to the MPEP site and has no effects alone. However, 5MPEP blocks the effects of both the allosteric antagonist MPEP and potentiators 3,3'-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB). This compound also blocks depolarization effects of both MPEP and CDPPB in neurons in the subthalamic nucleus. These novel compounds provide valuable new insight into the pharmacology of allosteric sites on G protein-coupled receptors and provide valuable new tools for determining the effects of allosteric site ligands in native systems.


Identification of five new bradykinin potentiating peptides (BPPs) from Bothrops jararaca crude venom by using electrospray ionization tandem mass spectrometry after a two-step liquid chromatography.
Bradykinin potentiating peptides (BPPs) from Bothrops jararaca venom were described in the middle of 1960s and were the first natural inhibitors of the angiotensin-converting enzyme displaying strong anti-hypertensive effects in human subjects. The BPPs can be recognized by their typical pyroglutamyl proline-rich oligopeptide sequences presenting invariably a proline residue at the C-terminus. In the present study, we identified 18 BPPs, most of them already described for the B. jararaca venom. We isolated and sequenced new peptides ranging from 5 to 14 amino acid residues exhibiting similar amino acid sequence features. The applied methodology consisted of a strait two-step liquid chromatography, followed by mass spectrometry analysis. Besides the amino acid sequence homology, the corresponding synthetic peptides were able to potentiate bradykinin on the isolated guinea-pig ileum.


The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies.
The prognostic role of human epidermal growth factor receptor 2 (HER2) in ovarian cancer has been investigated in previous studies, but the results remain controversial. Here we present a meta-analysis to systematically review the association between HER2 expression and ovarian cancer prognosis. Observational studies published until July 2017 were searched in Pubmed, Embase, and Cochrane library databases. Hazard ratios (HRs) for survival with 95% confidence intervals (CIs), subgroup analyses, publication bias and sensitivity analyses were implemented under a standard manner. Estimates of overall survival (OS), progress-free survival (PFS) and disease-free survival (DFS) were weighted and pooled using Der Simonian-Laird random-effect model. Thirty-four studies that include 5180 ovarian cancer patients were collected for analysis. Expression of HER2 was negatively correlated with clinical prognosis of overall survival (HR = 1.57, 95% CI: 1.31 to 1.89, P < 0.001) and disease-free survival / progress-free survival (HR = 1.26, 95% CI = 1.06 to 1.49) in ovarian cancers. The association between HER2 expression and poor ovarian cancer prognosis in overall survival was also statistically significant in subgroups of unclassified ovarian cancer, Caucasian population and Asian population, while irrespective of detection method. HER2 expression was related with poor prognosis in ovarian cancer patients and can be used as a predicting cancer prognostic biomarker in ovarian cancer patients.


The Sun's global magnetic field.
Our present-day understanding of solar and stellar magnetic fields is discussed from both an observational and theoretical viewpoint. To begin with, observations of the Sun's large-scale magnetic field are described, along with recent advances in measuring the spatial distribution of magnetic fields on other stars. Following this, magnetic flux transport models used to simulate photospheric magnetic fields and the wide variety of techniques used to deduce global coronal magnetic fields are considered. The application and comparison of these models to the Sun's open flux, hemispheric pattern of solar filaments and coronal mass ejections are then discussed. Finally, recent developments in the construction of steady-state global magnetohydrodynamic models are considered, along with key areas of future research.


Effect of ethanol and pH on the adsorption of acetaminophen (paracetamol) to high surface activated charcoal, in vitro studies.
Paracetamol (acetaminophen) intoxication often in combination with ethanol, is seen commonly in overdose cases. Doses of several grams might be close to the maximum adsorption capacity of the standard treatment dose (50g) of activated charcoal. The aim of this study was to determine the maximum adsorption capacity for paracetamol for two types of high surface-activated charcoal [Carbomix and Norit Ready-To-Use (not yet registered trademark in Denmark) both from Norit Cosmara, Amersfoort, The Netherlands] in simulated in vivo environments: At pH 1.2 (gastric environment), at pH 7.2 (intestinal environment), and with and without 10% ethanol. Activated charcoal, at both gastric or intestinal pHs, and paracetamol were mixed, resulting in activated charcoal-paracetamol ratios from 10:] to 1:1. In trials with ethanol, some of the gastric or intestinal fluid was replaced with an equivalent volume of ethanol, resulting in an ethanol concentration of 10% v/v. After incubation, the concentration of unabsorbed paracetamol was analyzed by high-performance liquid chromatography. The maximum adsorption capacity of paracetamol to activated charcoal was calculated as mg paracetamol adsorbed/g activated charcoal, using Langmuir's isotherm. Carbomix [95% confidence limits are shown in square brackets]: 623.7 [612.8;634.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 626.2 [611.6;640.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2); Norit Ready-To-Use: 693.6 [676.8;710.5] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 722.6 [687.4;757.9] mg paracetamol adsorbed/g activated charcoal (pH 7.2). For experiments with ethanol (10% v/v) the results with Carbomix were 465.7 [449.2;482.2] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 498.6 [481.8;515.6] mg paracetamol adsorbed/g activated charcoal (pH 7.2); with Norit Ready-To-Use: 617.2 [606.6;627.7] mg paracetamol adsorbed/g activated charcoal (pH 1.2), 640.6 [624.9;656.4] mg paracetamol adsorbed/g activated charcoal (pH 7.2). Under conditions simulating immediate treatment with charcoal, a standard dose of 50 g of either of the two tested activated charcoals adsorbed a sufficient amount of paracetamol to be beneficial in the treatment of the majority of overdoses of this drug. For both types of activated charcoal, with or without ethanol, there was no significant difference in the adsorption of paracetamol at pH 1.2 and 7.2. Norit Ready-To-Use had a larger maximum adsorption capacity than Carbomix, and was not as sensitive as Carbomix to environmental changes (pH and ethanol). The presence of 10% ethanol lowered the adsorption capacity of the two tested activated charcoal preparations by an amount that might be clinically relevant in cases of intoxications by high-gram doses.


[Induction of jaw bone formation by tooth autotransplantation].
A case-report of segmental underdevelopment of the alveolar process in the upper jaw of an eleven-year old girl is presented. At the site where the alveolar ridge was underdeveloped, two impacted malformed incisors were found. The malformed teeth had almost normal crowns, but the root-development had terminated 1-2 mm beyond the cementoenamel junction. The patient was treated by removal of the two malformed impacted teeth, followed by autotransplantation of the developing second premolar with the intention of inducing bone formation. The result was promising. After 3 years the alveolar process had developed to almost normal vertical hight. Some considerations are made regarding the possible origin of the bone induction factors in tooth buds. The fact that this patient demonstrated an underdevelopment of the alveolar process in spite of the formation of almost normal crowns, is taken as evidence that the bone stimulating principle in tooth buds are not to be found in the enamel organ proper, but must be related to Hertwig's epithelial sheath, root development and tooth eruption.


Mapping Transposon Insertions in Bacterial Genomes by Arbitrarily Primed PCR.
Transposons can be used to easily generate and label the location of mutations throughout bacterial and other genomes. Transposon insertion mutants may be screened for a phenotype as individual isolates, or by selection applied to a pool of thousands of mutants. Identifying the location of a transposon insertion is critical for connecting phenotype to the genetic lesion. In this unit, we present an easy and detailed approach for mapping transposon insertion sites using arbitrarily-primed PCR (AP-PCR). Two rounds of PCR are used to (1) amplify DNA spanning the transposon insertion junction, and (2) increase the specific yield of transposon insertion junction fragments for sequence analysis. The resulting sequence is mapped to a bacterial genome to identify the site of transposon insertion. In this protocol, AP-PCR as it is routinely used to map sites of transposon insertion within Staphylococcus aureus, is used to illustrate the principle. Guidelines are provided for adapting this protocol for mapping insertions in other bacterial genomes. Mapping transposon insertions using this method is typically achieved in 2 to 3 days if starting from a culture of the transposon insertion mutant. © 2017 by John Wiley & Sons, Inc.


Psychosocial work factors and first depressive episode: retrospective results from the French national SIP survey.
The objective was to explore the associations between psychosocial work factors and first depressive episode. Additional objectives included the study of the frequency and duration of exposure, and the evaluation of the induction period between exposures and outcome and of the reversibility of the effects. The study was based on a sample of 13,648 men and women from the 2006 national representative French SIP survey. Retrospective evaluation was performed for depressive episode for the whole life history, for psychological demands, skill discretion, social support, tension with the public, reward and work-life imbalance for each job, and within each job before and after each major change, and for time-varying covariates. The outcome was the first depressive episode. Statistical analysis was performed using weighted discrete time logistic regression model. High psychological demands and low social support were risk factors for first depressive episode for both genders. The risk increased with the frequency of exposure to these factors. Associations were found with the frequency of exposure to tension with the public among women and to work-life imbalance among men. The risk increased with the duration of exposure to psychological demands and low social support for both genders, however, these associations become non-significant when recent exposure was taken into account. Past exposure older than 2 years was not associated with the outcome. Associations between psychosocial work factors and first depressive episode were observed, including dose-response associations. However, after removal of the exposure, the risk may be reduced after 2 years.


Raman and autofluorescence spectrum dynamics along the HRG-induced differentiation pathway of MCF-7 cells.
Cellular differentiation proceeds along complicated pathways, even when it is induced by extracellular signaling molecules. One of the major reasons for this complexity is the highly multidimensional internal dynamics of cells, which sometimes causes apparently stochastic responses in individual cells to extracellular stimuli. Therefore, to understand cell differentiation, it is necessary to monitor the internal dynamics of cells at single-cell resolution. Here, we used a Raman and autofluorescence spectrum analysis of single cells to detect dynamic changes in intracellular molecular components. MCF-7 cells are a human cancer-derived cell line that can be induced to differentiate into mammary-gland-like cells with the addition of heregulin (HRG) to the culture medium. We measured the spectra in the cytoplasm of MCF-7 cells during 12 days of HRG stimulation. The Raman scattering spectrum, which was the major component of the signal, changed with time. A multicomponent analysis of the Raman spectrum revealed that the dynamics of the major components of the intracellular molecules, including proteins and lipids, changed cyclically along the differentiation pathway. The background autofluorescence signals of Raman scattering also provided information about the differentiation process. Using the total information from the Raman and autofluorescence spectra, we were able to visualize the pathway of cell differentiation in the multicomponent phase space.


Inflammatory Markers: C-Reactive Protein, Erythrocyte Sedimentation Rate, and Leukocyte Count in Vitamin D Deficient Patients with and without Chronic Kidney Disease.
Although some studies revealed a positive relationship between vitamin D3 deficiency and inflammatory markers, there have been also many studies that failed to find this relationship. The aim of this large scaled study is to determine the association between the level of plasma 25 hydroxy vitamin D3 [25-(OH) D3] and inflammatory markers in the general population without chronic kidney disease (CKD) and in patients with CKD. Participants with simultaneously measured inflammatory markers and 25-(OH) D3 levels were retrospectively analyzed (n = 1897). The incidence of all-cause inflammation infection, hospitalization, chronic renal failure, and vitamin B12 deficiency was evaluated. The medians of serum creatinine levels in subjects without renal failure were lower in 25-(OH) D3 deficient group. Patients with CKD were more likely to have vitamin D3 deficiency compared with normal GFR. 25-(OH) D3 levels were associated with a greater incidence of all-cause hospitalization, hypoalbuminemia, and vitamin B12 deficiency. However, there was no relationship between inflammatory markers and vitamin D3 levels. In 25-(OH) D3 deficient patients, inflammatory markers can be related to other inflammatory and infectious status such as malnutrition and cachexia. We believed that there must be a relationship between vitamin deficiency and inflammatory markers due to other causes than low 25-(OH) D3 status.


Monolithic and Flexible ZnS/SnO2 Ultraviolet Photodetectors with Lateral Graphene Electrodes.
A continuing trend of miniaturized and flexible electronics/optoelectronic calls for novel device architectures made by compatible fabrication techniques. However, traditional layer-to-layer structures cannot satisfy such a need. Herein, a novel monolithic optoelectronic device fabricated by a mask-free laser direct writing method is demonstrated in which in situ laser induced graphene-like materials are employed as lateral electrodes for flexible ZnS/SnO2 ultraviolet photodetectors. Specifically, a ZnS/SnO2 thin film comprised of heterogeneous ZnS/SnO2 nanoparticles is first coated on polyimide (PI) sheets by a solution process. Then, CO2 laser irradiation ablates designed areas of the ZnS/SnO2 thin film and converts the underneath PI into highly conductive graphene as the lateral electrodes for the monolithic photodetectors. This in situ growth method provides good interfaces between the graphene electrodes and the semiconducting ZnS/SnO2 resulting in high optoelectronic performance. The lateral electrode structure reduces total thickness of the devices, thus minimizing the strain and improving flexibility of the photodetectors. The demonstrated lithography-free monolithic fabrication is a simple and cost-effective method, showing a great potential for developement into roll-to-roll manufacturing of flexible electronics.


Rituals decrease the neural response to performance failure.
Rituals are found in all types of performance domains, from high-stakes athletics and military to the daily morning preparations of the working family. Yet despite their ubiquity and widespread importance for humans, we know very little of ritual's causal basis and how (if at all) they facilitate goal-directed performance. Here, in a fully pre-registered pre/post experimental design, we examine a candidate proximal mechanism, the error-related negativity (ERN), in testing the prediction that ritual modulates neural performance-monitoring. Participants completed an arbitrary ritual-novel actions repeated at home over one week-followed by an executive function task in the lab during electroencephalographic (EEG) recording. Results revealed that relative to pre rounds, participants showed a reduced ERN in the post rounds, after completing the ritual in the lab. Despite a muted ERN, there was no evidence that the reduction in neural monitoring led to performance deficit (nor a performance improvement). Generally, the findings are consistent with the longstanding view that ritual buffers against uncertainty and anxiety. Our results indicate that ritual guides goal-directed performance by regulating the brain's response to personal failure.


Optimal amount of basic fibroblast growth factor in gelatin sponges incorporating β-tricalcium phosphate with chondrocytes.
A gelatin sponge with slowly releasing basic fibroblast growth factor (b-FGF) enhances chondrogenesis. This study investigated the optimal amount of b-FGF in gelatin sponges to fabricate engineered cartilage. b-FGF (0, 10, 100, 500, 1000, and 2000 μg/cm(3))-impregnated gelatin sponges incorporating β-tricalcium phosphate (β-TCP) were produced. Chondrocytes were isolated from the auricular cartilage of C57B6J mice and expanded. The expanded auricular chondrocytes (10×10(6) cells/cm(3)) were seeded onto the gelatin sponges, which served as scaffolds. The construct assembly was implanted in the subcutaneous space of mice through a syngeneic fashion. Thereafter, constructs were retrieved at 2, 4, or 6 weeks. (1) Morphology: The size of implanted constructs was larger than the size of the scaffold with 500, 1000, and 2000 μg/cm(3) b-FGF-impregnated gelatin sponges incorporating β-TCP at 4 and 6 weeks after implantation. (2) The weight of the constructs increased roughly proportional to the increase in volume of the b-FGF-impregnated scaffold at 2, 4, and 6 weeks after implantation, except in the 2000 μg/cm(3) b-FGF-impregnated constructs group. (3) Histological examination: Extracellular matrix in the center of the constructs was observed in gelatin sponges impregnated with more than 100 μg/cm(3) b-FGF at 4 weeks after implantation. The areas of cells with an abundant extracellular matrix were positive for cartilage-specific marker type 2 collagen in the constructs. (4) Protein assay: Glycosaminoglycan and collagen type 2 expression were significantly increased at 4 and 6 weeks on implantation of gelatin sponges impregnated with more than 100 μg/cm(3) b-FGF. At 6 weeks after implantation, the ratio of type 2 collagen to type 1 collagen in constructs impregnated with 100 μg/cm(3) or more b-FGF was higher than that in mice auricular cartilage. Gelatin sponges impregnated with more than 100 μg/cm(3) b-FGF incorporating β-TCP with chondrocytes (10×10(6) cells/cm(3)) can fabricate engineered cartilage at 4 weeks after implantation.


[Chromosome nucleolus organizer regions of the African green monkey].
The silver staining Ag-I for detection of nucleolar organizer regions (NOR) in the African green monkey chromosomes was used. NOR were situated on the secondary constrictions of one pair of homologous marker chromosomes and consisted of two parts. A block of condensed chromatin was seen in the middle of the despiralized portion corresponding to the secondary constriction. The data suggest that the stalks of satellites of chromosomes, rather than satellites themselves, are regions of nucleolar organizer.


Chronic cyanide poisoning in relation to blindness and tropical neuropathy.
Within a group of 20 patients showing optic atrophy and macula degeneration, 14 patients could be examined for neurological and audiometric defects. In 6 patients neurological signs and symptoms were observed. Nine patients reported loss of hearing and in 3 of them a severe perceptive deafness was seen in the audiogram. In 3 of the 14 patients a combination of severe neurologic and audiologic symptoms developed and in two of them a high thiocyanate concentration in serum was observed. The occurrence of perceptive deafness and posterior column sensory loss in the lower extremities in four of the patients made the diagnosis of polyneuropathy the most plausible. Although a similarity to chronic myelopathies caused by nutritional cyanide poisoning cannot be denied, the mean thiocyanate concentration in plasma 24 mumol/L (1.39 mg/L), and the cyanide levels in the blood 0.09 mumol/L (2.3 micrograms/L) were substantially lower than those found in other individuals during periods of extreme drought in which food only consisted of the bitter variety of cassava. The role of cyanide in the etiopathology of this polyneuropathy is unknown.


Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus.
Animal and limited human studies have raised concerns as to the safety of in utero exposure to mycophenolate mofetil (MMF) and sirolimus (SRL) in transplant recipients. This study examined the outcomes of pregnancies with exposure to MMF or SRL from 30 female transplant recipients (39 pregnancies) who have reported pregnancies to the National Transplantation Pregnancy Registry. Data were collected via questionnaires, phone interviews and medical records. There were 18 kidney recipients reporting 26 pregnancies with exposure to MMF: 15 livebirths (LB), 11 spontaneous abortions (SA). Structural malformations were reported in four of the 15 children (26.7%) including: hypoplastic nails and shortened fifth fingers (one), microtia with cleft lip and palate (one), microtia alone (one), and neonatal death with multiple malformations (one). One kidney/pancreas (K/P) recipient reported one SA. Three liver recipients reported three pregnancies; two LB (no malformations), and one second trimester SA. Two heart recipients reported one LB (no malformations) and two SA. SRL exposures included seven recipients (four kidney, one K/P and two liver) reporting four LB (one infant whose mother was switched from MMF to SRL during late pregnancy had cleft lip and palate and microtia) and three SA. A higher incidence of structural malformations was seen with MMF exposures during pregnancy compared to the overall kidney transplant recipient offspring, while no structural defects have as yet been reported with early pregnancy sirolimus exposures. Centers are encouraged to report all pregnancy exposures in transplant recipients.


Variation of insulin-related peptides accompanying the differentiation of Aphis gossypii biotypes and their expression profiles.
Insulin signaling plays a critical role in regulating various aspects of insect biology, including development, reproduction, and the formation of wing polyphenism. This leads to differentiation among insect populations at different levels. The insulin family exhibits functional variation, resulting in diverse functional pathways. Aphis gossypii Glover, commonly known as the cotton-melon aphid, is a highly adaptable aphid species that has evolved into multiple biotypes. To understand the genetic structure of the insulin family and its evolutionary diversification and expression patterns in A. gossypii, we conducted studies using genome annotation files and RNA-sequencing data. Consequently, we identified 11 insulin receptor protein (IRP) genes in the genomes of the examined biotypes. Among these, eight AgosIRPs were dispersed across the X chromosome, while two were found in tandem on the A1 chromosome. Notably, AgosIRP2 exhibited alternative splicing, resulting in the formation of two isoforms. The AgosIRP genes displayed a high degree of conservation between Hap1 and Hap3, although some variations were observed between their genomes. For instance, a transposon was present in the coding regions of AgosIRP3 and AgosIRP9 in the Hap3 genome but not in the Hap1 genome. RNA-sequencing data revealed that four AgosIRPs were expressed ubiquitously across different morphs of A. gossypii, while others showed specific expression patterns in adult gynopara and adult males. Furthermore, the expression levels of most AgosIRPs decreased upon treatment with the pesticide acetamiprid. These findings demonstrate the evolutionary diversification of AgosIRPs between the genomes of the two biotypes and provide insights into their expression profiles across different morphs, developmental stages, and biotypes. Overall, this study contributes valuable information for investigating aphid genome evolution and the functions of insulin receptor proteins.


Appropriateness of parent-specific stature adjustment for US black children.
The appropriateness for US black children of a new method that considers parental statures when evaluating a child's length or stature is discussed. Although there are small differences in the average growth of blacks and whites, it is suggested that a single growth standard (the National Center for Health Statistics percentiles) is appropriate for the evaluation of length and stature of black children. Recent national data show no important differences between mean statures of black and white adults that would render the parent-specific method inappropriate for US blacks. Finally, there is no convincing evidence for differences between blacks and whites in parent-child relationships for stature. It is concluded that the new method is appropriate for US black children, and its use is recommended as an aid in determining the nature of statural growth problems.


Management of the marginal mandibular nerve during and after neck dissection.
Marginal mandibular nerve palsy (MMNP) is often an understated complication after neck dissection. This article reviews literature regarding anatomic landmarks that help define marginal mandibular nerve (MMN) during neck dissection, oncologic safety of surgical maneuvers, implications of MMNP, and reconstructive options. A thorough knowledge of anatomy of the nerve can aid in its preservation. Course, branching pattern and communications of MMN are extremely variable. The Hayes Martin method classically described to preserve the nerve may not be oncologically safe in patients with prefacial nodal involvement. MMNP significantly affects quality of life after neck dissection. Cause, timing, and degree of neural damage play an important role in determining diagnostic and therapeutic options to correct the deformity resulting from MMNP. Owing to treatment-related factors, functionality of local structures may be compromised, which limits available reconstructive options for the surgeon. This should favor a shift of management option toward more conservative procedures in patients treated for head and neck cancer. When oncologically safe, the MMN must always be preserved. The patient perceived deformity resulting from MMNP is significantly higher than clinician-detected rate. In select patients who are affected by significant smile asymmetry, multiple dynamic and static corrective procedures can be offered.


The binding, transport and fate of aluminium in biological cells.
Aluminium is the most abundant metal in the Earth's crust and yet, paradoxically, it has no known biological function. Aluminium is biochemically reactive, it is simply that it is not required for any essential process in extant biota. There is evidence neither of element-specific nor evolutionarily conserved aluminium biochemistry. This means that there are no ligands or chaperones which are specific to its transport, there are no transporters or channels to selectively facilitate its passage across membranes, there are no intracellular storage proteins to aid its cellular homeostasis and there are no pathways which evolved to enable the metabolism and excretion of aluminium. Of course, aluminium is found in every compartment of every cell of every organism, from virus through to Man. Herein we have investigated each of the 'silent' pathways and metabolic events which together constitute a form of aluminium homeostasis in biota, identifying and evaluating as far as is possible what is known and, equally importantly, what is unknown about its uptake, transport, storage and excretion.


Remarkable magnetism and ferromagnetic coupling in semi-sulfuretted transition-metal dichalcogenides.
Motivated by recent investigations of semi-decorated two dimensional honeycomb structures, we demonstrated, via spin-polarized molecular-dynamics simulations and density-functional-theory calculations, that semi-sulfuretted transition-metal dichalcogenides of MX type (M = V, Nb, Ta; X = S, Se, Te) are stable and display remarkable magnetism. The unpaired d electron of the transition-metal atom arising from the breakage of the M-X bond is the mechanism behind the induction of the magnetism. The remarkable magnetism of the transition-metal atoms is caused by ferromagnetic coupling due to the competitive effects of through-bond interactions and through-space interactions. This implies the existence of an infinite ferromagnetic sheet with structural integrity and magnetic homogeneity. The estimated Curie temperatures suggest that the ferromagnetism can be achieved above room temperature in the VS, VSe, VTe, NbTe and TaTe sheets. Depending on the species of the M and X atoms, the MX sheet can be a magnetic metal, magnetic semiconductor or half-metal. Furthermore, in contrary to the recently reported semi-hydrogenated and semi-fluorinated layered materials consisting of B, C, N, etc., the MX sheets with many unpaired d electrons can offer a much stronger spin polarization and possess a more stable ferromagnetic coupling, which is critical for practical nanoscale device applications.


The interactions of ants with their biotic environment.
This special feature results from the symposium 'Ants 2016: ant interactions with their biotic environments' held in Munich in May 2016 and deals with the interactions between ants and other insects, plants, microbes and fungi, studied at micro- and macroevolutionary levels with a wide range of approaches, from field ecology to next-generation sequencing, chemical ecology and molecular genetics. In this paper, we review key aspects of these biotic interactions to provide background information for the papers of this special feature After listing the major types of biotic interactions that ants engage in, we present a brief overview of ant/ant communication, ant/plant interactions, ant/fungus symbioses, and recent insights about ants and their endosymbionts. Using a large molecular clock-dated Formicidae phylogeny, we map the evolutionary origins of different ant clades' interactions with plants, fungi and hemiptera. Ants' biotic interactions provide ideal systems to address fundamental ecological and evolutionary questions about mutualism, coevolution, adaptation and animal communication.


Neuroprotective Strategies for Stroke by Natural Products: Advances and Perspectives.
Cerebral ischemic stroke is a disease with high prevalence and incidence. Its management focuses on rapid reperfusion with intravenous thrombolysis and endovascular thrombectomy. Both therapeutic strategies reduce disability, but the therapy time window is short, and the risk of bleeding is high. Natural products (NPs) have played a key role in drug discovery, especially for cancer and infectious diseases. However, they have made little progress in clinical translation and pose challenges to the treatment of stroke. Recently, with the investigation of precise mechanisms in cerebral ischemic stroke and the technological development of NP-based drug discovery, NPs are addressing these challenges and opening up new opportunities in cerebral stroke. Thus, in this review, we first summarize the structure and function of diverse NPs, including flavonoids, phenols, terpenes, lactones, quinones, alkaloids, and glycosides. Then we propose the comprehensive neuroprotective mechanism of NPs in cerebral ischemic stroke, which involves complex cascade processes of oxidative stress, mitochondrial damage, apoptosis or ferroptosis-related cell death, inflammatory response, and disruption of the blood-brain barrier (BBB). Overall, we stress the neuroprotective effect of NPs and their mechanism on cerebral ischemic stroke for a better understanding of the advances and perspective in NPs application that may provide a rationale for the development of innovative therapeutic regimens in ischemic stroke.


Maternal and Fetal Outcomes of Anticoagulation in Pregnant Women With Mechanical Heart Valves.
Anticoagulation for mechanical heart valves during pregnancy is essential to prevent thromboembolic events. Each regimen has drawbacks with regard to maternal or fetal risk. This meta-analysis sought to estimate and compare the risk of adverse maternal and fetal outcomes in pregnant women with mechanical heart valves who received different methods of anticoagulation. Studies were identified using a Medline search including all publications up to June 5, 2016. Study inclusion required reporting of maternal death, thromboembolism, and valve failure, and/or fetal spontaneous abortion, death, and congenital defects in pregnant women treated with any of the following: 1) a vitamin K antagonist (VKA) throughout pregnancy; 2) low-molecular-weight heparin (LMWH) throughout pregnancy; 3) LMWH for the first trimester, followed by a VKA (LMWH and VKA); or 4) unfractionated heparin for the first trimester, followed by a VKA (UFH and VKA). A total of 800 pregnancies from 18 publications were included. Composite maternal risk was lowest with VKA (5%), compared with LMWH (16%; ratio of averaged risk [RAR]: 3.2; 95% confidence interval [CI]: 1.5 to 7.5), LMWH and VKA (16%; RAR: 3.1; 95% CI: 1.2 to 7.5), or UFH and VKA (16%; RAR: 3.1; 95% CI: 1.5 to 7.1). Composite fetal risk was lowest with LMWH (13%; RAR: 0.3; 95% CI: 0.1 to 0.8), compared with VKA (39%), LMWH and VKA (23%), or UFH and VKA (34%). No significant difference in fetal risk was observed between women taking ≤5 mg daily warfarin and those with an LMWH regimen (RAR: 0.9; 95% CI: 0.3 to 2.4). VKA treatment was associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH throughout pregnancy was associated with the lowest risk of adverse fetal outcomes. Fetal risk was similar between women taking ≤5 mg warfarin daily and women treated with LMWH.