Molecular phylogeny, scale evolution and taxonomy of centrohelid heliozoa.
Heliozoa are ubiquitous, unicellular phagotrophs with slender radiating axopodia for trapping prey. We sequenced 18S rRNA genes from 35 cultured centrohelid heliozoa (18 studied by electron microscopy) and 28 environmental libraries (18 freshwater, 10 marine), yielding 97 new sequences, this exceeding described species. Phylogenetic analyses show two major groups and that ancestral centrohelids probably had inner plate-like tangential and distinct outer radial silica scales, the latter diverging early into contrasting scale types seen in extant Pterocystis/Choanocystis and Acanthocystis/Raphidiophryidae. Scales were lost at least thrice. Pterocystis is paraphyletic, as was the classical family Acanthocystidae; Heterophrys was polyphyletic. Using scale morphology and rRNA sequences, we establish new families Pterocystidae (Pterocystis, Raineriophrys, Chlamydaster), Marophryidae (type Marophrys (Heterophrys) marina gen. et comb. nov.) and Choanocystidae, new suborders Pterocystina (Pterocystidae, Choanocystidae, Heterophryidae) and Acanthocystina (Acanthocystidae, Raphidiophryidae, Marophryidae), and ten new Pterocystis, Acanthocystis and Choanocystis species. Most clades are exclusively freshwater or exclusively marine; evolutionary transitions between these habitats have been rare.


Current practice of hypoglycemia management in the ED.
To characterize hypoglycemia management and identify characteristics associated with refractory (need for additional treatment following initial management) and recurrent (adequate initial treatment followed by blood glucose [BG] ≤50 mg/dL) hypoglycemia. Retrospective review of adult emergency department (ED) patients who presented to a large academic medical center with hypoglycemia (BG ≤ 50 mg/dL) between January 2011 and July 2015. Data collection focused on BG measurements and treatment practices. Data are reported using descriptive statistics, Wilcoxon rank sum, and χ2 analysis as appropriate. Two hundred forty-four patients were included (mean age, 59 ± 18.7 years; weight, 85 ± 24.3 kg). Patients arriving via prehospital care (n = 124) were assessed faster in the ED (median, 25 minutes; interquartile range [IQR], 10-40 minutes) compared with ambulatory arrival (median, 43 minutes; IQR, 17-95 minutes; P = .0018). There were 174 patients with a BG ≤ 50 mg/dL in the ED. Of those, 108 (62.1%) were treated with intravascular bolus dextrose/intramuscular glucagon and 21 patients (12%) did not receive any treatment or food. The overall median time to treatment after identification of hypoglycemia was 12 minutes (IQR, 6-27.8 minutes); treatment was administered faster after bedside point-of-care testing assessment compared with when serum samples resulted (11 [IQR, 6-23.5] minutes vs 25 [IQR, 10.75-42.5] minutes, respectively; P = .015). The overall time to repeat BG was obtained 22 (IQR, 8-44) minutes after bolus treatment, but this interval increased with subsequent measurements. Refractory or recurrent hypoglycemia occurred in 30.3% of patients. Mean initial BG was lower in the subset of patients who developed refractory hypoglycemia compared with those who did not (35.1 ± 9.8 vs 37.6 ± 10.2 mg/dL, P = .079), although not statistically significant. Patients with recurrent hypoglycemia were also less likely to receive dextrose containing intravenous fluids compared with those without recurrent hypoglycemia (P = .028). Infection was the only associated characteristic with refractory or recurrent hypoglycemia (P = .021). Overall, 12% of patients did not receive treatment for hypoglycemia in the ED with a BG ≤ 50 mg/dL. Time to treatment after identification was faster when identified by care testing vs serum sample result. Time to repeat BG in the ED was relatively quick, but did increase over time. About one-third of patients had refractory or recurrent hypoglycemia and infection was associated with this occurrence. Lack of dextrose containing intravenous fluid was associated with the incidence of recurrent hypoglycemia.


Fructosamine is a useful indicator of hyperglycaemia and glucose control in clinical and epidemiological studies--cross-sectional and longitudinal experience from the AMORIS cohort.
Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively. The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes. From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively. All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA1c Pearson linear correlation coefficients in the range of 0.67-0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91-0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%. Fructosamine is closely associated with HbA1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.


The effectiveness of verbal versus activity groups in improving self-perceptions of interpersonal communication skills.
This study compares the efficacy of a verbal group with that of an activity group in an occupational therapy clinic during the treatment of interpersonal communication deficits at a psychiatric day treatment center. Outpatients were randomly assigned to the following groups: an experimental group, which received activity therapy (n = 7), an experimental group, which received verbal therapy (n = 6), and a control group, which was involved exclusively in the normal milieu therapy at the center (n = 6). The two experimental groups received one hour of treatment per week for eight weeks. The pretesting and posttesting of interpersonal communication skills were done with the Interpersonal Communication Inventory. The activity group used collages, problem-solving tasks, role-playing sessions, games, and drawing exercises. The verbal group used discussion exclusively. Both the activity and verbal groups were based on whether participants had the following: an adequate self-concept, the ability to be a good listener, the skill of expressing his or her thoughts and ideas clearly, the ability to cope with his or her emotions (particularly with angry feelings) and express them in a constructive way, and a willingness to disclose him- or herself to others freely and truthfully. A significantly higher level of interpersonal communication skills was attained by the activity group. Comparisons between both groups and the control group showed no significant differences.


Rewriting and suppressing UMLS terms for improved biomedical term identification.
Identification of terms is essential for biomedical text mining.. We concentrate here on the use of vocabularies for term identification, specifically the Unified Medical Language System (UMLS). To make the UMLS more suitable for biomedical text mining we implemented and evaluated nine term rewrite and eight term suppression rules. The rules rely on UMLS properties that have been identified in previous work by others, together with an additional set of new properties discovered by our group during our work with the UMLS. Our work complements the earlier work in that we measure the impact on the number of terms identified by the different rules on a MEDLINE corpus. The number of uniquely identified terms and their frequency in MEDLINE were computed before and after applying the rules. The 50 most frequently found terms together with a sample of 100 randomly selected terms were evaluated for every rule. Five of the nine rewrite rules were found to generate additional synonyms and spelling variants that correctly corresponded to the meaning of the original terms and seven out of the eight suppression rules were found to suppress only undesired terms. Using the five rewrite rules that passed our evaluation, we were able to identify 1,117,772 new occurrences of 14,784 rewritten terms in MEDLINE. Without the rewriting, we recognized 651,268 terms belonging to 397,414 concepts; with rewriting, we recognized 666,053 terms belonging to 410,823 concepts, which is an increase of 2.8% in the number of terms and an increase of 3.4% in the number of concepts recognized. Using the seven suppression rules, a total of 257,118 undesired terms were suppressed in the UMLS, notably decreasing its size. 7,397 terms were suppressed in the corpus. We recommend applying the five rewrite rules and seven suppression rules that passed our evaluation when the UMLS is to be used for biomedical term identification in MEDLINE. A software tool to apply these rules to the UMLS is freely available at http://biosemantics.org/casper.


An empirically-derived approach for investigating Health Information Technology: the Elementally Entangled Organisational Communication (EEOC) framework.
The purpose of this paper is to illustrate the Elementally Entangled Organisational Communication (EEOC) framework by drawing on a set of three case studies which assessed the impact of new Health Information Technology (HIT) on a pathology service. The EEOC framework was empirically developed as a tool to tackle organisational communication challenges in the implementation and evaluation of health information systems. The framework was synthesised from multiple research studies undertaken across a major metropolitan hospital pathology service during the period 2005 to 2008. These studies evaluated the impact of new HIT systems in pathology departments (Laboratory Information System) and an Emergency Department (Computerised Provider Order Entry) located in Sydney, Australia. Key dimensions of EEOC are illustrated by the following case studies: 1) the communication infrastructure between the Blood Bank and the ward for the coordination and distribution of blood products; 2) the organisational environment in the Clinical Chemistry and Haematology departments and their attempts to organise, plan and control the processing of laboratory specimens; and 3) the temporal make up of the organisation as revealed in changes to the way the Central Specimen Reception allocated, sequenced and synchronised work tasks. The case studies not only highlight the pre-existing communication architecture within the organisation but also the constitutive role communication plays in the way organisations go about addressing their requirements. HIT implementation involves a mutual transformation of the organisation and the technology. This is a vital consideration because of the dangers associated with poor organisational planning and implementation of HIT, and the potential for unintended adverse consequences, workarounds and risks to the quality and safety of patient care. The EEOC framework aims to account for the complex range of contextual factors and triggers that play a role in the success or otherwise of new HITs, and in the realisation of their innovation potential.


Interaction of Ochratoxin A and Its Thermal Degradation Product 2'R-Ochratoxin A with Human Serum Albumin.
Ochratoxin A (OTA) is a toxic secondary metabolite produced by several fungal species of the genus Penicillium and Aspergillus. 2′R-Ochratoxin A (2′R-OTA) is a thermal isomerization product of OTA formed during food processing at high temperatures. Both compounds are detectable in human blood in concentrations between 0.02 and 0.41 µg/L with 2′R-OTA being only detectable in the blood of coffee drinkers. Humans have approximately a fifty-fold higher exposure through food consumption to OTA than to 2′R-OTA. In human blood, however, the differences between the concentrations of the two compounds is, on average, only a factor of two. To understand these unexpectedly high 2′R-OTA concentrations found in human blood, the affinity of this compound to the most abundant protein in human blood the human serum albumin (HSA) was studied and compared to that of OTA, which has a well-known high binding affinity. Using fluorescence spectroscopy, equilibrium dialysis, circular dichroism (CD), high performance affinity chromatography (HPAC), and molecular modelling experiments, the affinities of OTA and 2′R-OTA to HSA were determined and compared with each other. For the affinity of HSA towards OTA, a logK of 7.0⁻7.6 was calculated, while for its thermally produced isomer 2′R-OTA, a lower, but still high, logK of 6.2⁻6.4 was determined. The data of all experiments showed consistently that OTA has a higher affinity to HSA than 2′R-OTA. Thus, differences in the affinity to HSA cannot explain the relatively high levels of 2′R-OTA found in human blood samples.


The role of foreign direct investment in the nutrition transition.
To examine the role of foreign direct investment (FDI) in the nutrition transition, focusing on highly processed foods. Data on FDI were identified from reports/databases and then compiled and analysed. A review of published literature on FDI into the food sector was conducted. The nutrition transition is a public health concern owing to its connection with the rising burden of obesity and diet-related chronic diseases in developing countries. Global health leaders are calling for action to address the threat. Highly processed foods often have considerable fat, sugar and salt content, and warrant closer examination. FDI into food processing, service and retail has risen rapidly since the 1980s, mainly from transnational food companies (TFCs) in developed countries. As FDI has risen, so has the proportion invested in highly processed foods for sale in the host market. FDI has proved more effective than trade in generating sales of highly processed foods, and enables TFCs to cut costs, gain market power and obtain efficiencies in distribution and marketing. The amount of FDI targeted at developing countries is increasing; while a disproportionate share enters the larger developing economies, foreign affiliates of TFCs are among the largest companies in low- and low- to middle-income countries. The effect of FDI is to make more highly processed foods available to more people. FDI has made it possible to lower prices, open up new purchasing channels, optimise the effectiveness of marketing and advertising, and increase sales. FDI has been a key mechanism in shaping the global market for highly processed foods. Notwithstanding the role of demand-side factors, it has played a role in the nutrition transition by enabling and promoting the consumption of these foods in developing countries. Empirical data on consumption patterns of highly processed foods in developing countries are critically needed, but since FDI is a long-term investment vehicle, it is reasonable to assume that availability and consumption of highly processed foods will continue to increase. FDI can, however, bring considerable benefits as well as risks. Through its position 'upstream', FDI would therefore be an appropriate entry-point to implement a range of public health policies to 'redirect' the nutrition transition.


ASPP [corrected] and cancer.
One of the most frequently mutated genes in human cancers, tumour suppressor p53 (TP53), can induce cell-cycle arrest and apoptosis. The apoptotic function of p53 is tightly linked to its tumour-suppression function and the efficacy of many cancer therapies depends on this. The identification of a new family of proteins, known as ASPPs (ankyrin-repeat-, SH3-domain- and proline-rich-region-containing proteins), has led to the discovery of a novel mechanism that selectively regulates the apoptotic function, but not the cell-cycle-arrest function, of p53, and gives an insight into how p53 responds to different stress signals. ASPPs might be new molecular targets for cancer therapy.


Efficacy of Dexmedetomidine as a Sole Sedative Agent in Small Diagnostic and Therapeutic Procedures: A Systematic Review.
Dexmedetomidine is an upcoming agent with sedative, anxiolytic, and analgesic properties. This review summarizes empirical evidence for the efficacy of dexmedetomidine as a sole sedative agent, and its effectiveness for small diagnostic and therapeutic procedure, in comparison with other frequently used sedatives. All randomized controlled trials on the effect of dexmedetomidine were reviewed. Pain level, patient satisfaction, operator satisfaction, procedure duration, recovery time, and hemodynamic and respiratory characteristics were examined. A total of 1993 patients (1,621 adults; 372 children) from 35 studies were included. In the adult studies, dexmedetomidine yielded significantly lower pain levels compared to the other sedatives (in 31.25% of the included studies) and significantly more patient satisfaction (68.2%). In studies on children, more favorable results concerning respiratory safety and the level of adequate sedation were found compared to the control sedatives. Implications for future studies are discussed.


Effects of intensive arm training with the rehabilitation robot ARMin II in chronic stroke patients: four single-cases.
Robot-assisted therapy offers a promising approach to neurorehabilitation, particularly for severely to moderately impaired stroke patients. The objective of this study was to investigate the effects of intensive arm training on motor performance in four chronic stroke patients using the robot ARMin II. ARMin II is an exoskeleton robot with six degrees of freedom (DOF) moving shoulder, elbow and wrist joints. Four volunteers with chronic (>or= 12 months post-stroke) left side hemi-paresis and different levels of motor severity were enrolled in the study. They received robot-assisted therapy over a period of eight weeks, three to four therapy sessions per week, each session of one hour.Patients 1 and 4 had four one-hour training sessions per week and patients 2 and 3 had three one-hour training sessions per week. Primary outcome variable was the Fugl-Meyer Score of the upper extremity Assessment (FMA), secondary outcomes were the Wolf Motor Function Test (WMFT), the Catherine Bergego Scale (CBS), the Maximal Voluntary Torques (MVTs) and a questionnaire about ADL-tasks, progress, changes, motivation etc. Three out of four patients showed significant improvements (p < 0.05) in the main outcome. The improvements in the FMA scores were aligned with the objective results of MVTs. Most improvements were maintained or even increased from discharge to the six-month follow-up. Data clearly indicate that intensive arm therapy with the robot ARMin II can significantly improve motor function of the paretic arm in some stroke patients, even those in a chronic state. The findings of the study provide a basis for a subsequent controlled randomized clinical trial.


Development and Quality of Barley Husk Adhesion Correlates With Changes in Caryopsis Cuticle Biosynthesis and Composition.
The caryopses of barley become firmly adhered to the husk during grain development through a cuticular cementing layer on the caryopsis surface. The degree of this attachment varies among cultivars, with poor quality adhesion causing "skinning", an economically significant grain quality defect for the malting industry. Malting cultivars encompassing a range of husk adhesion qualities were grown under a misting treatment known to induce skinning. Development of the cementing layer was examined by electron microscopy and compositional changes of the cementing layer were investigated with gas-chromatography followed by mass spectroscopy. Changes in gene expression during adhesion development were examined with a custom barley microarray. The abundance of transcripts involved early in cuticular lipid biosynthesis, including those encoding acetyl-CoA carboxylase, and all four members of the fatty acid elongase complex of enzymes, was significantly higher earlier in caryopsis development than later. Genes associated with subsequent cuticular lipid biosynthetic pathways were also expressed higher early in development, including the decarbonylation and reductive pathways, and sterol biosynthesis. Changes in cuticular composition indicate that lowered proportions of alkanes and higher proportions of fatty acids are associated with development of good quality husk adhesion, in addition to higher proportions of sterols.


Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer.
Increased urinary excretion of equol, a metabolite of the isoflavone daidzein, has been associated with a reduced risk of breast cancer. This risk reduction has generally been presumed to be a consequence of increased isoflavone consumption. However, only 30-40% of the population excretes more than trace amounts of equol, regardless of isoflavone intake. Accordingly, we hypothesized that the observed apparent protective effect of equol is at least in part attributable to hormonal differences between equol excretors and non-excretors, and that these differences are largely independent of isoflavone intake. We measured plasma hormone and sex hormone binding globulin (SHBG) concentrations in 14 normally cycling premenopausal women during each of three diet periods in which they consumed differing isoflavone doses (0.15, 1.0, and 2.0 mg/kg of body weight/day) as a component of soy protein isolate. The plasma hormone and SHBG concentrations of equol excretors (n = 5) were then compared with those of the non-excretors (n = 9). Results showed that even at the lowest dose, urinary equol excretion values for excretors far exceeded those for non-excretors consuming the highest dose. At all doses, equol excretors generally had lower concentrations of estrone, estrone-sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-sulfate, and cortisol and higher concentrations of SHBG and midluteal progesterone, a hormonal pattern overall consistent with lowered breast cancer risk. In conclusion, the association of equol excretion and lowered breast cancer risk may largely reflect the tendency of equol excretors to have more favorable hormonal profiles, as opposed to merely reflecting increased isoflavone intake. Equol may be a marker for the presence of colonic bacterial enzymatic activity that increases fecal steroid excretion. Alternatively, equol itself, even with very modest isoflavone intake, may exert beneficial effects on the regulation of endogenous hormones.


Neuroendoscopic treatment of arachnoid cysts of the quadrigeminal cistern: a series of 14 cases.
In this paper, the authors' goal was to evaluate the role of neuroendoscopy in the treatment of arachnoid cysts of the quadrigeminal cistern. Between March 1995 and February 2008, 14 patients affected by arachnoid cysts of the quadrigeminal cistern were treated endoscopically. The cysts were classified according to their anatomical and radiological appearance. The most frequent form (Type I) extended infratentorially and supratentorially with a dumbbell shape. Type II cysts were confined to the infratentorial space and were associated with the most severe and acute form of hydrocephalus. Type III cysts presented a significant asymmetric expansion toward the temporal fossa. Ten patients underwent an endoscopic procedure as primary treatment and 4 as an alternative to shunt revision. In 6 cases, the first endoscopic procedure was ventriculocystostomy (VC) together with endoscopic third ventriculostomy (ETV). In the other 8 cases, the first endoscopic procedure was VC alone. In the 6 cases in which VC was performed with an ETV, the procedure was successful, and the patients did not require further surgery. Of the 8 cases in which the first endoscopic procedure performed was VC without ETV, 7 underwent reoperation. Four of these patients underwent endoscopic procedures (by reopening the obstructed VC and performing ETV or cystocisternostomy) 2, 4, 4, and 5 months later with final success in all cases. Three patients (all of whom were previously treated using ventriculo- or cystoperitoneal shunts) required shunt reimplantation (complete failure). Subdural collection developed in 1 case, which was managed by transient insertion of a subduroperitoneal shunt. Neurological and developmental outcomes were good except for 1 patient who did not show improvement in preoperative developmental delay. No transient or permanent morbidity or mortality was observed. The analysis of this series suggests that arachnoid cysts of the quadrigeminal cistern and the associated hydrocephalus can be effectively treated by endoscopy; this approach allows the patient to be shunt independent in more than 78% of the cases. If endoscopy is used as first option, the success rate of endoscopic procedures observed in this series was 90%. Endoscopic third ventriculostomy should be associated with a VC to offer the highest success rate with a single procedure.


Chronic Disease Decision Making and "What Matters Most".
The increasing use of the question, "What matters most to you?" is a welcome development in the effort to provide patient-centered care. However, it is difficult for clinicians to translate answers to this question into treatment plans for chronic conditions, including recognizing when to consider options other than clinical practice guideline (CPG)-directed therapy. Goal elicitation is most helpful when a patient has different treatment options with clearly identifiable trade-offs. In the face of trade-offs, goal elicitation helps patients to prioritize among potentially competing outcomes. While decision aids (DAs) focus on trade-offs by delineating options and outcomes, the robust outcome data necessary to create DAs for older patients with multimorbidity are often lacking and even mild cognitive impairment makes the use of DAs difficult. The challenges for providing chronic disease care to older patients who are at risk for adverse events from CPG-directed therapy because of multimorbidity and/or frailty are to organize the complexity of individual combinations of diseases, conditions, and syndromes into common sets of trade-offs and to identify those goals or priorities that will directly inform a plan of care. J Am Geriatr Soc 68:474-477, 2020.


Synergistic effect of antibodies to human leukocyte antigens and defensins in pathogenesis of bronchiolitis obliterans syndrome after human lung transplantation.
This study aims to determine the role of antibodies to donor-mismatched human leukocyte antigen (HLA) developed during the post-transplant period in inducing defensins and their synergistic role in the pathogenesis of chronic rejection, bronchiolitis obliterans syndrome (BOS), after human lung transplantation (LTx). Bronchoalveolar lavage (BAL) and serum from 21 BOS+ LTx patients were assayed for β-defensins human neutrophil peptides (HNP) 1-3 (enzyme-linked immunosorbent assay [ELISA]) and anti-HLA antibodies (Luminex, Luminex Corp, Austin, TX). Human airway epithelial cells (AEC) were treated with anti-HLA antibodies, HNP-1/2, or both, and the levels of β-defensin were measured by ELISA. Using a mouse model of obliterative airway disease induced by anti-major histocompatibility (MHC) class-I antibodies, we quantitatively and qualitatively determined neutrophil infiltration by myeloperoxidase (MPO) staining and activity by MPO assay, and defensin levels in the BAL. In human LTx patients, higher defensin levels correlated with presence of circulating anti-HLA antibodies (p < 0.05). AEC treated with anti-HLA antibodies or HNP-1/2, produced β-defensin with synergistic effects in combination (612 ± 06 vs 520 ± 23 pg/ml anti-HLA antibody, or 590 ± 10 pg/ml for HNP treatment; p < 0.05). Neutrophil numbers (6-fold) and activity (5.5-fold) were higher in the lungs of mice treated with anti-MHC antibodies vs control. A 2-fold increase in α-defensin and β-defensin levels was also present in BAL on Day 5 after anti-MHC administrations. Anti-HLA antibodies developed during the post-transplant period and α-defensins stimulated β-defensin production by epithelial cells, leading to increased cellular infiltration and inflammation. Chronic stimulation of epithelium by antibodies to MHC and resulting increased levels of defensins induce growth factor production and epithelial proliferation contributing to the development of chronic rejection after LTx.


Carbon dioxide clathrate in the martian ice cap.
Measurements of the dissociation pressure of carbon dioxide hydrate show that this hydrate (CO(2) . 6H(2)O) is stable relative to solid CO(2) and water ice at temperatures above about 121 degrees K. Since this hydrate forms from finely divided ice and gaseous CO(2) in several hours at 150 degrees K, it is likely to be present in the martian ice cap. The ice cap can consist of water ice, water ice + CO(2) hydrate, or CO(2) hydrate + solid CO(2), but not water ice + solid CO(2).


Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms.
Genetic polymorphisms of human arylamine N-acetyltransferase 2 (NAT2) are responsible for interindividual variation in the acetylation of numerous drugs and in the transformation of aromatic and heterocyclic amines into carcinogenic intermediates. Although large interethnic variability in the frequency for NAT2 variant alleles has been reported, comparison of allele frequencies is hampered by differences in the criteria for the assignment of allelic variants. To avoid such sources of bias, in this review we analyze the occurrence of both interethnic and intraethnic variability for the seven commonest single nucleotide polymorphisms (SNP) in the NAT2 gene by using raw SNP data instead of inferred haplotypes. Besides the large interethnic variability observed for all SNPs except C282T, intraethnic variability for NAT2 SNPs was identified for the SNPs G191A among Caucasians (p<0.0001), T341C among Oriental (p<0.001) or African individuals (p<0.012), C481T among Oriental (p<0.001) or African individuals (p<0.001), and G590A among Oriental individuals (p<0.001). In contrast, no major intraethnic differences were identified for the SNPs C282T, A806G or G857A. Intraethnic variability may have relevant clinical implications. For instance, case-control NAT2 studies should not be extrapolated from one Oriental population to another. Nonsynonymous SNPs occur in 32% of alleles in Japanese individuals and in 47% of alleles in Chinese individuals, therefore the frequency of adverse effects and cancer related to slow acetylation is expected to be higher in individuals with Chinese descent than in those with Japanese descent. Intraethnic variability reinforces the need for proper selection of control subjects and points against the use of surrogate control groups for studies involving association of NAT2 alleles with adverse drug effects or spontaneous diseases.


First Report of Pepper Fruit Rot Caused by Fusarium concentricum in China.
Pepper (Capsicum annuum L.) is an important vegetable crop worldwide. Some Fusarium species can cause pepper fruit rot, leading to significant yield losses of pepper production and, for some Fusarium species, potential risk of mycotoxin contamination. A total of 106 diseased pepper fruit samples were collected from various pepper cultivars from seven provinces (Gansu, Hainan, Heilongjiang, Hunan, Shandong, Shanghai, and Zhejiang) in China during the 2012 growing season, where pepper production occurs on approximately 25,000 ha. Pepper fruit rot symptom incidence ranged from 5 to 20% in individual fields. Symptomatic fruit tissue was surface-sterilized in 0.1% HgCl2 for 1 min, dipped in 70% ethanol for 30 s, then rinsed in sterilized distilled water three times, dried, and plated in 90 mm diameter petri dishes containing potato dextrose agar (PDA). After incubation for 5 days at 28°C in the dark, putative Fusarium colonies were purified by single-sporing. Forty-three Fusarium strains were isolated and identified to species as described previously (1,2). Morphological characteristics of one strain were identical to those of F. concentricum. Aerial mycelium was reddish-white with an average growth rate of 4.2 to 4.3 mm/day at 25°C in the dark on PDA. Pigments in the agar were formed in alternating red and orange concentric rings. Microconidia were 0- to 1-septate, mostly 0-septate, and oval, obovoid to allantoid. Macroconidia were relatively slender with no significant curvature, 3- to 5-septate, with a beaked apical cell and a foot-shaped basal cell. To confirm the species identity, the partial TEF gene sequence (646 bp) was amplified and sequenced (GenBank Accession No. KC816735). A BLASTn search with TEF gene sequences in NCBI and the Fusarium ID databases revealed 99.7 and 100% sequence identity, respectively, to known TEF sequences of F. concentricum. Thus, both morphological and molecular criteria supported identification of the strain as F. concentricum. This strain was deposited as Accession MUCL 54697 (http://bccm.belspo.be/about/mucl.php). Pathogenicity of the strain was confirmed by inoculating 10 wounded, mature pepper fruits that had been harvested 70 days after planting the cultivar Zhongjiao-5 with a conidial suspension (1 × 106 spores/ml), as described previously (3). A control treatment consisted of inoculating 10 pepper fruits of the same cultivar with sterilized distilled water. The fruit were incubated at 25°C in a moist chamber, and the experiment was repeated independently in triplicate. Initially, green to dark brown lesions were observed on the outer surface of inoculated fruit. Typical soft-rot symptoms and lesions were observed on the inner wall when the fruit were cut open 10 days post-inoculation. Some infected seeds in the fruits were grayish-black and covered by mycelium, similar to the original fruit symptoms observed at the sampling sites. The control fruit remained healthy after 10 days of incubation. The same fungus was isolated from the inoculated infected fruit using the method described above, but no fungal growth was observed from the control fruit. To our knowledge, this is the first report of F. concentricum causing a pepper fruit rot. References: (1) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Ames, IA, 2006. (2) K. O'Donnell et al. Proc. Nat. Acad. Sci. USA 95:2044, 1998. (3) Y. Yang et al. 2011. Int. J. Food Microbiol. 151:150, 2011.


Roles of sodium hydrosulfide and sodium nitroprusside as priming molecules during drought acclimation in citrus plants.
Emerging evidence suggests that the gaseous molecules hydrogen sulfide (H2S) and nitric oxide (NO) enhances plant acclimation to stress; however, the underlying mechanism remains unclear. In this work, we explored if pretreatment of citrus roots with NaHS (a H2S donor) or sodium nitroprusside (SNP, a NO donor) for 2 days (d) could elicit long-lasting priming effects to subsequent exposure to PEG-associated drought stress for 21 d following a 5 d acclimation period. Detailed physiological study documented that both pretreatments primed plants against drought stress. Analysis of the level of nitrite, NOx, S-nitrosoglutahione reductase, Tyr-nitration and S-nitrosylation along with the expression of genes involved in NO-generation suggested that the nitrosative status of leaves and roots was altered by NaHS and SNP. Using a proteomic approach we characterized S-nitrosylated proteins in citrus leaves exposed to chemical treatments, including well known and novel S-nitrosylated targets. Mass spectrometry analysis also enabled the identification of 42 differentially expressed proteins in PEG alone-treated plants. Several PEG-responsive proteins were down-regulated, especially photosynthetic proteins. Finally, the identification of specific proteins that were regulated by NaHS and SNP under PEG conditions provides novel insight into long-term drought priming in plants and in a fruit crop such as citrus in particular.


Acoustic power measurement of high intensity focused ultrasound in medicine based on radiation force.
How to measure the acoustic power of HIFU is one of the most important tasks in its medical application. In the paper a whole series of formula for calculating the radiation force related to the acoustic power radiated by a single element focusing transducer and by the focusing transducer array were given. Various system of radiation force balance (RFB) to measure the acoustic power of HIFU in medicine were designed and applied in China. In high power experiments, the dependence of radiation force acting the absorbing target on the target position at the beam axis of focusing transducer was fined. There is a peak value of "radiation force" acting the absorbing target in the focal region when the acoustic power through the focal plane exceeds some threshold. In order to avoid this big measurement error caused by the 'peak effect' in focal region, the distance between the absorbing target of RFB and the focusing transducer or transducer array was defined to be equal to or less than 0.7 times of the focal length in the National Standard of China for the measurements of acoustic power and field characteristics of HIFU. More than six different therapeutic equipments of HIFU have been examined by RFB for measuring the acoustic power since 1998. These results show that RFB with the absorbing target is valid in the acoustic power range up to 500W with good linearity for the drive voltage squared of focusing transducer or array. The uncertainty of measurement is within +/-15%.


[Analysis on medication regularity and action mechanism of Tibetan medicine in treatment of spleen and stomach diseases based on data mining and integrated pharmacology].
To explore the medication regularity of Tibetan medicine in the treatment of spleen and stomach diseases, analyze the potential drug targets and interactions of the prescriptions, and reveal the mechanism of Tibetan medicine in the treatment of spleen and stomach diseases. The prescriptions in Tibetan medicine for treatment of spleen and stomach diseases were collected, and Traditional Chinese Medicine Inheritance Support System (TCMISS) was used to analyze the association rules between the herbs and discover the core herbs and new prescriptions. The integrated pharmacology platform V1.0 software was used to construct "herb-compound-target" network and investigate the interactions between various herbs and related pathways of Tibetan medicine Wuwei Shiliu powder in the treatment of spleen and stomach diseases. Among the 216 prescriptions of Tibetan medicine in the treatment of spleen and stomach diseases, pomegranate seed was used at a highest frequency (118 times), followed by white cardamom (107 times) and comatose (107 times). 12 new prescriptions were evolved by using the association rules (support>=34%, confidence>=0.85). 5 242 related drug targets and 20 related pathways were obtained from classic formula Wuwei Shiliu Powder (FDR<0.01). It was proposed that Tibetan medicine treatment for spleen and stomach diseases was mainly based on proliferation of "stomach fire" and the main drugs were for regulating Qi-flowing for strengthening spleen. The mechanism may be associated with regulation of digestive juice secretion, proton pump, mitochondria, regulation of intestinal digestion and immunity, the body's immunity to microorganisms function and other multiple targets and pathways to achieve the joint intervention.


High-order total variation-based multiplicative noise removal with spatially adapted parameter selection.
Multiplicative noise is one common type of noise in imaging science. For coherent image-acquisition systems, such as synthetic aperture radar, the observed images are often contaminated by multiplicative noise. Total variation (TV) regularization has been widely researched for multiplicative noise removal in the literature due to its edge-preserving feature. However, the TV-based solutions sometimes have an undesirable staircase artifact. In this paper, we propose a model to take advantage of the good nature of the TV norm and high-order TV norm to balance the edge and smoothness region. Besides, we adopt a spatially regularization parameter updating scheme. Numerical results illustrate the efficiency of our method in terms of the signal-to-noise ratio and structure similarity index.


A unifying model for the analysis of phenotypic, genetic, and geographic data.
Recognition of evolutionary units (species, populations) requires integrating several kinds of data, such as genetic or phenotypic markers or spatial information in order to get a comprehensive view concerning the differentiation of the units. We propose a statistical model with a double original advantage: (i) it incorporates information about the spatial distribution of the samples, with the aim to increase inference power and to relate more explicitly observed patterns to geography and (ii) it allows one to analyze genetic and phenotypic data within a unified model and inference framework, thus opening the way to robust comparisons between markers and possibly combined analyses. We show from simulated data as well as real data that our method estimates parameters accurately and is an improvement over alternative approaches in many situations. The power of this method is exemplified using an intricate case of inter- and intraspecies differentiation based on an original data set of georeferenced genetic and morphometric markers obtained on Myodes voles from Sweden. A computer program is made available as an extension of the R package Geneland.


Knowledge of and Attitudes toward Medical Professionalism among Students and Junior Doctors in Trinidad and Tobago.
The past decade has seen an increasing focus on professionalism within the medical school curriculum. This reflects the growing demand for doctors who demonstrate empathy and uphold the altruistic values of the Hippocratic Oath. Such is often challenged by the resource-constrained environments of developing nations requiring uniquely tailored interventions within these regions. As part of a wider effort to develop training of medical professionalism at our institution, an initiative was pursued to assess the current knowledge about and attitudes toward medical professionalism. The study was designed as a cross-sectional descriptive study of fourth and fifth year medical students and junior doctors. A questionnaire was adapted and revised from a previously published study. Questions were grouped into categories pertaining to knowledge about professionalism and attitudes toward professionalism. Overall, 191 questionnaires were analysed (168 students and 23 doctors). Junior doctors' scores were higher than medical students for all knowledge subscales but scores on the attitude subscales were significantly lower than medical students. Overall, in both groups, attitude scores were higher than knowledge scores. There was an overall trend of decreasing attitude scores as persons progressed through their training years and into clinical practice. Results demonstrate limited knowledge about medical professionalism but good attitudes toward this trait. Taken together, this perhaps highlights a receptivity toward more formal training within this area that is also justified by the marked decline in attitude scores over time.


miR-23a binds to p53 and enhances its association with miR-128 promoter.
Apoptosis plays an important role in cardiac pathology, but the molecular mechanism by which apoptosis regulated remains largely elusive. Here, we report that miR-23a promotes the apoptotic effect of p53 in cardiomyocytes. Our results showed that miR-23a promotes apoptosis induced by oxidative stress. In exploring the molecular mechanism by which miR-23a promotes apoptosis, we found that it sensitized the effect of p53 on miR-128 regulation. It promoted the association of p53 to the promoter region of miR-128, and enhanced the transcriptional activation of p53 on miR-128 expression. miR-128 can downregulate prohibitin expression, and subsequently promote apoptosis. Our data provides novel evidence revealing that miR-23a can stimulate transcriptional activity of p53.


Activity in the primary somatosensory cortex induced by reflexological stimulation is unaffected by pseudo-information: a functional magnetic resonance imaging study.
Reflexology is an alternative medical practice that produces beneficial effects by applying pressure to specific reflex areas. Our previous study suggested that reflexological stimulation induced cortical activation in somatosensory cortex corresponding to the stimulated reflex area; however, we could not rule out the possibility of a placebo effect resulting from instructions given during the experimental task. We used functional magnetic resonance imaging (fMRI) to investigate how reflexological stimulation of the reflex area is processed in the primary somatosensory cortex when correct and pseudo-information about the reflex area is provided. Furthermore, the laterality of activation to the reflexological stimulation was investigated. Thirty-two healthy Japanese volunteers participated. The experiment followed a double-blind design. Half of the subjects received correct information, that the base of the second toe was the eye reflex area, and pseudo-information, that the base of the third toe was the shoulder reflex area. The other half of the subjects received the opposite information. fMRI time series data were acquired during reflexological stimulation to both feet. The experimenter stimulated each reflex area in accordance with an auditory cue. The fMRI data were analyzed using a conventional two-stage approach. The hemodynamic responses produced by the stimulation of each reflex area were assessed using a general linear model on an intra-subject basis, and a two-way repeated-measures analysis of variance was performed on an intersubject basis to determine the effect of reflex area laterality and information accuracy. Our results indicated that stimulation of the eye reflex area in either foot induced activity in the left middle postcentral gyrus, the area to which tactile sensation to the face projects, as well as in the postcentral gyrus contralateral foot representation area. This activity was not affected by pseudo information. The results also indicate that the relationship between the reflex area and the projection to the primary somatosensory cortex has a lateral pattern that differs from that of the actual somatotopical representation of the body. These findings suggest that a robust relationship exists between neural processing of somatosensory percepts for reflexological stimulation and the tactile sensation of a specific reflex area.


Music exposure and hearing disorders: an overview.
It has been generally accepted that excessive exposure to loud music causes various hearing symptoms (e.g. tinnitus) and consequently leads to a risk of permanent hearing damage, known as noise-induced hearing loss (NIHL). Such potential risk of NIHL due to loud music exposure has been widely investigated in musicians and people working in music venues. With advancements in sound technology and rapid developments in the music industry, increasing numbers of people, particularly adolescents and young adults, are exposing themselves to music on a voluntary basis at potentially harmful levels, and over a substantial period of time, which can also cause NIHL. However, because of insufficient audiometric evidence of hearing loss caused purely by music exposure, there is still disagreement and speculation about the risk of hearing loss from music exposure alone. Many studies have suggested using advanced audiological measurements as more sensitive and efficient tools to monitor hearing status as early indicators of cochlear dysfunction. The purpose of this review is to provide further insight into the potential risk of hearing loss caused by exposure to loud music, and thus contribute to further raising awareness of music induced hearing loss.


Jaw muscles of New World squirrels.
The jaw, suprahyoid, and extrinsic tongue muscles are described for eight species of New World squirrels, spanning more than an order of magnitude in body mass. Anatomical differences are discussed in the light of body size, natural history, and phylogeny. The relative sizes of different muscles, their orientations, and the shapes and positions of their areas of attachment vary but show few trends in relation to body size. The anatomical differences are likewise not readily explained by the mechanical requirements of the animals' diets, which are similar. The most marked anatomical differences occur in Sciurillus (the pygmy tree squirrel), as well as those genera--Glaucomys (the flying squirrel) and Tamias (the chipmunk)--that are taxonomically most distinct from the tree squirrels. Sciurillus is noteworthy for its unusually small temporalis and an anterior deep masseter that is oriented to assist in retraction of the jaw. Tamias has a more vertically oriented temporalis and greater inclination in the anterior masseter muscles than the other squirrels, features that may be associated with its large diastema and relatively posteriorly situated cheek teeth, which in turn may relate to its having cheek pouches. Our results form a valuable database of information to be used in further studies of functional morphology and phylogeny.


The Alzheimer amyloid precursor is associated with the detergent-insoluble cytoskeleton.
The amyloid beta-protein (A beta P), the main component of neuritic plaques in Alzheimer's disease (AD), is derived by unknown mechanisms from a family of amyloid precursor proteins (APPs). Using a detergent extraction procedure, we have found that in brain and in neural cell lines, 50-90% of APP is bound to detergent-insoluble cytoskeleton. Labeling experiments performed in a C6 glioma cell line indicated that both cell surface and intracellular APPs are associated with the cytoskeleton. This association requires intact microtubules and is modulated by protein phosphorylation and by cell density. These findings suggest that the function of cellular APP, presently unknown, involves the cytoskeleton and particularly microtubules. The dynamic nature of the binding and its dependence on microtubules and protein phosphorylation suggest it as a possible target in AD, where abnormal cytoskeletal structures and protein phosphorylation have been reported. Altered cytoskeletal binding of APP might lead to its aberrant proteolysis and generation of the A beta P.


Interplay between Cytoplasmic and Nuclear Androgen Receptor Splice Variants Mediates Castration Resistance.
Androgen receptor splice variants (AR-V) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often coexpressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL. Here, it is demonstrated that AR-V1, -V4, and -V6 can dimerize with both AR-V7 and AR-FL. Consequently, AR-V7 and androgen-bound AR-FL induced nuclear localization of AR-V1, -V4, and -V6, and these variants, in turn, mitigated the ability of the antiandrogen enzalutamide to inhibit androgen-induced AR-FL nuclear localization. Interestingly, the impact of nuclear localization of AR-V4 and -V6 on AR transactivation differs from that of AR-V1. Nuclear localization leads to an increased ability of AR-V4 and -V6 to transactivate both canonical AR targets and AR-V-specific targets and to confer castration-resistant cell growth. However, although AR-V1, which lacks inherent transcriptional activity, appears to activate AR-FL in an androgen-independent manner, it significantly antagonizes AR-V7 transactivation. Together, these data demonstrate that the complex interactions among different AR-Vs and AR-FL play a significant role in castration-resistant disease. This study suggests important consequences for clinical castration resistance due to simultaneous expression of AR-FL and AR-Vs in patient tumors and suggests that dissecting these interactions should help develop effective strategies to disrupt AR-V signaling. Mol Cancer Res; 15(1); 59-68. ©2016 AACR.


The Liver-Stage Plasmodium Infection Is a Critical Checkpoint for Development of Experimental Cerebral Malaria.
Cerebral malaria is a life-threatening complication of malaria in humans, and the underlying pathogenic mechanisms are widely analyzed in a murine model of experimental cerebral malaria (ECM). Here, we show abrogation of ECM by hemocoel sporozoite-induced infection of a transgenic Plasmodium berghei line that overexpresses profilin, whereas these parasites remain fully virulent in transfusion-mediated blood infection. We, thus, demonstrate the importance of the clinically silent liver-stage infection for modulating the onset of ECM. Even though both parasites triggered comparable splenic immune cell expansion and accumulation of antigen-experienced CD8+ T cells in the brain, infection with transgenic sporozoites did not lead to cerebral vascular damages and suppressed the recruitment of overall lymphocyte populations. Strikingly, infection with the transgenic strain led to maintenance of CD115+Ly6C+ monocytes, which disappear in infected animals prone to ECM. An early induction of IL-10, IL-12p70, IL-6, and TNF at the time when parasites emerge from the liver might lead to a diminished induction of hepatic immunity. Collectively, our study reveals the essential role of early host interactions in the liver that may dampen the subsequent pro-inflammatory immune responses and influence the occurrence of ECM, highlighting a novel checkpoint in this fatal pathology.


Aquaporins in spinal cord injury: the janus face of aquaporin 4.
Although malfunction of spinal cord water channels (aquaporins, AQP) likely contributes to severe disturbances in ion/water homeostasis after spinal cord injury (SCI), their roles are still poorly understood. Here we report and discuss the potential significance of changes in the AQP4 expression in human SCI that generates glial fibrillary acidic protein (GFAP)-labeled astrocytes devoid of AQP4, and GFAP-labeled astroglia that overexpress AQP4. We used a rat model of contusion SCI to study observed changes in human SCI. AQP4-negative astrocytes are likely generated during the process of SCI-induced replacement of lost astrocytes, but their origin and role in SCI remains to be investigated. We found that AQP4-overexpression is likely triggered by hypoxia. Our transcriptional profiling of injured rat cords suggests that elevated AQP4-mediated water influx accompanies increased uptake of chloride and potassium ions which represents a protective astrocytic reaction to hypoxia. However, unbalanced water intake also results in astrocytic swelling that can contribute to motor impairment, but likely only in milder injuries. In severe rat SCI, a low abundance of AQP4-overexpressing astrocytes was found during the motor recovery phase. Our results suggest that severe rat contusion SCI is a better model to analyze AQP4 functions after SCI. We found that AQP4 increases in the chronic post-injury phase are associated with the development of pain-like behavior in SCI rats, while possible mechanisms underlying pain development may involve astrocytic swelling-induced glutamate release. In contrast, the formation and size of fluid-filled cavities occurring later after SCI does not appear to be affected by the extent of increased AQP4 levels. Therefore, the effect of therapeutic interventions targeting AQP4 will depend not only on the time interval after SCI or animal models, but also on the balance between protective role of increased AQP4 in hypoxia and deleterious effects of ongoing astrocytic swelling.


Social Media Guidelines for Anatomists.
Social Media has changed the way that individuals interact with each other - it has brought considerable benefits, yet also some challenges. Social media in anatomy has enabled anatomists all over the world to engage, interact and form new collaborations that otherwise would not have been possible. In a relatively small discipline where individuals may be working as the only anatomist in an institution, having such a virtual community can be important. Social media is also being used as a means for anatomists to communicate with the current generation of students as well as members of the public. Posting appropriate content is one of the challenges raised by social media use in anatomy. Human cadaveric material is frequently shared on social media and there is divided opinion among anatomists on whether or not such content is appropriate. This article explores the uses and challenges of social media use in the field of anatomy and outlines guidelines on how social media can be used by anatomists globally, while maintaining professional and ethical standards. Creating global guidelines has shown to be difficult due to the differences in international law for the use of human tissue and also the irregularities in acquiring informed consent for capturing and sharing cadaveric images. These nuances may explain why cadaveric images are frequently shared on social media. This article proposes that as standard practice, anatomists obtain informed consent from donors before sharing images of cadaveric material on social media and ensure posts include a statement stating the same.


Terahertz-wave parametric oscillator with a misalignment-resistant tuning cavity.
We demonstrate a terahertz-wave parametric oscillator (TPO) with a corner-cube resonator consisting of a corner-cube prism (CCP) and a flat mirror. By using the cavity configuration proposed in this Letter, the generation of tunable monochromatic terahertz (THz) waves can be achieved just by rotating the flat mirror instead of rotating the TPO cavity relative to the pump beam. The THz-wave output intensity and pulse width can be controlled periodically by rotating the CCP around the cavity axis. The TPO stability against cavity misalignment is significantly improved by at least 1 to 2 orders of magnitude compared with the conventional plane-parallel resonator configuration.


MfLIP1, a gene encoding an extracellular lipase of the lipid-dependent fungus Malassezia furfur.
Malassezia furfur is a dimorphic fungus and a member of the normal cutaneous microflora of humans. However, it is also a facultative pathogen, associated with a wide range of skin diseases. One unusual feature of M. furfur is an absolute dependency on externally provided lipids which the fungus hydrolyses by lipolytic activity to release fatty acids necessary for both growth and pathogenicity. In this study, the cloning and characterization of the first gene encoding a secreted lipase of M. furfur possibly associated with this activity are reported. The gene, MfLIP1, shows high sequence similarity to other known extracellular lipases, but is not a member of a lipase gene family in M. furfur. MfLIP1 consists of 1464 bp, encoding a protein with a molecular mass of 54.3 kDa, a conserved lipase motif and an N-terminal signal peptide of 26 aa. By using a genomic library, two other genes were identified flanking MfLIP1, one of them encoding a putative secreted catalase, the other a putative amine oxidase. The cDNA of MfLIP1 was expressed in Pichia pastoris and the biochemical properties of the recombinant lipase were analysed. MfLip1 is most active at 40 degrees C and the pH optimum was found to be 5.8. The lipase hydrolysed lipids, such as Tweens, frequently used as the source of fatty acids in M. furfur media, and had minor esterase activity. Furthermore, the lipase is inhibited by different bivalent metal ions. This is the first molecular description of a secreted lipase from M. furfur.


Global variation in grip strength: a systematic review and meta-analysis of normative data.
weak grip strength is a key component of sarcopenia and is associated with subsequent disability and mortality. We have recently established life course normative data for grip strength in Great Britain, but it is unclear whether the cut points we derived for weak grip strength are suitable for use in other settings. Our objective was to investigate differences in grip strength by world region using our data as a reference standard. we searched MEDLINE and EMBASE for reporting age- and gender-stratified normative data for grip strength. We extracted each item of normative data and converted it on to a Z-score scale relative to our British centiles. We performed meta-regression to pool the Z-scores and compare them by world region. our search returned 806 abstracts. Sixty papers met inclusion criteria and reported on 63 different samples. Seven UN regions were represented, although most samples (n = 44) were based in developed regions. We extracted 726 normative data items relating to 96,537 grip strength observations. Normative data from developed regions were broadly similar to our British centiles, with a pooled Z-score 0.12 SDs (95% CI: 0.07, 0.17) above the corresponding British centiles. By comparison, normative data from developing regions were clearly lower, with a pooled Z-score of -0.85 SDs (95% CI: -0.94, -0.76). our findings support the use of our British grip strength centiles and their associated cut points in consensus definitions for sarcopenia and frailty across developed regions, but highlight the need for different cut points in developing regions.


The Effect of Tribbles-Related Protein 3 on ER Stress-Suppressed Insulin Gene Expression in INS-1 Cells.
The highly developed endoplasmic reticulum (ER) structure in pancreatic beta cells is heavily involved in insulin biosynthesis. Thus, any perturbation in ER function inevitably impacts insulin biosynthesis. Recent studies showed that the expression of tribbles-related protein 3 (TRB3), a mammalian homolog of Drosophilia tribbles, in various cell types is induced by ER stress. Here, we examined whether ER stress induces TRB3 expression in INS-1 cells and found that TRB3 mediates ER stress-induced suppression of insulin gene expression. The effects of tunicamycin and thapsigargin on insulin and TRB3 expression in INS-1 cells were measured by Northern and Western blot analysis, respectively. The effects of adenovirus-mediated overexpression of TRB3 on insulin, PDX-1 and MafA gene expression in INS-1 cells were measured by Northern blot analysis. The effect of TRB3 on insulin promoter was measured by transient transfection study with constructs of human insulin promoter. The treatment of INS-1 cells with tunicamycin and thapsigargin decreased insulin mRNA expression, but increased TRB3 protein expression. Adenovirus-mediated overexpression of TRB3 decreased insulin gene expression in a dose-dependent manner. A transient transfection study showed that TRB3 inhibited insulin promoter activity, suggesting that TRB3 inhibited insulin gene expression at transcriptional level. Adenovirus-mediated overexpression of TRB3 also decreased PDX-1 mRNA expression, but did not influence MafA mRNA expression. This study showed that ER stress induced TRB3 expression, but decreased both insulin and PDX-1 gene expression in INS-1 cells. Our data suggest that TRB3 plays an important role in ER stress-induced beta cell dysfunction.


A complementary role for tetraspanin superfamily member CD151 and ADP purinergic P2Y12 receptor in platelets.
P2Y12 receptor is required for sustained activation of integrin αIIbβ3, irreversible platelet aggregation and thrombus stabilisation. Tetraspanin superfamily member CD151 associates with integrin αIIbβ3 and plays critical roles in regulation of thrombus growth and stability in vivo. The possible functional relationship between P2Y12 and CD151 in a molecular cluster in platelets may affect thrombus formation. Hence our aim was to investigate the physical and functional requirements for this association in platelets. Our investigations reveal a specific and constitutive association between CD151 and P2Y12 receptor in human platelets shown by immunoprecipitation/western blot studies and by flow cytometry. Specifically, the prominent association involves CD151 with P2Y12 oligomers, and to a lesser extent P2Y12 monomers. This association is not altered by platelet aggregation induced by different agonists. There is also a distinct complex of tetraspanin CD151 with ADP purinergic receptor P2Y12 but not P2Y1. P2Y12 oligomer interaction with CD151 is selective as compared to other tetraspanins. To investigate the functional relationship between these receptors in platelets we used wild-type or CD151 knockout (KO) mice treated with either PBS or 50 mg/kg clopidogrel. CD151 KO mice treated with clopidogrel exhibited synergy in delayed kinetics of clot retraction, in PAR-4 and collagen-mediated platelet aggregation, platelet spreading on fibrinogen and without restricting cAMP inhibition. Clopidogrel treated CD151 KO arterioles showed smaller and less stable thrombi with increased tendency to embolise ex vivo and in vivo. These studies demonstrate a complementary role between CD151 and P2Y12 receptor in platelets in regulating thrombus growth and stability.


Spike train processing by a silicon neuromorph: the role of sublinear summation in dendrites.
A dendritic tree, as part of a silicon neuromorph, was modeled in VLSI as a multibranched, passive cable structure with multiple synaptic sites that either depolarize or hyperpolarize local "membrane patches," thereby raising or lowering the probability of spike generation of an integrate-and-fire "soma." As expected from previous theoretical analyses, contemporaneous synaptic activation at widely separated sites on the artificial tree resulted in near-linear summation, as did neighboring excitatory and inhibitory activations. Activation of synapses of the same type close in time and space produced local saturation of potential, resulting in spike train processing capabilities not possible with linear summation alone. The resulting sublinear synaptic summation, as well as being physiologically plausible, is sufficient for a variety of spike train processing functions. With the appropriate arrangement of synaptic inputs on its dendritic tree, a neuromorph was shown to discriminate input pulse intervals and patterns, pulse train frequencies, and detect correlation between input trains.


Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory.
Aplysia cytoplasmic polyadenylation element binding (CPEB) protein, a translational regulator that recruits mRNAs and facilitates translation, has been shown to be a key component in the formation of long-term memory. Experimental data show that CPEB exists in at least a low-molecular weight coiled-coil oligomeric form and an amyloid fiber form involving the Q-rich domain (CPEB-Q). Using a coarse-grained energy landscape model, we predict the structures of the low-molecular weight oligomeric form and the dynamics of their transitions to the β-form. Up to the decamer, the oligomeric structures are predicted to be coiled coils. Free energy profiles confirm that the coiled coil is the most stable form for dimers and trimers. The structural transition from α to β is shown to be concentration dependent, with the transition barrier decreasing with increased concentration. We observe that a mechanical pulling force can facilitate the α-helix to β-sheet (α-to-β) transition by lowering the free energy barrier between the two forms. Interactome analysis of the CPEB protein suggests that its interactions with the cytoskeleton could provide the necessary mechanical force. We propose that, by exerting mechanical forces on CPEB oligomers, an active cytoskeleton can facilitate fiber formation. This mechanical catalysis makes possible a positive feedback loop that would help localize the formation of CPEB fibers to active synapse areas and mark those synapses for forming a long-term memory after the prion form is established. The functional role of the CPEB helical oligomers in this mechanism carries with it implications for targeting such species in neurodegenerative diseases.


Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis.
We have developed and optimized a microfluidic device platform for the capture and analysis of circulating pancreatic cells (CPCs) and pancreatic circulating tumor cells (CTCs). Our platform uses parallel anti-EpCAM and cancer-specific mucin 1 (MUC1) immunocapture in a silicon microdevice. Using a combination of anti-EpCAM and anti-MUC1 capture in a single device, we are able to achieve efficient capture while extending immunocapture beyond single marker recognition. We also have detected a known oncogenic KRAS mutation in cells spiked in whole blood using immunocapture, RNA extraction, RT-PCR and Sanger sequencing. To allow for downstream single-cell genetic analysis, intact nuclei were released from captured cells by using targeted membrane lysis. We have developed a staining protocol for clinical samples, including standard CTC markers; DAPI, cytokeratin (CK) and CD45, and a novel marker of carcinogenesis in CPCs, mucin 4 (MUC4). We have also demonstrated a semi-automated approach to image analysis and CPC identification, suitable for clinical hypothesis generation. Initial results from immunocapture of a clinical pancreatic cancer patient sample show that parallel capture may capture more of the heterogeneity of the CPC population. With this platform, we aim to develop a diagnostic biomarker for early pancreatic carcinogenesis and patient risk stratification.


Limitation on stabilizing plane waves via time-delay feedback.
Previous work has demonstrated the possibility of stabilizing plane wave solutions of one-dimensional systems using a spatially local form of time-delayed feedback. We show that the natural extension of this method to two-dimensional systems fails due to the presence of torsion-free unstable perturbations. Linear stability analysis of the complex Ginzburg-Landau equation reveals that long wavelength, transverse wave instabilities cannot be suppressed by the method of extended time-delay autosynchronization. The conclusion follows from symmetry considerations and therefore applies to a wide class of models with simple plane wave solutions.


Atopic dermatitis: Role of the skin barrier, environment, microbiome, and therapeutic agents.
Atopic dermatitis (AD) is a chronic, inflammatory skin disorder characterized by eczematous and pruritic skin lesions. In recent decades, the prevalence of AD has increased worldwide, most notably in developing countries. The enormous progress in our understanding of the complex composition and functions of the epidermal barrier allows for a deeper appreciation of the active role that the skin barrier plays in the initiation and maintenance of skin inflammation. The epidermis forms a physical, chemical, immunological, neuro-sensory, and microbial barrier between the internal and external environment. Not only lesional, but also non-lesional areas of AD skin display many morphological, biochemical and functional differences compared with healthy skin. Supporting this notion, genetic defects affecting structural proteins of the skin barrier, including filaggrin, contribute to an increased risk of AD. There is evidence to suggest that natural environmental allergens and man-made pollutants are associated with an increased likelihood of developing AD. A compromised epidermal barrier predisposes the skin to increased permeability of these compounds. Numerous topical and systemic therapies for AD are currently available or in development; while anti-inflammatory therapy is central to the treatment of AD, some existing and novel therapies also appear to exert beneficial effects on skin barrier function. Further research on the skin barrier, particularly addressing epidermal differentiation and inflammation, lipid metabolism, and the role of bacterial communities for skin barrier function, will likely expand our understanding of the complex etiology of AD and lead to identification of novel targets and the development of new therapies.


Readmissions of adults within three age groups following hospitalization for pneumonia: Analysis from the Nationwide Readmissions Database.
While 30-day readmissions following hospitalization for pneumonia have been well-studied in the elderly, their burden in young adults remains poorly understood. To study patterns of readmissions following hospitalization for pneumonia across age groups and insurance payers. In the Nationwide Readmission Database for the years 2013 and 2014 we identified all adults (≥18 years) discharged alive after a hospitalization with the primary diagnosis of pneumonia, and examined rates of readmissions within 30-days of discharge. Using covariates included in the Center for Medicare & Medicaid Services risk-adjustment model for pneumonia readmissions in a multivariable regression model for survey data, we identified predictors of 30-day readmission. We identified 629,939 index pneumonia hospitalizations with a weighted estimate of 1,472,069 nationally. Overall, 16.2% of patients were readmitted within 30 days of their hospitalization for pneumonia, with 30-day readmission rates of 12.4% in the 18-44 year age-group, 16.1% in the 45-64 year age-group, and 16.7% in the ≥65-year age-group. In risk-adjusted analyses, compared with elderly, middle-aged adults were more likely to be readmitted (risk-adjusted OR 1.05, 95% CI 1.03-1.07). Mean cost per readmission was also highest for this age group at $15,976. Middle-aged adults experience substantial rates of 30-day readmission that are comparable to those over 65 years of age, with a higher cost per readmission event. Future efforts are needed to identify potential interventions to alleviate the high burden of pneumonia readmissions in middle-aged adults.


Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-positive breast cancer.
Increased activity of amino acid transporters has been observed in a wide variety of cancers. However, whether amino acid metabolism is related to estrogen receptor-positive (ER+) breast cancer has been less well studied. We identified the rate-limiting enzyme involved in amino acid metabolism associated with ER+ breast cancer by integrating numerous bioinformatics tools and laboratory studies. The bioinformatics analysis revealed that highly expressed genes in ER+ breast cancer patients were correlated with breast cancer-related pathways, including ESR1 and PI3K signaling. The metabolic signaling and the amino acid metabolism were significantly regulated in breast neoplasms. We used the ER+ breast cancer cell line MCF-7 and breast cancer tissue from National Cheng Kung University Hospital to validate our findings in bioinformatics. In estradiol-treated MCF-7 cells, genes associated with anabolic metabolism of serine and methionine and genes associated with catabolic metabolism of tyrosine, phenylalanine and arginine were upregulated. Furthermore, the expression levels of ARG2, PSAT1, PSPH, TH, PAH, and MAT1A mRNA were increased in breast cancer patients relative to controls. The aforementioned genes were also found to be highly correlated with distant metastasis-free survival in breast cancer patients. High expression levels of ARG2, CBS, PHGDH, AHCY, HAL, TDO2, SHMT2, MAT1A, MAT2A, GLDC, GLS2, BCAT2, GLUD1, PAH and MTR contributed to poor prognoses, whereas high mRNA expression levels of HECA, CTH, PRODH, TAT, and MAT2B were correlated with good prognoses. FDA-approved drugs, including piperlongumine, ellipticine, etidronic acid, harmine, and meclozine, may have novel therapeutic effects in ER+ patients based on connectivity map (CMap) analyses. Collectively, our present study demonstrated that amino acid metabolism genes play crucial roles in tumor development and may serve as prospective drug targets or biomarkers for ER+ breast cancer.


Hypnotizability and spatial attentional functions.
Many theories of hypnotic responding have proposed that differences in hypnotic trait rely on differences in frontal attentional functions. Evidence of hypnotizability-related attentional abilities are, however, very scant. This study was designed to investigate the relationship between hypnotizability and executive control components of attention in the spatial domain. We chose the Attention Network Test that enables to analyze alerting, orienting and executive control functions by measuring reaction times (RTs) to targets cued for different locations in space. According to Posner theory, alerting, orienting and executive control effects were found in both groups. No differences between highly susceptible (Highs) and low susceptible individuals (Lows) on executive control functions were found. However, in Highs alerting was significantly smaller than in Lows and Highs were significantly faster than Lows in the no and central cue conditions. These findings suggest that Highs would be endowed with a basal higher efficiency in achieving and maintaining their readiness to respond to incoming stimuli. This relation between hypnotizability and alerting, is discussed in terms of a possible more efficient noradrenergic activity driven by frontal attentional systems.


The Burden of Cardiovascular Disease in Sub-Saharan Africa and the Black Diaspora.
For over four decades the National Medical Association (NMA) and the Association of Black Cardiologists (ABC) have sought to bring to national attention the disparate burden of cardiovascular disease (CVD) among African Americans. However, systematic inquiry has been inadequate into the burden of CVD in the poor countries of Sub-Saharan Africa (SSA) and the African diaspora in the Americas outside the USA. However, recently, the Global Burden of Disease Study (GBD) has offered new tools for such inquiry. Several initial efforts in that direction using 2010 data have been published. This article highlights some new findings for SSA for 2016. It also suggests that NMA and ABC further this effort by direct advocacy and collaboration with the GBD to make estimates of CVD burden in African Americans and South American Blacks explicitly available in future iterations.


The effect of stimulus predictability and age on human tracking eye movements.
Human tracking eye movements were recorded in healthy volunteers of varying age. The target motion was either predictable (pure sinusoids or sinusoidal frequency sweep) or unpredictable (pseudorandomized). Gain and phase values for the tracking and the smooth pursuit eye movement signal were calculated as a function of target frequency from 0.2 to 2 Hz. Max. target velocity was 20 or 40 deg/sec. In the low frequency area the smooth pursuit gain for predictable stimulation was higher than the gain elicited by the pseudorandomized stimulation. In the high-frequency area, gain values did not differ significantly. For the predictable stimulation, the phase of the smooth component was always a lag, increasing with increasing frequency. At low frequencies of the pseudorandomized signal a phase lead was observed. At higher frequencies the lead turned into a lag that was greater than for the predictable stimulation. The young and old groups showed reduced smooth pursuit gain values, compared with the main group specially when the target waveform was pseudorandomized. The reduced smooth pursuit ability was mostly compensated for by an increased amount of saccades.


Effects of Bluetooth-Enabled Desk Ellipticals on Office Work Performance: Rationale, Design, and Protocol for a Randomized Trial With Overweight and Obese Adults.
Workplaces that provide opportunities for physical activity without requiring extra time for activity could help counteract the obesity epidemic. Desk ellipticals can contribute to activity-supportive workplace environments; however, the feasibility of engaging employees in pedaling ellipticals during simultaneous office work has not been well evaluated. We aim to present the rationale and methods from an ongoing randomized trial with overweight and obese employees that will evaluate (1) the effects of pedaling a compact desk elliptical on work performance and (2) the influence of different incentive types and schedules on desk pedaling quantity. Overweight and obese medical center employees are being recruited in dyads for a 2 (gift card type: healthier food vs Amazon) by 3 (gift card schedule: immediate incentive contingent on individual pedaling quantity; immediate incentive partially contingent on dyads' joint pedaling quantity; and delayed noncontingent pedaling incentive) cluster randomized within-subjects factorial trial. All participants receive a Bluetooth-enabled desk elliptical for 4 weeks and access to a mobile app that provides real-time pedaling feedback. The primary aims are to assess (1) change in employee work performance from pre- to postelliptical installation via employee and supervisor ratings and (2) effects of gift card type and schedule on quantity of objectively measured desk pedaling completed. Data collection is ongoing. We expect to complete main outcome analyses in 2020. This trial represents one of the earliest attempts to assess the effects of desk pedaling and pedaling-incentive types in real-world offices. It could help bridge the research-to-practice gap by providing evidence on whether desk pedaling can be sustained without compromising work performance. DERR1-10.2196/16275.


Antiparasitic properties of leaf extracts derived from selected Nicotiana species and Nicotiana tabacum varieties.
Within the traditional pharmacopeia, tobacco (Nicotiana spp.) is often cited as an efficient pesticide. This activity is generally attributed to nicotine, but tobacco plants contain other alkaloids that could potentially contribute to this effect. In this study, we tested methanolic extracts of N. glutinosa, N. glauca, N. debneyi, and N. tabacum (putrescine N-methyltransferase line, burley TN90 and Stella, Virginia ITB 683 and K326), selected according to alkaloid content. Their antiparasitic activity was evaluated in bioassays against adult fleas (Ctenocephalides felis), blowfly (Lucilia cuprina) larvae, nematodes (Caenorhabditis elegans), and ticks (Rhipicephalus sanguineus larvae and adults, Ixodes ricinus nymphs). None of the extracts killed fleas and blowfly larvae effectively at the concentrations tested. Only N. tabacum K326 and N. glutinosa exhibited moderate anthelmintic activity. All extracts significantly repelled R. sanguineus ticks, but not I. ricinus, and the nicotine-rich extracts rapidly knocked down all tick species and stages at high concentrations. The link between nicotine and tick knockdown was confirmed by successfully testing the pure alkaloid at concentrations found in the tobacco extracts. In contrast, repellent activity could not be correlated to the individually tested alkaloids (nicotine, nornicotine, anabasine, anatabine), although anatabine and nornicotine were active in the tick bioassay at high concentrations.


Perspectives on pain and depression.
The health care system is often unsuccessful in the treatment of the patient experiencing chronic pain. Chronic pain is often complicated by a variety of psychiatric conditions that make it difficult to engage and treat patients. This generates frustration and pessimism in the physician. The patient may be afflicted by the syndrome of an affective disorder, demoralized by the unintended circumstances of their life, unable to meet the demands of stressors because of a lack of inherent capacities, or helplessly trapped by poor choices and repeated unproductive actions. The physician's interest and the patient's optimism can be restored and sustained by utilizing a systematic interdisciplinary approach utilizing the four perspectives of diseases, life stories, dimensions, and behaviors to evaluate the patient who is disabled by depression and chronic pain. The design of a comprehensive treatment plan involves the determination of each perspective's contribution to the patient's suffering. The process of formulation recognizes that the perspectives are distinct from one another but complementary in illuminating the various reasons for a patient's suffering. The perspectives offer a recipe for designing a rational treatment plan rather than trying to reduce the individual patient's complexity into a one-dimensional construct. This approach increases the probability of a successful outcome for both patient and physician.


Pore-forming toxins: ancient, but never really out of fashion.
Pore-forming toxins (PFTs) are virulence factors produced by many pathogenic bacteria and have long fascinated structural biologists, microbiologists and immunologists. Interestingly, pore-forming proteins with remarkably similar structures to PFTs are found in vertebrates and constitute part of their immune system. Recently, structural studies of several PFTs have provided important mechanistic insights into the metamorphosis of PFTs from soluble inactive monomers to cytolytic transmembrane assemblies. In this Review, we discuss the diverse pore architectures and membrane insertion mechanisms that have been revealed by these studies, and we consider how these features contribute to binding specificity for different membrane targets. Finally, we explore the potential of these structural insights to enable the development of novel therapeutic strategies that would prevent both the establishment of bacterial resistance and an excessive immune response.


A neural model of surface perception: lightness, anchoring, and filling-in.
A neural model is proposed of how the visual system processes natural images under variable illumination conditions to generate surface lightness percepts. Previous models clarify how the brain can compute relative contrast. The anchored Filling-In Lightness Model (aFILM) clarifies how the brain 'anchors' lightness percepts to determine an absolute lightness scale that uses the full dynamic range of neurons. The model quantitatively simulates lightness anchoring properties (Articulation, Insulation, Configuration, Area Effect) and other lightness data (discounting the illuminant, the double brilliant illusion, lightness constancy and contrast, Mondrian contrast constancy, Craik-O'Brien-Cornsweet illusion). The model clarifies how retinal processing stages achieve light adaptation and spatial contrast adaptation, and how cortical processing stages fill-in surface lightness using long-range horizontal connections that are gated by boundary signals. The new filling-in mechanism runs 1000 times faster than diffusion mechanisms of previous filling-in models.


Role of interferon antagonist activity of rabies virus phosphoprotein in viral pathogenicity.
The fixed rabies virus (RV) strain Nishigahara kills adult mice after intracerebral inoculation, whereas the chicken embryo fibroblast cell-adapted strain Ni-CE causes nonlethal infection in adult mice. We previously reported that the chimeric CE(NiP) strain, which has the phosphoprotein (P protein) gene from the Nishigahara strain in the genetic background of the Ni-CE strain, causes lethal infection in adult mice, indicating that the P gene is responsible for the different pathogenicities of the Nishigahara and Ni-CE strains. Previous studies demonstrated that RV P protein binds to the interferon (IFN)-activated transcription factor STAT1 and blocks IFN signaling by preventing its translocation to the nucleus. In this study, we examine the molecular mechanism by which RV P protein determines viral pathogenicity by comparing the IFN antagonist activities of the Nishigahara and Ni-CE P proteins. The results, obtained from both RV-infected cells and cells transfected to express P protein only, show that Ni-CE P protein is significantly impaired for its capacity to block IFN-activated STAT1 nuclear translocation and, consequently, inhibits IFN signaling less efficiently than Nishigahara P protein. Further, it was demonstrated that a defect in the nuclear export of Ni-CE P protein correlates with a defect in its ability to cause the mislocalization of STAT1. These data provide the first evidence that the capacity of the RV P protein to inhibit STAT1 nuclear translocation and IFN signaling correlates with the viral pathogenicity.


Reduced Reelin expression accelerates amyloid-beta plaque formation and tau pathology in transgenic Alzheimer's disease mice.
In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-beta plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-beta peptides, the significant increase in number and size of amyloid-beta plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-beta plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-beta plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-beta plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-beta deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.


Evaluating sex and gender competencies in the medical curriculum: a case study.
Sex and gender differences exist in the manifestation and prevalence of many conditions and diseases. Yet many clinician training programs neglect to integrate this information across their curricula. This study aimed to measure the sex and gender medical knowledge of medical students enrolled in a program without an explicit directive to integrate sex and gender differences across a block system of core subjects. A forced-choice instrument consisting of 35 multiple-choice and true or false questions was adapted from an evaluation tool used in the European Curriculum in Gender Medicine held at Charité Hospital, Berlin, in September 2010. Fourth-year (response rate 93%) and second-year (response rate 70%) students enrolled in Mayo Medical School completed the instrument. More than 50% of students in both classes indicated that topics related to sex and gender were covered in gynecology, cardiology, and pediatrics, and <20% of students indicated inclusion of such topics in nephrology, neurology, and orthopedics. More than twice as many second-year students indicated that topics dealing with sex and gender were included in immunology course material compared with fourth-year students. A consensus of written comments indicated that concepts of sex and gender-based medicine need to be embedded into existing curriculum, with an emphasis on clinically relevant information. Although this study represents only one medical school in the United States, information regarding sex and gender aspects of medicine is not consistently included in this curriculum without an explicit directive. These results can provide guidance for curriculum improvement to train future physicians.


MOGAD patient autoantibodies induce complement, phagocytosis, and cellular cytotoxicity.
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.


Helicobacter hepaticus infection in BALB/c mice abolishes subunit-vaccine-induced protection against M. tuberculosis.
BCG, the only licensed vaccine against tuberculosis (TB), provides geographically variable protection, an effect ascribed to exposure to environmental mycobacteria (EM). Here we show that altering the intestinal microbiota of mice by early-life infection with the commensal bacterium Helicobacter hepaticus (Hh) increases their susceptibility to challenge with Mycobacterium tuberculosis (Mtb). Furthermore Hh-infected mice immunised parenterally with the recombinant subunit vaccine, human adenovirus type 5 expressing the immunodominant antigen 85A of Mtb (Ad85A), display a reduced lung immune response and protection against Mtb challenge is also reduced. Expression of interleukin 10 (IL10) messenger RNA is increased in the colon of Hh infected mice. Treatment of Hh-infected Ad85A-immunised mice with anti-IL10 receptor antibody, following challenge with Mtb, restores the protective effect of the vaccine. These data show for the first time that alteration of the intestinal microbiota by addition of a single commensal organism can profoundly influence protection induced by a TB subunit vaccine via an IL10-dependent mechanism, a result with implications for the deployment of such vaccines in the field.


Prepulse inhibition of acoustic startle in spontaneously hypertensive rats.
Prepulse inhibition is modulated by dopaminergic drugs and is disrupted in attention-deficit hyperactivity disorder, as well as mental illnesses such as schizophrenia. Spontaneously hypertensive rats (SHR) have been proposed as an animal model of attention-deficit hyperactivity disorder and show marked alterations of dopaminergic regulation of behaviour. SHR showed significantly lower startle amplitude than Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, but no difference in startle habituation. Baseline percentage prepulse inhibition was higher in SHR and WKY rats than in SD rats. Treatment with amphetamine caused significant disruption of prepulse inhibition in SHR and WKY rats, but not SD rats. In contrast, treatment with apomorphine caused prepulse-dependent disruption of prepulse inhibition in SD rats only. Both MK-801 and 8-OH-DPAT treatment caused disruption of prepulse inhibition in all three rat strains. This study shows differential changes in startle level and prepulse inhibition in SHR, however these rats are not uniformly different from either WKY rats or SD rats and WKY rats differ in a number of respects from SD rats. In conclusion, these data further reveal altered dopaminergic regulation of behaviour in SHR, but also shows that caution is needed about the control strain used to compare these animals with.


Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry.
Radical prostatectomy is a common treatment option for prostate cancer before it has spread beyond the prostate. Examination for surgical margins is performed post-operatively with positive margins reported to occur in 6.5-32% of cases. Rapid identification of cancerous tissue during surgery could improve surgical resection. Desorption electrospray ionization (DESI) is an ambient ionization method which produces mass spectra dominated by lipid signals directly from prostate tissue. With the use of multivariate statistics, these mass spectra can be used to differentiate cancerous and normal tissue. The method was applied to 100 samples from 12 human patients to create a training set of MS data. The quality of the discrimination achieved was evaluated using principal component analysis - linear discriminant analysis (PCA-LDA) and confirmed by histopathology. Cross validation (PCA-LDA) showed >95% accuracy. An even faster and more convenient method, touch spray (TS) mass spectrometry, not previously tested to differentiate diseased tissue, was also evaluated by building a similar MS data base characteristic of tumor and normal tissue. An independent set of 70 non-targeted biopsies from six patients was then used to record lipid profile data resulting in 110 data points for an evaluation dataset for TS-MS. This method gave prediction success rates measured against histopathology of 93%. These results suggest that DESI and TS could be useful in differentiating tumor and normal prostate tissue at surgical margins and that these methods should be evaluated intra-operatively.