Prevalence of HIV in workforces in southern Africa, 2000-2001.
Most data on HIV prevalence in low-risk populations in sub-Saharan Africa are drawn from sentinel surveys of pregnant women attending antenatal clinics and are not representative of formal sector workforces. We surveyed workforces in southern Africa to determine HIV prevalence among formally employed, largely male populations. Voluntary, anonymous, unlinked seroprevalence surveys of 34 workforces with 44,000 employees were carried out in South Africa, Botswana, and Zambia in 2000-2001. Results were stratified to obtain estimates of prevalence by industrial sector, location, age, sex, and job level. Average HIV prevalence for the entire sample was 16.6% (95% CI: 16.3-17.0%). Country-wide prevalence was 14.5% (14.1-14.9%) in South Africa, 17.9% (17.1-18.7%) in Zambia, and 24.6% (23.6-25.7%) in Botswana. Among industrial sectors, mining (18.0%, 17.6-18.5%) and metal processing (17.3%, 15.9-18.7%) had the highest infection rates. Males, who comprised 85% of participants of known sex, were more likely (16.3%, 15.3-17.4%) to be infected than were females (10.7%, 8.7-12.7%). Contract (23%, 21.9-24.1%), unskilled (18.3%, 17.5-19.1%), and semi-skilled workers (18.7%, 18.1-19.4%) were much more likely to be infected than were skilled workers (10.5%, 9.5-11.4%) and managers (4.5%, 3.4-5.6%). Participation in the surveys averaged 63% of eligible employees. HIV prevalence among formally employed workers in southern Africa shows different patterns than among antenatal clinic attendees. Anonymous workplace surveys generate prevalence estimates for demographic groups that are not represented in antenatal surveys and can strengthen support for prevention and treatment interventions.


Bridging Behavioral Science with Cancer Prevention and Control: Contributions of an NCI Working Group (2009-2019).
Human behavior plays a central role in cancer-related morbidity and mortality. Much behavior is, in turn, attributable to several core biological, cognitive, emotional, motivational, and interpersonal processes. Understanding the systematic and interactive impact of these processes can inform efforts to address cancer-relevant outcomes such as tobacco use, reliance on cancer misinformation, engagement in genetic testing, adherence to treatment, and acceptance of palliative care. Here, we review efforts of the NCI-supported Cognitive, Affective, and Social Processes in Health Research working group. Since 2009, this group has endeavored to advance the integration of basic behavioral science with cancer prevention and control by addressing topics such as the degree to which behavioral interventions alter cognitions underlying behavior, how technological innovations might facilitate behavioral measurement and intervention in areas such as smoking cessation, whether decision science principles might be applied to genetic testing decisions, how the cognitive effects of chemotherapy impair self-regulation, and the extent to which emotional factors drive palliative care decisions. The group has initiated numerous activities to build capacity for research in these areas including state-of-the-science meetings, written syntheses, conference symposia, and training workshops. We conclude with reflections about future needs as well as how to sustain such integrative efforts.


Phylodynamic evidence of the migration of turnip mosaic potyvirus from Europe to Australia and New Zealand.
Turnip mosaic virus (TuMV) is a potyvirus that is transmitted by aphids and infects a wide range of plant species. We investigated the evolution of this pathogen by collecting 32 isolates of TuMV, mostly from Brassicaceae plants, in Australia and New Zealand. We performed a variety of sequence-based phylogenetic and population genetic analyses of the complete genomic sequences and of three non-recombinogenic regions of those sequences. The substitution rates, divergence times and phylogeographical patterns of the virus populations were estimated. Six inter- and seven intralineage recombination-type patterns were found in the genomes of the Australian and New Zealand isolates, and all were novel. Only one recombination-type pattern has been found in both countries. The Australian and New Zealand populations were genetically different, and were different from the European and Asian populations. Our Bayesian coalescent analyses, based on a combination of novel and published sequence data from three non-recombinogenic protein-encoding regions, showed that TuMV probably started to migrate from Europe to Australia and New Zealand more than 80 years ago, and that distinct populations arose as a result of evolutionary drivers such as recombination. The basal-B2 subpopulation in Australia and New Zealand seems to be older than those of the world-B2 and -B3 populations. To our knowledge, our study presents the first population genetic analysis of TuMV in Australia and New Zealand. We have shown that the time of migration of TuMV correlates well with the establishment of agriculture and migration of Europeans to these countries.


Flare and optical transfer function.
The optical image quality is influenced by aberrations, by diffraction, and by other factors, such as flare or stray light originating from the badly polished surfaces of lenses, from the edges of the mount, from striations and bubbles in the glass, and from unwanted double reflections. These effects are harmful, but they cannot always be avoided. Their influence on the measured optical transfer function depends on the measuring method used and on the kind of test object. Experimental results are described.


Miz1 is a critical repressor of cdkn1a during skin tumorigenesis.
The transcription factor Miz1 forms repressive DNA-binding complexes with the Myc, Gfi-1 and Bcl-6 oncoproteins. Known target genes of these complexes encode the cyclin-dependent kinase inhibitors (CKIs) cdkn2b (p15(Ink4)), cdkn1a (p21(Cip1)), and cdkn1c (p57(Kip2)). Whether Miz1-mediated repression is important for control of cell proliferation in vivo and for tumor formation is unknown. Here we show that deletion of the Miz1 POZ domain, which is critical for Miz1 function, restrains the development of skin tumors in a model of chemically-induced, Ras-dependent tumorigenesis. While the stem cell compartment appears unaffected, interfollicular keratinocytes lacking functional Miz1 exhibit a reduced proliferation and an accelerated differentiation of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tumorigenesis, proliferation and normal differentiation are restored in animals lacking cdkn1a, but not in those lacking cdkn2b. Our data demonstrate that Miz1-mediated attenuation of cell cycle arrest pathways via repression of cdkn1a has a critical role during tumorigenesis in the skin.


The septate junction protein caspr is required for structural support and retention of KCNQ4 at calyceal synapses of vestibular hair cells.
The afferent innervation contacting the type I hair cells of the vestibular sensory epithelia form distinct calyceal synapses. The apposed presynaptic and postsynaptic membranes at this large area of synaptic contact are kept at a remarkably regular distance. Here, we show by freeze-fracture electron microscopy that a patterned alignment of proteins at the calyceal membrane resembles a type of intercellular junction that is rare in vertebrates, the septate junction (SJ). We found that a core molecular component of SJs, Caspr, colocalizes with the K(+) channel KCNQ4 at the postsynaptic membranes of these calyceal synapses. Immunolabeling and ultrastructural analyses of Caspr knock-out mice reveal that, in the absence of Caspr, the separation between the membranes of the hair cells and the afferent neurons is conspicuously irregular and often increased by an order of magnitude. In these mutants, KCNQ4 fails to cluster at the postsynaptic membrane and appears diffused along the entire calyceal membrane. Our results indicate that a septate-like junction provides structural support to calyceal synaptic contact with the vestibular hair cell and that Caspr is required for the recruitment or retention of KCNQ4 at these synapses.


Relationship between mobility, violence and HIV/STI among female sex workers in Andhra Pradesh, India.
Violence and mobility have been identified as critical factors contributing to the spread of HIV worldwide. This study aimed to assess the independent and combined associations of mobility and violence with sexual risk behaviors and HIV, STI prevalence among female sex workers (FSWs) in India. Data were drawn from a cross-sectional, bio-behavioral survey conducted among 2042 FSWs across five districts of southern India in 2005-06. Regression models were used to estimate odds ratios and 95% confidence intervals (CIs) for sexual risk behaviors and HIV infection based on experience of violence and mobility after adjusting for socio-demographic and sex work related characteristics. One-fifth of FSWs (19%) reported experiencing violence; 68% reported travelling outside their current place of residence at least once in the past year and practicing sex work during their visit. Mobile FSWs were more likely to report violence compared to their counterparts (23% vs. 10%, p < 0.001). Approximately 1 in 5 tested positive for HIV. In adjusted models, FSWs reporting both mobility and violence as compared to their counterparts were more likely to be infected with HIV (Adjusted odds ratio (adjusted OR): 2.07, 95% CI: 1.42-3.03) and to report unprotected sex with occasional (adjusted OR: 2.86, 95% CI: 1.76-4.65) and regular clients (adjusted OR: 2.07, 95% CI: 1.40-3.06). The findings indicate that mobility and violence were independently associated with HIV infection. Notably, the combined effect of mobility and violence posed greater HIV risk than their independent effect. These results point to the need for the provision of an enabling environment and safe spaces for FSWs who are mobile, to augment existing efforts to reduce the spread of HIV/AIDS.


Retinal axon misrouting at the optic chiasm in mice with neural tube closure defects.
In a new mouse mutant, circletail (Crc), failure of neural tube closure (embryonic day [E] 8-9) is associated with errors in retinal axon projection at the optic chiasm (E12-18), such that many axons normally projecting contralaterally instead grow to ipsilateral targets. Although the architecture of the chiasmatic region is altered, neurons and glia containing putative cues for axon guidance are present. The aberrant ipsilateral-projecting cells originate from a nonrandom expansion of the wild-type uncrossed retinal region. These axon pathway defects are found in two other mutants with cephalic neural tube defects (NTD), loop-tail (Lp) and Pax3 (splotch; Sp(2H)). Crc is phenotypically similar to Lp, exhibiting an open neural tube from midbrain to tail (craniorachischisis), while splotch has spina bifida with or without a cranial NTD. The retinal axon abnormalities occur only in the presence of NTD and not in homozygous mutants lacking cranial NTD. Thus, failure of neural tube closure is associated with failure of many retinal axons to cross the ventral midline. This study therefore reveals an unexpected connection between closure of the neural tube at the dorsal midline and development of ventral axon tracts. genesis 27:32-47, 2000.


Behavioural response to the Covid-19 pandemic in South Africa.
Given the economic and social divide that exists in South Africa, it is critical to manage the health response of its residents to the Covid-19 pandemic within the different socio-economic contexts that define the lived realities of individuals. The objective of this study is to analyse the Covid-19 preventive behaviour and the socio-economic drivers behind the health-response behaviour. The study employs data from waves 1 and 2 of South Africa's nationally representative National Income Dynamics Study (NIDS)-Coronavirus Rapid Mobile Survey (CRAM). The nationally representative panel data has a sample of 7073 individuals in Wave 1 and 5676 individuals in Wave 2. The study uses bivariate statistics, concentration indices and multivariate estimation techniques, ranging from a probit, control-function approach, special-regressor method and seemingly unrelated regression to account for endogeneity while identifying the drivers of the response behaviour. The findings indicate enhanced behavioural responsiveness to Covid-19. Preventive behaviour is evolving over time; the use of face mask has overtaken handwashing as the most utilised preventive measure. Other measures, like social distancing, avoiding close contact, avoiding big groups and staying at home, have declined between the two periods of the study. There is increased risk perception with significant concentration among the higher income groups, the educated and older respondents. Our findings validate the health-belief model, with perceived risk, self-efficacy, perceived awareness and barriers to preventive strategy adoption identified as significant drivers of health-response behaviour. Measures such as social distancing, avoiding close contact, and the use of sanitisers are practised more by the rich and educated, but not by the low-income respondents. The respondents from lower socio-economic backgrounds are associated with optimism bias and face barriers to the adoption of preventive strategies. This requires targeted policy attention in order to make response behaviour effective.


Ovarian cancer stage, variation in transvaginal ultrasound examination rates and the impact of an urgent referral pathway: A national ecological cohort study.
The aim of this study was to determine whether variation in transvaginal ultrasound examination rates in Danish general practice populations is associated with ovarian cancer outcomes, and to explore the impact of the introduction of a cancer patient pathway for ovarian cancer. We performed a national register-based cohort study of gynecological cancer-free women aged 40 years or above, living in Denmark and listed with a specific general practitioner in 2004-2014. Practice populations were divided into quartiles according to the general practitioners' transvaginal ultrasound propensity in the preceding year. Associations between transvaginal ultrasound rates and ovarian cancer outcomes were analyzed using Poisson and logistic regression. We included 2769 general practices with 1 739 422 listed women, of whom 5325 were diagnosed with ovarian cancer during the study period. Practices varied twofold in transvaginal ultrasound rates before and after the implementation of the cancer patient pathway. Before the cancer patient pathway was introduced, women listed with practices with the highest transvaginal ultrasound rates were diagnosed with earlier stages of ovarian cancer (odds ratio 1.38, 95% confidence interval 1.06 to 1.81) and had a higher proportion of borderline tumors (incidence rate ratio 1.38, 95% confidence interval 1.10 to 1.75) compared with women least exposed to transvaginal ultrasound. After the cancer patient pathway, no significant differences were identified between the groups. Before the cancer patient pathway, women exposed most to transvaginal ultrasound were significantly more likely to be diagnosed with early stage ovarian cancer compared with those least exposed to transvaginal ultrasound. After the cancer patient pathway was implemented, the difference disappeared. This suggests that increased awareness and access to transvaginal ultrasound is useful for diagnosing early-stage ovarian cancer.


Hypersensitivity Reaction Associated with Abacavir Therapy in an Indian HIV Patient - A Case Report.
The most important and unique adverse effect of abacavir (ABC) is fatal hypersensitivity reaction (HSR). The objective of this report is to describe a case of ABC induced HSR that occurred in an Indian HIV patient during treatment. Although this adverse effect is not uncommon, it is perhaps underreported or has never been reported so far in an Indian case scenario. A 44-year-old known case of HIV-1 was admitted in view of his worsening condition and very low CD4 cell counts 3 cells/μL. He was on anti-retroviral therapy since three years but not regular. On the basis of treatment failure, non-compliance and progressive low CD4 counts, the anti HIV regime was switched over to abacavir 600 mg+ atazanavir/ ritonavir 300mg/100mg Two weeks after ABC therapy he presented with maculopapular rash, headache and signs of hepatic damage (serum AST, ALP and ALT increased to 3-4 fold) suggestive of hypersensitivity reaction. As we know discontinuation of the drug is the ultimate litmus test to confirm diagnosis of drug induced adverse reaction. We did confirm ABC induced HSR by de-challenge wherein, rash disappeared within 2-3 days and LFT came back to normal within 5 days. However, no rechallenge was done. HSR was more in favour of ABC because atazanavir failed to produce any similar reaction after re-challenge.


Car travel time and accessibility by bus to general practitioner services: a study using patient registers and GIS.
Accessibility to general practitioner (GP) surgeries was investigated in a population study of East Anglia (Cambridgeshire, Norfolk and Suffolk) in the United Kingdom. Information from patient registers was combined with details of general practitioner surgery locations, road network characteristics, bus routes and community transport services, and a geographical information system (GIS) was used to calculate measures of accessibility to surgeries by public and private transport. Outcome measures included car travel times and indicators of the extent to which bus services could be used to visit GP surgeries. These variables were aggregated for wards or parishes and then compared with socio-economic characteristics of the populations living in those areas. The results indicated that only 10% of residents faced a car journey of more than 10 min to a GP. Some 13% of the population could not reach general medical services by daily bus. For 5% of the population, the car journey to the nearest surgery was longer than 10 min and there was no suitable bus service each weekday. In the remoter rural parishes, the lowest levels of personal mobility and the highest health needs indicators were found in the places with no daytime bus service each weekday and no community transport. The overall extent of accessibility problems and the existence of inverse care law effects in some rural localities have implications for the NHS, which aims to provide an equitable service to people wherever they live. The research also demonstrates the potential of patient registers and GIS as research and planning tools, though the practical difficulties of using these data sources and techniques should not be underestimated.


A determining factor for insect feeding preference in the silkworm, Bombyx mori.
Feeding preference is critical for insect adaptation and survival. However, little is known regarding the determination of insect feeding preference, and the genetic basis is poorly understood. As a model lepidopteran insect with economic importance, the domesticated silkworm, Bombyx mori, is a well-known monophagous insect that predominantly feeds on fresh mulberry leaves. This species-specific feeding preference provides an excellent model for investigation of host-plant selection of insects, although the molecular mechanism underlying this phenomenon remains unknown. Here, we describe the gene GR66, which encodes a putative bitter gustatory receptor (GR) that is responsible for the mulberry-specific feeding preference of B. mori. With the aid of a transposon-based, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) system, the GR66 locus was genetically mutated, and homozygous mutant silkworm strains with truncated gustatory receptor 66 (GR66) proteins were established. GR66 mutant larvae acquired new feeding activity, exhibiting the ability to feed on a number of plant species in addition to mulberry leaves, including fresh fruits and grain seeds that are not normally consumed by wild-type (WT) silkworms. Furthermore, a feeding choice assay revealed that the mutant larvae lost their specificity for mulberry. Overall, our findings provide the first genetic and phenotypic evidences that a single bitter GR is a major factor affecting the insect feeding preference.


A Rare Consequence after Shoulder Dislocation in a Professional Cyclist: A Case Report.
Background: Cycling is a popular source of recreation and physical activity for children and adults. With regard to the total number of sports injuries, cycling has the highest absolute number of injuries per year in the United States population. Cycling injuries can be classified into bicycle contact, traumatic, or overuse injuries. Aim of this study: The aims of this case report are to report a rare clinical complication of glenohumeral joint anterior dislocation that resulted in a patient experiencing continuous GHJ dislocations secondary to involuntary violent muscular spasms and emphasize the role of the physical therapist's differential diagnosis and clinical decision-making process in a patient following direct access referral. Case presentation: A professional 23-year-old cyclist presented to a physical therapist with spontaneous multidirectional dislocations to the right shoulder after the recurrence of trauma occurred during a recent cycling race. The dislocations do not occur at night, but occur during the day, randomly, and mostly associated with changes in the patient's psychological conditions. Directly from the clinical history, the physical therapist identified a neuro-physiological orange flag as well as an orthopedic red flag and, therefore, decided it was appropriate to refer the patient to a neurologist. It was determined by the physical therapist to be a priority to focus on the patient's neurologic status and then to evaluate the orthopedic problem. The neurological examination revealed a condition of spontaneous multidirectional dislocation associated with recurrent antero-posterior pain spasms of the shoulder joint. The neurologist prescribed medication. Following the second cycle of medication assumption, the patient was able to continue physiotherapy treatment and was referred to the orthopedic specialist to proceed with shoulder stabilization surgery. Discussion and conclusion: Currently, the diagnosis of this unusual clinical condition is still unclear. It is a shared opinion of the authors that the trauma during the past bicycle race awakened an underlying psychological problem of the patient that resulted in a clinical condition of weakness of all the structures of the shoulder, such that these spasms could result in multiple multidirectional dislocations.


Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response.
A long-standing paradox in the study of T cell antigen recognition is that of the high specificity-low affinity T cell receptor (TCR)-major histocompatibility complex peptide (MHCp) interaction. The existence of multivalent TCRs could resolve this paradox because they can simultaneously improve the avidity observed for monovalent interactions and allow for cooperative effects. We have studied the stoichiometry of the TCR by Blue Native-polyacrylamide gel electrophoresis and found that the TCR exists as a mixture of monovalent (alphabetagammaepsilondeltaepsilonzetazeta) and multivalent complexes with two or more ligand-binding TCRalpha/beta subunits. The coexistence of monovalent and multivalent complexes was confirmed by electron microscopy after label fracture of intact T cells, thus ruling out any possible artifact caused by detergent solubilization. We found that although only the multivalent complexes become phosphorylated at low antigen doses, both multivalent and monovalent TCRs are phosphorylated at higher doses. Thus, the multivalent TCRs could be responsible for sensing low concentrations of antigen, whereas the monovalent TCRs could be responsible for dose-response effects at high concentrations, conditions in which the multivalent TCRs are saturated. Thus, besides resolving TCR stoichiometry, these data can explain how T cells respond to a wide range of MHCp concentrations while maintaining high sensitivity.


Biomarkers to Guide Medical Therapy in Primary Aldosteronism.
Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin; biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies including dietary sodium restriction, steroidal and non-steroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multi-modal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed.


Hidden localization motifs: naturally occurring peroxisomal targeting signals in non-peroxisomal proteins.
Can sequence segments coding for subcellular targeting or for posttranslational modifications occur in proteins that are not substrates in either of these processes? Although considerable effort has been invested in achieving low false-positive prediction rates, even accurate sequence-analysis tools for the recognition of these motifs generate a small but noticeable number of protein hits that lack the appropriate biological context but cannot be rationalized as false positives. We show that the carboxyl termini of a set of definitely non-peroxisomal proteins with predicted peroxisomal targeting signals interact with the peroxisomal matrix protein receptor peroxin 5 (PEX5) in a yeast two-hybrid test. Moreover, we show that examples of these proteins - chicken lysozyme, human tyrosinase and the yeast mitochondrial ribosomal protein L2 (encoded by MRP7) - are imported into peroxisomes in vivo if their original sorting signals are disguised. We also show that even prokaryotic proteins can contain peroxisomal targeting sequences. Thus, functional localization signals can evolve in unrelated protein sequences as a result of neutral mutations, and subcellular targeting is hierarchically organized, with signal accessibility playing a decisive role. The occurrence of silent functional motifs in unrelated proteins is important for the development of sequence-based function prediction tools and the interpretation of their results. Silent functional signals have the potential to acquire importance in future evolutionary scenarios and in pathological conditions.


Effects of perceived risk and strength of affiliation on decisions to help others: toward a convergence of evolutionary and social psychology.
In this study, the influence of perceived affiliation with a target and perceived risk on decisions to act altruistically were investigated. These are variables which have been suggested by the social and evolutionary psychology literatures, respectively. 12 participants responded to automobile accident scenarios that combined risk and affiliation with a target in descriptions of opportunities to render aid. Participants reported a lower likelihood to help when perceived risk was high, but only if their perceived affiliation with the targets was low or moderate; tendency to help highly affiliated targets was uniformly high throughout all risk conditions. Participants' ratings of certainty in their decisions to render aid were directly related to both perceived risk and perceived affiliation with a target. Decisions were arrived at more slowly when perceived risk and perceived affiliation were both moderate. Therefore, both risk and affiliation were considered by participants when deciding whether to act altruistically. This illustrates a convergence of predictions from social and evolutionary psychology.


Chemoattractant receptors and leukocyte recruitment: more than cell migration.
Chemoattractants induce cell migration through the activation of a distinct family of structurally related heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Over the past few years, several receptors in this family have been identified that recognize different classes of chemoattractants but do not induce cell migration. These atypical "chemoattractant receptors" are unable to activate transduction events that lead directly to cell migration, but appear nonetheless to play a nonredundant role in leukocyte recruitment by shaping the chemoattractant gradient, either by removing, transporting, or concentrating their cognate ligands.


Hypokalemia associated with mifepristone use in the treatment of Cushing's syndrome.
Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia. Mifepristone, a potent antagonist of glucocorticoid receptors, has a high risk of adrenal insufficiency, despite high cortisol levels. Mifepristone is associated with hypokalemia due to spill-over effect of cortisol on unopposed mineralocorticoid receptors. Given the lack of a biochemical parameter to assess improvement, the dosing of mifepristone is based on clinical progress. Patients on mifepristone require anticipation of toxicity, especially when the dose is escalated. The half-life of mifepristone is 85 h, requiring prolonged monitoring for toxicity, even after the medication is held.


Construction of age model for the evaluation of swallowing function using photo sensors.
For the realization of better in-home nursing environment, understanding the swallowing function and its process are quite essential to realize appropriate rehabilitation policies and dietary menus to prevent aspirations. However, the swallowing function is currently examined using mainly large-scale and expensive methods such as video fluoroscopic examination of swallowing, mesophagia fiber, palatal pressure measurement, CT, and cine MRI, which are difficult to be used at patients' homes. This paper proposes an age model, which applies a self organization map (SOM) to evaluate the swallowing function. As parameters to make the SOM, the lead time, the geniohyoid muscle, and the thyroid muscle are measured using photo sensors with a little invasiveness. To verify the effectiveness of our swallowing function map, the age of the subject determined by the map is compared with his/her actual age. As a result of the comparison, the root mean square error was 6.28 years.


Isolation and characterization of a conserved porin protein from Helicobacter pylori.
Helicobacter pylori is a causative agent of gastritis in humans and is correlated with gastric ulcer formation. Infections with this bacterium have proven difficult to treat with antimicrobial agents. To better understand how this bacterium transports compounds such as antimicrobial agents across its outer membrane, identification of porin proteins is important. We have recently identified a family of H. pylori porins (HopA to HopD) (M. M. Exner, P. Doig, T. J. Trust, and R. E. W. Hancock, Infect. Immun. 63:1567-1572, 1995). Here, we report on an unrelated porin species (HopE) from this bacterium. This protein had a apparent molecular mass of 31 kDa and was seen to form 50- and 90-kDa aggregates that were designated putative dimeric and trimeric forms, respectively. The protein was purified to homogeneity and, with a model planar lipid membrane system, was shown to act as a nonselective pore with a single channel conductance in 1.0 M KCl of 1.5 nS, similarly to other bacterial nonspecific porins. An internal peptide sequence of HopE shared homology with the P2 porin of Haemophilus influenzae. HopE was also shown to be antigenic in vivo as assessed by sera taken from H. pylori-infected individuals and was immunologically conserved with both patient sera and specific monoclonal antibodies. From these data, it appears that HopE is a major nonselective porin of H. pylori. The implications of these findings are discussed.


Patterns of breast magnetic resonance imaging use in community practice.
Breast magnetic resonance imaging (MRI) is increasingly used for breast cancer screening, diagnostic evaluation, and surveillance. However, we lack data on national patterns of breast MRI use in community practice. To describe patterns of breast MRI use in US community practice during the period 2005 through 2009. Observational cohort study using data collected from 2005 through 2009 on breast MRI and mammography from 5 national Breast Cancer Surveillance Consortium registries. Data included 8931 breast MRI examinations and 1,288,924 screening mammograms from women aged 18 to 79 years. We calculated the rate of breast MRI examinations per 1000 women with breast imaging within the same year and described the clinical indications for the breast MRI examinations by year and age. We compared women screened with breast MRI to women screened with mammography alone for patient characteristics and lifetime breast cancer risk. The overall rate of breast MRI from 2005 through 2009 nearly tripled from 4.2 to 11.5 examinations per 1000 women, with the most rapid increase from 2005 to 2007 (P = .02). The most common clinical indication was diagnostic evaluation (40.3%), followed by screening (31.7%). Compared with women who received screening mammography alone, women who underwent screening breast MRI were more likely to be younger than 50 years, white non-Hispanic, and nulliparous and to have a personal history of breast cancer, a family history of breast cancer, and extremely dense breast tissue (all P < .001). The proportion of women screened using breast MRI at high lifetime risk for breast cancer (>20%) increased during the study period from 9% in 2005 to 29% in 2009. Use of breast MRI for screening in high-risk women is increasing. However, our findings suggest that there is a need to improve appropriate use, including among women who may benefit from screening breast MRI.


Catechol-functionalized hydrogels: biomimetic design, adhesion mechanism, and biomedical applications.
Hydrogels are a unique class of polymeric materials that possess an interconnected porous network across various length scales from nano- to macroscopic dimensions and exhibit remarkable structure-derived properties, including high surface area, an accommodating matrix, inherent flexibility, controllable mechanical strength, and excellent biocompatibility. Strong and robust adhesion between hydrogels and substrates is highly desirable for their integration into and subsequent performance in biomedical devices and systems. However, the adhesive behavior of hydrogels is severely weakened by the large amount of water that interacts with the adhesive groups reducing the interfacial interactions. The challenges of developing tough hydrogel-solid interfaces and robust bonding in wet conditions are analogous to the adhesion problems solved by marine organisms. Inspired by mussel adhesion, a variety of catechol-functionalized adhesive hydrogels have been developed, opening a door for the design of multi-functional platforms. This review is structured to give a comprehensive overview of adhesive hydrogels starting with the fundamental challenges of underwater adhesion, followed by synthetic approaches and fabrication techniques, as well as characterization methods, and finally their practical applications in tissue repair and regeneration, antifouling and antimicrobial applications, drug delivery, and cell encapsulation and delivery. Insights on these topics will provide rational guidelines for using nature's blueprints to develop hydrogel materials with advanced functionalities and uncompromised adhesive properties.


Transformative ties: gendered violence, forms of recovery, and shifting subjectivities in Chile.
Although a significant body of scholarship on trauma has emerged in medical anthropology, there has been little examination of how gendered expectations shape the aftermath of extreme human experience, forms of recovery, and subjectivity. Here, I show how domestic and other forms of violence have shaped Luz's suffering in the dictatorial (1973-90) and officially democratic (1990-present) eras in Chile. I then elucidate how Luz's engagement with Safe Space, an NGO connected to UN violence against women frameworks, and other globally connected women's groups, have allowed her to generate transformative ties with other women. These relationships provide support for Luz's self-defined project of transforming herself and society, largely in relationship to gendered expectations, so that her recovered sense of self will have more of a home in the world, outside the boundaries of narrowly defined gender roles. This analysis is based on ethnographic research in Santiago, Chile, over 19 months in 2000-04 and 2009, including participant-observation at two domestic violence centers and life history interviews with 18 women who sought help there.


RUNX1 and CBFβ-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development.
Inversion of chromosome 16 is a consistent finding in patients with acute myeloid leukemia subtype M4 with eosinophilia, which generates a CBFB-MYH11 fusion gene. It is generally considered that CBFβ-SMMHC, the fusion protein encoded by CBFB-MYH11, is a dominant negative repressor of RUNX1. However, recent findings challenge the RUNX1-repression model for CBFβ-SMMHC-mediated leukemogenesis. To definitively address the role of Runx1 in CBFB-MYH11-induced leukemia, we crossed conditional Runx1 knockout mice (Runx1f/f) with conditional Cbfb-MYH11 knockin mice (Cbfb+/56M). On Mx1-Cre activation in hematopoietic cells induced by poly (I:C) injection, all Mx1-CreCbfb+/56M mice developed leukemia in 5 months, whereas no leukemia developed in Runx1f/fMx1-CreCbfb+/56M mice, and this effect was cell autonomous. Importantly, the abnormal myeloid progenitors (AMPs), a leukemia-initiating cell population induced by Cbfb-MYH11 in the bone marrow, decreased and disappeared in Runx1f/fMx1-CreCbfb+/56M mice. RNA-seq analysis of AMP cells showed that genes associated with proliferation, differentiation blockage, and leukemia initiation were differentially expressed between Mx1-CreCbfb+/56M and Runx1f/fMx1-CreCbfb+/56M mice. In addition, with the chromatin immunocleavage sequencing assay, we observed a significant enrichment of RUNX1/CBFβ-SMMHC target genes in Runx1f/fMx1-CreCbfb+/56M cells, especially among downregulated genes, suggesting that RUNX1 and CBFβ-SMMHC mainly function together as activators of gene expression through direct target gene binding. These data indicate that Runx1 is indispensable for Cbfb-MYH11-induced leukemogenesis by working together with CBFβ-SMMHC to regulate critical genes associated with the generation of a functional AMP population.


Poly-dA:dT tracts form an in vivo nucleosomal turnstile.
Nucleosomes regulate many DNA-dependent processes by controlling the accessibility of DNA, and DNA sequences such as the poly-dA:dT element are known to affect nucleosome binding. We demonstrate that poly-dA:dT tracts form an asymmetric barrier to nucleosome movement in vivo, mediated by ATP-dependent chromatin remodelers. We theorize that nucleosome transit over poly-A elements is more energetically favourable in one direction, leading to an asymmetric arrangement of nucleosomes around these sequences. We demonstrate that different arrangements of poly-A and poly-T tracts result in very different outcomes for nucleosome occupancy in yeast, mouse, and human, and show that yeast takes advantage of this phenomenon in its promoter architecture.


p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells.
T cell senescence is thought to contribute to immune function decline, but the pathways that mediate senescence in these cells are not clear. Here, we evaluated T cell populations from healthy volunteers and determined that human CD8+ effector memory T cells that reexpress the naive T cell marker CD45RA have many characteristics of cellular senescence, including decreased proliferation, defective mitochondrial function, and elevated levels of both ROS and p38 MAPK. Despite their apparent senescent state, we determined that these cells secreted high levels of both TNF-α and IFN-γ and showed potent cytotoxic activity. We found that the senescent CD45RA-expressing population engaged anaerobic glycolysis to generate energy for effector functions. Furthermore, inhibition of p38 MAPK signaling in senescent CD8+ T cells increased their proliferation, telomerase activity, mitochondrial biogenesis, and fitness; however, the extra energy required for these processes did not arise from increased glucose uptake or oxidative phosphorylation. Instead, p38 MAPK blockade in these senescent cells induced an increase in autophagy through enhanced interactions between p38 interacting protein (p38IP) and autophagy protein 9 (ATG9) in an mTOR-independent manner. Together, our findings describe fundamental metabolic requirements of senescent primary human CD8+ T cells and demonstrate that p38 MAPK blockade reverses senescence via an mTOR-independent pathway.


Putting a price tag on novel autologous cellular therapies.
Cell therapies, especially autologous therapies, pose significant challenges to researchers who wish to move from small, probably academic, methods of manufacture to full commercial scale. There is a dearth of reliable information about the costs of operation, and this makes it difficult to predict with confidence the investment needed to translate the innovations to the clinic, other than as small-scale, clinician-led prescriptions. Here, we provide an example of the results of a cost model that takes into account the fixed and variable costs of manufacture of one such therapy. We also highlight the different factors that influence the product final pricing strategy. Our findings illustrate the need for cooperative and collective action by the research community in pre-competitive research to generate the operational models that are much needed to increase confidence in process development for these advanced products.


Socio-demographic and clinical determinants of self-care in adults with type 2 diabetes: a multicentre observational study.
To describe self-care as defined by the Middle Range Theory of Self-Care of Chronic Illness and to identify clinical and socio-demographic determinants in a T2DM population. A multicentre observational cross-sectional study was conducted involving 540 adults with a confirmed diagnosis of T2DM from six outpatient diabetes services in Italy. Socio-demographic and clinical data were collected from medical records. The Self-Care of Diabetes Inventory (SCODI) was used to measure self-care maintenance, monitoring, management, and confidence dimensions. For each separate scale, scores were standardized 0-100 with higher SCODI scores indicating better self-care; a score ≥ 70 is adequate. Multiple quantile regression models were performed to identify determinants of each self-care dimension. Self-care maintenance (median = 81.3) and self-care confidence (median = 79.5) were adequate in most of the subjects. Self-care monitoring was adequate in only half of the sample (median = 70.6). Self-care management was poor (median = 59.4). Lower self-care maintenance was associated with lower self-care confidence (p < 0.001). Lower self-care monitoring was associated with being male (p < 0.001), having lower self-care confidence (p < 001), and having diabetes for < 10 years (p < 0.001). Lower self-care management was associated with being male (p = 0.002), being older (p = 0.005), having a low income (p = 0.030), being employed (p = 0.008), having missed diabetes education in the last year (p = 0.002), and lower self-care confidence (p < 0.0001). Lower self-care confidence was associated with having diabetes for < 10 years (p = 0.008), and having at least one comorbid condition (p = 0.006). Determinants of self-care maintenance, monitoring, management and confidence include both clinical and socio-demographic variables. Modifiable determinants such as self-care confidence and diabetes self-care management education could be used to tailor interventions to improve diabetes self-care.


A Survey of Labor and Delivery Practices in New York City during the COVID-19 Pandemic.
Recently, a novel coronavirus, precisely severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), that causes the disease novel coronavirus disease 2019 (COVID-19) has been declared a worldwide pandemic. Over a million cases have been confirmed in the United States. As of May 5, 2020, New York State has had over 300,000 cases and 24,000 deaths with more than half of the cases and deaths occurring in New York City (NYC). Little is known, however, of how this virus impacts pregnancy. Given this lack of data and the risk for severe disease in this relatively immunocompromised population, further understanding of the obstetrical management of COVID-19, as well as hospital level preparation for its control, is crucial. Guidance has come from expert opinion, professional societies and public health agencies, but to date, there is no report on how obstetrical practices have adapted these recommendations to their local situations. We therefore developed an internet-based survey to elucidate the practices put into place to guide the care of obstetrical patients during the COVID-19 pandemic. We surveyed obstetrical leaders in four academic medical centers in NYC who were implementing and testing protocols at the height of the pandemic. We found that all sites made changes to their practices, and that there appeared to be agreement with screening and testing for COVID-19, as well as labor and delivery protocols, for SARS-CoV-2-positive patients. We found less consensus with respect to inpatient antepartum fetal surveillance. We hope that this experience is useful to other centers as they formulate their plans to face this pandemic. KEY POINTS: · Practices changed to accommodate public health needs.. · Most practices are screened for novel COVID-19 on admission.. · Fetal testing in COVID-19 patients varied..


The population genetics of the Jewish people.
Adherents to the Jewish faith have resided in numerous geographic locations over the course of three millennia. Progressively more detailed population genetic analysis carried out independently by multiple research groups over the past two decades has revealed a pattern for the population genetic architecture of contemporary Jews descendant from globally dispersed Diaspora communities. This pattern is consistent with a major, but variable component of shared Near East ancestry, together with variable degrees of admixture and introgression from the corresponding host Diaspora populations. By combining analysis of monoallelic markers with recent genome-wide variation analysis of simple tandem repeats, copy number variations, and single-nucleotide polymorphisms at high density, it has been possible to determine the relative contribution of sex-specific migration and introgression to map founder events and to suggest demographic histories corresponding to western and eastern Diaspora migrations, as well as subsequent microevolutionary events. These patterns have been congruous with the inferences of many, but not of all historians using more traditional tools such as archeology, archival records, linguistics, comparative analysis of religious narrative, liturgy and practices. Importantly, the population genetic architecture of Jews helps to explain the observed patterns of health and disease-relevant mutations and phenotypes which continue to be carefully studied and catalogued, and represent an important resource for human medical genetics research. The current review attempts to provide a succinct update of the more recent developments in a historical and human health context.


Phonemic fluency and brain connectivity in age-related macular degeneration: a pilot study.
Age-related macular degeneration (AMD), the leading cause of blindness in developed nations, has been associated with poor performance on tests of phonemic fluency. This pilot study sought to (1) characterize the relationship between phonemic fluency and resting-state functional brain connectivity in AMD patients and (2) determine whether regional connections associated with phonemic fluency in AMD patients were similarly linked to phonemic fluency in healthy participants. Behavior-based connectivity analysis was applied to resting-state, functional magnetic resonance imaging data from seven patients (mean age=79.9±7.5 years) with bilateral AMD who completed fluency tasks prior to imaging. Phonemic fluency was inversely related to the strength of functional connectivity (FC) among six pairs of brain regions, representing eight nodes: left opercular portion of inferior frontal gyrus (which includes Broca's area), left superior temporal gyrus (which includes part of Wernicke's area), inferior parietal lobe (bilaterally), right superior parietal lobe, right supramarginal gyrus, right supplementary motor area, and right precentral gyrus. The FC of these reference links was not related to phonemic fluency among 32 healthy individuals (16 younger adults, mean age=23.5±4.6 years and 16 older adults, mean age=68.3±3.4 years). Compared with healthy individuals, AMD patients exhibited higher mean connectivity within the reference links and within the default mode network, possibly reflecting compensatory changes to support performance in the setting of reduced vision. These findings are consistent with the hypothesis that phonemic fluency deficits in AMD reflect underlying brain changes that develop in the context of AMD.


Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer.
To investigate the relationship of hypoxia-inducible factor-1alpha (HIF-1alpha) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. The expression of HIF-1alpha was assessed by immunohistochemistry in 187 patients with T(2-4) N(0-1) breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity. Overall response to therapy progressively decreased with increasing tumor HIF-1alpha (P < 0.05), and HIF-1alpha was an independent predictor of response (P < 0.048). HIF-1alpha expression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1alpha-negative tumors. HIF-1alpha expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1alpha expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.


HIV epidemic appraisals for assisting in the design of effective prevention programmes: shifting the paradigm back to basics.
To design HIV prevention programmes, it is critical to understand the temporal and geographic aspects of the local epidemic and to address the key behaviours that drive HIV transmission. Two methods have been developed to appraise HIV epidemics and guide prevention strategies. The numerical proxy method classifies epidemics based on current HIV prevalence thresholds. The Modes of Transmission (MOT) model estimates the distribution of incidence over one year among risk-groups. Both methods focus on the current state of an epidemic and provide short-term metrics which may not capture the epidemiologic drivers. Through a detailed analysis of country and sub-national data, we explore the limitations of the two traditional methods and propose an alternative approach. We compared outputs of the traditional methods in five countries for which results were published, and applied the numeric and MOT model to India and six districts within India. We discovered three limitations of the current methods for epidemic appraisal: (1) their results failed to identify the key behaviours that drive the epidemic; (2) they were difficult to apply to local epidemics with heterogeneity across district-level administrative units; and (3) the MOT model was highly sensitive to input parameters, many of which required extraction from non-regional sources. We developed an alternative decision-tree framework for HIV epidemic appraisals, based on a qualitative understanding of epidemiologic drivers, and demonstrated its applicability in India. The alternative framework offered a logical algorithm to characterize epidemics; it required minimal but key data. Traditional appraisals that utilize the distribution of prevalent and incident HIV infections in the short-term could misguide prevention priorities and potentially impede efforts to halt the trajectory of the HIV epidemic. An approach that characterizes local transmission dynamics provides a potentially more effective tool with which policy makers can design intervention programmes.


Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study.
Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age. After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD. Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.


Sex differences in the brain: a whole body perspective.
Most writing on sexual differentiation of the mammalian brain (including our own) considers just two organs: the gonads and the brain. This perspective, which leaves out all other body parts, misleads us in several ways. First, there is accumulating evidence that all organs are sexually differentiated, and that sex differences in peripheral organs affect the brain. We demonstrate this by reviewing examples involving sex differences in muscles, adipose tissue, the liver, immune system, gut, kidneys, bladder, and placenta that affect the nervous system and behavior. The second consequence of ignoring other organs when considering neural sex differences is that we are likely to miss the fact that some brain sex differences develop to compensate for differences in the internal environment (i.e., because male and female brains operate in different bodies, sex differences are required to make output/function more similar in the two sexes). We also consider evidence that sex differences in sensory systems cause male and female brains to perceive different information about the world; the two sexes are also perceived by the world differently and therefore exposed to differences in experience via treatment by others. Although the topic of sex differences in the brain is often seen as much more emotionally charged than studies of sex differences in other organs, the dichotomy is largely false. By putting the brain firmly back in the body, sex differences in the brain are predictable and can be more completely understood.


TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.
Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.


Contribution of goal-directed ultrasonography to clinical decision-making for emergency physicians.
To determine the contribution of goal-directed right upper quadrant (RUQ) ultrasonography (US) on real-time decision-making of attending emergency physicians by evaluating their level of certainty for admission, surgery, medical treatment, additional laboratory and radiological investigations and discharge. The study was conducted at an urban university tertiary care emergency department with an annual census of 60,000 adult patients. Patients with acute non-traumatic RUQ pain presenting to the emergency department during the 8-month study period were enrolled into the study. Primary outcome measures were level of certainty for admission to the hospital, emergency surgery, medical treatment, additional laboratory and radiological analyses and discharge from the emergency department. There was a significant difference between the pre-US and post-US certainty of the decision to perform additional diagnostic studies (56 vs 72, p = 0.01) but not in the other outcomes (treatment, admission, surgery and discharge). After categorising the physicians' decisions into low, intermediate and high, US had an effect on all primary outcomes and on all categories. This effect was most evident in the moderate category where the physicians were undecided for all primary outcomes. US performed by emergency department physicians affects the certainty of their decisions in patients presenting with RUQ pain. This effect is more evident on the decision to perform additional diagnostic studies and in patients about whom physicians are undecided.


Serotonin: a double-edged sword for the liver?
Since the discovery of the impact of serotonin in liver regeneration, this molecule has gained considerable attention in liver physio-pathology. Platelet-derived serotonin initiates liver regeneration after partial hepatectomy in various rodent models. Serotonin agonism stabilizes the hepatic microcirculation and prevents small-for-size liver graft failure. Similarly, serotonin receptor agonists improve the sinusoidal perfusion of aged liver and restore the deficient liver regeneration in old mice through a pathway dependent on vascular endothelial growth factor. Beside hepatocyte proliferation, cholangiocytes have been shown to be able to deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree. Increasing evidence indicates that serotonin is involved in many pathological conditions of the liver. For example, serotonin promotes tissue repair after ischemia/reperfusion injury. Reactive oxygen species generated by serotonin degradation contribute to steatohepatitis in rodent models. Serotonin aggravates viral hepatitis, again through vasoactive effects on the microcirculation, and plays a crucial role in the progression of hepatic fibrosis. Finally, serotonin may facilitate tumor growth of primary liver carcinoma like cholangiocarcinoma and hepatocellular carcinoma. These findings make serotonin both friend and foe for the liver. Whichever, these new data emphasize the potential of serotonin as a pharmacological target in liver disease.


Statin Adherence: Does Gender Matter?
Cardiovascular disease (CVD) continues to be the leading cause of death for men and women in the USA. Statins have contributed significantly to noted declines in cardiovascular-related mortality in the last decade; however, the benefit of statins is inequitable across genders. Women continue to be less likely to take statins and to meet target LDL goals than men. As a possible contributing factor to this disparity, we explore the evidence for gender-based differences in provision of, and adherence to statins. Compared with men, women are less likely to adhere to statins. Potential reasons for this gender difference in use of statins can be observed across all phases of adherence including both intentional and unintentional non-adherence. Notable gender-specific contributing factors for statin non-adherence include decreased provider and patient awareness of CVD risk among women, higher risk of statin intolerance among women, and competing demands associated with family caregiving responsibilities. Similar to limitations in the broader CVD literature, there is inadequate inclusion of gender-specific analyses in statin-related trials. Gender-based disparities in statin adherence can be linked to both provider level, psychosocial, and medication intolerance factors. Interventions designed to improve statin adherence should take gender-specific challenges into consideration such as women being older at the time of increased CVD risk, higher rates of statin intolerance, and potentially greater caregiving responsibilities.


Quantifying the performance limitations of older and younger adults in a target acquisition task.
In a stationary target acquisition task, both 65-year-old and 20-year-old adults exhibited a negatively accelerated curvilinear relationship between the spatial variability of submovement endpoints and average submovement velocity. For high velocities, the variability was greater for the older adults. This elevated motor noise is considered a primary cause of their slower performance. Both age groups also exhibited a linear relationship between submovement duration and the logarithm of submovement relative accuracy. A stochastic model indicates that the two age groups were similar in the strategies they used to compose single movements from a variety of submovements. However, when performing sequences of movements containing varied target distances, older adults exhibited a repetition effect whereas younger adults exhibited a contrast effect. Older adults may plan movements individually, whereas younger adults plan sequences.


Possible pitfalls in rat extended dermal toxicity testing: an hepatic-ocular syndrome.
During a sub-chronic dermal toxicity study, hepatic and ocular toxicity were detected unrelated to the compound being tested. The changes in the liver were characterized by hepatic centrilobular degeneration and fibrosis due to chronic passive congestion. Clinical chemistry results confirmed the active hepatic damage and cholestasis. The ocular changes were limited to the retina where diffuse retinal atrophy was seen originating adjacent to the optic nerve and progressing centrifugally. It is suggested that as a consequence of the bandaging technique, a state of passive congestion and cholestasis resulted. The decrease in flow of bile acids to the intestine caused disturbances in vitamin E absorption. The deficiency of the antioxidant vitamin was responsible for the retinal changes seen.


Combining scattering analysis and atomistic simulation of wood-water interactions.
Molecular-scale interactions between water and cellulose microfibril bundles in plant cell walls are not fully understood, despite their crucial role for many applications of plant biomass. Recent advances in X-ray and neutron scattering analysis allow more accurate interpretation of experimental data from wood cell walls. At the same time, microfibril bundles including hemicelluloses and water can be modelled at atomistic resolution. Computing scattering patterns from atomistic models enables a new, complementary approach to decipher some of the most fundamental questions at this level of the hierarchical cell wall structure. This article introduces studies related to moisture behavior of wood with small/wide-angle X-ray/neutron scattering and atomistic simulations, recent attempts to combine these two approaches, and perspectives and open questions for future research using this powerful combination. Finally, we discuss the opportunities of the combined method in relation to applications of lignocellulosic materials.


Fluoride curcumin derivatives: new mitochondrial uncoupling agents.
The mitochondrial effects of two fluoride curcumin derivatives were studied. They induced the collapse of mitochondrial membrane potential (DeltaPsi), increased mitochondrial respiration, and decreased O(2)*- production and promoted Ca(2+) release. These effects were reversed by the recoupling agent 6-Ketocholestanol, but not by cyclosporin A, an inhibitor of the permeability transition pore (PTP), suggesting that these compounds act as uncoupling agents. This idea was reinforced by the analysis of the physico-chemical properties of the compounds indicating, that they are mainly in the anionic form in the mitochondrial membrane. Moreover, they are able to induce PTP opening by promoting the oxidation of thiol groups and the release of cytochrome c, making these two molecules potential candidates for induction of apoptosis.


Association of type 2 diabetes with brain atrophy and cognitive impairment.
We investigated the associations of diabetes and hypertension with imaging biomarkers (markers of neuronal injury and ischemic damage) and with cognition in a population-based cohort without dementia. Participants (n = 1,437, median age 80 years) were evaluated by a nurse and physician and underwent neuropsychological testing. A diagnosis of cognitively normal, mild cognitive impairment (MCI), or dementia was made by an expert panel. Participants underwent MRI to determine cortical and subcortical infarctions, white matter hyperintensity (WMH) volume, hippocampal volume (HV), and whole brain volume (WBV). The medical records were reviewed for diabetes and hypertension in midlife or later. Midlife diabetes was associated with subcortical infarctions (odds ratio, 1.85 [95% confidence interval, 1.09-3.15]; p = 0.02), reduced HV (-4% [-7 to -1.0]; p = 0.01), reduced WBV (-2.9% [-4.1 to -1.6]), and prevalent MCI (odds ratio, 2.08; p = 0.01). The association between diabetes and MCI persisted with adjustment for infarctions and WMH volume but was attenuated after adjustment for WBV (1.60 [0.87-2.95]; p = 0.13) and HV (1.82 [1.00-3.32]; p = 0.05). Midlife hypertension was associated with infarctions and WMH volume and was marginally associated with reduced performance in executive function. Effects of late-life onset of diabetes and hypertension were few. Midlife onset of diabetes may affect late-life cognition through loss of brain volume. Midlife hypertension may affect executive function through ischemic pathology. Late-life onset of these conditions had fewer effects on brain pathology and cognition.


Improving the linearity of the Michelson interferometric angular measurement by a parameter compensation method.
A parameter compensation method is developed to improve the linearity of the Michelson interferometric angular measurement. The formulas for the exact calculation of the parameters are presented; different cases are discussed. By introducing a weight function in the calculation, we can change the distribution of the linearity over the whole range of measurement. The theoretical analysis and the experimental results show that this method greatly improves the linearity of the measurement even for a large range of measurement.


Sex- and gonad-affecting scent compounds and 3 male pheromones in the rat.
This study was aimed at identifying sex pheromones of the rat (Rattus norvegicus). We characterized the volatiles and semivolatiles of rat preputial gland and voided urine by using gas chromatography-mass spectrometry (GC-MS) and quantified them by their GC areas (abundances) and percentage of GC areas (relative abundances). Although all the compounds other than 4-heptanone and phenol detected were shared by males and females, the quantities for some of these sex-common compounds exhibited sexual dimorphism and decreased with gonadectomy. Thus, these compounds might be sex pheromones. Among them, squalene from preputial glands and 2-heptanone and 4-ethyl phenol from urine were 3 major compounds. They were richer in males and could be suppressed by castration. Adding any of the 3 compounds (at a concentration higher than its physiological level in male urine) to castrated male urine (CMU) increased the attractiveness of CMU to sex-naive females. Adding the 3 together (at the levels in normal male urine) to CMU significantly increased the attractiveness of CMU to females. However, such combination did not fully restore females' preference for urine from intact males, suggesting that some other trace compounds such as 4-heptanone and phenol might also play some roles in sex attractiveness. Thus, squalene, 2-heptanone, and 4-ethyl phenol were indeed male pheromone molecules in rats. Our study also indicates that E,E-beta-farnesene and E-alpha-farnesene, both richer in females than males, might be putative female pheromones.


Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses.
Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells. Moreover, conditional inactivation of DL4 in lymph node fibroblasts resulted in impaired follicular helper T cell differentiation and, consequently, in reduced numbers of germinal center B cells and absence of high-affinity antibodies. Our data demonstrate previously unknown roles for DL ligand-expressing fibroblasts in SLO niches as drivers of multiple Notch-mediated immune differentiation processes.


Comparative environmental impacts of glyphosate and conventional herbicides when used with glyphosate-tolerant and non-tolerant crops.
The introduction of glyphosate-tolerant (GT) crops is expected to mitigate the environmental contamination by herbicides because glyphosate is less persistent and toxic than the herbicides used on non-GT crops. Here, we compared the environmental balances of herbicide applications for both crop types in three French field trials. The dynamic of herbicides and their metabolites in soil, groundwater and air was simulated with PRZM model and compared to field measurements. The associated impacts were aggregated with toxicity potentials calculated with the fate and exposure model USES for several environmental endpoints. The impacts of GT systems were lower than those of non-GT systems, but the accumulation in soils of one glyphosate metabolite (aminomethylphosphonic acid) questions the sustainability of GT systems. The magnitude of the impacts depends on the rates and frequency of glyphosate application being highest for GT maize monoculture and lowest for combination of GT oilseed rape and non-GT sugarbeet crops.


A survey of accessibility and utilisation of chiropractic services for wheelchair-users in the United Kingdom: What are the issues?
People with physical disabilities experience barriers to healthcare across all services despite a legal and moral obligation to the contrary. Complementary medicine is considered as supplementary to conventional care and integration of these approaches is essential to achieve optimal care. This paper explores the utilisation of chiropractic services and practitioner experiences of treating wheelchair-users which appears under-reported. A 20 item questionnaire was posted to 250 randomly selected chiropractors registered with the General Chiropractic Council. Follow-up questionnaires were sent 7 days after the initial return date. Quantitative data were subjected to frequency analysis. The response rate was 64% (n = 161). The majority (66%) of chiropractors had been in practice less than 10 years and were practice owners (50%). Fifty-two percent of chiropractors sampled had treated a patient in a wheelchair in the previous 5 years. The majority (87%) had treated between 1 and 5 such patients. Patients with multiple sclerosis, stroke and cerebral palsy most commonly presented for treatment. The majority of patients' presenting complaint was musculoskeletal in origin, primarily for pain control. Only 13% of respondents worked in a fully accessible clinic. Impracticality of alterations was the most common reason for inaccessibility. Wheelchair-users seem to be an underserved patient group in relation to chiropractic services. Chiropractic management is primarily utilised for pain control in patients with physical disabilities in which mobility may be improved or maintained. Co-management of wheelchair-users with GPs appears to be desirable in order to achieve optimal patient care however more research is required regarding the efficacy of chiropractic treatment for a range of disabling conditions. Physical access was identified as a key barrier to accessing care.


Ethanol Modulation is Quantitatively Determined by the Transmembrane Domain of Human α1 Glycine Receptors.
Mutagenesis and labeling studies have identified amino acids from the human α1 glycine receptor (GlyR) extracellular, transmembrane (TM), and intracellular domains in mediating ethanol (EtOH) potentiation. However, limited high-resolution structural data for physiologically relevant receptors in this Cys-loop receptor superfamily have made pinpointing the critical amino acids difficult. Homologous ion channels from lower organisms provide conserved models for structural and functional properties of Cys-loop receptors. We previously demonstrated that a single amino acid variant of the Gloeobacter violaceus ligand-gated ion channel (GLIC) produced EtOH and anesthetic sensitivity similar to that of GlyRs and provided crystallographic evidence for EtOH binding to GLIC. We directly compared EtOH modulation of the α1 GlyR and GLIC to a chimera containing the TM domain from human α1 GlyRs and the ligand-binding domain of GLIC using 2-electrode voltage-clamp electrophysiology of receptors expressed in Xenopus laevis oocytes. EtOH potentiated α1 GlyRs in a concentration-dependent manner in the presence of zinc-chelating agents, but did not potentiate GLIC at pharmacologically relevant concentrations. The GLIC/GlyR chimera recapitulated the EtOH potentiation of GlyRs, without apparent sensitivity to zinc chelation. For chimera expression in oocytes, it was essential to suppress leakage current by adding 50 μM picrotoxin to the media, a technique that may have applications in expression of other ion channels. Our results are consistent with a TM mechanism of EtOH modulation in Cys-loop receptors. This work highlights the relevance of bacterial homologs as valuable model systems for studying ion channel function of human receptors and demonstrates the modularity of these channels across species.


A Case of Ventriculitis Associated with Renal Abscess Caused by Serotype K1 Klebsiella pneumoniae.
Recently, serotype K1 Klebsiella pneumoniae has been a major agent of an invasive syndrome characterized by liver abscess and its metastatic infection. Extrahepatic infection and its characteristics in patients with renal abscess caused by K. pneumoniae are poorly understood, and few cases of central nervous system infection have been reported. This is a report of 80-year-old woman with uncontrolled type 2 diabetes mellitus with renal abscess caused by serotype K1 K. pneumoniae, complicated with ventriculitis despite of appropriate use of antibiotics. Physicians need to be aware of possibility of metastatic infection in patients with serotype K1 K. pneumoniae infection, if they develop neurologic symptom and focus of infection is still present.


[Influence of subclinical atherosclerosis on diastolic function in individuals free of cardiovascular disease].
it is plausible that subclinical atherosclerosis alters coronary reserve and impairs diastolic function of the left ventricle. However, the relationship between subclinical stages of atherosclerosis and diastolic function has not been established in subjects free of cardiovascular disease. to test the hypothesis that subclinical atherosclerosis has a negative association with diastolic function. individuals > 35 years old, free of cardiovascular disease, with normal blood pressure and negative treadmill stress test, were selected to have common carotid intima-media thickness (IMT) assessed by ultrasound and parameters of diastolic function by echocardiography, primarily tissue Doppler E'/A' ratio. forty-eight subjects were studied, aged 56 ± 10 years, 67% females. Composite common carotid IMT had a significant negative correlation with tissue Doppler E'/A' ratio (r = - 0.437, p = 0.002). Individuals in the fourth quartile of IMT had a significant lower tissue Doppler E'/A' ratio (0.76 ± 0.25), as compared with the first (1.2 ± 0.29), second (1.2 ± 0.36) and third quartiles (1.1 ± 0.25) - p = 0.002. Composite common carotid IMT in the fourth quartile (> 0.8 mm) independently predicted E'/A' ratio (p = 0.02), after adjustment for potentially confounding variables, such as age, female gender, waist circumference, diastolic blood pressure, HDL-cholesterol and Framingham Risk. early stage of subclinical atherosclerotic disease is negatively associated with diastolic function parameters in healthy individuals, regardless of age and clinical characteristics.


Spreading on viscoelastic solids: are contact angles selected by Neumann's law?
The spreading of liquid drops on soft substrates is extremely slow, owing to strong viscoelastic dissipation inside the solid. A detailed understanding of the spreading dynamics has remained elusive, partly owing to the difficulty in quantifying the strong viscoelastic deformations below the contact line that determine the shape of moving wetting ridges. Here we present direct experimental visualisations of the dynamic wetting ridge using shadowgraphic imaging, complemented with measurements of the liquid contact angle. It is observed that the wetting ridge exhibits a rotation that follows exactly the dynamic liquid contact angle - as was previously hypothesized [Karpitschka et al., Nat. Commun., 2015, 6, 7891]. This experimentally proves that, despite the contact line motion, the wetting ridge is still governed by Neumann's law. Furthermore, our experiments suggest that moving contact lines lead to a variable surface tension of the substrate. We therefore set up a new theory that incorporates the influence of surface strain, for the first time including the so-called Shuttleworth effect into the dynamical theory for soft wetting. It includes a detailed analysis of the boundary conditions at the contact line, complemented by a dissipation analysis, which shows, again, the validity of Neumann's balance.


Reducing Maternal Deaths in Ethiopia: Results of an Intervention Programme in Southwest Ethiopia.
In a large population in Southwest Ethiopia (population 700,000), we carried out a complex set of interventions with the aim of reducing maternal mortality. This study evaluated the effects of several coordinated interventions to help improve effective coverage and reduce maternal deaths. Together with the Ministry of Health in Ethiopia, we designed a project to strengthen the health-care system. A particular emphasis was given to upgrade existing institutions so that they could carry out Basic (BEmOC) and Comprehensive Emergency Obstetric Care (CEmOC). Health institutions were upgraded by training non-clinical physicians and midwives by providing the institutions with essential and basic equipment, and by regular monitoring and supervision by staff competent in emergency obstetric work. In this implementation study, the maternal mortality ratio (MMR) was the primary outcome. The study was carried out from 2010 to 2013 in three districts, and we registered 38,312 births. The MMR declined by 64% during the intervention period from 477 to 219 deaths per 100,000 live births (OR 0.46; 95% CI 0.24-0.88). The decline in MMR was higher for the districts with CEmOC, while the mean number of antenatal visits for each woman was 2.6 (Inter Quartile Range 2-4). The percentage of pregnant women who attended four or more antenatal controls increased by 20%, with the number of women who delivered at home declining by 10.5% (P<0.001). Similarly, the number of deliveries at health posts, health centres and hospitals increased, and we observed a decline in the use of traditional birth attendants. Households living near to all-weather roads had lower maternal mortality rates (MMR 220) compared with households without roads (MMR 598; OR 2.72 (95% CI 1.61-4.61)). Our results show that it is possible to achieve substantial reductions in maternal mortality rates over a short period of time if the effective coverage of well-known interventions is implemented.


Maintenance of long-term clinical benefit with sirolimus-eluting coronary stents: three-year results of the RAVEL trial.
The use of sirolimus-eluting coronary stents has been associated with a nearly complete elimination of restenosis at 6 months and with a very low 1-year incidence of major adverse cardiac events (MACE). This analysis examined whether these beneficial effects persist over the longer term. This multicenter trial randomly assigned 238 patients to revascularization of single, de novo, native coronary artery lesions with sirolimus-eluting versus conventional bare-metal stents. Survival free from target lesion revascularization (TLR), target vessel failure (TVF), and MACE up to 3 years of follow-up was compared between the 2 treatment groups. Complete data sets were available in 94.2% of patients treated with sirolimus-eluting stents and in 94.1% of patients randomized to the control group. The cumulative 1-, 2-, and 3-year event-free survival rates were 99.2%, 96.5%, and 93.7% for TLR and 95.8%, 92.3%, and 87.9% for TVF, respectively, in the sirolimus-eluting stent group, versus 75.9%, 75.9%, and 75.0% for TLR and 71.2%, 69.4%, and 67.3% for TVF in the control group (P<0.001 for both comparisons at 3 years). Rates of MACE at 3 years were 15.8% in patients randomly assigned to sirolimus-eluting stents versus 33.1% in patients assigned to bare-metal stents (P=0.002). One patient treated with a sirolimus-eluting stent died of a cardiac cause between 12 and 36 months. Treatment of de novo coronary stenosis with sirolimus-eluting stents was associated with a sustained clinical benefit and very low rates of TLR and of other MACE up to 3 years after device implantation.


Glycosylphosphatidylinositol anchor analogues sequester cholesterol and reduce prion formation.
A hallmark of prion diseases is the conversion of the host-encoded prion protein (PrP(C) where C is cellular) into an alternatively folded, disease-related isoform (PrP(Sc), where Sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. The formation of PrP(Sc) is dependent upon the presence of PrP(C) in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. PrP(C) is targeted to these lipid rafts because it is attached to membranes via a glycosylphosphatidylinositol anchor. Here, we show that treatment of prion-infected neuronal cell lines (ScN2a, ScGT1, or SMB cells) with synthetic glycosylphosphatidylinositol analogues, glucosamine-phosphatidylinositol (glucosamine-PI) or glucosamine 2-O-methyl inositol octadecyl phosphate, reduced the PrP(Sc) content of these cells in a dose-dependent manner. In addition, ScGT1 cells treated with glucosamine-PI did not transmit infection following intracerebral injection to mice. Treatment with glucosamine-PI increased the cholesterol content of ScGT1 cell membranes and reduced activation of cytoplasmic phospholipase A(2) (PLA(2)), consistent with the hypothesis that the composition of cell membranes affects key PLA(2)-dependent signaling pathways involved in PrP(Sc) formation. The effect of glucosamine-PI on PrP(Sc) formation was also reversed by the addition of platelet-activating factor. Glucosamine-PI caused the displacement of PrP(C) from lipid rafts and reduced expression of PrP(C) at the cell surface, putative sites for PrP(Sc) formation. We propose that treatment with glucosamine-PI modifies local micro-environments that control PrP(C) expression and activation of PLA(2) and subsequently inhibits PrP(Sc) formation.


Aptamer-recognized carbohydrates on the cell membrane revealed by super-resolution microscopy.
Carbohydrates are one of the most important components on the cell membrane, which participate in various physiological activities, and their aberrant expression is a consequence of pathological changes. In previous studies, carbohydrate analysis basically relied on lectins. However, discrimination between lectins still exists due to their multivalent character. Furthermore, the structures obtained by carbohydrate-lectin crosslinking confuse our direct observation to some extent. Fortunately, the emergence of aptamers, which are smaller and more flexible, has provided us an unprecedented choice. Herein, an aptamer recognition method with high precise localization was developed for imaging membrane-bound N-acetylgalactosamine (GalNAc). By using direct stochastic optical reconstruction microscopy (dSTORM), we compared this aptamer recognition method with the lectin recognition method for visualizing the detailed structure of GalNAc at the nanometer scale. The results indicated that GalNAc forms irregular clusters on the cell membrane with a resolution of 23 ± 7 nm by aptamer recognition. Additionally, when treated with N-acetylgalactosidase, the aptamer-recognized GalNAc shows a more significant decrease in cluster size and localization density, thus verifying better specificity of aptamers than lectins. Collectively, our study suggests that aptamers can act as perfect substitutes for lectins in carbohydrate labeling, which will be of great potential value in the field of super-resolution fluorescence imaging.


Widespread triggering of nonvolcanic tremor in California.
We identified seven locations on or near the transform plate boundary in California where nonvolcanic tremor was triggered by the 2002 Denali earthquake. This result implies that the conditions essential for nonvolcanic tremor exist in a range of tectonic environments. Models explaining tremor typically require conditions endemic to subduction zones, that is, high temperatures and fluid pressures, because previously tremor was nearly exclusively documented in subduction zones. The absence of tremor in geothermal areas is inconsistent with such models. Additionally, we found no correlation between creeping or locked faults and tremor, contrary to predictions of frictional models of tremor.


Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly.
Neuromyelitis optica (NMO) is thought to be caused by immunoglobulin G autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4). A recent study (Hinson et al. (2012) Proc Natl Acad Sci USA 109:1245-1250) reported that NMO-IgG inhibits AQP4 water permeability directly and causes rapid cellular internalization of the M1 but not M23 isoform of AQP4, resulting in AQP4 clustering, enhanced complement-dependent cytotoxicity, and tissue swelling. Here, we report evidence challenging this proposed mechanism of NMO-IgG-mediated pathology. We measured osmotic water permeability by stopped-flow light scattering on plasma membrane vesicles isolated from AQP4-expressing CHO cells, an approach that can detect changes in water permeability as small as 5% and is not confounded by internalization effects. We found similar single-molecule water permeability for M1-AQP4 tetramers and M23-AQP4 clusters (orthogonal arrays of particles, OAPs). Exposure of AQP4 to high concentrations of NMO-IgG from six seropositive NMO patients, and to high-affinity recombinant monoclonal NMO antibodies, did not reduce AQP4 water permeability. Also, NMO-IgG did not reduce water permeability in AQP4-reconstituted proteoliposomes. In transfected cells expressing M1- or M23-AQP4 individually, NMO-IgG caused more rapid internalization of M23- than M1-AQP4. In cells coexpressing both isoforms, M1- and M23-AQP4 comingled in OAPs that were internalized together in response to NMO-IgG. Super-resolution imaging and native gel electrophoresis showed that the size of AQP4 OAPs was not altered by NMO sera or recombinant NMO antibodies. We conclude that NMO-IgG does not: (i) inhibit AQP4 water permeability, (ii) cause preferential internalization of M1-AQP4, or (iii) cause intramembrane AQP4 clustering.


Diversity of Streptomyces spp. in Eastern Himalayan region - computational RNomics approach to phylogeny.
Isolation and characterization of actinomycetes from soil samples from altitudinal gradient of North-East India were investigated for computational RNomics based phylogeny. A total of 52 diverse isolates of Streptomyces from the soil samples were isolated on four different media and from these 6 isolates were selected on the basis of cultural characteristics, microscopic and biochemical studies. Sequencing of 16S rDNA of the selected isolates identified them to belong to six different species of Streptomyces. The molecular morphometric and physico-kinetic analysis of 16S rRNA sequences were performed to predict the diversity of the genus. The computational RNomics study revealed the significance of the structural RNA based phylogenetic analysis in a relatively diverse group of Streptomyces.


Trusted and doubted: Discourses of parenting training in two Swedish official inquiries, 1947 and 2008.
The aim of this study was to analyse discourses of parenting training in official inquires in Sweden that explicitly deal with the bringing up of children and parental education and how the representations of the problems and their solutions affect parental subject positions in the early welfare state and at the onset of the 21st century. We carried out a discourse analysis of two public inquiries of 1947 and 2008, drawing on theories about governmentality and power regimes. Tools from political discourse analysis were used to investigate the objectives of political discourse practices. Both inquiries referred to a context of change and new life demands as a problem. Concerning suggestions for solutions, there were discrepancies in parents' estimated need of expert knowledge and in descriptions of parental capacity. In a discourse of trust and doubt, the parents in 1947 were positioned as trusted welfare partners and secure raisers of future generations, and in 2008, as doubted adults, feared to be faltering in their child-rearing tasks. The analysis revealed how governmental problem descriptions, reasoning about causes and suggestions of solutions influenced parents' subject positions in a discourse of trust and doubt, and made way for governmental interventions with universal parenting training in the 21st century.


Rapid identification and mapping of insertion sequences in Escherichia coli genomes using vectorette PCR.
Insertion sequences (IS) are small DNA segments capable of transposing within and between prokaryotic genomes, often causing insertional mutations and chromosomal rearrangements. Although several methods are available for locating ISs in microbial genomes, they are either labor-intensive or inefficient. Here, we use vectorette PCR to identify and map the genomic positions of the eight insertion sequences (IS1, 2, 3, 4, 5, 30, 150, and 186) found in E. coli strain CGSC6300, a close relative of MG1655 whose genome has been sequenced. Genomic DNA from strain CGSC6300 was digested with a four-base cutter Rsa I and the resulting restriction fragments ligated onto vectorette units. Using IS-specific primers directed outward from the extreme ends of each IS and a vectorette primer, flanking DNA fragments were amplified from all but one of the 37 IS elements identified in the genomic sequence of MG1655. Purification and sequencing of the PCR products confirmed that they are IS-associated flanking DNA fragments corresponding to the known IS locations in the MG1655 genome. Seven additional insertions were found in strain CGSC6300 indicating that very closely related isolates of the same laboratory strain (the K12 isolate) may differ in their IS complement. Two other E. coli K12 derivatives, TD2 and TD10, were also analyzed by vectorette PCR. They share 36 of the MG1655 IS sites as well as having 16 and 18 additional insertions, respectively. This study shows that vectorette PCR is a swift, efficient, reliable method for typing microbial strains and identifying and mapping IS insertion sites present in microbial genomes. Unlike Southern hybridization and inverse PCR, our approach involves only one genomic digest and one ligation step. Vectorette PCR is then used to simultaneously amplify all IS elements of a given type, making it a rapid and sensitive means to survey IS elements in genomes. The ability to rapidly identify the IS complements of microbial genomes should facilitate subtyping closely related pathogens during disease outbreaks.


Lighting Up Biosensors: Now and the Decade To Come.
Optical biosensors are defined as portable optical devices that use biorecognition molecules to interrogate a sample for the presence of a target. The capabilities of optical biosensors have expanded rapidly with advances in miniature optical components and molecular engineering. Biosensors to meet the needs in health and environmental monitoring and food safety have become commercially available, with many more in the pipeline. We review the innovative approaches to overcoming existing hurdles to practical biosensor designs and explore potential areas for future breakthroughs in optical biosensor technology.