Racial and ethnic disparities in access to care for children with special health care needs.
Numerous studies have examined racial and ethnic differences in access to and utilization of health services. However, few studies have addressed these issues with respect to children with special health care needs. This study examines whether disparities in access and utilization are present among black, white, and Hispanic children identified as having special health care needs. We analyzed data on 57 553 children younger than 18 years old included in the 1994-95 National Health Interview Survey on Disability. Of these, 10 169, or 17.7% of the sample, were identified as having an existing special health care need. Bivariate and multivariate analyses were used to assess how race and ethnicity are related to measures of access and utilization, such as usual source of care, missed care, and use of physician and hospital services. Our analyses show that among children with special health care needs, minorities were more likely than white children to be without health insurance coverage (13.2% vs 10.3%; P <.01), to be without usual source of care (6.7% vs 4.3%; P <.01), and to report inability to get needed medical care (3.9% vs 2.8%; P <.05). Also, white children with special health care needs were more likely than their minority counterparts to have used physician services (88.6 vs 85.0; P <.01); however, minority children with special health care needs were more likely to have been hospitalized during the past year (7.6% vs 6.3%; P < 0.5). After adjustments for confounding variables (income, insurance coverage, health status, and other variables), racial and ethnic differences in access and utilization were attenuated but remained significant for several measures (without a usual source of care, receipt of care outside of a doctor's office or HMO, no regular clinician, no doctor contacts in past year, and volume of doctor contacts). Gaps in access were more frequent and generally larger for Hispanic children with special health care needs. Our analysis indicates that access and utilization disparities remain between white and minority children with special health care needs, with Hispanic children experiencing especially disparate care.


Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients.
Reconstitution of cytomegalovirus (CMV)-specific CD8(+) T cells is essential to the control of CMV infection in CMV-positive recipients (R(+)) after allogeneic hematopoietic stem cell transplantation (HCT). Six-color flow cytometry was used to assess the functional profile of CMV-specific CD8(+) T cells in 62 of 178 R(+) HCT recipients followed virologically for CMV reactivation. R(+) recipients receiving grafts from CMV-negative donors (D(-); D(-)/R(+)) reconstituted fewer multifunctional CD8(+) T cells expressing tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1beta (MIP-1beta), and CD107 in addition to interferon-gamma (IFN-gamma), compared with D(+)/R(+) recipients. Unlike monofunctional CD8(+) T cells secreting IFN-gamma, which were abundantly generated during CMV reactivation in D(-)/R(+) recipients, the relative lack of multifunctional CD8(+) T cells persisted until at least 1 year post-HCT. D(-)/R(+) recipients were more likely to require recurrent and prolonged use of antivirals. These findings were robust to statistical adjustment for pretransplant factors, as well as for posttransplant factors including graft-versus-host disease (GVHD) and its treatment by steroids. These analyses suggest that D(+)/R(+) transplants, on average, generate higher levels of multifunctional CMV-specific T cells and require less antiviral therapy compared with D(-)/R(+) HCT recipients. These results highlight the benefit of D(+) donors in improving outcomes of R(+) HCT recipients by reducing the duration and recurrent need of antiviral treatment, aided by increased levels of multifunctional CMV-specific T cells.


A Systematic Review on the Effectiveness of Pre-Harvest Meat Safety Interventions in Pig Herds to Control Salmonella and Other Foodborne Pathogens.
This systematic review aimed to assess the effectiveness of pre-harvest interventions to control the main foodborne pathogens in pork in the European Union. A total of 1180 studies were retrieved from PubMed® and Web of Science for 15 pathogens identified as relevant in EFSA's scientific opinion on the public health hazards related to pork (2011). The study selection focused on controlled studies where a cause-effect could be attributed to the interventions tested, and their effectiveness could be inferred. Altogether, 52 studies published from 1983 to 2020 regarding Campylobacter spp., Clostridium perfringens, Methicillin-resistant Staphylococcus aureus, Mycobacterium avium, and Salmonella spp. were retained and analysed. Research was mostly focused on Salmonella (n = 43 studies). In-feed and/or water treatments, and vaccination were the most tested interventions and were, overall, successful. However, the previously agreed criteria for this systematic review excluded other effective interventions to control Salmonella and other pathogens, like Yersinia enterocolitica, which is one of the most relevant biological hazards in pork. Examples of such successful interventions are the Specific Pathogen Free herd principle, stamping out and repopulating with disease-free animals. Research on other pathogens (i.e., Hepatitis E, Trichinella spiralis and Toxoplasma gondii) was scarce, with publications focusing on epidemiology, risk factors and/or observational studies. Overall, high herd health coupled with good management and biosecurity were effective to control or prevent most foodborne pathogens in pork at the pre-harvest level.


miRdSNP: a database of disease-associated SNPs and microRNA target sites on 3'UTRs of human genes.
Single nucleotide polymorphisms (SNPs) can lead to the susceptibility and onset of diseases through their effects on gene expression at the posttranscriptional level. Recent findings indicate that SNPs could create, destroy, or modify the efficiency of miRNA binding to the 3'UTR of a gene, resulting in gene dysregulation. With the rapidly growing number of published disease-associated SNPs (dSNPs), there is a strong need for resources specifically recording dSNPs on the 3'UTRs and their nucleotide distance from miRNA target sites. We present here miRdSNP, a database incorporating three important areas of dSNPs, miRNA target sites, and diseases. miRdSNP provides a unique database of dSNPs on the 3'UTRs of human genes manually curated from PubMed. The current release includes 786 dSNP-disease associations for 630 unique dSNPs and 204 disease types. miRdSNP annotates genes with experimentally confirmed targeting by miRNAs and indexes miRNA target sites predicted by TargetScan and PicTar as well as potential miRNA target sites newly generated by dSNPs. A robust web interface and search tools are provided for studying the proximity of miRNA binding sites to dSNPs in relation to human diseases. Searches can be dynamically filtered by gene name, miRBase ID, target prediction algorithm, disease, and any nucleotide distance between dSNPs and miRNA target sites. Results can be viewed at the sequence level showing the annotated locations for miRNA target sites and dSNPs on the entire 3'UTR sequences. The integration of dSNPs with the UCSC Genome browser is also supported. miRdSNP provides a comprehensive data source of dSNPs and robust tools for exploring their distance from miRNA target sites on the 3'UTRs of human genes. miRdSNP enables researchers to further explore the molecular mechanism of gene dysregulation for dSNPs at posttranscriptional level. miRdSNP is freely available on the web at http://mirdsnp.ccr.buffalo.edu.


Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent.
Hemodynamic abnormalities are important in the pathogenesis of the excess mesangial matrix deposition of diabetic and other glomerulopathies. p38-Mitogen-activated protein (MAP) kinase, an important intracellular signaling molecule, is activated in the glomeruli of diabetic rats. We studied, in human mesangial cells, the effect of stretch on p38 MAP kinase activation and the role of p38 MAP kinase in stretch-induced fibronectin and transforming growth factor-beta1 (TGF-beta1) accumulation. p38 MAP kinase was activated by stretch in a rapid (11-fold increase at 30 min, P < 0.001) and sustained manner (3-fold increase at 33 h, P < 0.001); this activation was mediated by protein kinase C (PKC). Stretch-induced fibronectin and TGF-beta1 protein levels were completely abolished (100% inhibition, P < 0.001; and 92% inhibition, P < 0.01, respectively) by SB203580, a specific p38 MAP kinase inhibitor. At 33 h, TGF-beta1 blockade did not affect stretch-induced fibronectin production, but partially prevented stretch-induced p38 MAP kinase activation (59% inhibition, P < 0.05). TGF-beta1 induced fibronectin accumulation after 72 h of exposure via a p38 MAP kinase-dependent mechanism (30% increase over control, P < 0.01). In human mesangial cells, stretch activates, via a PKC-dependent mechanism, p38 MAP kinase, which independently induces TGF-beta1 and fibronectin. In turn, TGF-beta1 contributes to maintaining late p38 MAP kinase activation, which perpetuates fibronectin accumulation.


High consumptions of grain, fish, dairy products and combinations of these are associated with a low prevalence of metabolic syndrome.
To analyse the relation between various food groups and the frequency of insulin resistance syndrome (IRS). A sample of 912 men aged 45-64 years was randomly selected. Questionnaires on risk factors and a three consecutive day food diary were completed. Height, weight, waist circumference, and blood pressure were measured. A fasting blood sample was analysed for lipid and glucose measurements. The NCEP-ATP-III definition was used to assess IRS. Data were analysed according to quintiles of food groups and medians of dairy products, fish, or cereal grains. The prevalence of IRS was 23.5%. It reached 29.0%, 28.1% and 28.1% when the intake was below the median for fish, dairy products, and grain, respectively. When consumptions of all three types of food were higher than the median, the prevalence reached 13.1%, and when they were lower, the prevalence was 37.9% (p<0.001). In logistic regression adjusted for confounders (centre, age, physical activities, education level, smoking, dieting, alcohol intake, treatments for hypertension and dyslipidaemia, energy intake, and diet quality index) the odds ratios for IRS (above median value v below) were 0.51 (95% confidence interval, 0.36 to 0.71) for fish, 0.67 (0.47 to 0.94) for dairy products, and 0.69 (0.47 to 1.01) for grain. When intakes of all three kinds of food were high, the OR was 0.22 (0.10 to 0.44). A high consumption of dairy products, fish, or cereal grains is associated with a lower probability of IRS. The probability decreases when intakes of all three types of food were high.


Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD),.
The mechanisms underlying eye-related complications with dupilumab are poorly understood. This study aimed to determine the incidence and characteristics of ocular complications with dupilumab and the prevalence of comorbid allergic contact dermatitis in the same subpopulation. This is a retrospective chart review of 48 patients with atopic dermatitis who received dupilumab. For patients with eye involvement at first follow-up, we discuss the presence of eyelid dermatitis, blepharitis, or conjunctivitis and analyze available patch test findings in patients with ocular complications while treated with dupilumab. A total of 14 patients (29.2%) showed eye involvement while on dupilumab, all of whom experienced eye involvement prior to dupilumab. The results of the patch test were most commonly positive for emulsifier/surfactants (42.5%) and fragrances (30.4%). Nine patients experienced improvement with allergen avoidance subsequent to patch testing, and four of nine patients' conditions cleared almost entirely. This is a non-randomized study in a small cohort of patients. Only 18 patients had their disease confirmed by an ophthalmologist. All patients with eye involvement while on dupilumab had a history of eye involvement prior to dupilumab, suggest that dupilumab may encourage rather than cause ocular surface inflammation. Significant improvement after patch testing in nearly half of patients suggests that allergic contact dermatitis contributes to some cases of dupilumab-associated eye complications.


Including Functional Annotations and Extending the Collection of Structural Classifications of Protein Loops (ArchDB).
Loops represent an important part of protein structures. The study of loop is critical for two main reasons: First, loops are often involved in protein function, stability and folding. Second, despite improvements in experimental and computational structure prediction methods, modeling the conformation of loops remains problematic. Here, we present a structural classification of loops, ArchDB, a mine of information with application in both mentioned fields: loop structure prediction and function prediction. ArchDB (http://sbi.imim.es/archdb) is a database of classified protein loop motifs. The current database provides four different classification sets tailored for different purposes. ArchDB-40, a loop classification derived from SCOP40, well suited for modeling common loop motifs. Since features relevant to loop structure or function can be more easily determined on well-populated clusters, we have developed ArchDB-95, a loop classification derived from SCOP95. This new classification set shows a ~40% increase in the number of subclasses, and a large 7-fold increase in the number of putative structure/function-related subclasses. We also present ArchDB-EC, a classification of loop motifs from enzymes, and ArchDB-KI, a manually annotated classification of loop motifs from kinases. Information about ligand contacts and PDB sites has been included in all classification sets. Improvements in our classification scheme are described, as well as several new database features, such as the ability to query by conserved annotations, sequence similarity, or uploading 3D coordinates of a protein. The lengths of classified loops range between 0 and 36 residues long. ArchDB offers an exhaustive sampling of loop structures. Functional information about loops and links with related biological databases are also provided. All this information and the possibility to browse/query the database through a web-server outline an useful tool with application in the comparative study of loops, the analysis of loops involved in protein function and to obtain templates for loop modeling.


Involvement of the 4-1BB/4-1BBL pathway in control of monocyte numbers by invariant NKT cells.
4-1BB is expressed on invariant (i)NKT cells, but its role is unclear. We showed previously that iNKT cells are involved in control of monocyte numbers during influenza A virus (IAV) infection and now question the role of the 4-1BB costimulatory pathway in the cross-talk between these cells. We found that iNKT cells and monocytes interact to promote expression of 4-1BB and 4-1BBL, respectively. Blockade of 4-1BB/L pathway under resting coculture conditions increased apoptosis of iNKT cells and monocytes. However, activation of iNKT cells overrides this survival signal, causing marked apoptosis of monocytes independent of 4-1BB/L. Blocking 4-1BBL in alpha-galactosylceramide-activated iNKT-monocyte cocultures reduced iNKT proliferation and abrogated monocytic IL-12 production. In vivo, expression of 4-1BB and 4-1BBL is increased on iNKT cells and Ly6C(hi) monocytes, respectively, during IAV infection, and there were lower frequencies of apoptosing Ly6C(hi) monocytes in the blood of iNKT knockout mice and higher numbers of monocytes in lungs compared with infected wild-type mice. Adoptive transfer of iNKT cells into the lungs of these mice reduced lung Ly6C(hi) monocytes levels, even when iNKT cells were preincubated with 4-1BB blocking Abs. These findings suggest that under resting conditions, 4-1BB/L engagement during iNKT-monocyte interaction promotes survival of these cells. When iNKT cells are activated, whether by alpha-galactosylceramide or during IAV infection, iNKT cells induced apoptosis of monocytes via a 4-1BB/L-independent mechanism, reducing monocyte numbers. 4-1BB/L costimulation amplified monocyte-mediated proliferation of iNKT cells, indirectly providing a method for monocytes to control their own numbers during infection.


Elimination of cancer stem-like cells and potentiation of temozolomide sensitivity by Honokiol in glioblastoma multiforme cells.
Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.


Microcytic hypochromic anemia: should high performance liquid chromatography be used routinely for screening anemic and antenatal patients?
Hemoglobinopathies are the most common inherited red cell disorders worldwide. Identification of these disorders is immensely important epidemiologically and for improved management protocols. Our aim was to determine the prevalence of hemoglobinopathies in patients with microcytic hypochromic anemia and to assess the suitability of using high performance liquid chromatography (HPLC) routinely for screening antenatal cases and patients with anemia. A total of 4335 cases received from Mar 2007 to Nov 2011 were studied for various hemoglobinopathies and variants on BIO RAD 'VARIANT' analyzer. Of the 4335 cases studied, 2119 were antenatal cases, 1710 patients with other disorders and 506 family studies. Of these, 688 cases displayed abnormal hemoglobin fractions on HPLC of which 140 were antenatal women. There were 455 cases of β thalassemia trait, 24 β thalassemia major, 20 thalassemia inter-media, 54 sickle cell trait, fivesickle cell disease, 21 double heterozygous β thalassemia-sickle cell trait, nineand 4 Hb D- Punjab heterozygous and homozygous respectively, three Hb D β Thalassemia trait, 20 and 37 Hb E homozygous and heterozygous respectively, three Hb E β Thalassemia trait and four cases of Hb Q India. Twenty nine adults had isolated HbF elevation. Our study found a high prevalence (15.8%) of hemoglobinopathies amongst microcytic hypochromic anemia and antenatal cases. An accurate diagnosis helps in preventing unnecessary iron loading. Screening all antenatal cases with anemia helps in timely antenatal counseling, thus preventing the psychological trauma of bearing a transfusion dependent child for life.


WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus.
Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.


Risk factors for recurrence of haemoptysis following bronchial artery embolisation for life-threatening haemoptysis.
Life-threatening haemoptysis is a frequent and often fatal complication in areas with a high prevalence of tuberculosis (TB). Bronchial artery embolisation remains the standard initial treatment. Subsequent curative measures, such as surgical resection of the focus of haemorrhage, are generally recommended to prevent recurrence, but risk-based selection criteria have not been established. To identify risk factors for the recurrence of haemoptysis following embolisation. Baseline characteristics were obtained from consecutive patients with life-threatening haemoptysis who were successfully embolised and followed up for at least 12 months. Recurrence of haemoptysis was observed in 47% and was associated with increased mortality compared to patients without recurrence (31% vs. 10%, P = 0.021). Patients with recurrence experienced residual mild haemoptysis beyond the first week after embolisation (odds ratio [OR] 7.2), received blood transfusions (OR 5.3) or presented with an aspergilloma (OR 5.1). Conversely, the presence of active TB amenable to treatment (OR 0.3) protected patients from these events. Radiographic or angiographic appearance did not predict recurrence. Recurrence of haemoptysis following embolisation for life-threatening haemoptysis is common and is associated with high mortality. The results of this study can contribute to the risk assessment of these patients and guide decisions regarding the urgency of definitive therapy.


Field evaluation of a novel colorimetric method--double-site enzyme-linked lactate dehydrogenase immunodetection assay--to determine drug susceptibilities of Plasmodium falciparum clinical isolates from northwestern Thailand.
A double-site enzyme-linked lactate dehydrogenase enzyme immunodetection assay was tested against field isolates of Plasmodium falciparum for assessing in vitro drug susceptibilities to a wide range of antimalarial drugs. Its sensitivity allowed the use of parasite densities as low as 200 parasites/microl of blood. Being a nonisotopic, colorimetric assay, it lies within the capabilities of a modest laboratory at the district level.


Quality of care from the elderly person's perspective: subjective importance and perceived reality.
The aim of this study was to carry out a theoretically-based survey of elderly persons' perceptions of quality of care, in terms of their evaluations of actual care conditions, as well as the subjective importance they ascribe to these. The sample consisted of 428 elderly (> or = 60 years) persons, in four different care environments: a geriatric department (N = 51); persons receiving home nursing (N = 111); nursing homes (N = 111); and service homes (N = 154) in two Swedish cities. Data were collected by way of personal interviews, structured from the questionnaire, Quality from the Patients' Perspective (QPP). The QPP is theory-based and consists of 40 items covering 17 factors. Each item was evaluated in two ways by the respondent: assessment of perceived reality, and evaluation of subjective importance (Likert scales). The results show that personal characteristics, such as age, sex, and self-rated health, had a limited effect on reports of what were regarded as highly important care characteristics, as well as on ratings of actual care conditions. Psychological well-being was strongly related to perceived reality ratings: a favorable well-being covaried with favorable ratings and vice versa. Considerable differences were noted in both types of ratings when the four types of care environments were compared. On the subjective importance scales, persons living in service homes reported lower scores, particularly on the scales designed to measure the medical-technical competence of the caregivers. On the perceived reality scales, the participants in service homes and the geriatric department scored lower.(ABSTRACT TRUNCATED AT 250 WORDS)


Yeast glycolytic oscillations that are not controlled by a single oscillophore: a new definition of oscillophore strength.
Biochemical oscillations, such as glycolytic oscillations, are often believed to be caused by a single so-called 'oscillophore'. The main characteristics of yeast glycolytic oscillations, such as frequency and amplitude, are however controlled by several enzymes. In this paper, we develop a method to quantify to which extent any enzyme determines the occurrence of oscillations. Principles extrapolated from metabolic control analysis are applied to calculate the control exerted by individual enzymes on the real and imaginary parts of the eigenvalues of the Jacobian matrix. We propose that the control exerted by an enzyme on the real part of the smallest eigenvalue, in terms of absolute value, quantifies to which extent that enzyme contributes to the emergence of instability. Likewise the control exerted by an enzyme on the imaginary part of complex eigenvalues may serve to quantify the extent to which that enzyme contributes to the tendency of the system to oscillate. The method was applied both to a core model and to a realistic model of yeast glycolytic oscillations. Both the control over stability and the control over oscillatory tendency were distributed among several enzymes, of which glucose transport, pyruvate decarboxylase and ATP utilization were the most important. The distributions of control were different for stability and oscillatory tendency, showing that control of instability does not imply control of oscillatory tendency nor vice versa. The control coefficients summed up to 1, suggesting the existence of a new summation theorem. These results constitute proof that glycolytic oscillations in yeast are not caused by a single oscillophore and provide a new, subtle, definition for the oscillophore strength of an enzyme.


Laser patterning for the study of MSC cardiogenic differentiation at the single-cell level.
Mesenchymal stem cells (MSCs) have been cited as contributors to heart repair through cardiogenic differentiation and multiple cellular interactions, including the paracrine effect, cell fusion, and mechanical and electrical couplings. Due to heart-muscle complexity, progress in the development of knowledge concerning the role of MSCs in cardiac repair is heavily based on MSC-cardiomyocyte coculture. In conventional coculture systems, however, the in vivo cardiac muscle structure, in which rod-shaped cells are connected end-to-end, is not sustained; instead, irregularly shaped cells spread randomly, resulting in randomly distributed cell junctions. Consequently, contact-mediated cell-cell interactions (e.g., the electrical triggering signal and the mechanical contraction wave that propagate through MSC-cardiomyocyte junctions) occur randomly. Thus, the data generated on the beneficial effects of MSCs may be irrelevant to in vivo biological processes. In this study, we explored whether cardiomyocyte alignment, the most important phenotype, is relevant to stem cell cardiogenic differentiation. Here, we report (i) the construction of a laser-patterned, biochip-based, stem cell-cardiomyocyte coculture model with controlled cell alignment; and (ii) single-cell-level data on stem cell cardiogenic differentiation under in vivo-like cardiomyocyte alignment conditions.


Tailoring fluorescent strigolactones for in vivo investigations: a computational and experimental study.
Strigolactones (SLs) are a new class of plant hormones whose role has been recently defined in shoot branching, root development and architecture, and nodulation. They are also active in the rhizosphere as signalling molecules in the communication between plants, AMF (arbuscular mycorrhizal fungi) and parasitic weeds. In spite of the crucial and multifaceted biological role of SLs, the current knowledge on the SL biosynthetic pathway and the perception/transduction mechanism is still incomplete. Both genetic and molecular approaches are required to understand the molecular mechanism by which SLs regulate plant development. Our contribution to this topic is the design and synthesis of fluorescent labelled SL analogues to be used as probes for the detection in vivo of the receptor(s). Knowledge of the putative receptor structure will boost the research on analogues of the natural substrates as required for agricultural applications.


BIOMEDICINE: 'Glue Grant' Boosts Cell Signaling Consortium.
The National Institute of General Medical Sciences (NIGMS) is using a novel funding approach to bind together researchers in cutting-edge fields at many institutions, allowing them to transcend their individual areas of expertise. NIGMS has awarded $5 million a year for 5 years to a group of scientists studying cellular signaling. To speed their findings into the public domain and make them available for use in drug testing, members of the project have agreed to post new results in a public database and forgo some patent and authorship claims.


Organisational resilience following the Darfield earthquake of 2010.
This paper presents the preliminary findings of a study on the resilience and recovery of organisations following the Darfield earthquake in New Zealand on 4 September 2010. Sampling included organisations proximal and distal to the fault trace, organisations located within central business districts, and organisations from seven diverse industry sectors. The research captured information on the challenges to, the impacts on, and the reflections of the organisations in the first months of recovery. Organisations in central business districts and in the hospitality sector were most likely to close, while organisations that had perishable stock and livestock were more heavily reliant on critical services. Staff well-being, cash flow, and customer loss were major concerns for organisations across all sectors. For all organisations, the most helpful factors in mitigating the effects of the earthquake were their relationship with staff members, the design and type of buildings, and critical service continuity or swift reinstatement of services.


The effectiveness of platform screen doors for the prevention of subway suicides in South Korea.
Subway suicide can significantly impact the general public. Platform Screen Doors (PSDs) are considered to be an effective strategy to prevent suicides at subway stations, but the evidence on their effectiveness is limited. We assessed the effectiveness of installing half- and full-height platform screen doors in reducing subway suicides using Poisson regression analysis. Ten-year monthly panel data for 121 subway stations between 2003 and 2012 in the Seoul metropolitan area were used for the analysis. We found that installing PSDs decreases fatal suicide cases by 89% (95% CI: 57-97%). We also found that the installation of full-height PSDs resulted in the elimination of subway suicides by completely blocking access to the track area; however, half-height PSDs, which do not extend to the ceiling of the platform, were not as effective as full-height ones. Our findings were based on the data from a single subway operator for a limited period of time. Accordingly, we did not consider the possibility that some passengers choose to die at a station run by other operators. Our study did not examine the potential substitution effects of other suicide methods. Installing physical barriers at subway stations can be an effective strategy to reduce the number of subway suicides; however, half-height PSDs are not as effective as full-height ones, even when they are as high as the height of an adult. Thus, these barriers should be made high enough so that nobody can climb over them.


Two step procedure for early diagnosis of polycystic kidney disease with polymorphic DNA markers on both sides of the gene.
Polymorphic DNA markers can now be used for presymptomatic and prenatal diagnosis of the autosomal dominant form of polycystic kidney disease (PKD). A detailed map is known for the chromosomal region around the PKD1 gene on the short arm of chromosome 16. We present here a simple, two step procedure for diagnosis of PKD1 by family studies. Using this approach, at least 92% of random subjects are informative for polymorphic DNA markers bracketing the PKD1 gene. The recombination rate between these flanking markers is on average 10%. In non-recombinants (90% of family members), the accuracy of diagnosis using DNA markers is greater than 99%. We conclude that sufficient well defined DNA markers are now available for routine diagnosis of PKD1. We recommend, however, that prenatal diagnosis of PKD by chorionic villi sampling should be attempted only after the linkage phase of the DNA markers has been established by haplotyping the index family. Since autosomal dominant PKD has been found to be genetically heterogeneous, families should be of sufficient size to rule out the rare form of PKD not caused by a mutation on the short arm of chromosome 16.


Tumor clone dynamics in lethal prostate cancer.
It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.


A High-Fat/High-Protein, Atkins-Type Diet Exacerbates Clostridioides (Clostridium) difficile Infection in Mice, whereas a High-Carbohydrate Diet Protects.
Clostridioides difficile (formerly Clostridium difficile) infection (CDI) can result from the disruption of the resident gut microbiota. Western diets and popular weight-loss diets drive large changes in the gut microbiome; however, the literature is conflicted with regard to the effect of diet on CDI. Using the hypervirulent strain C. difficile R20291 (RT027) in a mouse model of antibiotic-induced CDI, we assessed disease outcome and microbial community dynamics in mice fed two high-fat diets in comparison with a high-carbohydrate diet and a standard rodent diet. The two high-fat diets exacerbated CDI, with a high-fat/high-protein, Atkins-like diet leading to severe CDI and 100% mortality and a high-fat/low-protein, medium-chain-triglyceride (MCT)-like diet inducing highly variable CDI outcomes. In contrast, mice fed a high-carbohydrate diet were protected from CDI, despite the high levels of refined carbohydrate and low levels of fiber in the diet. A total of 28 members of the Lachnospiraceae and Ruminococcaceae decreased in abundance due to diet and/or antibiotic treatment; these organisms may compete with C. difficile for amino acids and protect healthy animals from CDI in the absence of antibiotics. Together, these data suggest that antibiotic treatment might lead to loss of C. difficile competitors and create a favorable environment for C. difficile proliferation and virulence with effects that are intensified by high-fat/high-protein diets; in contrast, high-carbohydrate diets might be protective regardless of the source of carbohydrate or of antibiotic-driven loss of C. difficile competitors.IMPORTANCE The role of Western and weight-loss diets with extreme macronutrient composition in the risk and progression of CDI is poorly understood. In a longitudinal study, we showed that a high-fat/high-protein, Atkins-type diet greatly exacerbated antibiotic-induced CDI, whereas a high-carbohydrate diet protected, despite the high monosaccharide and starch content. Our study results, therefore, suggest that popular high-fat/high-protein weight-loss diets may enhance CDI risk during antibiotic treatment, possibly due to the synergistic effects of a loss of the microorganisms that normally inhibit C. difficile overgrowth and an abundance of amino acids that promote C. difficile overgrowth. In contrast, a high-carbohydrate diet might be protective, despite reports on the recent evolution of enhanced carbohydrate metabolism in C. difficile.


Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins.
The molecular interactions of the Src homology 2 (SH2) domain and the N-terminal proline-rich sequence motifs (pro-1 to pro-5) of the SH2 protein Shb with other components were presently characterised. Using a degenerate phosphopeptide library the preferred binding site for the Shb SH2 domain was determined to pTyr-Thr/Val/Ile-X-Leu at positions +1 to +3 relative the phosphotyrosine residue. Experiments with competing peptides and platelet-derived growth factor (PDGF) beta-receptor mutants with Y to F substitutions in autophosphorylation sites revealed multiple binding sites for the Shb SH2 domain in the receptor. The Shb SH2 domain also binds to in vitro phosphorylated fibroblast growth factor receptor-1 (FGFR-1) mainly through position Y776. The receptor experiments suggest that other residues besides the +1 to +3 positions may also be of significance for Shb binding. The pro-4/pro-5 motif of Shb binds in vitro particularly well to the Src, p85 alpha PI3-kinase and Eps8 SH3 domains expressed as GST fusion proteins. However, the GST-SH3 domain fusion proteins tested bind in vitro to peptides corresponding to the pro-1 to pro-5 motifs of Shb with low affinity and selectivity, suggesting that sequences outside the core proline motif may also be important for Shb-SH3 domain interactions. In vivo association between Shb-SH3 domain proteins v-Src and Eps8 was detected by coimmunoprecipitation. PDGF treatment did not affect the association between Eps8 and Shb. The data suggest that Shb is an adaptor protein linking SH3 domain proteins to tyrosine kinases or other tyrosine phosphorylated proteins.


The field-testing of a novel integrated mapping protocol for neglected tropical diseases.
Vertical control and elimination programs focused on specific neglected tropical diseases (NTDs) can achieve notable success by reducing the prevalence and intensity of infection. However, many NTD-endemic countries have not been able to launch or scale-up programs because they lack the necessary baseline data for planning and advocacy. Each NTD program has its own mapping guidelines to collect missing data. Where geographic overlap among NTDs exists, an integrated mapping approach could result in significant resource savings. We developed and field-tested an innovative integrated NTD mapping protocol (Integrated Threshold Mapping (ITM) Methodology) for lymphatic filariasis (LF), trachoma, schistosomiasis and soil-transmitted helminths (STH). The protocol is designed to be resource-efficient, and its specific purpose is to determine whether a threshold to trigger public health interventions in an implementation unit has been attained. The protocol relies on World Health Organization (WHO) recommended indicators in the disease-specific age groups. For each disease, the sampling frame was the district, but for schistosomiasis, the sub-district rather than the ecological zone was used. We tested the protocol by comparing it to current WHO mapping methodologies for each of the targeted diseases in one district each in Mali and Senegal. Results were compared in terms of public health intervention, and feasibility, including cost. In this study, the ITM methodology reached the same conclusions as the WHO methodologies regarding the initiation of public health interventions for trachoma, LF and STH, but resulted in more targeted intervention recommendations for schistosomiasis. ITM was practical, feasible and demonstrated an overall cost saving compared with the standard, non-integrated, WHO methodologies. This integrated mapping tool could facilitate the implementation of much-needed programs in endemic countries.


Final report on the safety assessment of Basic Violet 1, Basic Violet 3, and Basic Violet 4.
Basic Violet 3, Basic Violet 1, and Basic Violet 4 are triphenylmethane dyes that function as direct (nonoxidative) hair colorants. No current uses or use concentrations in cosmetics are reported. The term Gentian Violet is used synonymously with Basic Violet 1 and Basic Violet 3, although the chemical structures of these 2 dyes are not the same. The Cosmetic Ingredient Review Expert Panel noted that Basic Violet 1, 3, and 4 contain quaternary ammonium ions, and therefore the rate of penetration across the epidermis is expected to be slow. The panel concluded that because of the carcinogenic potential of these dyes, insufficient data exist to support the safety of Basic Violet 1, 3, and 4 in cosmetic formulation. Dermal absorption data and a risk assessment are needed to complete this safety assessment.


Targeting tumour-initiating cells with TRAIL based combination therapy ensures complete and lasting eradication of multiple myeloma tumours in vivo.
Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138(+) and CD138(-) cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138(-) MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138(-) cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138(+) cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138(+) cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138(-) cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138(-) cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.


A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide.
The complementary DNA encoding a 585-amino acid parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor with seven potential membrane-spanning domains was cloned by COS-7 expression using an opossum kidney cell complementary DNA (cDNA) library. The expressed receptor binds PTH and PTHrP with equal affinity, and both ligands equivalently stimulate adenylate cyclase. Striking homology with the calcitonin receptor and lack of homology with other G protein-linked receptors indicate that receptors for these calcium-regulating hormones are related and represent a new family.


5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease.
Inflammatory bowel disease (IBD) is classically subdivided into ulcerative colitis (UC) and Crohn's disease (CD). Patients with IBD have increased risk for colorectal cancer. Because the pathogenesis of colorectal carcinoma has not been entirely defined yet and there is no ideal treatment for colon cancer, cancer prevention has become increasingly important in patients with IBD. The two adopted methods to prevent the development of colon cancer in clinical practice include the prophylactic colectomy and colonoscopic surveillance. But patients and physicians seldom accept colectomy as a routine preventive method and most patients do not undergo appropriate colonoscopic surveillance. Chemoprevention refers to the use of natural or synthetic chemical agents to reverse, suppress, or to delay the process of carcinogenesis. Chemoprevention is a particularly useful method in the management of patients at high risk for the development of specific cancers based on inborn genetic susceptibility, the presence of cancer-associated disease, or other known risk factors. Prevention of colorectal cancer by administration of chemopreventive agents is one of the most promising options for IBD patients who are at increased risks of the disease. The chemopreventive efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against intestinal tumors has been well established. But with reports that NSAIDs aggravated the symptoms of colitis, their sustained use for the purpose of cancer chemoprevention has been relatively contraindicated in IBD patients. Another hopeful candidate chemoprevention drug for IBD patients is 5-aminosalicylic acid (5-ASA), which is well tolerated by most patients and has limited systemic adverse effects, and no gastrointestinal toxicity. 5-ASA lacks the well-known side effects of long-term NSAIDs use. Retrospective correlative studies have suggested that the long-term use of 5-ASA in IBD patients may significantly reduce the risk of development of colorectal cancer. According to the literature, this agent might well satisfy clinical expectations with respect to a safe and effective chemopreventive agent.


Splicing mutations in glycogen-storage disease type II: evaluation of the full spectrum of mutations and their relation to patients' phenotypes.
Glycogen-storage disease type II is an autosomal recessive-inherited disorder due to the deficiency of acid α-glucosidase. A large number of mutations in the acid α-glucosidase gene have been described to date. Among them, ~15% are variations that may affect mRNA splicing process. In this study, we have for the first time comprehensively reviewed the available information on splicing mutations of the acid α-glucosidase gene and we have evaluated their possible impact on the splicing process using different in silico approaches. Out of the 39 different GAA-sequence variations described, an in silico analysis using seven different programs showed that 97% of them are predicted to have an impact on the splicing process. Moreover, this analysis showed a quite good correlation between the impact of the mutation on the splicing process and the clinical phenotype. In addition, we have performed the functional characterization of three novel sequence variants found in Italian patients and still uncharacterized. Using a minigene system, we have confirmed their pathogenic nature. In conclusion, this study has shown that in silico analysis represents a useful tool to select mutations that affect the splicing process of the acid α-glucosidase gene and provides an updated picture of all this kind of mutations reported till now.


Probing the Cl--pumping photocycle of pharaonis halorhodopsin: Examinations with bacterioruberin, an intrinsic dye, and membrane potential-induced modulation of the photocycle.
Halorhodopsin (HR) functions as a light-driven inward Cl- pump. The Cl- transfer process of HR from Natronomonas pharaonis (NpHR) was examined utilizing a mutant strain, KM-1, which expresses large amount of NpHR in a complex with the carotenoid bacterioruberin (Brub). When Cl- was added to unphotolyzed Cl--free NpHR-Brub complex, Brub caused the absorption spectral change in response to the Cl- binding to NpHR through the altered electrostatic environment and/or distortion of its own configuration. During the Cl--puming photocycle, on the other hand, oppositely directed spectral change of Brub appeared during the O intermediate formation and remained until the decay of the last intermediate NpHR'. These results indicate that Cl- is released into the cytoplasmic medium during the N to O transition, and that the subsequent NpHR' still maintains an altered protein conformation while another Cl- already binds in the vicinity of the Schiff base. Using the cell envelope vesicles, the effect of the interior negative membrane potential on the photocycle was examined. The prominent effect appeared in the shift of the N-O quasi-equilibrium toward N, supporting Cl- release during the N to O transition. The membrane potential had a much larger effect on the Cl- transfer in the cytoplasmic half channel compared to that in the extracellular half channel. This result may reflect the differences in dielectric constants and/or lengths of the pathways for Cl- transfers during N to O and O to NpHR' transitions.


Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.
To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records. A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.


Prevalence of multisite musculoskeletal symptoms: a French cross-sectional working population-based study.
The musculoskeletal disorders in working population represent one of the most worrying work-related health issues at the present time and although the very great majority of available data on the subject focus on musculoskeletal disorders defined by anatomical site, a growing number of studies indicate the low prevalence of disorders strictly confined to a specific anatomical site. The objective of this study was to describe the prevalence and characteristics of multisite musculoskeletal symptoms (multisite MS) in a large French working population. This study was performed on surveillance data of the cross-sectional survey (2002-2005) conducted by a network of occupational physicians in the working population of the Loire Valley region (from 20 to 59 years old). Data concerning MS were collected in the waiting room of the occupational physicians by means of the self-administrated standardized NORDIC questionnaire. The study population comprised 3,710 workers (2,162 men (58%) and 1,548 women (42%)) with a mean age of 38.4 years (standard deviation: 10.4 years). The prevalence of MS during the past 12 months was 83.8% with 95% confidence interval of [82.8-85.3] for men and 83.9% [82.0-85.7] for women. The prevalence of subacute MS (lasting at least 30 days) over the past 12 months was 32.8% [30.9-34.8] for men and 37.3% [34.9-39.7] for women. Two-thirds of workers reported MS in more than one anatomical site and about 20% reported MS lasting at least 30 days in more than one anatomical site. The anatomical sites most frequently associated with other MS were the upper back, hip, elbow and neck. The majority of these multisite MS were widespread, involving at least two of the three anatomical regions (upper limb, axial region and lower limb). The frequency and extent of multisite MS reported by workers are considerable. Further research must be conducted in this field in order to provide a better understanding of the characteristics and determinants of these multisite MS.


Challenges, strategies, and gender relations among parents of children recently diagnosed with type 1 diabetes.
This study explored (a) parents' process of changes and challenges in their patterns of daily activities after the onset of diabetes in their children; and (b) how personal gender relations can restrain or create functional strategies for managing the changes and challenges of illness. Interviews were conducted with 21 mothers and 15 fathers of 23 children with type 1 diabetes 8 to 10 months after onset. Using a constant comparative analysis method, the core category depicts how the illness forced parents to reconstruct their family project with respect to patterns of daily activities and gender structures. The emerging subcategories of reinforced mothering and adjusted fathering illustrate the parents' effort to handle contemporary and contradictory demands. With increased knowledge of the dynamics of gender relations of families in the context of a child's illness, health care professionals can assist in promoting well-being and functional strategies in families when a child is newly diagnosed with diabetes.


Diagnostic percutaneous transthoracic needle biopsy does not affect survival in stage I lung cancer.
Lung cancer dissemination has been cited as a potential adverse consequence of diagnostic percutaneous transthoracic needle biopsy (PTNB) of lung nodules. Despite multiple reports in the literature of malignant spread along the needle track, the potential effect of lung cancer dissemination after PTNB on survival is unknown. To evaluate whether diagnostic PTNB is associated with increased risk of lung cancer death. This study included 8,607 cases of surgically resected stage I non-small cell lung cancer diagnosed between 1991 and 1999 from the Surveillance, Epidemiology, and End Results (SEER) registry linked to Medicare records. Overall and lung cancer-specific survival of patients who had and did not have PTNB was compared using Kaplan-Meier curves. Stratified survival analyses and Cox regression were used to compare survival with adjustment for potential confounders. Approximately 36% of patients underwent diagnostic PTNB. Overall and lung cancer-specific survival did not differ in patients that underwent PTNB as part of their cancer diagnostic work-up and those who did not (p = 0.57 and 0.46, respectively). In stratified and multivariate analysis, PTNB was not associated with an increased risk of death after controlling for age, race, income, access to care, comorbidities, tumor histology and size, and type of treatment received. In this large national sample, preoperative PTNB was not associated with increased risk of death. These data suggest that PTNB can be safely used for the work-up of pulmonary nodules when there is a suspicion of lung cancer.


Attention modulates neuronal correlates of interhemispheric integration and global motion perception.
In early retinotopic areas of the human visual system, information from the left and right visual hemifields (VHFs) is processed contralaterally in two hemispheres. Despite this segregation, we have the perceptual experience of a unified, coherent, and uninterrupted single visual field. How exactly the visual system integrates information from the two VHFs and achieves this perceptual experience still remains largely unknown. In this study using fMRI, we explored candidate areas that are involved in interhemispheric integration and the perceptual experience of a unified, global motion across VHFs. Stimuli were two-dimensional, computer-generated objects with parts in both VHFs. The retinal image in the left VHF always remained stationary, but in the experimental condition, it appeared to have local motion because of the perceived global motion of the object. This perceptual effect could be weakened by directing the attention away from the global motion through a demanding fixation task. Results show that lateral occipital areas, including the medial temporal complex, play an important role in the process of perceptual experience of a unified global motion across VHFs. In early areas, including the lateral geniculate nucleus and V1, we observed correlates of this perceptual experience only when attention is not directed away from the object. These findings reveal effects of attention on interhemispheric integration in motion perception and imply that both the bilateral activity of higher-tier visual areas and feedback mechanisms leading to bilateral activity of early areas play roles in the perceptual experience of a unified visual field.


Systematic analyses of genes associated with radiosensitizing effect by celecoxib, a specific cyclooxygenase-2 inhibitor.
To investigate genes regulated by COX-2 or a COX-2 specific inhibitor, celecoxib, in irradiated cancer cells, we analyzed changes in gene expression using complementary DNA microarray following celecoxib or combined celecoxib and ionizing radiation (IR) treatment in a stable COX-2 knockdown A549 (AS) and a mock cell line (AN). Thirty-six genes were differentially expressed by COX-2 knockdown. Celecoxib changed the expressions of 40 and 69 genes in AN and AS cells, respectively. Twenty-seven genes were synchronously regulated by COX-2 and celecoxib. Among these, celecoxib regulated ras homolog gene family B and mitosin protein expression in a COX-2 dependent manner, especially in irradiated cells. In addition, we identified 11 genes that changed by more than 1.5 times the expected additive values after celecoxib and IR treatment. The current study may provide evidence that COX-2 or celecoxib regulates various intracellular functions in addition to their enzymatic activity regulation. We also identified candidate molecules that may be responsible for COX-2-dependent radiosensitization by celecoxib.


ARTMAP neural networks for information fusion and data mining: map production and target recognition methodologies.
The Sensor Exploitation Group of MIT Lincoln Laboratory incorporated an early version of the ARTMAP neural network as the recognition engine of a hierarchical system for fusion and data mining of registered geospatial images. The Lincoln Lab system has been successfully fielded, but is limited to target/non-target identifications and does not produce whole maps. Procedures defined here extend these capabilities by means of a mapping method that learns to identify and distribute arbitrarily many target classes. This new spatial data mining system is designed particularly to cope with the highly skewed class distributions of typical mapping problems. Specification of canonical algorithms and a benchmark testbed has enabled the evaluation of candidate recognition networks as well as pre- and post-processing and feature selection options. The resulting mapping methodology sets a standard for a variety of spatial data mining tasks. In particular, training pixels are drawn from a region that is spatially distinct from the mapped region, which could feature an output class mix that is substantially different from that of the training set. The system recognition component, default ARTMAP, with its fully specified set of canonical parameter values, has become the a priori system of choice among this family of neural networks for a wide variety of applications.


ATG3 proteins possess a unique amphipathic α-helix essential for the Atg8/LC3 lipidation reaction.
In our recent paper, we uncovered that ATG3 exhibits a large degree of structural dynamics on autophagic membranes to efficiently carry out LC3 lipidation. ATG3 proteins possess an amphipathic α-helix (AH) identified by a small number of bulky and hydrophobic residues. This biophysical fingerprint allows for transient membrane association of ATG3 and facilitates its enzymatic reaction. This study will pave the way for a structural and mechanistic understanding of how membrane association of ATG proteins is orchestrated during autophagosome formation.


The evolution of tonsil surgery and rethinking the surgical approach to obstructive sleep-disordered breathing in children.
Within the last 10 to 15 years, a significant amount of research in tonsil surgery has focused on reduction of post-operative pain and recovery time. In order to minimize or avoid morbidity, a number of otolaryngologists in the United States and Europe have revived a historical procedure, previously known as 'tonsillotomy', specifically for those patients with obstructive sleep-disordered breathing (OSDB) due to adenotonsillar hypertrophy. More recently, surgeons have used terms such as partial tonsillectomy, partial intracapsular tonsillectomy or subtotal tonsillectomy to describe their procedure and have employed a variety of modern instrumentation. This return to a 'partial' procedure has generated a debate similar to that which occurred amongst tonsil surgeons about 100 years ago, when tonsillotomy was the most commonly performed procedure. Today, concerns about regrowth and problems with infection of the remaining tonsillar tissue have been raised. Such concerns, combined with an incomplete understanding of why the 'partial' procedure was abandoned in the early twentieth century, may explain why tonsil surgeons hesitate to change their approach to patients with OSDB due to adenotonsillar hypertrophy. These issues can be addressed in a meaningful way only through a detailed review of the evolution of tonsil surgery, which is presented here. This information, along with a summary of the last 10 years' experience with these techniques, supports the use of a 'partial' procedure in children with OSDB due to adenotonsillar hypertrophy. Future areas of research are also discussed.


Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells.
Cilia, either motile or immotile, exist on most cells in the human body. There are several different mechanisms of ciliogenesis, which enable the production of many kinds of cilia and flagella: motile and immotile, transient and long-lived. These can be linked to the cell cycle or associated with differentiation. A primary cilium is extended from a basal body analogous to the mitotic centrioles, whereas the several hundred centrioles needed to form the cilia of a multi-ciliated cell can be generated by centriolar or acentriolar pathways. Little is known about the molecular control of these pathways and most of our knowledge comes from ultrastructural studies. The increasing number of genetic diseases linked to dysfunctional cilia and basal bodies has renewed interest in this area, and recent proteomic and cell biological studies in model organisms have helped to shed light on the molecular components of these enigmatic organelles.


Rehabilitation for participation in life after spinal cord injury - clinician responses to a preliminary conceptual framework.
To explore face validity of a preliminary conceptual framework for rehabilitation (the HEAR Framework), which is grounded in the narratives of people with spinal cord injury. Using a quantitative online survey, experienced spinal cord injury rehabilitation practitioners were asked to compare the overall Framework, and its three components and nine elements, against usual practice. Participants rated the helpfulness and ease of implementation of each component. Perceived training needs, to support the implementation of the Framework were also explored. Respondents were given the opportunity to provide qualitative feedback about the Framework. Thirty-four participants completed the survey. Median rating of congruence of the Framework with usual practice was 6 (out of 10). The Help component of the Framework was rated as more like usual practice than the Encourage and Accept components. Median rating of the potential helpfulness to practice, of all the elements of the Framework was 5 (out of 5). Participants rated the elements within the Help component of the Framework as easiest to implement. Teaching assertiveness, promoting flexible thinking and fostering responsive communication were the highest rated training topics related to implementation of the Framework. Face validity testing suggests the preliminary HEAR Framework is promising as a basis for spinal cord injury rehabilitation theory. Broad-based testing is required to progress the promise of the Framework.IMPLICATIONS FOR REHABILITATIONSpinal cord injury rehabilitation lacks conceptual frameworks to guide practice.This validity study suggests moderate alignment between the preliminary HEAR Framework and usual practice (based on the perceptions of professionals in a spinal cord injury service).The Framework may be useful to individual rehabilitation practitioners as a basis for clinical reflection.The Framework may be useful as a practice development tool for teams of rehabilitation practitioners.


Programmed Self-Assembly of Branched Nanocrystals with an Amphiphilic Surface Pattern.
Site-selective surface modification on the shape-controlled nanocrystals is a key approach in the programmed self-assembly of inorganic colloidal materials. This study demonstrates a simple methodology to gain self-assemblies of semiconductor nanocrystals with branched shapes through tip-to-tip attachment. Short-chained water-soluble cationic thiols are employed as a surface ligand for CdSe tetrapods and CdSe/CdS core/shell octapods. Because of the less affinity of arm-tip to the surface ligands compared to the arm-side wall, the tip-surface becomes uncapped to give a hydrophobic nature, affording an amphiphilic surface pattern. The amphiphilic tetrapods aggregated into porous agglomerates through tip-to-tip connection in water, while they afforded a hexagonally arranged Kagome-like two-dimensional (2D) assembly by the simple casting of aqueous dispersion with the aid of a convective self-assembly mechanism. A 2D net-like assembly was similarly obtained from amphiphilic octapods. A dissipative particle dynamics simulation using a planar tripod model with an amphiphilic surface pattern reproduced the formation of the Kagome-like assembly in a 2D confined space, demonstrating that the lateral diffusion of nanoparticles and the firm contacts between the hydrophobic tips play crucial roles in the self-assembly.


Critical initial real-space refinement in the structure determination of arginine kinase.
Arginine kinase (AK), a homologue of creatine kinase, catalyses the reversible transfer of a phosphoryl group between a guanidino phosphate and ADP. The family of phosphagen kinases eluded structure determination for over 25 years until an inactive form creatine kinase (CK) structure was determined [Fritz-Wolf et al. (1996). Nature (London), 381, 341-345]. The structure determination of the active-form transition-state complex was non-trivial, owing to the distant relatedness and domain reorientation of AK compared with CK. Phases from a molecular-replacement solution of the large domain, supplemented by single isomorphous replacement and inter-crystal averaging, did not reveal interpretable electron density for the small domain. Reciprocal-space refinement of the initial model (Rfree = 0.54) by any of the commonly used methods, including post facto application of maximum-likelihood methods, led to overfitting without significant improvement of the partial initial model. By contrast, in the local real-space refinements which proved successful, the interdependence of atoms is limited to immediate neighbors, and atomic positions are not influenced by errors or omissions in remote parts of the structure. Modest improvement was possible without overfitting, and this was critical to the calculation of improved phases. Phases were refined and extended from 4.0 to 2.5 A resolution by Fourier inversion of omit maps, combination with isomorphous replacement phases and averaging between crystal forms, after several batches of real- and reciprocal-space atomic refinement. The final structure refinement, against a 1.86 A cryo data set yielded a high-quality model with R = 0.196 and Rfree = 0.224.


CANNABIS LEGALIZATION IN STATE LEGISLATURES: PUBLIC HEALTH OPPORTUNITY AND RISK.
Cannabis is widely used in the U.S. and internationally despite its illicit status, but that illicit status is changing. In the U.S., 33 states and the District of Columbia have legalized medical cannabis, and 11 states and D.C. have legalized adult use cannabis. A majority of state medical cannabis laws and all but two state adult use laws are the result of citizen ballot initiatives, but state legislatures are beginning to seriously consider adult use legislation. From a public health perspective, cannabis legalization presents a mix of potential risks and benefits, but a legislative approach offers an opportunity to improve on existing legalization models passed using the initiative process that strongly favor business interests over public health. To assess whether state legislatures are acting on this opportunity, this article examines provisions of proposed adult use cannabis legalization bills active in state legislatures as of February 2019 to evaluate the inclusion of key public health best practices based on successful tobacco and alcohol control public health policy frameworks. Given public support for legalization, further adoption of state adult use cannabis laws is likely, but legalization should not be viewed as a binary choice between total prohibition and laissez faire commercialization. The extent to which adult use cannabis laws incorporate or reject public health best practices will strongly affect their impact, and health advocates should work to influence the construction of such laws to prioritize public health and learn from past successes and failures in regulating other substances.


Nuclear heat shock response and novel nuclear domain 10 reorganization in respiratory syncytial virus-infected a549 cells identified by high-resolution two-dimensional gel electrophoresis.
The pneumovirus respiratory syncytial virus (RSV) is a leading cause of epidemic respiratory tract infection. Upon entry, RSV replicates in the epithelial cytoplasm, initiating compensatory changes in cellular gene expression. In this study, we have investigated RSV-induced changes in the nuclear proteome of A549 alveolar type II-like epithelial cells by high-resolution two-dimensional gel electrophoresis (2DE). Replicate 2D gels from uninfected and RSV-infected nuclei were compared for changes in protein expression. We identified 24 different proteins by peptide mass fingerprinting after matrix-assisted laser desorption ionization-time of flight mass spectrometry (MS), whose average normalized spot intensity was statistically significant and differed by +/-2-fold. Notable among the proteins identified were the cytoskeletal cytokeratins, RNA helicases, oxidant-antioxidant enzymes, the TAR DNA binding protein (a protein that associates with nuclear domain 10 [ND10] structures), and heat shock protein 70- and 60-kDa isoforms (Hsp70 and Hsp60, respectively). The identification of Hsp70 was also validated by liquid chromatography quadropole-TOF tandem MS (LC-MS/MS). Separate experiments using immunofluorescence microscopy revealed that RSV induced cytoplasmic Hsp70 aggregation and nuclear accumulation. Data mining of a genomic database showed that RSV replication induced coordinate changes in Hsp family proteins, including the 70, 70-2, 90, 40, and 40-3 isoforms. Because the TAR DNA binding protein associates with ND10s, we examined the effect of RSV infection on ND10 organization. RSV induced a striking dissolution of ND10 structures with redistribution of the component promyelocytic leukemia (PML) and speckled 100-kDa (Sp100) proteins into the cytoplasm, as well as inducing their synthesis. Our findings suggest that cytoplasmic RSV replication induces a nuclear heat shock response, causes ND10 disruption, and redistributes PML and Sp100 to the cytoplasm. Thus, a high-resolution proteomics approach, combined with immunofluorescence localization and coupled with genomic response data, yielded unexpected novel insights into compensatory nuclear responses to RSV infection.


Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1.
E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT.


Corynebacterium spp as causative agents of microbial keratitis.
To report the clinical and microbiological profile of keratitis caused by Corynebacterium spp. The medical and microbiology records of 22 patients, who had presented at the L V Prasad Eye Institute, Bhubaneswar, between June 2009 and December 2012, and whose corneal scrapings had yielded significant growth of Corynebacterium spp, were retrospectively reviewed. A detailed ocular examination was performed before the respective corneal scraping was sent for a microbiological work-up. The data collected from each record included age, gender, predisposing factors (ocular and systemic), clinical presentation, management and outcome of treatment. The mean age of the patients was 43.8±24.4 years. Ocular predisposing factor was present in 14 (63.6%) eyes. Surgical intervention was required in 12 (54.5%) patients. In vitro susceptibility (Kirby-Bauer disc diffusion method) results of Corynebacterium spp to vancomycin (17/19, 89.5%), cefazolin (16/20, 80%), chloramphenicol (11/20, 55%), ofloxacin (13/19, 68.4%), ciprofloxacin (10/20, 50%) and gatifloxacin (10/19, 52.6%) were variable. Drug resistance (more than one drug) was seen in nine (40.9%) Corynebacterium isolates, of which, two (22.2%) showed multidrug resistance to three or more classes of antibiotics. Corynebacteria can cause severe corneal infection requiring surgical intervention.


Ovalopodium desertum n. sp. and the phylogenetic relationships of Cochliopodiidae (Amoebozoa).
An amoeba isolated from a weakly saline semi-desert pond in Kazakhstan (Central Asia) resembles a small Cochliopodium in the light microscope, but has a dorsal fibrous cell coat without scales. Thus it can be identified morphologically as a new species of Ovalopodium Sawyer, 1980, and it is herein named O. desertum. Phylogenetic analysis of the SSU rRNA gene sequences of the new species and four Cochliopodium spp. sequenced additionally shows that Ovalopodium desertum is a sister clade to a robustly monophyletic Cochliopodium. The close relationship between Ovalopodium and Cochliopodium is also confirmed by the analysis of SSU rRNA secondary structure showing the specific helices in the region V5 in all species of both genera. Analysis of actin gene sequences fails to resolve the position of Ovalopodium but demonstrates that Parvamoeba Rogerson, 1993 is probably related to Cochliopodium. The position of Cochliopodiidae within Amoebozoa remains unresolved, despite our efforts to resolve it using broader taxonomic sampling of Amoebozoa, testing alternative tree topologies and removing the fast-evolving sites. Among sequenced genera, Parvamoeba and Endostelium Olive et al., 1984 are probable relatives to Cochliopodiidae. Molecular trees weakly support an inclusion of the family in Flabellinia (Discosea), but more phylogenomic data are necessary to test this hypothesis.


The Stanford experience of heart transplantation over five decades.
Since 1968, heart transplantation has become the definitive treatment for patients with end-stage heart failure. We aimed to summarize our experience in heart transplantation at Stanford University since the first transplantation performed over 50 years ago. From 6 January 1968 to 30 November 2020, 2671 patients presented to Stanford University for heart transplantation, of which 1958 were adult heart transplantations. Descriptive analyses were performed for patients in 1968-95 (n = 639). Stabilized inverse probability weighting was applied to compare patients in 1996-2006 (n = 356) vs. 2007-19 (n = 515). Follow-up data were updated through 2020. The primary endpoint was all-cause mortality. Prior to weighting, recipients in 2007-19 vs. those in 1996-2006 were older and had heavier burden of chronic diseases. After the application of stabilized inverse probability weighting, the distance organ travelled increased from 84.2 ± 111.1 miles to 159.3 ± 169.9 miles from 1996-2006 to 2007-19. Total allograft ischaemia time also increased over time (199.6 ± 52.7 vs. 225.3 ± 50.0 min). Patients in 2007-19 showed superior survival than those in 1996-2006 with a median survival of 12.1 vs. 11.1 years. In this half-century retrospective descriptive study from one of the largest heart transplant programmes in the USA, long-term survival after heart transplantation has improved over time despite increased recipient and donor age, worsening comorbidities, increased technical complexity, and prolonged total allograft ischaemia time. Further investigation is warranted to delineate factors associated with the excellent outcomes observed in this study.


PIPKs are essential for rhizoid elongation and caulonemal cell development in the moss Physcomitrella patens.
PtdIns-4,5-bisphosphate is a lipid messenger of eukaryotic cells that plays a critical role in processes such as cytoskeleton organization, intracellular vesicular trafficking, secretion, cell motility, regulation of ion channels and nuclear signalling pathways. The enzymes responsible for the synthesis of PtdIns(4,5)P₂ are phosphatidylinositol phosphate kinases (PIPKs). The moss Physcomitrella patens contains two PIPKs, PpPIPK1 and PpPIPK2. To study their physiological role, both genes were disrupted by targeted homologous recombination and as a result mutant plants with lower PtdIns(4,5)P₂ levels were obtained. A strong phenotype for pipk1, but not for pipk2 single knockout lines, was obtained. The pipk1 knockout lines were impaired in rhizoid and caulonemal cell elongation, whereas pipk1-2 double knockout lines showed dramatic defects in protonemal and gametophore morphology manifested by the absence of rapidly elongating caulonemal cells in the protonemal tissue, leafy gametophores with very short rhizoids, and loss of sporophyte production. pipk1 complemented by overexpression of PpPIPK1 fully restored the wild-type phenotype whereas overexpression of the inactive PpPIPK1E885A did not. Overexpression of PpPIPK2 in the pipk1-2 double knockout did not restore the wild-type phenotype demonstrating that PpPIPK1 and PpPIPK2 are not functionally redundant. In vivo imaging of the cytoskeleton network revealed that the shortened caulonemal cells in the pipk1 mutants was the result of the absence of the apicobasal gradient of cortical F-actin cables normally observed in wild-type caulonemal cells. Our data indicate that both PpPIPKs play a crucial role in the development of the moss P. patens, and particularly in the regulation of tip growth.


Glycoside hydrolases family 20 (GH20) represent putative virulence factors that are shared by animal pathogenic oomycetes, but are absent in phytopathogens.
Although interest in animal pathogenic oomycetes is increasing, the molecular basis mediating oomycete-animal relationships remains virtually unknown. Crinkler (CRN) genes, which have been traditionally associated with the cytotoxic activity displayed by plant pathogenic oomycetes, were recently detected in transcriptome sequences from the entomopathogenic oomycete Lagenidium giganteum, suggesting that these genes may represent virulence factors conserved in both animal and plant pathogenic oomycetes. In order to further characterize the L. giganteum pathogenome, an on-going genomic survey was mined to reveal novel putative virulence factors, including canonical oomycete effectors Crinkler 13 (CRN13) orthologs. These novel sequences provided a basis to initiate gene expression analyses and determine if the proposed L. giganteum virulence factors are differentially expressed in the presence of mosquito larvae (Aedes aegypti). Sequence analyses revealed that L. giganteum express CRN13 transcripts. The predicted proteins, like other L. giganteum CRNs, contained a conserved LYLA motif at the N terminal, but did not display signal peptides. In contrast, other potential virulence factors, such as Glycoside Hydrolases family 20 (hexosaminidase) and 37 (trehalase) proteins (GH20 and GH37), contained identifiable signal peptides. Genome mining demonstrated that GH20 genes are absent from phytopathogenic oomycete genomes, and that the L. giganteum GH20 sequence is the only reported peronosporalean GH20 gene. All other oomycete GH20 homologs were retrieved from animal pathogenic, saprolegnialean genomes. Furthermore, phylogenetic analyses demonstrated that saprolegnialean and peronosporalean GH20 protein sequences clustered in unrelated clades. The saprolegnialean GH20 sequences appeared as a strongly supported, monophyletic group nested within an arthropod-specific clade, suggesting that this gene was acquired via a lateral gene transfer event from an insect or crustacean genome. In contrast, the L. giganteum GH20 protein sequence appeared as a sister taxon to a plant-specific clade that included exochitinases with demonstrated insecticidal activities. Finally, gene expression analyses demonstrated that the L. giganteum GH20 gene expression level is significantly modulated in the presence of mosquito larvae. In agreement with the protein secretion predictions, CRN transcripts did not show any differential expression. These results identified GH20 enzymes, and not CRNs, as potential pathogenicity factors shared by all animal pathogenic oomycetes.


Health behavior change in hearing healthcare: a discussion paper.
Health behavior change (HBC) refers to facilitating changes to habits and/or behavior related to health. In healthcare practice, it is quite common that the interactions between practitioner and patient involve conversations related to HBC. This could be mainly in relation to the practitioner trying to directly persuade the patients to make some changes in their health behavior. However, the patients may not be motivated to do so as they do not see this change as important. For this reason, direct persuasion may result in a breakdown of communication. In such instances, alternative approaches and means of indirect persuasion, such as empowering the patient and their family members, could be helpful. Furthermore, there are several models and/or theories proposed which explain the health behavior and also provide a structured framework for health behavior change. Many such models/approaches have been proven effective in facilitating HBC and health promotion in areas such as cessation of smoking, weight loss and so on. This paper provides an overview of main models/theories related to HBC and some insights into how these models/approaches could be adapted to facilitate behavior change in hearing healthcare, mainly in relation to: i) hearing help-seeking and hearing-aid uptake; and ii) hearing conservation in relation to music-induced hearing loss (MIHL). In addition, elements of current research related to this area and future directions are highlighted.


Opposing plant community responses to warming with and without herbivores.
If controls over primary productivity and plant community composition are mainly environmental, as opposed to biological, then global change may result in large-scale alterations in ecosystem structure and function. This view appears to be favored among investigations of plant biomass and community responses to experimental and observed warming. In far northern and arctic ecosystems, such studies predict increasing dominance of woody shrubs with future warming and emphasize the carbon (C)-sequestration potential and consequent atmospheric feedback potential of such responses. In contrast to previous studies, we incorporated natural herbivory by muskoxen and caribou into a 5-year experimental investigation of arctic plant community response to warming. In accordance with other studies, warming increased total community biomass by promoting growth of deciduous shrubs (dwarf birch and gray willow). However, muskoxen and caribou reduced total community biomass response, and responses of birch and willow, to warming by 19%, 46%, and 11%, respectively. Furthermore, under warming alone, the plant community shifted after 5 years away from graminoid-dominated toward dwarf birch-dominated. In contrast, where herbivores grazed, plant community composition on warmed plots did not differ from that on ambient plots after 5 years. These results highlight the potentially important and overlooked influences of vertebrate herbivores on plant community response to warming and emphasize that conservation and management of large herbivores may be an important component of mitigating ecosystem response to climate change.


A revised model for mitochondrial dysfunction in Duchenne muscular dystrophy.
We recently identified a signaling pathway that links the upregulation of miR-379 with a mitochondrial response in dystrophic muscle. In the present commentary, we explain the significance that this pathway may have in mitochondrial dysfunction in Duchenne muscular dystrophy (DMD). We identified the upregulation of miR-379 in the serum and muscles of DMD animal models and patients. We found that miR-379 is one of very few miRNAs whose expression was normalized in DMD patients treated with glucocorticoid. We identified EIF4G2 as a miR-379 target, which may promote mitochondrial oxidative phosphorylation (OxPhos) in the skeletal muscle. We found enriched EIF4G2 expression in oxidative fibers, and identified the mitochondrial ATP synthase subunit DAPIT as a translational target of EIF4G2. The identified signaling cascade, which comprises miR-379, EIF4G2 and DAPIT, may link the glucocorticoid treatment in DMD to a recovered mitochondrial ATP synthesis rate. We propose an updated model of mitochondrial dysfunction in DMD.


Involvement of individual subsites and secondary substrate binding sites in multiple attack on amylose by barley alpha-amylase.
Barley alpha-amylase 1 (AMY1) hydrolyzed amylose with a degree of multiple attack (DMA) of 1.9; that is, on average, 2.9 glycoside bonds are cleaved per productive enzyme-substrate encounter. Six AMY1 mutants, spanning the substrate binding cleft from subsites -6 to +4, and a fusion protein, AMY1-SBD, of AMY1 and the starch binding domain (SBD) of Aspergillus niger glucoamylase were also analyzed. DMA of the subsite -6 mutant Y105A and AMY1-SBD increased to 3.3 and 3.0, respectively. M53E, M298S, and T212W at subsites -2, +1/+2, and +4, respectively, and the double mutant Y105A/T212W had decreased DMA of 1.0-1.4. C95A (subsite -5) had a DMA similar to that of wild type. Maltoheptaose (G7) was always the major initial oligosaccharide product. Wild-type and the subsite mutants released G6 at 27-40%, G8 at 60-70%, G9 at 39-48%, and G10 at 33-44% of the G7 rate, whereas AMY1-SBD more efficiently produced G8, G9, and G10 at rates similar to, 66%, and 60% of G7, respectively. In contrast, the shorter products appeared with large individual differences: G1, 0-15%; G2, 8-43%; G3, 0-22%; and G4, 0-11% of the G7 rate. G5 was always a minor product. Multiple attack thus involves both longer translocation of substrate in the binding cleft upon the initial cleavage to produce G6-G10, essentially independent of subsite mutations, and short-distance moves resulting in individually very different rates of release of G1-G4. Accordingly, the degree of multiple attack as well as the profile of products can be manipulated by structural changes in the active site or by introduction of extra substrate binding sites.


A strategy to improve the efficiency of hole transporting materials: introduction of a highly symmetrical core.
The electronic, optical and hole transport properties of three new hole transporting materials (HTMs) with a planar core have been investigated by using density functional theory and Marcus theory. A reliable semi-rational formula was adopted to calculate the highest occupied molecular orbital (HOMO) levels of new HTMs. The results showed that the HOMO levels of new HTMs were 0.07-0.30 eV lower than those of Spiro-OMeTAD, and their absorption peaks appeared outside or close to the visible region and overlapped slightly with the absorption band of perovskites. Moreover, the Stokes shifts of the designing molecules were calculated to lie in a range from 72 to 124 nm, meaning that they could undergo large geometrical changes on excitation. More importantly, the hole mobility of new HTMs (0.099-0.27 cm2 v-1 s-1) was approximately two orders of magnitude higher than that of Spiro-OMeTAD (0.0056 cm2 v-1 s-1) due to strong hole coupling from a face-to-face packing pattern. Our results indicated that planar core-based HTMs could become potential candidates to replace the widely established Spiro-OMeTAD.


Examining overlap and homogeneity in ASD, ADHD, and OCD: a data-driven, diagnosis-agnostic approach.
The validity of diagnostic labels of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) is an open question given the mounting evidence that these categories may not correspond to conditions with distinct etiologies, biologies, or phenotypes. The objective of this study was to determine the agreement between existing diagnostic labels and groups discovered based on a data-driven, diagnosis-agnostic approach integrating cortical neuroanatomy and core-domain phenotype features. A machine learning pipeline, called bagged-multiview clustering, was designed to discover homogeneous subgroups by integrating cortical thickness data and measures of core-domain phenotypic features of ASD, ADHD, and OCD. This study was conducted using data from the Province of Ontario Neurodevelopmental Disorders (POND) Network, a multi-center study in Ontario, Canada. Participants (n = 226) included children between the ages of 6 and 18 with a diagnosis of ASD (n = 112, median [IQR] age = 11.7[4.8], 21% female), ADHD (n = 58, median [IQR] age = 10.2[3.3], 14% female), or OCD (n = 34, median [IQR] age = 12.1[4.2], 38% female), as well as typically developing controls (n = 22, median [IQR] age = 11.0[3.8], 55% female). The diagnosis-agnostic groups were significantly different than each other in phenotypic characteristics (SCQ: χ2(9) = 111.21, p < 0.0001; SWAN: χ2(9) = 142.44, p < 0.0001) as well as cortical thickness in 75 regions of the brain. The analyses revealed disagreement between existing diagnostic labels and the diagnosis-agnostic homogeneous groups (normalized mutual information < 0.20). Our results did not support the validity of existing diagnostic labels of ASD, ADHD, and OCD as distinct entities with respect to phenotype and cortical morphology.


The role of the cerebellum in dynamic changes of the sense of body ownership: a study in patients with cerebellar degeneration.
The sense of the body is deeply rooted in humans, and it can be experimentally manipulated by inducing illusions in at least two aspects: a subjective feeling of ownership and a proprioceptive sense of limb position. Previous studies mapped these different aspects onto anatomically distinct neuronal regions, with the ventral premotor cortex processing subjective experience of ownership and the inferior parietal lobule processing proprioceptive calibration. Lines of evidence suggest an involvement also of the cerebellum, but its precise role is not clear yet. To investigate the contribution of the cerebellum in the sense of body ownership, we applied the rubber-hand illusion paradigm in 28 patients affected by neurodegenerative cerebellar ataxia, selectively involving the cerebellum, and in 26 age-matched control participants. The rubber hand illusion is established by synchronous stroking of the participants' real unseen hand and a visible fake hand. Short asynchronous stroking does not bring about the illusion. We tested the subjective experience of the illusion, evaluated through a questionnaire and the proprioceptive drift of the real unseen hand toward the viewed rubber hand. In patients with cerebellar ataxia, we observed reduced sense of the subjective illusory experience specifically after synchronous stroking. In contrast, the proprioceptive drift was enhanced after synchronous and after asynchronous stimulation. These findings support the contention that the mechanisms underlying the presence of the illusion and the proprioceptive drift may be differently affected in different conditions. Impairment of the subjective sense of the illusion in cerebellar patients might hint at an involvement of cerebellar-premotor networks, whereas the proprioceptive drift typically associated with synchronous stroking appears to rely on other circuits, likely involving the cerebellum and the parietal regions.