The sialomucin CD164 (MGC-24v) is an adhesive glycoprotein expressed by human hematopoietic progenitors and bone marrow stromal cells that serves as a potent negative regulator of hematopoiesis.
Mucin-like molecules represent an emerging family of cell surface glycoproteins expressed by cells of the hematopoietic system. We report the isolation of a cDNA clone that encodes a novel transmembrane isoform of the mucin-like glycoprotein MGC-24, expressed by both hematopoietic progenitor cells and elements of the bone marrow (BM) stroma. This molecule was clustered as CD164 at the recent workshop on human leukocyte differentiation antigens. CD164 was identified using a retroviral expression cloning strategy and two novel monoclonal antibody (MoAb) reagents, 103B2/9E10 and 105.A5. Both antibodies detected CD164/MGC-24v protein expression by BM stroma and subpopulations of the CD34(+) cells, which include the majority of clonogenic myeloid (colony-forming unit-granulocyte-macrophage [CFU-GM]) and erythroid (blast-forming unit-erythroid [BFU-E]) progenitors and the hierarchically more primitive precursors (pre-CFU). Biochemical and functional characterization of CD164 showed that this protein represents a homodimeric molecule of approximately 160 kD. Functional studies demonstrate a role for CD164 in the adhesion of hematopoietic progenitor cells to BM stromal cells in vitro. Moreover, antibody ligation of CD164 on primitive hematopoietic progenitor cells characterized by the cell surface phenotype CD34(BRIGHT)CD38(-) results in the decreased recruitment of these cells into cell cycle, suggesting that CD164 represents a potent signaling molecule with the capacity to suppress hematopoietic cell proliferation.


Diagnosis and management of adult pyogenic osteomyelitis of the cervical spine.
Establishing the diagnosis of cervical osteomyelitis in a timely fashion is critical to prevent catastrophic neurological injury. In the modern imaging era, magnetic resonance imaging in particular has facilitated the diagnosis of cervical osteomyelitis, even before the onset of neurological signs or symptoms. Nevertheless, despite advancements in diagnosis, disagreement remains regarding appropriate surgical treatment. The role of instrumentation and type of graft material after cervical decompression remain controversial. The authors describe the epidemiological features, pathogenesis, and diagnostic evaluation, and the surgical and nonsurgical interventions that can be used to treat osteomyelitis of the cervical spine. They also review the current debate about the role of instrumentation in preventing spinal deformity after surgical decompression for cervical osteomyelitis. Based on this review, the authors conclude that nonsurgical therapy is appropriate if neurological signs or symptoms, instability, deformity, or spinal cord compression are absent. Surgical decompression, debridement, stabilization, and deformity correction are the goals once the decision to perform surgery has been made. The roles of autogenous graft, instrumentation, and allograft have not been clearly delineated with Class I data, but the authors believe that spinal stability and decompression override creating an environment that can be completely sterilized by antibiotic drugs.


A mimicry of an acute coronary syndrome.
A 79-year-old woman was out in the garden having lunch on a hot summer's day. She developed stabbing chest pains more severe on her left side, associated with radiation down her left arm. Severity was 7 out of 10. There was no relief of pain with glyceryl trinitrate spray. Risk factors for ischaemic heart disease include hyperlipidaemia, being an ex-smoker 40 years ago, no history of diabetes or hypertension. There was a family history of her father having a myocardial infarction at the age of 54. ECG revealed widespread deep symmetrical T-wave inversion in the chest leads and lateral limb leads. The patient's serum creatine kinase level was 180 IU/l (normaL range 30-135), troponin I level was 6.56 g/l (normal range 0-0.10), D-dimer was negative and random serum cholesterol level was 5.3 mmol/l (3.8-5.2). Significant coronary stenoses were excluded. A left ventriculogram revealed a hyperkinetic base and a dyskinetic apical region of the left ventricle. Echocardiography showed normal valves, basal septal hypertrophy and a dilated akinetic apex, with the region of akinesia spanning more than the arterial territory. Takotsubo cardiomyopathy. Treatment with aspirin, ACE inhibitor, beta blocker and a statin.


Niche and neutral models predict asymptotically equivalent species abundance distributions in high-diversity ecological communities.
A fundamental challenge in ecology is to understand the mechanisms that govern patterns of relative species abundance. Previous numerical simulations have suggested that complex niche-structured models produce species abundance distributions (SADs) that are qualitatively similar to those of very simple neutral models that ignore differences between species. However, in the absence of an analytical treatment of niche models, one cannot tell whether the two classes of model produce the same patterns via similar or different mechanisms. We present an analytical proof that, in the limit as diversity becomes large, a strong niche model give rises to exactly the same asymptotic form of SAD as the neutral model, and we verify the analytical predictions for a Panamanian tropical forest data set. Our results strongly suggest that neutral processes drive patterns of relative species abundance in high-diversity ecological communities, even when strong niche structure exists. However, neutral theory cannot explain what generates high diversity in the first place, and it may not be valid in low-diversity communities. Our results also confirm that neutral theory cannot be used to infer an absence of niche structure or to explain ecosystem function.


Universal Recommendations for the Management of Acute Diarrhea in Nonmalnourished Children.
Despite a substantial consistency in recommendations for the management of children with acute gastroenteritis (AGE), a high variability in clinical practice and a high rate of inappropriate medical interventions persist in both developing and developed countries.The aim of this study was to develop a set of clinical recommendations for the management of nonseverely malnourished children with AGE to be applied worldwide. The Federation of International Societies of Pediatric Gastroenterology, Hepatology, and Nutrition (FISPGHAN) Working Group (WG) selected care protocols on the management of acute diarrhea in infants and children aged between 1 month and 18 years. The WG used a 3-step approach consisting of: systematic review and comparison of published guidelines, agreement on draft recommendations using Delphi methodology, and external peer-review and validation of recommendations. A core of recommendations including definition, diagnosis, nutritional management, and active treatment of AGE was developed with an overall agreement of 91% (range 80%-96%). A total of 28 world experts in pediatric gastroenterology and emergency medicine successively validated the set of 23 recommendations with an agreement of 87% (range 83%-95%). Recommendations on the use of antidiarrheal drugs and antiemetics received the lowest level of agreement and need to be tailored at local level. Oral rehydration and probiotics were the only treatments recommended. Universal recommendations to assist health care practitioners in managing children with AGE may improve practitioners' compliance with guidelines, reduce inappropriate interventions, and significantly impact clinical outcome and health care-associated costs.


Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis.
The comparative effectiveness of rheumatoid arthritis therapies is uncertain. To compare the benefits and harms of disease-modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis. Records limited to the English language and studies of adults were identified by using MEDLINE, EMBASE, The Cochrane Library, and International Pharmaceutical Abstracts from 1980 to September 2007. Two persons independently selected relevant head-to-head trials and prospective cohort studies with at least 100 participants and 12-week follow-up and relevant good- or fair-quality meta-analyses that compared benefits or harms of 11 drug therapies. For harms, they included retrospective cohort studies. Information on study design, interventions, outcomes, and quality were extracted according to a standard protocol. Head-to-head trials (n = 23), mostly examining synthetic DMARDs, showed no clinically important differences in efficacy among synthetic DMARDs (limited to methotrexate, leflunomide, and sulfasalazine) or among anti-tumor necrosis factor drugs (adalimumab, etanercept, and infliximab). Monotherapy with anti-tumor necrosis factor drugs resulted in better radiographic outcomes than did methotrexate but no important differences in clinical outcomes (for example, 20%, 50%, or 70% improvement according to American College of Rheumatology response criteria). Various combinations of biological DMARDs plus methotrexate improved clinical response rates and functional outcomes more than monotherapy with either methotrexate or biological DMARDs. In patients whose monotherapy failed, combination therapy with synthetic DMARDs improved response rates. Numbers and types of short-term adverse events were similar for biological and synthetic DMARDs. The evidence was insufficient to draw conclusions about differences for rare but serious adverse events for biological DMARDs. Most studies were short-term efficacy trials conducted in selected populations with few comorbid conditions. Limited available comparative evidence does not support one monotherapy over another for adults with rheumatoid arthritis. Although combination therapy is more effective for patients whose monotherapy fails, the evidence is insufficient to draw firm conclusions about whether one combination or treatment strategy is better than another or is the best treatment for early rheumatoid arthritis.


Development of the crop residue and rangeland burning in the 2014 National Emissions Inventory using information from multiple sources.
Biomass burning has been identified as an important contributor to the degradation of air quality because of its impact on ozone and particulate matter. One component of the biomass burning inventory, crop residue burning, has been poorly characterized in the National Emissions Inventory (NEI). In the 2011 NEI, wildland fires, prescribed fires, and crop residue burning collectively were the largest source of PM2.5. This paper summarizes our 2014 NEI method to estimate crop residue burning emissions and grass/pasture burning emissions using remote sensing data and field information and literature-based, crop-specific emission factors. We focus on both the postharvest and pre-harvest burning that takes place with bluegrass, corn, cotton, rice, soybeans, sugarcane and wheat. Estimates for 2014 indicate that over the continental United States (CONUS), crop residue burning excluding all areas identified as Pasture/Grass, Grassland Herbaceous, and Pasture/Hay occurred over approximately 1.5 million acres of land and produced 19,600 short tons of PM2.5. For areas identified as Pasture/Grass, Grassland Herbaceous, and Pasture/Hay, biomass burning emissions occurred over approximately 1.6 million acres of land and produced 30,000 short tons of PM2.5. This estimate compares with the 2011 NEI and 2008 NEI as follows: 2008: 49,650 short tons and 2011: 141,180 short tons. Note that in the previous two NEIs rangeland burning was not well defined and so the comparison is not exact. The remote sensing data also provided verification of our existing diurnal profile for crop residue burning emissions used in chemical transport modeling. In addition, the entire database used to estimate this sector of emissions is available on EPA's Clearinghouse for Inventories and Emission Factors (CHIEF, http://www3.epa.gov/ttn/chief/index.html ). Estimates of crop residue burning and rangeland burning emissions can be improved by using satellite detections. Local information is helpful in distinguishing crop residue and rangeland burning from all other types of fires.


Chronic bronchitis and chronic obstructive pulmonary disease.
Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB.


The oxylipin signal jasmonic acid is activated by an enzyme that conjugates it to isoleucine in Arabidopsis.
Despite its importance in a variety of plant defense responses, our understanding of how jasmonic acid (JA) functions at the biochemical level is limited. Several amino acid conjugates of JA were tested for their ability to complement the JA-insensitive Arabidopsis thaliana mutant jar1-1. Unlike free JA, JA-Ile inhibited root growth in jar1-1 to the same extent as in the wild type, whereas JA-Val, JA-Leu, and JA-Phe were ineffective inhibitors in both genotypes. Thin-layer chromatography and gas chromatography-mass spectrometry (GC-MS) analysis of products produced in vitro by recombinant JAR1 demonstrated that this enzyme forms JA-amido conjugates with several amino acids, including JA-Ile. JA-Val, -Leu, -Ile, and -Phe were each quantified in Arabidopsis seedlings by GC-MS. JA-Ile was found at 29.6 pmole g(-1) fresh weight (FW) in the wild type but was more than sevenfold lower in two jar1 alleles. JA-Leu, -Val, and -Phe were present at only low levels in both genotypes. Expression of wild-type JAR1 in transgenic jar1-1 plants restored sensitivity to JA and elevated JA-Ile to the same level as in the wild type. The ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) conjugated to JA was also found in plant tissue at 18.4 pmole g(-1) FW. JA-ACC was determined not be an effective jasmonate root inhibitor, and surprisingly, was twofold higher in the mutants than in the wild type. This suggests that another JA-conjugating enzyme(s) is present in Arabidopsis. Synthesis of JA-ACC might provide a mechanism to coregulate the availability of JA and ACC for conversion to the active hormones JA-Ile and ethylene, respectively. We conclude that JAR1 is a JA-amino synthetase that is required to activate JA for optimal signaling in Arabidopsis. Plant hormone activation by conjugation to amino acids and the enzymes involved in their formation were previously unknown.


Potassium-and silver-double-ion-exchanged slab glass waveguides: characterization and modeling.
Double-ion-exchanged glass waveguides are made first by a potassium-ion exchange followed by a silver-ion exchange. The inverse WKB method is used to determine the index profile. It is shown that a combination of a truncated quadratic function and a complementary error function represents the refractive index best. A direct WKB method is employed to find the maximum index change and the diffusion coefficient of the second exchange process. The concentration of silver, potassium, and sodium ions are measured by an x-ray photoelectron spectroscopy technique. The results agree well with the index profile when a quadratic function is used.


Sincipital Encephaloceles: A Study of Associated Brain Malformations.
The aim of this study was to evaluate the associated intracranial malformations in patients with sincipital encephaloceles. A hospital-based cross-sectional study was conducted over 8 years from June 2007 to May 2015 on 28 patients. The patients were evaluated by either computed tomography or magnetic resonance imaging whichever was feasible. Encephaloceles were described with respect to their types, contents, and extensions. A note was made on the associated malformations with sincipital encephaloceles. Fifty percent of the patients presented before the age of 3 years and both the sexes were affected equally. Nasofrontal encephalocele was the most common type seen in 13 patients (46.4%), and corpus callosal agenesis (12 patients) was the most common associated malformation. Other malformations noted were arachnoid cyst (10 patients), hydrocephalus (7 patients), and agyria-pachygyria complex (2 patients). Capital Brain malformations are frequently encountered in children with sincipital encephaloceles. Detail radiological evaluation is necessary to plan treatment and also to prognosticate such rare malformations.


Laser action in Tb(OH)3/SiO2 photonic crystals.
Photonic crystals of Tb(OH)(3)/SiO(2) core/shell nanospheres with different periodicities were used as a resonant cavity to explore laser action. By changing the particle size, the optical stop band of the photonic crystals can be tuned to coincide with the multiple emission bands of terbium ions. An overlap of the stop band on the multiple emissions of the active materials embedded inside the photonic crystals offered a good chance for resonance. Lasing emissions arising from terbium ions occurred near the band edge of the PCs were demonstrated.


Collapse dynamics of super-Gaussian Beams.
We investigate the self-focusing dynamics of super-Gaussian optical beams in a Kerr medium. We find that up to several times the critical power for self-focusing, super-Gaussian beams evolve towards a Townes profile. At higher powers the super-Gaussian beams form rings which break into filaments as a result of noise. Our results are consistent with the observed self-focusing dynamics of femtosecond laser pulses in air [1] in which filaments are formed along a ring about the axis of the initial beam where the initial beam did not form a ring.


Extensive geographical mixing of 2009 human H1N1 influenza A virus in a single university community.
Despite growing interest in the molecular epidemiology of influenza virus, the pattern of viral spread within individual communities remains poorly understood. To determine the phylogeography of influenza virus in a single population, we examined the spatial diffusion of H1N1/09 influenza A virus within the student body of the University of California, San Diego (UCSD), sampling for a 1-month period between October and November 2009. Despite the highly focused nature of our study, an analysis of complete viral genome sequences revealed between 24 and 33 independent introductions of H1N1/09 into the UCSD community, comprising much of the global genetic diversity in this virus. These data were also characterized by a relatively low level of on-campus transmission as well as extensive spatial mixing, such that there was little geographical clustering by either student residence or city ZIP code. Most notably, students experiencing illness on the same day and residing in the same dorm possessed phylogenetically distinct lineages. H1N1/09 influenza A virus is therefore characterized by a remarkable spatial fluidity, which is likely to impede community-based methods for its control, including class cancellations, quarantine, and chemoprophylaxis.


Applications of digital holographic microscopy in therapeutic evaluation of Chinese herbal medicines.
Therapeutic use of Chinese herbal medicines (CHMs) is a new approach to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The detection of soma volume and neurite outgrowth of living neurons is a highly relevant biomarker related to various application fields, including therapy efficacy and drug safety evaluation. Through the use of digital holographic microscopy (DHM), we may evaluate the therapeutic effect of CHMs in curing neurodegeneration. Panax ginseng has been used in traditional Chinese herbal medicine for centuries. In this study, DHM is applied to monitor the three-dimensional morphology change of retinoic acid-induced human neuroblastoma SH-SY5Y cells during Panax ginseng treatment. We demonstrate the capability of DHM to detect noninvasively SH-SY5Y cell apoptosis and rescue through the measurement of neuronal volume and neurite outgrowth regulation without any labeling reagent. Through DHM, we observed the phase images of the rapidly shrinking cells with decreasing soma volume and shortening neurite outgrowth during glutamate treatments. Then shrinkage in glutamate-induced cells is significantly alleviated during Panax ginseng treatment. The results through DHM are consistent with the result from MTT assay for assessing cell viability during Panax ginseng treatment. Thus, we suggest that application of DHM for measuring soma volume and neurite outgrowth of living neurons may be one appropriate therapeutic evaluation for CHMs.


Effects of coating a titanium alloy with fibronectin on the expression of osteoblast gene markers in the MC3T3 osteoprogenitor cell line.
A number of environmental and patient-related factors contribute to implant failure. A significant fraction of these failures can be attributed to limited osseointegration resulting from poor bone healing responses. The overall goal of this study was to determine whether surface treatment of a titanium-aluminum-vanadium alloy (Ti-6Al-4V) implant material in combination with a biomimetic protein coating could promote the differentiation of attached osteoblastic cells. The specific aims of the study were to investigate whether osteoprogenitor cells cultured on a rigorously cleaned implant specimen showed a normal pattern of differentiation and whether preadsorbed fibronectin accelerated or enhanced osteoblast differentiation. Ti-6Al-4V disks were rigorously cleaned, passivated in nitric acid, and dry heat- sterilized; some of the disks were then coated with 1 nmol/L fibronectin. MC3T3 osteoprogenitor cells were then cultured on the pretreated disks for several weeks. Quantitative real-time polymerase chain reaction was performed to measure changes over time in the mRNA levels of osteoblast genes. Fibronectin increased the peak expression of all analyzed osteoblast gene markers. "Early" genes that normally mark the proliferative phase (0 to 10 days) of osteoblastic development showed peak expression within the first 10 days after cell attachment to the titanium alloy. In contrast, "late" genes that normally mark the differentiation (10 to 20 days) and mineralization (20 to 36 days) phases of osteoblastogenesis achieved peak expression only after approximately 3 to 4 weeks of culture. Osteoprogenitors cultured on a rigorously cleaned Ti-6Al-4V alloy were found to demonstrate a normal pattern of osteoblast differentiation. Preadsorbed fibronectin was observed to stimulate osteoblast differentiation during the mineralization phase of osteoblastogenesis.


Complications of Intrathecal Chemotherapy in Adults: Single-Institution Experience in 109 Consecutive Patients.
Acute lymphoblastic leukemia and other aggressive lymphoid malignancies like Burkitt leukemia/lymphoma have high incidence of central nervous system (CNS) involvement. Various solid tumors, most notably breast cancer, can also metastasize into the CNS as a late stage complication causing devastating effects. Intrathecal (IT) chemotherapy consisting of methotrexate, cytarabine, or the two in combination is frequently used for the prophylaxis and treatment of CNS metastasis. Because of the high toxicity of these chemotherapeutic agents, however, their side effect profiles are potentially catastrophic. The incidence of neurotoxicity secondary to IT chemotherapy is well defined in the pediatric literature but is poorly reported in adults. Here, we investigated the incidence of neurologic and nonneurologic side effects secondary to IT chemotherapy in 109 consecutive adult patients over a two-year time period at hospitals associated with our institution. Of 355 IT chemotherapy treatments received by these patients, 11 (3.10%) resulted in paresthesias or paralysis, which we defined as significant neurologic events in our analysis. We also examined minor events that arose after IT chemotherapy, including back pain, headache, fever, vomiting, and asthenia. At least one of these occurred after 30.70% of IT chemotherapy doses. Clinicians involved in the care of patients receiving IT chemotherapy should be aware of these findings and consider treatment options lower rate of neurotoxicity such as high-dose systemic methotrexate.


Computing Curvature Sensitivity of Biomolecules in Membranes by Simulated Buckling.
Membrane curvature sensing, where the binding free energies of membrane-associated molecules depend on the local membrane curvature, is a key factor to modulate and maintain the shape and organization of cell membranes. However, the microscopic mechanisms are not well understood, partly due to absence of efficient simulation methods. Here, we describe a method to compute the curvature dependence of the binding free energy of a membrane-associated probe molecule that interacts with a buckled membrane, which has been created by lateral compression of a flat bilayer patch. This buckling approach samples a wide range of curvatures in a single simulation, and anisotropic effects can be extracted from the orientation statistics. We develop an efficient and robust algorithm to extract the motion of the probe along the buckled membrane surface, and evaluate its numerical properties by extensive sampling of three coarse-grained model systems: local lipid density in a curved environment for single-component bilayers, curvature preferences of individual lipids in two-component membranes, and curvature sensing by a homotrimeric transmembrane protein. The method can be used to complement experimental data from curvature partition assays and provides additional insight into mesoscopic theories and molecular mechanisms for curvature sensing.


Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.


Multicomponent ionic liquid CMC prediction.
We created a model to predict CMC of ILs based on 704 experimental values published in 43 publications since 2000. Our model was able to predict CMC of variety of ILs in binary or ternary system in a presence of salt or alcohol. The molecular volume of IL (Vm), solvent-accessible surface (Ŝ), solvation enthalpy (ΔsolvG∞), concentration of salt (Cs) or alcohol (Ca) and their molecular volumes (Vms and Vma, respectively) were chosen as descriptors, and Kernel Support Vector Machine (KSVM) and Evolutionary Algorithm (EA) as regression methodologies to create the models. Data was split into training and validation set (80/20) and subjected to bootstrap aggregation. KSVM provided better fit with average R2 of 0.843, and MSE of 0.608, whereas EA resulted in R2 of 0.794 and MSE of 0.973. From the sensitivity analysis it was shown that Vm and Ŝ have the highest impact on ILs micellization in both binary and ternary systems, however surprisingly in the presence of alcohol the Vm becomes insignificant/irrelevant. Micelle stabilizing or destabilizing influence of the descriptors depends upon the additives. Previous attempts at modelling the CMC of ILs was generally limited to small number of ILs in simplified (binary) systems. We however showed successful prediction of the CMC over a range of different systems (binary and ternary).


Experience-dependent enhancement of linguistic pitch representation in the brainstem is not specific to a speech context.
Neural representation of pitch is influenced by lifelong experiences with music and language at both cortical and subcortical levels of processing. The aim of this article is to determine whether neural plasticity for pitch representation at the level of the brainstem is dependent upon specific dimensions of pitch contours that commonly occur as part of a native listener's language experience. Brainstem frequency following responses (FFRs) were recorded from Chinese and English participants in response to four Mandarin tonal contours presented in a nonspeech context in the form of iterated rippled noise. Pitch strength (whole contour, 250 msec; 40-msec segments) and pitch-tracking accuracy (whole contour) were extracted from the FFRs using autocorrelation algorithms. Narrow band spectrograms were used to extract spectral information. Results showed that the Chinese group exhibits smoother pitch tracking than the English group in three out of the four tones. Moreover, cross-language comparisons of pitch strength of 40-msec segments revealed that the Chinese group exhibits more robust pitch representation of those segments containing rapidly changing pitch movements across all four tones. FFR spectral data were complementary showing that the Chinese group exhibits stronger representation of multiple pitch-relevant harmonics relative to the English group across all four tones. These findings support the view that at early preattentive stages of subcortical processing, neural mechanisms underlying pitch representation are shaped by particular dimensions of the auditory stream rather than speech per se. Adopting a temporal correlation analysis scheme for pitch encoding, we propose that long-term experience sharpens the tuning characteristics of neurons along the pitch axis with enhanced sensitivity to linguistically relevant variations in pitch.


International Society of Paediatric Surgical Oncology (IPSO) Surgical Practice Guidelines.
Most children with tumors will require one or more surgical interventions as part of the care and treatment, including making a diagnosis, obtaining adequate venous access, performing a surgical resection for solid tumors (with staging and reconstruction), performing procedures for cancer prevention and its late effects, and managing complications of treatment; all with the goal of improving survival and quality of life. It is important for surgeons to adhere to sound pediatric surgical oncology principles, as they are closely associated with improved local control and survival. Unfortunately, there is a significant disparity in survival rates in low and middle income countries, when compared to those from high income countries. The International Society of Paediatric Surgical Oncology (IPSO) is the leading organization that deals with pediatric surgical oncology worldwide. This organization allows experts in the field from around the globe to gather and address the surgical needs of children with cancer. IPSO has been invited to contribute surgical guidance as part of the World Health Organization Initiative for Childhood Cancer. One of our goals is to provide surgical guidance for different scenarios, including those experienced in High- (HICs) and Low- and Middle-Income Countries (LMICs). With this in mind, the following guidelines have been developed by authors from both HICs and LMICs. These have been further validated by experts with the aim of providing evidence-based information for surgeons who care for children with cancer. We hope that this initiative will benefit children worldwide in the best way possible. Simone Abib, IPSO President Justin T Gerstle, IPSO Education Committee Chair Chan Hon Chui, IPSO Secretary.


Progress in cerebrovascular disease: local cerebral blood flow by xenon enhanced CT.
A noninvasive technique for measuring local cerebral blood flow (LCBF) by xenon enhanced x-ray transmission computed tomography (CT) has been developed an reported quite extensively in recent years. In this method, nonradioactive xenon gas in inhaled and the temporal changes in radiographic enhancement produced by the inhalation are measured by sequential computed tomography. Time dependent xenon concentrations within various tissue segments in the brain are used to derive both local partition coefficient (lambda) and LCBF. An assessment of this method reveals that although it provides functional mapping of blood flow with excellent anatomic specificity, there are distinct limitations. The assumptions underlying this methodology are examined and problems associated with various potential applications of this technique are discussed.


Phylogeography of Biomphalaria glabrata and B. pfeifferi, important intermediate hosts of Schistosoma mansoni in the New and Old World tropics.
The historical phylogeography of the two most important intermediate host species of the human blood fluke Schistosoma mansoni, B. glabrata in the New World, and B. pfeifferi in the Old World, was investigated using partial 16S and ND1 sequences from the mitochondrial genome. Nuclear sequences of an actin intron and internal transcribed spacer (ITS)-1 were also obtained, but they were uninformative for the relationships among populations. Phylogenetic analyses based on mtDNA revealed six well-differentiated clades within B. glabrata: the Greater Antilles, Venezuela and the Lesser Antilles, and four geographically overlapping Brazilian clades. Application of a Biomphalaria-specific mutation rate gives an estimate of the early Pleistocene for their divergence. The Brazilian clades were inferred to be the result of fragmentation, due possibly to climate oscillations, with subsequent range expansion producing the overlapping ranges. Within the Venezuela and Lesser Antilles clade, lineages from each of these areas were estimated to have separated approximately 740 000 years ago. Compared to B. glabrata, mitochondrial sequences of B. pfeifferi are about 4x lower in diversity, reflecting a much younger age for the species, with the most recent common ancestor of all haplotypes estimated to have existed 880 000 years ago. The oldest B. pfeifferi haplotypes occurred in southern Africa, suggesting it may have been a refugium during dry periods. A recent range expansion was inferred for eastern Africa less than 100 000 years ago. Several putative species and subspecies, B. arabica, B. gaudi, B. rhodesiensis and B. stanleyi, are shown to be undifferentiated from other B. pfeifferi populations.


The Association Between Liver and Tumor [18F]FDG Uptake in Patients with Diffuse Large B Cell Lymphoma During Chemotherapy.
The aim of this study was to explore the association between liver, mediastinum and tumor 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake during chemotherapy in diffuse large B cell lymphoma (DLBCL). Nineteen patients with proven DLBCL underwent positron emission tomography (PET)/X-ray computed tomography scan at baseline, 1 week and 2 cycles after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy, and again after chemotherapy completion. The mean and maximal standardized uptake value (SUVmean and SUVmax) of the liver and mediastinum were measured and correlated with the tumor SUVmax, SUVsum, whole-body metabolic tumor volume (MTVwb), and total lesion glycolysis (TLG). At baseline, both the liver and mediastinum SUVmean and SUVmax correlated inversely with the tumor MTVwb or TLG (p < 0.01 or 0.001). The liver SUVmean and SUVmax increased significantly after 1 week of R-CHOP therapy and remained at the high level until chemotherapy completion. The mediastinum SUVmean and SUVmax remained stable during chemotherapy. The tumor SUVmax, SUVsum, MTVwb, and TLG decreased significantly after 1 week of R-CHOP therapy. The change of the liver SUVmean correlated inversely with the change of tumor MTVwb and TLG after 1 week of chemotherapy (p < 0.05, respectively). The intersubject variability of liver and mediastinum [18F]FDG uptake ranged from 11 to 26 %. The liver [18F]FDG uptake increased significantly after R-CHOP therapy. One of the possible reasons is the distribution of a greater fraction of the tracer to healthy tissues rather than tumor after effective chemotherapy. The variability of the liver [18F]FDG uptake during chemotherapy might affect the visual analysis of the interim PET scan and this needs to be confirmed in future studies with a large patient cohort. In addition, the intersubject variability of the liver and mediastinum [18F]FDG uptake should be considered.


Colorectal cancer screening in older men and women: qualitative research findings and implications for intervention.
As part of the formative research for developing interventions to increase colorectal cancer screening in men and women aged 50 and older, 14 focus groups were conducted to identify (1) knowledge, attitudes, and beliefs about colorectal cancer and colorectal cancer screening, (2) barriers to screening, and (3) strategies for motivating and supporting behavior change. Participants had either private insurance or Medicare and reported different levels of experience with colorectal cancer screening. Overall, they were poorly informed about colorectal cancer and the possible benefits of screening, reporting little or no information from physicians or mass media, negative attitudes toward screening procedures, and fear of cancer. Despite references to the subject matter as embarrassing or private, both men and women, African Americans and whites, appeared to talk candidly and comfortably in the permissive context of the focus group. This study's findings suggest that public education campaigns, decision aids, and targeted interventions are urgently needed to put colorectal cancer screening on the public's "radar screen," to increase awareness of the prevention and early detection benefits of screening, and to encourage people 50 and older-and the health care providers who serve them-to make screening a high priority.


Diverging destinies: how children are faring under the second demographic transition.
In this article, I argue that the trends associated with the second demographic transition are following two trajectories and leading to greater disparities in children's resources. Whereas children who were born to the most-educated women are gaining resources, in terms of parents' time and money, those who were born to the least-educated women are losing resources. The forces behind these changes include feminism, new birth control technologies, changes in labor market opportunities, and welfare-state policies. I contend that Americans should be concerned about the growing disparity in parental resources and that the government can do more to close the gap between rich and poor children.


Sperm of colourful males are better protected against oxidative stress.
Sperm cells are highly vulnerable to free radicals, and sperm quality and male fertility are critically affected by oxidative stress. Recently, sexual ornaments, particularly carotenoid-based colourful traits, have been proposed to depend on a male's capacity to resist oxidative stress, and thus to signal sperm quality. We conducted an experimental test of this hypothesis on great tits Parus major, in which adults are sexually dichromatic in carotenoid-based breast plumage. We report the first evidence that ornaments and sperm quality may be linked through oxidative stress. When experimentally subjected to oxidative stress resulting from increased workload, less colourful males suffered a greater reduction in sperm motility and swimming ability, and increased levels of sperm lipid peroxidation compared to more colourful males. Moreover, the level of sperm lipid peroxidation was negatively correlated with sperm quality. Finally, carotenoid supplementation increased sperm quality of less colourful males, suggesting that pale males are deficient in carotenoid antioxidants.


Ligation of HLA class II molecules promotes sensitivity to CD95 (Fas antigen, APO-1)-mediated apoptosis.
CD95 (Fas antigen/APO-1) is up-regulated in activated lymphocytes, and monoclonal antibody (mAb) to CD95 induces apoptosis. HLA class II molecules play a key role in antigen presentation, ligation of which induces signal transduction. We examined 18 lymphoid cell lines (15 B cell and 3 T cell lines) to investigate the effects of ligation of HLA class II molecules on CD95-mediated apoptosis. All of the five immature B cell lines were sensitive to anti-CD95 mAb, and ligation of HLA class II molecules promoted CD95-mediated apoptosis. In seven B-blastoid cell lines, two Burkitt lines were resistant to anti-CD95 mAb in spite of high expression of CD95. In three of five non-Burkitt B-blastoid lines, CD95-mediated apoptosis was augmented by treatment with anti-HLA class II mAb, while the other two lines lacking CD95 were resistant to anti-CD95 mAb. Three plasmacytic cell lines showed CD95-mediated apoptosis, but enhancement by anti-HLA class I mAb was slight in one cell line and was not observed in the other two lines. Out of three HLA class II antigen-positive T cell lines, CD95-mediated apoptosis was observed to some degree in one call line but was not promoted by the treatment with anti-HLA class II mAb, and the other two cell lines were resistant to anti-CD95 mAb. Ligation of HLA class II molecules did not alter CD95 expression in the five cell lines examined, except Su-DHL-4 originated from a follicular lymphoma, which showed slight up-regulation. Taken together, ligation of HLA class II molecules apparently promotes CD95-mediated apoptosis in immature B cells and non-Burkitt B blasts. These findings highlight the role of HLA class II molecules in CD95-mediated apoptosis, which may facilitate rapid clearance of functionally useless cells from the immune system and might be involved in negative selection of B cells.


Learning from contract change in primary care dentistry: A qualitative study of stakeholders in the north of England.
The aim of this research was to explore and synthesise learning from stakeholders (NHS dentists, commissioners and patients) approximately five years on from the introduction of a new NHS dental contract in England. The case study involved a purposive sample of stakeholders associated with a former NHS Primary Care Trust (PCT) in the north of England. Semi-structured interviews were conducted with 8 commissioners of NHS dental services and 5 NHS general dental practitioners. Three focus group meetings were held with 14 NHS dental patients. All focus groups and interviews were audio recorded and transcribed verbatim. The data were analysed using a framework approach. Four themes were identified: 'commissioners' views of managing local NHS dental services'; 'the risks of commissioning for patient access'; 'costs, contract currency and commissioning constraints'; and 'local decision-making and future priorities'. Commissioners reported that much of their time was spent managing existing contracts rather than commissioning services. Patients were unclear about the NHS dental charge bands and dentists strongly criticised the contract's target-driven approach which was centred upon them generating 'units of dental activity'. NHS commissioners remained relatively constrained in their abilities to reallocate dental resources amongst contracts. The national focus upon practitioners achieving their units of dental activity appeared to outweigh interest in the quality of dental care provided.


Sparse Power-Law Network Model for Reliable Statistical Predictions Based on Sampled Data.
A projective network model is a model that enables predictions to be made based on a subsample of the network data, with the predictions remaining unchanged if a larger sample is taken into consideration. An exchangeable model is a model that does not depend on the order in which nodes are sampled. Despite a large variety of non-equilibrium (growing) and equilibrium (static) sparse complex network models that are widely used in network science, how to reconcile sparseness (constant average degree) with the desired statistical properties of projectivity and exchangeability is currently an outstanding scientific problem. Here we propose a network process with hidden variables which is projective and can generate sparse power-law networks. Despite the model not being exchangeable, it can be closely related to exchangeable uncorrelated networks as indicated by its information theory characterization and its network entropy. The use of the proposed network process as a null model is here tested on real data, indicating that the model offers a promising avenue for statistical network modelling.


Effects of Psychotropics on the Microbiome in Patients With Depression and Anxiety: Considerations in a Naturalistic Clinical Setting.
The antibacterial effects of psychotropics may be part of their pharmacological effects when treating depression. However, limited studies have focused on gut microbiota in relation to prescribed medication. We longitudinally investigated the relationship between patients' prescribed medications and intestinal bacterial diversity in a naturalistic treatment course for patients with major depressive disorders and anxiety disorders. Patients were recruited and their stool was collected at 3 time points during their usual psychiatric treatments. Gut microbiota were analyzed using 16S rRNA gene sequencing. We examined the impact of psychotropics (i.e., antidepressants, anxiolytics, antipsychotics) on their gut microbial diversity and functions. We collected 246 stool samples from 40 patients. Despite no differences in microbial diversity between medication groups at the baseline, over the course of treatment, phylogenic diversity whole-tree diversity decreased in patients on antipsychotics compared with patients without (P = .027), and beta diversity followed this trend. Based on a fixed-effect model, antipsychotics predicted microbial diversity; the higher doses correlated with less diversity based on the Shannon index and phylogenic diversity whole tree (estimate = -0.00254, SE = 0.000595, P < .0001; estimate = -0.02644, SE = 0.00833, P = .002, respectively). Antipsychotics may play a role in decreasing the alpha diversity of the gut microbiome among patients with depression and anxiety, and our results indicate a relationship with medication dosage. Future studies are warranted and should consider patients' types and doses of antipsychotics in order to further elucidate the mechanisms of gut-brain interactions in psychiatric disorders.


Gender and psychiatric disorders in children with epilepsy. A meta-analysis.
The objective of the study was to assess the influence of gender on psychiatric disorders in children with epilepsy (CWE). A systematic review of the literature on risk factors for psychiatric disorder in CWE published between 2004 and June 2018 was undertaken. Studies including data on gender that permitted the calculation of a risk ratio (RR) were included in the meta-analysis. A meta-regression was conducted to examine the contribution of setting of the survey and the inclusion of learning disabilities. Thirty-nine papers were included in the review. The male/female RR in CWE for Attention Deficit Hyperactivity Disorder (ADHD) was 1.49 (Confidence Interval (CI): 1.24-1.79), autistic spectrum disorder (ASD) 1.67 (CI: 1.47 to 1.90), anxiety 1.00 (CI: 0.90-1.12), and depression 0.93 (CI 0.41-2.09). More boys than girls had ADHD and ASD, but in relative terms, the RR male/female was lower in CWE than the RR in the general population reported in other studies. Meta-regression indicated that the inclusion of children with intellectual disability (mental retardation) or the setting (community vs hospital) did not have a significant impact. Compared with girls in the general population, girls with epilepsy seem to be at a higher risk of being diagnosed with ADHD/ASD as the gender ratio is more equal. This could be related to differences in the assessment of CWE and/or a shared pathogenesis between psychiatric conditions and epilepsy.


Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism.
To evaluate the effects of the non-selective, non-steroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2-/- and PTGS2-/+) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P < 0.05). After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively (P < 0.01). Addition of 10 μmol/L PGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P < 0.05) and 47% (0.4 mg/mL; P < 0.01). Finally, growth of PTGS2-/- and PTGS2+/- kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. ASA reduces early renal growth and development but the role of prostaglandins in this may be minor.


Quantitative Electrochemical DNA Microarray on a Monolith Electrode with Ten Attomolar Sensitivity, 100% Specificity, and Zero Background.
Circulating microRNA are promising diagnostic and prognostic biomarkers of disease in quantitative blood tests. A label-free, PCR-free, electrochemical microarray technology on a monolith electrode is described, with 10 attomolar (aM) sensitivity and responsiveness to binding of <1 zeptomole of target to immobilized ssDNA probes with zero background. Specificity is 100% in a mixture with five nonspecific miRNA each with a 103-fold higher concentration. Direct measurement on plasma-derived miRNA without cDNA conversion and PCR demonstrated multiplexing and near-ideal quantitative correlation with an equivalent pure sample. The dynamic range is a target concentration ranging from 10-2 to 103 femtomolar (fM). This PCR-free novel technology can be applied as a test for cancer diagnosis/prognosis to detect 103 copies of a miRNA sequence in RNA extracted from 100 μL of plasma.


An Orthogonal D2 O-Based Induction System that Provides Insights into d-Amino Acid Pattern Formation by Radical S-Adenosylmethionine Peptide Epimerases.
Radical S-adenosyl methionine peptide epimerases (RSPEs) are an enzyme family that accomplishes regiospecific and irreversible introduction of multiple d-configured residues into ribosomally encoded peptides. Collectively, RSPEs can generate diverse epimerization patterns in a wide range of substrates. Previously, the lack of rapid methods to localize epimerized residues has impeded efforts to investigate the function and applicative potential of RSPEs. An efficient mass spectrometry-based assay is introduced that permits characterization of products generated in E. coli. Applying this to a range of non-natural peptide-epimerase combinations, it is shown that the d-amino acid pattern is largely but not exclusively dictated by the core peptide sequence, while the epimerization order is dependent on the enzyme-leader pair. RSPEs were found to be highly promiscuous, which allowed for modular introduction of peptide segments with defined patterns.


QM/MM X-ray refinement of zinc metalloenzymes.
Zinc metalloenzymes play an important role in biology. However, due to the limitation of molecular force field energy restraints used in X-ray refinement at medium or low resolutions, the precise geometry of the zinc coordination environment can be difficult to distinguish from ambiguous electron density maps. Due to the difficulties involved in defining accurate force fields for metal ions, the QM/MM (quantum-mechanical/molecular-mechanical) method provides an attractive and more general alternative for the study and refinement of metalloprotein active sites. Herein we present three examples that indicate that QM/MM based refinement yields a superior description of the crystal structure based on R and R(free) values and on the inspection of the zinc coordination environment. It is concluded that QM/MM refinement is an useful general tool for the improvement of the metal coordination sphere in metalloenzyme active sites.


Topological mechanics of knots and tangles.
Knots play a fundamental role in the dynamics of biological and physical systems, from DNA to turbulent plasmas, as well as in climbing, weaving, sailing, and surgery. Despite having been studied for centuries, the subtle interplay between topology and mechanics in elastic knots remains poorly understood. Here, we combined optomechanical experiments with theory and simulations to analyze knotted fibers that change their color under mechanical deformations. Exploiting an analogy with long-range ferromagnetic spin systems, we identified simple topological counting rules to predict the relative mechanical stability of knots and tangles, in agreement with simulations and experiments for commonly used climbing and sailing bends. Our results highlight the importance of twist and writhe in unknotting processes, providing guidance for the control of systems with complex entanglements.


Drinking typography established by scheduled induction predicts chronic heavy drinking in a monkey model of ethanol self-administration.
We have developed an animal model of alcohol self-administration that initially employs schedule-induced polydipsia (SIP) to establish reliable ethanol consumption under open access (22 h/d) conditions with food and water concurrently available. SIP is an adjunctive behavior that is generated by constraining access to an important commodity (e.g., flavored food). The induction schedule and ethanol polydipsia generated under these conditions affords the opportunity to investigate the development of drinking typologies that lead to chronic, excessive alcohol consumption. Adult male cynomolgus monkeys (Macaca fascicularis) were induced to drink water and 4% (w/v in water) ethanol by a Fixed-Time 300 seconds (FT-300 seconds) schedule of banana-flavored pellet delivery. The FT-300 seconds schedule was in effect for 120 consecutive sessions, with daily induction doses increasing from 0.0 to 0.5 g/kg to 1.0 g/kg to 1.5 g/kg every 30 days. Following induction, the monkeys were allowed concurrent access to 4% (w/v) ethanol and water for 22 h/day for 12 months. Drinking typographies during the induction of drinking 1.5 g/kg ethanol emerged that were highly predictive of the daily ethanol intake over the next 12 months. Specifically, the frequency in which monkeys ingested 1.5 g/kg ethanol without a 5-minute lapse in drinking (defined as a bout of drinking) during induction strongly predicted (correlation 0.91) subsequent ethanol intake over the next 12 months of open access to ethanol. Blood ethanol during induction were highly correlated with intake and with drinking typography and ranged from 100 to 160 mg% when the monkeys drank their 1.5 g/kg dose in a single bout. Forty percent of the population became heavy drinkers (mean daily intakes >3.0 g/kg for 12 months) characterized by frequent "spree" drinking (intakes >4.0 g/kg/d). This model of ethanol self-administration identifies early alcohol drinking typographies (gulping the equivalent of 6 drinks) that evolve into chronic heavy alcohol consumption in primates (drinking the equivalent of 16 to 20 drinks per day). The model may aid in identifying biological risks for establishing harmful alcohol drinking.


[DNA-polymerase activity and DNA synthesis in the hepatocyte nuclear matrix].
The comparative analysis of DNA-synthetase activity of hepatocytes, isolated nuclei and nuclear matrix from normal and regenerating rat liver was performed. The highest enrichment with newly-synthesized DNA was registered in the DNA fraction associated with the nuclear matrix both in vivo and in vitro. The functioning of DNA polymerases alpha and beta in the matrix was shown. Our results indicate that DNA polymerase beta is more firmly bound with the nuclear matrix in the cells of normal liver but this enzyme is eluted almost completely from the nuclei of regenerating liver cells. At the first moment after gamma-irradiation of rats the preferential initiation of unscheduled DNA synthesis in vivo has been observed on the nuclear skeletal structures. This may serve as an indication on the possibility that DNA repair process occurs on the nuclear matrix.


Exhaled air dispersion during coughing with and without wearing a surgical or N95 mask.
We compared the expelled air dispersion distances during coughing from a human patient simulator (HPS) lying at 45° with and without wearing a surgical mask or N95 mask in a negative pressure isolation room. Airflow was marked with intrapulmonary smoke. Coughing bouts were generated by short bursts of oxygen flow at 650, 320, and 220L/min to simulate normal, mild and poor coughing efforts, respectively. The coughing jet was revealed by laser light-sheet and images were captured by high definition video. Smoke concentration in the plume was estimated from the light scattered by smoke particles. Significant exposure was arbitrarily defined where there was ≥ 20% of normalized smoke concentration. During normal cough, expelled air dispersion distances were 68, 30 and 15 cm along the median sagittal plane when the HPS wore no mask, a surgical mask and a N95 mask, respectively. In moderate lung injury, the corresponding air dispersion distances for mild coughing efforts were reduced to 55, 27 and 14 cm, respectively, p < 0.001. The distances were reduced to 30, 24 and 12 cm, respectively during poor coughing effort as in severe lung injury. Lateral dispersion distances during normal cough were 0, 28 and 15 cm when the HPS wore no mask, a surgical mask and a N95 mask, respectively. Normal cough produced a turbulent jet about 0.7 m towards the end of the bed from the recumbent subject. N95 mask was more effective than surgical mask in preventing expelled air leakage during coughing but there was still significant sideway leakage.


Detecting Bacterial Surface Organelles on Single Cells Using Optical Tweezers.
Bacterial cells display a diverse array of surface organelles that are important for a range of processes such as intercellular communication, motility and adhesion leading to biofilm formation, infections, and bacterial spread. More specifically, attachment to host cells by Gram-negative bacteria are mediated by adhesion pili, which are nanometers wide and micrometers long fibrous organelles. Since these pili are significantly thinner than the wavelength of visible light, they cannot be detected using standard light microscopy techniques. At present, there is no fast and simple method available to investigate if a single cell expresses pili while keeping the cell alive for further studies. In this study, we present a method to determine the presence of pili on a single bacterium. The protocol involves imaging the bacterium to measure its size, followed by predicting the fluid drag based on its size using an analytical model, and thereafter oscillating the sample while a single bacterium is trapped by an optical tweezer to measure its effective fluid drag. Comparison between the predicted and the measured fluid drag thereby indicate the presence of pili. Herein, we verify the method using polymer coated silica microspheres and Escherichia coli bacteria expressing adhesion pili. Our protocol can in real time and within seconds assist single cell studies by distinguishing between piliated and nonpiliated bacteria.


Researchers', Regulators', and Sponsors' Views on Pediatric Clinical Trials: A Multinational Study.
The last decade has seen dramatic changes in the regulatory landscape to support more trials involving children, but child-specific challenges and inequitable conduct across income regions persist. The goal of this study was to describe the attitudes and opinions of stakeholders toward trials in children, to inform additional strategies to promote more high-quality, relevant pediatric trials across the globe. Key informant semi-structured interviews were conducted with stakeholders (researchers, regulators, and sponsors) who were purposively sampled from low- to middle-income countries and high-income countries. The transcripts were thematically analyzed. Thirty-five stakeholders from 10 countries were interviewed. Five major themes were identified: addressing pervasive inequities (paucity of safety and efficacy data, knowledge disparities, volatile environment, double standards, contextual relevance, market-driven forces, industry sponsorship bias and prohibitive costs); contending with infrastructural barriers (resource constraints, dearth of pediatric trial expertise, and logistical complexities); navigating complex ethical and regulatory frameworks ("draconian" oversight, ambiguous requirements, exploitation, excessive paternalism and precariousness of coercion versus volunteerism); respecting uniqueness of children (pediatric research paradigms, child-appropriate approaches, and family-centered empowerment); and driving evidence-based child health (advocacy, opportunities, treatment access, best practices, and research prioritization). Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children, but they contend that inequities and political, regulatory, and resource barriers continue to exist. Embedding trials as part of routine clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders recommended increasing international collaboration, establishing centralized trials infrastructure, and aligning research to child health priorities to encourage trials that address global child health care needs.


On-Demand Electrochemical Synthesis of Tetrakisacetonitrile Copper(I) Triflate and Its Application in the Aerobic Oxidation of Alcohols.
An on-demand electrochemical synthesis of copper(I) triflate under both batch and continuous flow conditions has been developed. A major benefit of the electrochemical methodology is that the only byproduct of the reaction is hydrogen gas, which obviates the need for workup and purification, and water is not incorporated into the product. Upon completion of the electrochemical synthesis, solutions are directly transferred or dispensed into reaction mixtures for the catalytic oxidation of benzyl alcohol with no requirement for workup or purification.


The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Moderna COVID-19 Vaccine - United States, December 2020.
On December 18, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Moderna COVID-19 (mRNA-1273) vaccine (ModernaTX, Inc; Cambridge, Massachusetts), a lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccine encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). This vaccine is the second COVID-19 vaccine authorized under an EUA for the prevention of COVID-19 in the United States (2). Vaccination with the Moderna COVID-19 vaccine consists of 2 doses (100 μg, 0.5 mL each) administered intramuscularly, 1 month (4 weeks) apart. On December 19, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation* for use of the Moderna COVID-19 vaccine in persons aged ≥18 years for the prevention of COVID-19. To guide its deliberations regarding the vaccine, ACIP employed the Evidence to Recommendation (EtR) Framework,† using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.§ Use of all COVID-19 vaccines authorized under an EUA, including the Moderna COVID-19 vaccine, should be implemented in conjunction with ACIP's interim recommendations for allocating initial supplies of COVID-19 vaccines (3). The ACIP recommendation for the use of the Moderna COVID-19 vaccine under EUA is interim and will be updated as additional information becomes available.


Exploiting natural variation to uncover candidate genes that control element accumulation in Arabidopsis thaliana.
The plant ionome varies both inter- and intraspecifically despite the highly conserved roles for particular elements across the plant kingdom. Element storage requires transport across the plasma membrane and commonly deposition within the central vacuole. Therefore, tonoplast transport characteristics can be highly influential in controlling the plant ionome. As a result, individual cell types of the same plant, each with unique transcriptomes and vacuolar proteomes, can display very different elemental profiles. Here we address the use of natural variation in Arabidopsis thaliana for identifying genes involved in elemental accumulation. We present a conceptual framework, exploiting publicly available leaf ionomic and transcriptomic data across 31 Arabidopsis accessions, that promises to accelerate conventional forward genetics approaches for candidate gene discovery. Utilizing this framework, we identify numerous genes with documented roles in accumulation of calcium, magnesium and zinc and implicate additional candidate genes. Where appropriate, we discuss their role in cell-specific elemental accumulation. Currently, this framework could represent an alternate approach for identifying genes suitable for element biofortification of plants. Integration of additional cell-specific and whole-plant 'omics' datasets across Arabidopsis accessions under diverse environmental conditions should enable this concept to be developed into a scalable and robust tool for linking genotype and phenotype.


The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations.
The HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir (TFV), abacavir, didanosine and stavudine can select for K65R, whereas zidovudine (AZT) and stavudine can select for thymidine analogue mutations (TAMs) in HIV-1 reverse transcriptase (RT). HIV-1 with TAMs shows reduced susceptibility to all NRTIs, most notably AZT, whereas HIV-1 with K65R shows reduced susceptibility to all NRTIs except AZT. K65R and TAMs rarely occur together in patients. However, when present together, K65R can restore susceptibility to AZT. This study characterizes the underlying mechanisms of resistance of these RT mutants to TFV and AZT. K65R mediated decreased binding/incorporation of TFV and AZT (increased Ki/Km of 7.1- and 4.3-fold, respectively), but also decreased excision of TFV and AZT (0.7- and 0.3-fold, respectively) when compared with wild-type RT. By contrast, TAMs mediated increased TFV and AZT excision (11- and 5.4-fold, respectively), and showed no changes in binding/incorporation. When these mutations were combined, K65R reversed TAM-mediated AZT resistance by strongly reducing AZT excision. Molecular modelling studies suggest that K65R creates additional hydrogen bonds that reduce the conformational mobility of RT, resulting in reduced polymerization and excision. Thus, consistent with clinical HIV-1 genotyping data, there appears to be no net NRTI resistance benefit for TAMs and K65R to develop together in patients taking AZT and TFV disoproxil fumarate, where the TAM pathway alone provides the greatest resistance for both drugs.


Renal impairment associated with the pre-operative administration of recombinant interleukin-2.
1. The T-cell-derived cytokine interleukin-2 may be used to reverse the immune suppression associated with major surgery. However, both major surgical procedures and recombinant interleukin-2 therapy are known to induce renal dysfunction. 2. Eighteen patients were randomized to receive either recombinant interleukin-2 (18 x 10(6) i.u./day) or placebo, given subcutaneously for 3 days before undergoing curative colorectal cancer surgery. Indices of renal function were determined pre-operatively and for 21 days after surgery. 3. Pre-operative recombinant interleukin-2 was found to significantly increase, compared with placebo controls, N-acetyl-beta-D-glucosaminidase [peak levels 28 (SEM 2) versus 11 (SEM 3) i.u./mmol of Cr] and gamma-glutamyltransferase [peak levels 5.3 (SEM 0.6) versus 2.4 (SEM 0.2) i.u./mmol/l] and decrease urinary fractional excretion of sodium [peak difference 0.32 (SEM 0.06) versus 0.76 (SEM 0.08)] (all P < 0.05). Significantly increased urinary excretions of creatinine, N-acetyl-beta-D-glucosaminidase and gamma-glutamyltransferase were also identified after surgery. All variables returned to pretreatment limits by the seventh day post-operatively, except N-acetyl-beta-D-glucosaminidase, which was still significantly elevated 21 days after surgery. No differences in the serum concentrations of sodium, creatinine or urea were observed before or after surgery in either group. 4. Recombinant interleukin-2, when given in the preoperative period, was associated with significant renal dysfunction. However, routine monitoring of serum indices (i.e. sodium, urea, creatinine and albumin) failed to detect such renal damage.(ABSTRACT TRUNCATED AT 250 WORDS)


Career Barriers of Chinese Self-Expatriate Women: Neither Double Jeopardy nor Ethnic Prominence.
The study explored barriers to career progression of Chinese self-initiated expatriate (SIE) women in the United Kingdom using semi-structured interviews with two matched samples of Chinese SIE and native Caucasian British women. Double jeopardy and ethnic prominence offered the theoretical backdrop. Common gender-related career hindering factors emerged in both groups. However, no barriers due to ethnicity per se emerged for the Chinese SIE women, whilst their narrations revealed that the Chinese stereotype had rather facilitated their careers in the host country. Furthermore, they did not view self-expatriation as a particularly challenging endeavor. None of the two interpretative frameworks deployed, double jeopardy and ethnic prominence, could account for the findings. The study implies that the effects of ethnicity on self-expatriation experiences and outcomes may be contingent on SIEs' ethnic and cultural origins. In addition, the findings imply that women who self-expatriate to escape gendered opportunities in their home countries may face similar gender-related barriers in host countries.


Obesity and hypertension: roles of hyperinsulinemia, sympathetic nervous system and intrarenal mechanisms.
Hypertension is a well-recognized complication of obesity. However, the mechanisms for the development of obesity hypertension are not known. One mechanism proposed is that the hyperinsulinemia present in obese hypertensive patients causes hypertension via sodium retaining and/or sympathetic nervous system stimulatory effects. However, numerous studies in dogs have revealed no evidence for such chronic pressor actions of hyperinsulinemia. This is in close agreement with studies in human insulinoma patients that show marked hyperinsulinemia and normal blood pressure. The appropriateness of the dog as an experimental model is strengthened by reports from our laboratory and others that inducing obesity in dogs reproduces many of the characteristics of obesity in humans, including insulin resistance, hyperinsulinemia, sodium retention, hypertriglyceridemia and hypertension. Recent studies in obese dogs have indicated that significant increases in renal medullary cellularity and intercellular matrix deposition could contribute to the sodium retention and hypertension. Additional evidence suggests that sympathetic nervous system stimulation also may contribute to the elevated blood pressure. However, the mechanisms through which obesity induces these changes and the temporal relationship between these factors and the development of the hypertension remains to be determined.


How clay particulates affect flow cessation and the coiling stability of yield stress-matched cementing suspensions.
The remarkable increase in the flow resistance of dense suspensions can hinder 3D-printing processes on account of flow cessation in the extruder, and filament fragility/rupture following deposition. Understanding the nature of rheological changes that occur is critical to manipulate flow conditions or to dose flow modifiers for 3D-printing. Therefore, this paper elucidates the influences of clay particulates on controlling flow cessation and the shape stability of dense cementing suspensions that typically feature poor printability. A rope coiling method was implemented with varying stand-off distances to probe the buckling stability and tendency to fracture of dense suspensions that undergo stretching and bending during deposition. The contributions of flocculation and short-term percolation due to the kinetics of structure formation to deformation rate were deconvoluted using a stepped isostress method. It is shown that the shear stress indicates a divergence with a power-law scaling when the particle volume fraction approaches the jamming limit; φ → φj ≈ φmax. Such a power-law divergence of the shear stress decreases by a factor of 10 with increasing clay dosage. Such behavior in clay-containing suspensions arises from a decrease in the relative packing fraction (φ/φmax) and the formation of fractally-architected aggregates with stronger interparticle interactions, whose uniform arrangement controls flow cessation in the extruder and suspension homogeneity, thereby imparting greater buckling stability. The outcomes offer new insights for assessing/improving the extrudability and printability behavior during slurry-based 3D-printing process.


Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease.
The corpus striatum serves a critical function in inhibiting involuntary, intrusive movements. Striatal degeneration in Huntington's disease results in a loss of motor inhibition, manifested by abnormal involuntary choreiform movements. Sensorimotor inhibition, or "gating", can be measured in humans using the startle reflex: the startle reflex is normally inhibited when the startling stimulus is preceded 30-500 ms earlier by a weak prepulse. In the present study, prepulse inhibition (PPI) was measured in patients with Huntington's disease to quantify and characterise sensorimotor gating. Compared with age matched controls, patients with Huntington's disease exhibit less PPI. Startle gating deficits are evident in patients with Huntington's disease when startle is elicited by either acoustic or tactile stimuli. Even with stimuli that elicit maximal PPI in normal subjects, patients with Huntington's disease exhibit little or no PPI, and their pattern of startle gating does not show the normal modulatory effects usually elicited by changing the prepulse interval or intensity. Startle amplitude and habituation and latency facilitation are largely intact in these patients, although reflex latency is significantly slowed. In patients with Huntington's disease, startle reflex slowing correlates with cognitive impairment measured by the dementia rating scale, and with the performance disruptive effects of interference measured by the Stroop test. These findings document a profound disruption of sensorimotor gating in patients with Huntington's disease and are consistent with preclinical findings that identify the striatum and striatopallidal GABAergic efferent circuitry as critical substrates for sensorimotor gating of the startle reflex.


A phase II comparative study of gross tumor volume definition with or without PET/CT fusion in dosimetric planning for non-small-cell lung cancer (NSCLC): primary analysis of Radiation Therapy Oncology Group (RTOG) 0515.
Radiation Therapy Oncology Group (RTOG) 0515 is a Phase II prospective trial designed to quantify the impact of positron emission tomography (PET)/computed tomography (CT) compared with CT alone on radiation treatment plans (RTPs) and to determine the rate of elective nodal failure for PET/CT-derived volumes. Each enrolled patient underwent definitive radiation therapy for non-small-cell lung cancer (≥ 60 Gy) and had two RTP datasets generated: gross tumor volume (GTV) derived with CT alone and with PET/CT. Patients received treatment using the PET/CT-derived plan. The primary end point, the impact of PET/CT fusion on treatment plans was measured by differences of the following variables for each patient: GTV, number of involved nodes, nodal station, mean lung dose (MLD), volume of lung exceeding 20 Gy (V20), and mean esophageal dose (MED). Regional failure rate was a secondary end point. The nonparametric Wilcoxon matched-pairs signed-ranks test was used with Bonferroni adjustment for an overall significance level of 0.05. RTOG 0515 accrued 52 patients, 47 of whom are evaluable. The follow-up time for all patients is 12.9 months (2.7-22.2). Tumor staging was as follows: II = 6%; IIIA = 40%; and IIIB = 54%. The GTV was statistically significantly smaller for PET/CT-derived volumes (98.7 vs. 86.2 mL; p < 0.0001). MLDs for PET/CT plans were slightly lower (19 vs. 17.8 Gy; p = 0.06). There was no significant difference in the number of involved nodes (2.1 vs. 2.4), V20 (32% vs. 30.8%), or MED (28.7 vs. 27.1 Gy). Nodal contours were altered by PET/CT for 51% of patients. One patient (2%) has developed an elective nodal failure. PET/CT-derived tumor volumes were smaller than those derived by CT alone. PET/CT changed nodal GTV contours in 51% of patients. The elective nodal failure rate for GTVs derived by PET/CT is quite low, supporting the RTOG standard of limiting the target volume to the primary tumor and involved nodes.


Bone Deformities as a Complication of Giant Thoracic Aortic Aneurysm.
The contained rupture of thoracic aortic aneurysm and related bone deformities is a rare condition. The diagnosis is critical due to potential and fatal complications. Radiologic evaluation is required to show the location, extension, and complications. Herein we present the X-ray radiography, ultrasonography, computed tomography, and magnetic resonance images of a giant dissected and contained rupture of the thoracic aortic aneurysm. The aneurysm destructed the adjacent vertebrae and rib, resulting in compression of dural sac and spinal cord, and obliteration of the neural foramina. Our case demonstrates a gigantic expansion of an aneurysm (14 cm) with chronic skeletal complications.


Validation of the Korean Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale.
Impulse-control disorder is an important nonmotor symptom of Parkinson's disease (PD) that can lead to financial and social problems, and be related to a poor quality of life. A nationwide multicenter prospective study was performed with the aim of validating the Korean Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease Rating Scale (K-QUIP-RS). The K-QUIP-RS was constructed using forward and backward translation, and pretesting of the prefinal version. PD patients on stable medical condition were recruited from 27 movement-disorder clinics. Participants were assessed using the K-QUIP-RS and evaluated for parkinsonian motor and nonmotor statuses and for PD-related quality of life using a predefined evaluation battery. The test-retest reliability of the K-QUIP-RS was assessed over an interval of 10-14 days, and correlations between the KQUIP-RS and other clinical scales were analyzed. This study enrolled 136 patients. The internal consistency of the K-QUIP-RS was indicated by a Cronbach's α coefficient of 0.846, as was the test-retest reliability by a Guttman split-half coefficient of 0.808. The total K-QUIP-RS score was positively correlated with the scores for depression and motivation items on the Unified PD Rating Scale (UPDRS), Montgomery-Asberg Depression Scale, and Rapid-Eye-Movement Sleep-Behavior-Disorders Questionnaire. The total K-QUIP-RS score was also correlated with the scores on part II of the UPDRS and the PD Quality of Life-39 questionnaire, and the dopaminergic medication dose. The K-QUIP-RS appears to be a reliable assessment tool for impulse-control and related behavioral disturbances in the Korean PD population.


Arsenic in Chinese coals: distribution, modes of occurrence, and environmental effects.
Arsenic, one of the most hazardous elements occurring in coals, can be released to the environment during coal processing and combustion. Based on the available literature and published results obtained in our laboratory, the content, distribution and the modes of occurrence of As in Chinese coals, and its environmental and impacts are reviewed in this article. With the 4763 sets of data (from the literature) rearranged, the arithmetic mean As concentration of each province and weighted mean As concentration of the entire country (using the expected coal reserves as the weighting factor) were calculated. The weighted mean As concentration in Chinese coals is 3.18 mg/kg, with As concentration increasing from northern China to southern China. The As concentration in coal varies with coal-forming ages and coal ranks. Arsenic has several modes of occurrence in coals. According to results obtained by other studies and our own experiments, As is mainly associated with mineral matter (such as pyrite and other sulfide minerals) in coals, although a significant amount of arsenic is associated with organic matter. The accumulation of As in coal is controlled by many geological factors during coal-forming processes, including plant decomposition, sedimentary environments, and epigenetic hydrothermal activity. During the combustion of coal, As is released to the air, water, and soil, causing serious environmental pollution. More than 45% of the coal consumed in China is utilized by power plants, and it is estimated that nearly 522 tonnes, 21 tonnes and 252 tonnes of As are emitted into the atmosphere by industries, residential buildings and coal-fired power plants, respectively, every year.


TiO2 anatase with a bandgap in the visible region.
TiO2 anatase plays a central role in energy and environmental research. A major bottleneck toward developing artificial photosynthesis with TiO2 is that it only absorbs ultraviolet light, owing to its large bandgap of 3.2 eV. If one could reduce the bandgap of anatase to the visible region, TiO2-based photocatalysis could become a competitive clean energy source. Here, using scanning tunneling microscopy and spectroscopy in conjunction with density functional theory calculations, we report the discovery of a highly reactive titanium-terminated anatase surface with a reduced bandgap of less than 2 eV, stretching into the red portion of the solar spectrum. By tuning the surface preparation conditions, we can reversibly switch between the standard anatase surface and the newly discovered low bandgap surface phase. The identification of a TiO2 anatase surface phase with a bandgap in the visible and high chemical reactivity has important implications for solar energy conversion, photocatalysis, and artificial photosynthesis.


Macrophage responses to the physical burden of cell-sized particles.
The role of a biophysical signal on cell response has excited tremendous interest recently. Herein, we exploited an "intake method" together with uniform autofluorescent cell-sized particles to investigate macrophage responses against different particle burdens. Our work not only revealed an insatiable macrophage uptake of cell-sized microparticles (MPs) but also widened the theoretical size and volume range for particle entry. MPs outperform NPs in the utmost volume of intracellular particles, indicating a converse size-associated event than originally anticipated. Such a superior volume burden (2.64-fold of the cell volume) for MPs is highly correlated to less membrane loss (19-fold below that for NPs) and more evident deformation of the cell membrane/nucleus. In addition, the cells with a high burden of MPs exhibit moderate migration activity, which is in line with mild cytokine release. These results highlight the indispensable role of physical burden on the regulation of macrophage functions, providing important views for desired biological outcomes and minimal side effects.


Neurocognitive function in obstructive sleep apnoea: a meta-review.
Adult obstructive sleep apnoea (OSA) is associated with cognitive dysfunction. While many review articles have attempted to summarize the evidence for this association, it remains difficult to determine which domains of cognition are affected by OSA. This is because of marked differences in the nature of these reviews (e.g. many are unsystematic) and the many different tasks and domains assessed. This paper addresses this issue by comparing the results of only systematic reviews or meta-analyses assessing the effects of OSA on cognition, the relationship between OSA severity and cognition, and/or the effects of treatment on cognition in OSA. Electronic databases and hand-searching were undertaken to select reviews that reported on these areas. We found 33 reviews; five reviews met predetermined, stringent selection criteria. The majority of reviews supported deficits in attention/vigilance, delayed long-term visual and verbal memory, visuospatial/constructional abilities, and executive function in individuals with OSA. There is also general agreement that language ability and psychomotor function are unaffected by OSA. Data are equivocal for the effects of OSA on working memory, short-term memory and global cognitive functioning. Attention/vigilance dysfunction appears to be associated with sleep fragmentation and global cognitive function with hypoxaemia. Continuous positive airway pressure treatment of OSA appears to improve executive dysfunction, delayed long-term verbal and visual memory, attention/vigilance and global cognitive functioning. In order to improve our understanding of cognitive dysfunction in OSA, future research should pay particular attention to participant characteristics, measures of disease severity and choice of neuropsychological tests.


Intracellular cystine loading inhibits transport in the rabbit proximal convoluted tubule.
Cystinosis is an autosomal recessive disorder characterized by a high intracellular cystine concentration. To establish an in vitro model of this disorder and examine the mechanism of the proximal tubule transport defect seen with elevated intracellular cystine concentrations, rabbit proximal convoluted tubules (PCT) were perfused in vitro. PCTs were loaded with cystine using cystine dimethyl ester, a permeative methyl ester derivative. Bath cystine dimethyl ester (0.5 mM) reduced volume absorption (Jv) (0.67 +/- 0.07 to 0.15 +/- 0.09 nl/mm.min, P less than 0.01), bicarbonate transport (JTCO2) (47.2 +/- 4.9 to 11.1 +/- 2.8 pmol/mm.min, P less than 0.001) and glucose transport (JGLU) (34.1 +/- 1.5 to 19.7 +/- 1.5 pmol/mm.min, P less than 0.001). The methyl esters of leucine (0.5 mM), and tryptophan (0.5 and 2.0 mM) had no effect on these parameters. To examine if intracellular reduction of cystine to cysteine could contribute to the inhibition in transport, the effect of bath cysteine methyl ester on proximal tubular transport was examined. Bath cysteine methyl ester (2 but not 0.5 mM) resulted in an inhibition in Jv, JGLU, and JTCO2. Cystine dimethyl ester had no effect on mannitol or bicarbonate permeability. These data are consistent with intracellular proximal tubular cystine accumulation resulting in an inhibition of active transport.


Experience of a tertiary care center on 100 newborns with neural tube defects.
The aim of this study was to analyze the sociodemographic features, postoperative complications, long-term problems, and cost of care of patients followed in the neonatal intensive care unit (NICU) with a diagnosis of neural tube defects (NTDs). Babies with NTD followed in the Neonatology Unit of Ondokuz Mayıs University Faculty of Medicine between January 2003 and December 2011 were analyzed retrospectively. One hundred (1.2%) of 8408 babies admitted to the NICU were diagnosed as NTD during the study period. Of the cases with NTD, 74% of mothers were graduates of primary school/illiterate, and none had used folic acid (FA) preconceptionally. Prenatal diagnosis was made in 72%, but parents had chosen not to terminate the pregnancy. The most frequent type and site of NTD was meningomyelocele (82%) of the lumbosacral region (36%). In 80% of the babies, the NTD sac was closed with in the first 72 hours of life. The most frequently observed postoperative complications were wound infection and septicemia. The mortality rate of babies with NTD during the follow-up period was 7%, and all deaths occurred in the first year of life. Sixty-two percent of the patients had neurologic deficits on follow-up. Patients were rehospitalized during the follow-up for an average of 2.9 times. Neural tube defect (NTD) is a disabling problem, with operations, rehospitalizations and other costly treatments. Maternal education regarding preconceptional FA use/fortification of food with FA and appropriate guidance to the family with prenatal diagnosis will decrease the incidence and burden of the disease.


Acute ingestion of catechin-rich green tea improves postprandial glucose status and increases serum thioredoxin concentrations in postmenopausal women.
Elevated postprandial hyperglycaemia and oxidative stress increase the risks of type 2 diabetes and CVD. Green tea catechin possesses antidiabetic properties and antioxidant capacity. In the present study, we examined the acute and continuous effects of ingestion of catechin-rich green tea on postprandial hyperglycaemia and oxidative stress in healthy postmenopausal women. Participants were randomly assigned into the placebo (P, n 11) or green tea (GT, n 11) group. The GT group consumed a catechin-rich green tea (catechins 615 mg/350 ml) beverage per d for 4 weeks. The P group consumed a placebo (catechins 92 mg/350 ml) beverage per d for 4 weeks. At baseline and after 4 weeks, participants of each group consumed their designated beverages with breakfast and consumed lunch 3 h after breakfast. Venous blood samples were collected in the fasted state (0 h) and at 2, 4 and 6 h after breakfast. Postprandial glucose concentrations were 3 % lower in the GT group than in the P group (three-factor ANOVA, group × time interaction, P< 0·05). Serum concentrations of the derivatives of reactive oxygen metabolites increased after meals (P< 0·05), but no effect of catechin-rich green tea intake was observed. Conversely, serum postprandial thioredoxin concentrations were 5 % higher in the GT group than in the P group (three-factor ANOVA, group × time interaction, P< 0·05). These findings indicate that an acute ingestion of catechin-rich green tea has beneficial effects on postprandial glucose and redox homeostasis in postmenopausal women.


A five-amino-acid deletion of the eastern equine encephalitis virus capsid protein attenuates replication in mammalian systems but not in mosquito cells.
Eastern equine encephalitis virus (EEEV) is a human and veterinary pathogen that causes sporadic cases of fatal neurological disease. We previously demonstrated that the capsid protein of EEEV is a potent inhibitor of host cell gene expression and that this function maps to the amino terminus of the protein. We now identify amino acids 55 to 75, within the N terminus of the capsid, as critical for the inhibition of host cell gene expression. An analysis of stable EEEV replicons expressing mutant capsid proteins corroborated these mapping data. When deletions of 5 to 20 amino acids within this region of the capsid were introduced into infectious EEEV, the mutants exhibited delayed replication in Vero cells. However, the replication of the 5-amino-acid deletion mutant in C710 mosquito cells was not affected, suggesting that virus replication and assembly were affected in a cell-specific manner. Both 5- and 20-amino-acid deletion mutant viruses exhibited increased sensitivity to interferon (IFN) in cell culture and impaired replication and complete attenuation in mice. In summary, we have identified a region within the capsid protein of EEEV that contributes to the inhibition of host gene expression and to the protection of EEEV from the antiviral effects of IFNs. This region is also critical for EEEV pathogenesis.


Albinterferon Alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 1.
The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 μg every week, or albIFN 900 or 1200 μg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg because of increased pulmonary adverse events (AEs) in the 1200-μg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. The primary objective of showing noninferiority of albIFN 900 μg (P < .001) and 1200 μg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-μg groups. albIFN 900 μg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.


Protein delivery using engineered virus-like particles.
Over the years, researchers have developed several methods to deliver macromolecules into the cytosol and nucleus of living cells. However, there are limitations to all of these methods. The problems include (i) inefficient uptake, (ii) endosomal entrapment, (iii) delivery that is restricted to certain cell types, and (iv) damage to cells in the delivery process. Retroviral vectors are often used for gene delivery; however, integration of the genome of retroviral vector into the host genome can have serious consequences. Here we describe a safe alternative in which virus-like particles (VLPs), derived from an avian retrovirus, are used to deliver protein to cells. We show that these VLPs are a highly adaptable platform that can be used to deliver proteins either as part of Gag fusion proteins (intracellular delivery) or on the surface of VLPs. We generated VLPs that contain Gag-Cre recombinase, Gag-Fcy::Fur, and Gag-human caspase-8 as a proof-of-concept and demonstrated that the encapsidated proteins are active in recipient cells. In addition, we show that murine IFN-γ and human TNF-related apoptosis-inducing ligand can be displayed on the surface of VLPs, and that these modified VLPs can cause the appropriate response in cells, as evidenced by phosphorylation of STAT1 and induction of cell death, respectively.