COVID-19 Vaccine Effectiveness in Oncology Patients.
Oncology patients are at greater risk of morbidity and mortality from coronavirus disease 2019 (COVID-19) infection than the general population. Patients with malignancies were prioritized in vaccine distribution to confer protection to a vulnerable population. However, immunocompromised patients were not included in the initial COVID-19 vaccine trials. Will patients with cancer mount an adequate serologic response to vaccination to be protected from COVID-19 infection? Overall, oncology patients had diminished antibody response to the COVID-19 vaccines compared with healthy patients. The patients with the lowest seroconversion rates were those who received anti-CD20 monoclonal antibody therapy, Bruton tyrosine kinase inhibitor therapy, stem cell transplantation, and chimeric antigen receptor T-cell therapy. Although the response may not be robust, expert organizations strongly recommend that oncology patients should pursue COVID-19 vaccination and booster to ensure some degree of protection from infection. Immunocompromised patients should continue to practice mask wearing, social distancing, and proper hand hygiene to minimize the risk of contracting COVID-19.


Kaposi's sarcoma-associated herpesvirus inhibits interleukin-4-mediated STAT6 phosphorylation to regulate apoptosis and maintain latency.
Cytokine-mediated JAK/STAT signaling controls numerous important biologic responses like immune function, cellular growth, and differentiation. Inappropriate activation of this signaling pathway is associated with a range of malignancies. Kaposi's sarcoma-associated herpesvirus (KSHV) is the infectious viral agent associated with Kaposi's sarcoma and may also contribute to B-cell disorders, which include primary effusion lymphoma (PEL) and multicentric Castleman's disease. However, regulation of cytokine-mediated lymphocytic immune response by KSHV is not fully understood. In this report, we demonstrate that KSHV suppresses the interleukin-4 (IL-4)-stimulated immune response of B-lymphocyte activation and cell proliferation. Moreover, we show that the latency-associated nuclear antigen (LANA) encoded by KSHV is essential for viral blocking of IL-4-induced signaling. LANA reduces phosphorylation of the signal transducers and activators of transcription 6 (STAT6) on Y-641 and concomitantly its DNA binding ability. Importantly, knockdown of endogenous STAT6 dramatically increases the sensitivity of PEL cells to low-serum stress or chemical-mediated cellular apoptosis and reactivation of KSHV from latent replication. Thus, these findings suggest that the IL-4/STAT6 signaling network is precisely controlled by KSHV for survival, maintenance of latency, and suppression of the host cytokine immune response of the virus-infected cells.


The chemistry of John Dalton's color blindness.
John Dalton described his own color blindness in 1794. In common with his brother, he confused scarlet with green and pink with blue. Dalton supposed that his vitreous humor was tinted blue, selectively absorbing longer wavelengths. He instructed that his eyes should be examined after his death, but the examination revealed that the humors were perfectly clear. In experiments presented here, DNA extracted from his preserved eye tissue showed that Dalton was a deuteranope, lacking the middlewave photopigment of the retina. This diagnosis is shown to be compatible with the historical record of his phenotype, although it contradicts Thomas Young's belief that Dalton was a protanope.


Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen.
As with many other viruses, the initial cell attachment of rotaviruses, which are the major causative agent of infantile gastroenteritis, is mediated by interactions with specific cellular glycans. The distally located VP8* domain of the rotavirus spike protein VP4 (ref. 5) mediates such interactions. The existing paradigm is that 'sialidase-sensitive' animal rotavirus strains bind to glycans with terminal sialic acid (Sia), whereas 'sialidase-insensitive' human rotavirus strains bind to glycans with internal Sia such as GM1 (ref. 3). Although the involvement of Sia in the animal strains is firmly supported by crystallographic studies, it is not yet known how VP8* of human rotaviruses interacts with Sia and whether their cell attachment necessarily involves sialoglycans. Here we show that VP8* of a human rotavirus strain specifically recognizes A-type histo-blood group antigen (HBGA) using a glycan array screen comprised of 511 glycans, and that virus infectivity in HT-29 cells is abrogated by anti-A-type antibodies as well as significantly enhanced in Chinese hamster ovary cells genetically modified to express the A-type HBGA, providing a novel paradigm for initial cell attachment of human rotavirus. HBGAs are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori and noroviruses. Our crystallographic studies show that the A-type HBGA binds to the human rotavirus VP8* at the same location as the Sia in the VP8* of animal rotavirus, and suggest how subtle changes within the same structural framework allow for such receptor switching. These results raise the possibility that host susceptibility to specific human rotavirus strains and pathogenesis are influenced by genetically controlled expression of different HBGAs among the world's population.


Prevalence of obesity, tobacco use, and alcohol consumption by socioeconomic status among six communities in Nicaragua.
To describe the prevalence of noncommunicable disease (NCD) risk factors (overweight/obesity, tobacco smoking, and alcohol consumption) and identify correlations between these and sociodemographic characteristics in western and central Nicaragua. This was a cross-sectional study of 1 355 participants from six communities in Nicaragua conducted in September 2007-July 2009. Demographic and NCD risk-related health behavior information was collected from each individual, and their body mass index (BMI), blood pressure, diabetes status, and renal function were assessed. Data were analyzed using descriptive statistics, bivariate analyses, and (non-stratified and stratified) logistic regression models. Of the 1 355 study participants, 22.0% were obese and 55.1% were overweight/obese. Female sex, higher income, and increasing age were significantly associated with obesity. Among men, lifelong urban living correlated with obesity (Odds Ratio [OR] = 4.39, 1.18-16.31). Of the total participants, 31.3% reported ever smoking tobacco and 47.7% reported ever drinking alcohol. Both tobacco smoking and alcohol consumption were strikingly more common among men (OR = 13.0, 8.8-19.3 and 15.6, 10.7-22.6, respectively) and lifelong urban residents (OR = 2.42, 1.31-4.47 and 4.10, 2.33-7.21, respectively). There was a high prevalence of obesity/overweight across all income levels. Women were much more likely to be obese, but men had higher rates of tobacco and alcohol use. The rising prevalence of NCD risk factors among even the poorest subjects suggests that an epidemiologic transition in underway in western and central Nicaragua whereby NCD prevalence is shifting to all segments of society. Raising awareness that health clinics can be used for chronic conditions needs to be priority.


Systolic Blood Pressure Within 24 Hours After Thrombectomy for Acute Ischemic Stroke Correlates With Outcome.
Current guidelines suggest treating blood pressure above 180/105 mm Hg during the first 24 hours in patients with acute ischemic stroke undergoing any form of recanalization therapy. Currently, no studies exist to guide blood pressure management in patients with stroke treated specifically with mechanical thrombectomy. We aimed to determine the association between blood pressure parameters within the first 24 hours after mechanical thrombectomy and patient outcomes. We retrospectively studied a consecutive sample of adult patients who underwent mechanical thrombectomy for acute ischemic stroke of the anterior cerebral circulation at 3 institutions from March 2015 to October 2016. We collected the values of maximum, minimum, and average values of systolic blood pressure, diastolic blood pressure, and mean arterial pressures in the first 24 hours after mechanical thrombectomy. Primary and secondary outcomes were patients' functional status at 90 days measured on the modified Rankin scale and the incidence and severity of intracranial hemorrhages within 48 hours. Associations were explored using an ordered multivariable logistic regression analyses. A total of 228 patients were included (mean age 65.8±14.3; 104 males, 45.6%). Maximum systolic blood pressure independently correlated with a worse 90-day modified Rankin scale and hemorrhagic complications within 48 hours (adjusted odds ratio=1.02 [1.01-1.03], P=0.004; 1.02 [1.01-1.04], P=0.002; respectively) in multivariable analyses, after adjusting for several possible confounders. Higher peak values of systolic blood pressure independently correlated with worse 90-day modified Rankin scale and a higher rate of hemorrhagic complications. Further prospective studies are warranted to identify whether systolic blood pressure is a therapeutic target to improve outcomes.


The worldwide challenge of the dementias: a role for B vitamins and homocysteine?
Dementia has reached epidemic proportions, with an estimated 4.6 million new cases worldwide each year. With an aging world population, the prevalence of dementia will increase dramatically in the next few decades. Of the predicted 114 million who will have dementia in 2050, about three-quarters will live in less developed regions. Although strongly age-related, dementia is not an inevitable part of aging but is a true disease, caused by exposure to several genetic and nongenetic risk factors. Prevention will be possible when the nongenetic risk factors have been identified. Apart from age, more than 20 nongenetic risk factors have been postulated, but very few have been established by randomized intervention studies. Elevated blood concentrations of total homocysteine and low-normal concentrations of B vitamins (folate, vitamin B12, and vitamin B6) are candidate risk factors for both Alzheimer's disease and vascular dementia. Seventy-seven cross-sectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins. Biologically plausible mechanisms have been proposed to account for these associations, including atrophy of the cerebral cortex, but a definite causal pathway has yet to be shown. Raised plasma total homocysteine is a strong prognostic marker of future cognitive decline, and is common in world populations. Low-normal concentrations of the B vitamins, the main determinant of homocysteine concentrations, are also common and occur in particularly vulnerable sections of the population, such as infants and elderly. Large-scale randomized trials of homocysteine-lowering vitamins are needed to see if a proportion of dementia in the world can be prevented.


Trust and trustworthiness in young and older adults.
In a series of 1-shot economic trust games in which participants could make real monetary profits, but also risked losing money, 2 studies compared young and older adults' trust (amount invested with trustees) and trustworthiness (amount returned to investors by trustees). In Study 1, young (n = 35) and older (n = 32) participants acted as investors, and the age of simulated trustees (young, older) was manipulated. In Study 2, young (n = 61) and older (n = 67) participants acted in real life as both investors and trustees. They completed 2 face-to-face trust games with same- and other-age partners, and 3 anonymous trust games with same-, other-, and unknown-age partners. Study 1 found that young and older participants rate older trustees as appearing more trustworthy than young trustees, but neither group invest more with older than young trustees. Rather, older participants were more likely than young participants to invest money averaged across trustee age. In Study 2, there were no age-related differences in trust, but older adults were more trustworthy than young adults in anonymous games with same- and unknown-age partners. It was also found that young adults demonstrate greater reputational concerns than older adults by reciprocating more trust when face-to-face than anonymous. We discuss the complex influences of age on trust game investing and reciprocation, as well as the implications for older adults' wellbeing and financial security.


Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.
Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.


Protective influences of N-acetylcysteine against alcohol abstinence-induced depression by regulating biochemical and GRIN2A, GRIN2B gene expression of NMDA receptor signaling pathway in rats.
Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague-Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1, GRIN2A, GRIN2B genes for the N-methyl d-aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A, GRIN2B gene expression of NMDAR signaling pathway in rats.


Toxicological assessment of the anti-salmon lice drug diflubenzuron on Atlantic cod Gadus morhua.
Increasing use of the chitin synthesis inhibitor diflubenzuron against the ectoparasitic salmon louse Lepeophtheirus salmonis in marine aquaculture has raised concerns over its environmental impacts. This study evaluated how diflubenzuron affects Atlantic cod Gadus morhua, a fish species often found near Atlantic salmon Salmo salar farms, focusing on uptake kinetics and hepatic transcriptional responses. Two experiments were conducted, one time-series trial in which the fish were given a daily dose (3 mg kg-1 fish) of diflubenzuron for 14 d followed by a 3 wk depuration period, and one dose-response trial with increasing concentrations (3, 10 and 50 mg kg-1 fish). The highest diflubenzuron concentrations were found in the liver at Day 15. No detectable levels of diflubenzuron were found in liver or muscle 3 wk after the end of the treatment. At the molecular level, small effects of diflubenzuron treatment on gene transcription were observed. In the time-series experiment, the strongest effects were seen at Day 8, with 2 transcripts being upregulated (bclx2 and cpt1a) and 8 transcripts being downregulated (gstp1, gstm1, gstt1, ugt1a, nat2, cat, p53 and slc16a9a). Five transcripts (cyp3a, cpt1a, ptgs2, elovl5 and mapk1) responded significantly to diflubenzuron exposure in the dose-response experiment. This study shows that diflubenzuron can be taken up by Atlantic cod, that it is rapidly cleared from the body and that when present this pharmaceutical causes only small effects on the expression of genes involved in detoxification pathways. Taken together, our data suggest that accumulated diflubenzuron at the levels studied would have a relatively small effect on wild Atlantic cod.


Analytical studies of fronts, colonies, and patterns: Combination of the Allee effect and nonlocal competition interactions.
We present an analytic study of traveling fronts, localized colonies, and extended patterns arising from a reaction-diffusion equation which incorporates simultaneously two features: the well-known Allee effect and spatially nonlocal competition interactions. The former is an essential ingredient of most systems in population dynamics and involves extinction at low densities, growth at higher densities, and saturation at still higher densities. The latter feature is also highly relevant, particularly to biological systems, and goes beyond the unrealistic assumption of zero-range interactions. We show via exact analytic methods that the combination of the two features yields a rich diversity of phenomena and permits an understanding of a variety of issues including spontaneous appearance of colonies.


Reward and motivation systems: a brain mapping study of early-stage intense romantic love in Chinese participants.
Early-stage romantic love has been studied previously in the United States and United Kingdom (Aron et al. [2005]: J Neurophysiol 94:327–337; Bartels and Zeki [2000]: Neuroreport 11:3829–3834; Ortigue et al. [2007]: J Cogn Neurosci 19:1218–1230), revealing activation in the reward and motivation systems of the brain. In this study, we asked what systems are activated for early-stage romantic love in Easterners, specifically Chinese participants? Are these activations affected by individual differences within a cultural context of Traditionality and Modernity? Also, are these brain activations correlated with later satisfaction in the relationship? In Beijing, we used the same procedure used by Aron et al. (Aron et al. [2005]: J Neurophysiol 94:327–337). The stimuli for 18 Chinese participants were a picture of the face of their beloved, the face of a familiar acquaintance, and a countback task. We found significant activations specific to the beloved in the reward and motivation systems, particularly, the ventral tegmental area and the caudate. The mid-orbitofrontal cortex and cerebellum were also activated, whereas amygdala, medial orbitofrontal, and medial accumbens activity were decreased relative to the familiar acquaintance. Self-reported Traditionality and Modernity scores were each positively correlated with activity in the nucleus accumbens, although in different regions and sides of the brain. Activity in the subgenual area and the superior frontal gyrus was associated with higher relationship happiness at 18-month follow-up. Our results show that midbrain dopamine-rich reward/motivation systems were activated by early-stage romantic love in Chinese participants, as found by other studies. Neural activity was associated with Traditionality and Modernity attitudes as well as with later relationship happiness for Chinese participants.


More Feedback Is Better than Less: Learning a Novel Upper Limb Joint Coordination Pattern with Augmented Auditory Feedback.
Motor learning is a process whereby the acquisition of new skills occurs with practice, and can be influenced by the provision of feedback. An important question is what frequency of feedback facilitates motor learning. The guidance hypothesis assumes that the provision of less augmented feedback is better than more because a learner can use his/her own inherent feedback. However, it is unclear whether this hypothesis holds true for all types of augmented feedback, including for example sonified information about performance. Thus, we aimed to test what frequency of augmented sonified feedback facilitates the motor learning of a novel joint coordination pattern. Twenty healthy volunteers first reached to a target with their arm (baseline phase). We manipulated this baseline kinematic data for each individual to create a novel target joint coordination pattern. Participants then practiced to learn the novel target joint coordination pattern, receiving either feedback on every trial i.e., 100% feedback (n = 10), or every other trial, i.e., 50% feedback (n = 10; acquisition phase). We created a sonification system to provide the feedback. This feedback was a pure tone that varied in intensity in proportion to the error of the performed joint coordination relative to the target pattern. Thus, the auditory feedback contained information about performance in real-time (i.e., "concurrent, knowledge of performance feedback"). Participants performed the novel joint coordination pattern with no-feedback immediately after the acquisition phase (immediate retention phase), and on the next day (delayed retention phase). The root-mean squared error (RMSE) and variable error (VE) of joint coordination were significantly reduced during the acquisition phase in both 100 and 50% feedback groups. There was no significant difference in VE between the groups at immediate and delayed retention phases. However, at both these retention phases, the 100% feedback group showed significantly smaller RMSE than the 50% group. Thus, contrary to the guidance hypothesis, our findings suggest that the provision of more, concurrent knowledge of performance auditory feedback during the acquisition of a novel joint coordination pattern, may result in better skill retention.


Fecal incontinence in US adults: epidemiology and risk factors.
The study aims were to estimate the prevalence of different types and frequencies of fecal incontinence (FI), describe demographic factors, and identify risk factors. The National Health and Nutrition Examination Survey (NHANES) assesses health status in the civilian noninstitutionalized US population. The validated Fecal Incontinence Severity Index was added to NHANES in 2005-2006. Participants were 2229 women and 2079 men aged 20 years or older. FI was defined as accidental leakage of solid, liquid, or mucus at least once in the preceding month. Sampling weights were used to obtain prevalence estimates for the national population. Multivariate logistic regression identified independent risk factors. The estimated prevalence of FI in noninstitutionalized US adults is 8.3% (95% confidence interval, 7.1-9.5) and consists of liquid stool in 6.2%, solid stool in 1.6%, and mucus in 3.1%. It occurs at least weekly in 2.7%. Prevalence is similar in women (8.9%) and men (7.7%) and increases with age from 2.6% in 20 to 29 year olds up to 15.3% in participants aged 70 years and older. FI is not significantly associated with race/ethnicity, education, income, or marital status after adjusting for age. Independent risk factors in women are advancing age, loose or watery stools, more than 21 stools per week, multiple chronic illnesses, and urinary incontinence. Independent risk factors in men are age, loose or watery stools, poor self-rated health, and urinary incontinence. FI is a prevalent age-related disorder. Chronic diarrhea is a strong modifiable risk factor that may form the basis for prevention and treatment.


Synthetic and degradable patches: an emerging solution for rotator cuff repair.
The use of rotator cuff augmentation has increased dramatically over the last 10 years in response to the high rate of failure observed after non-augmented surgery. However, although augmentations have been shown to reduce shoulder pain, there is no consensus or clear guideline as to what is the safest or most efficacious material. Current augmentations, either available commercially or in development, can be classified into three categories: non-degradable structures, extra cellular matrix (ECM)-based patches and degradable synthetic scaffolds. Non-degradable structures have excellent mechanical properties, but can cause problems of infection and loss of integrity in the long-term. ECM-based patches usually demonstrate excellent biological properties in vitro, but studies have highlighted complications in vivo due to poor mechanical support and to infection or inflammation. Degradable synthetic scaffolds represent the new generation of implants. It is proposed that a combination of good mechanical properties, active promotion of biological healing, low infection risk and bio-absorption are the ideal characteristics of an augmentation material. Among the materials with these features, those processed by electrospinning have shown great promis. However, their clinical effectiveness has yet to be proven and well conducted clinical trials are urgently required.


Conditioned Medium Reconditions Hippocampal Neurons against Kainic Acid Induced Excitotoxicity: An In Vitro Study.
Stem cell therapy is gaining attention as a promising treatment option for neurodegenerative diseases. The functional efficacy of grafted cells is a matter of debate and the recent consensus is that the cellular and functional recoveries might be due to "by-stander" effects of grafted cells. In the present study, we investigated the neuroprotective effect of conditioned medium (CM) derived from human embryonic kidney (HEK) cells in a kainic acid (KA) induced hippocampal degeneration model system in in vitro condition. Hippocampal cell line was exposed to KA (200 µM) for 24 hrs (lesion group) whereas, in the treatment group, hippocampal cell line was exposed to KA in combination with HEK-CM (KA + HEK-CM). We observed that KA exposure to cells resulted in significant neuronal loss. Interestingly, HEK-CM cotreatment completely attenuated the excitotoxic effects of KA. In HEK-CM cotreatment group, the cell viability was ~85-95% as opposed to 47% in KA alone group. Further investigation demonstrated that treatment with HEK-CM stimulated the endogenous cell survival factors like brain derived neurotrophic factors (BDNF) and antiapoptotic factor Bcl-2, revealing the possible mechanism of neuroprotection. Our results suggest that HEK-CM protects hippocampal neurons against excitotoxicity by stimulating the host's endogenous cell survival mechanisms.


Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5.
Proteolysis of the Glu(441)-Ala(442) bond in the glycosaminoglycan (GAG) β domain of the versican-V1 variant by a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif (ADAMTS) proteases is required for proper embryo morphogenesis. However, the processing mechanism and the possibility of additional ADAMTS-cleaved processing sites are unknown. We demonstrate here that if Glu(441) is mutated, ADAMTS5 cleaves inefficiently at a proximate upstream site but normally does not cleave elsewhere within the GAGβ domain. Chondroitin sulfate (CS) modification of versican is a prerequisite for cleavage at the Glu(441)-Ala(442) site, as demonstrated by reduced processing of CS-deficient or chondroitinase ABC-treated versican-V1. Site-directed mutagenesis identified the N-terminal CS attachment sites Ser(507) and Ser(525) as essential for processing of the Glu(441)-Ala(442) bond by ADAMTS5. A construct including only these two GAG chains, but not downstream GAG attachment sites, was cleaved efficiently. Therefore, CS chain attachment to Ser(507) and Ser(525) is necessary and sufficient for versican proteolysis by ADAMTS5. Mutagenesis of Glu(441) and an antibody to a peptide spanning Thr(432)-Gly(445) (i.e. containing the scissile bond) reduced versican-V1 processing. ADAMTS5 lacking the C-terminal ancillary domain did not cleave versican, and an ADAMTS5 ancillary domain construct bound versican-V1 via the CS chains. We conclude that docking of ADAMTS5 with two N-terminal GAG chains of versican-V1 via its ancillary domain is required for versican processing at Glu(441)-Ala(442). V1 proteolysis by ADAMTS1 demonstrated a similar requirement for the N-terminal GAG chains and Glu(441). Therefore, versican cleavage can be inhibited substantially by mutation of Glu(441), Ser(507), and Ser(525) or by an antibody to the region of the scissile bond.


Subjective sleep quality and daytime sleepiness in late midlife and their association with age-related changes in cognition.
In an increasingly aged population, sleep disturbances and neurodegenerative disorders have become a major public health concern. Poor sleep quality and cognitive changes are complex health problems in aging populations that are likely to be associated with increased frailty, morbidity, and mortality, and to be potential risk factors for further cognitive impairment. We aimed to evaluate whether sleep quality and excessive daytime sleepiness may be considered as early predictors of cognitive impairment. The objective of this study was to examine whether subjective sleep quality and daytime sleepiness are associated with cognition in middle-aged males. A total of 189 healthy males born in 1953 were considered as participants for the study. Based on previous cognitive assessments, the participants were selected for the study as cognitively improved (N = 97) or cognitively impaired (N = 92). The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale measured subjective sleep quality and daytime sleepiness, respectively. Depressive symptoms were determined using Beck's Depression Inventory (BDI-II). A neuropsychological battery was administered to confirm group differences in cognitive functioning at the time when sleep data were collected. Compared with cognitively improved males, the cognitively impaired group reported significantly lower subjective sleep quality (5.40 ± 3.81 vs. 4.39 ± 2.40, p = 0.03). Forty-one percent of the sample exhibited poor sleep quality and 15% experienced excessive daytime sleepiness. There were few correlations between sleep parameters and cognitive test performance in the combined sample. Self-reported poor sleep quality was related to cognitive changes, whereas daytime sleepiness was not related. Our results suggest that sleep quality may be an early marker of cognitive decline in midlife.


Managing the unmanaged: a case study of intra-institutional determinants of uncompensated care at healthcare institutions with differing ownership models.
This study presents a case analysis of how 3 urban medical centers with differing ownership models, within 1 metropolitan area, ration access to uncompensated care to uninsured patients. Data was triangulated from 3 sources: hospital financial reports by service line for a fiscal year, a survey of 292 self-pay patients, and the self-pay policies and practices of clerical personnel described in a previous publication. Although the public, for-profit and not-for-profit institutions used different strategies for managing self-pays, there were also commonalities in the experiences indigent patients reported. The public institution provided the broadest access to the largest percentage of self-pay patients but offset the burden with the most successful prepayment and collection practices. The for-profit site obeyed federal regulations mandating emergency care but severely curtailed other services, and the not-for-profit limited assess (but not to the extent of the for-profit) and pursued collection (but not to the extent of the public). At all sites, actual practices by clerical staff often diverged from institutions' written self-pay policies. The probability of being turned away because of inability to pay ranged from 0% to 40% with front line personnel exercising considerable discretion on a case-by-case basis. Large institutional providers balance their particular social and legal obligations with strategies to limit access and optimize prepayment and collection. Stated policies generally do not reflect the practices of personnel. Uninsured patients are forced to navigate a capricious system that manages them as a liability rather than as a legitimate client.


From DNA to ecological performance: Effects of anthropogenic noise on a reef-building mussel.
Responses of marine invertebrates to anthropogenic noise are insufficiently known, impeding our understanding of ecosystemic impacts of noise and the development of mitigation strategies. We show that the blue mussel, Mytilus edulis, is negatively affected by ship-noise playbacks across different levels of biological organization. We take a novel mechanistic multi-method approach testing and employing established ecotoxicological techniques (i.e. Comet Assay and oxidative stress tests) in combination with behavioral and physiological biomarkers. We evidence, for the first time in marine species, noise-induced changes in DNA integrity (six-fold higher DNA single strand-breaks in haemocytes and gill epithelial cells) and oxidative stress (68% increased TBARS in gill cells). We further identify physiological and behavioral changes (12% reduced oxygen consumption, 60% increase in valve gape, 84% reduced filtration rate) in noise-exposed mussels. By employing established ecotoxicological techniques we highlight impacts not only on the organismal level, but also on ecological performance. When investigating species that produce little visually obvious responses to anthropogenic noise, the above mentioned endpoints are key to revealing sublethal effects of noise and thus enable a better understanding of how this emerging, but often overlooked stressor, affects animals without complex behaviors. Our integrated approach to noise research can be used as a model for other invertebrate species and faunal groups, and inform the development of effective methods for assessing and monitoring noise impacts. Given the observed negative effects, noise should be considered a potential confounding factor in studies involving other stressors.


A mathematical model for dorsal closure.
During embryogenesis, drosophila embryos undergo epithelial folding and unfolding, which leads to a hole in the dorsal epidermis, transiently covered by an extraembryonic tissue called the amnioserosa. Dorsal closure (DC) consists of the migration of lateral epidermis towards the midline, covering the amnioserosa. It has been extensively studied since numerous physical mechanisms and signaling pathways present in DC are conserved in other morphogenetic events and wound healing in many other species (including vertebrates). We present here a simple mathematical model for DC that involves a reduced number of parameters directly linked to the intensity of the forces in the presence and which is applicable to a wide range of geometries of the leading edge (LE). This model is a natural generalization of the very interesting model proposed in Hutson et al. (2003). Being based on an ordinary differential equation (ODE) approach, the previous model had the advantage of being even simpler, but this restricted significantly the variety of geometries that could be considered and thus the number of modified dorsal closures that could be studied. A partial differential equation (PDE) approach, as the one developed here, allows considering much more general situations that show up in genetically or physically perturbed embryos and whose study will be essential for a proper understanding of the different components of the DC process. Even for native embryos, our model has the advantage of being applicable since an early stages of DC when there is no antero-posterior symmetry (approximately verified only in the late phases of DC). We validate our model in a native setting and also test it further in embryos where the zipping force is perturbed through the expression of spastin (a microtubule severing protein). We obtain variations of the force coefficients that are consistent with what was previously described for this setting.


Development and initial validation of the obsessive beliefs questionnaire and the interpretation of intrusions inventory.
In 1995 the Obsessive Compulsive Cognitions Working Group initiated a collective process to develop two measures of cognition relevant to current cognitive-behavioural models of OCD. An earlier report (Behav. Res. Therapy, 35 (1997) 667) describes the original process of defining relevant domains. This article describes the subsequent steps of the development and validation process: item generation, scale reduction, and initial examination of reliability and validity. Two scales were developed. The Obsessive Beliefs Questionnaire consists of 87 items representing dysfunctional assumptions covering six domains: overestimation of threat, tolerance of uncertainty, importance of thoughts, control of thoughts, responsibility, and perfectionism. The Interpretation of Intrusions Inventory consists of 31 items that refer to interpretations of intrusions that have occurred recently. Three of the above domains are represented: importance of thoughts, control of thoughts, and responsibility. The item reduction and validation analyses were conducted on clinical and non-clinical samples from multiple sites. Initial examination of reliability and validity indicates excellent internal consistency and stability and encouraging evidence of validity. However, high correlations indicating overlap between some of the scales, particularly importance of thoughts, control of thoughts, and responsibility will need to be addressed in subsequent empirical and theoretical investigations.


Consensus on international guidelines for management of groin hernias.
Groin hernia management has a significant worldwide diversity with multiple surgical techniques and variable outcomes. The International guidelines for groin hernia management serve to help in groin hernia management, but the acceptance among general surgeons remains unknown. The aim of our study was to gauge the degree of agreement with the guidelines among health care professionals worldwide. Forty-six key statements and recommendations of the International guidelines for groin hernia management were selected and presented at plenary consensus conferences at four international congresses in Europe, the America's and Asia. Participants could cast their votes through live voting. Additionally, a web survey was sent out to all society members allowing online voting after each congress. Consensus was defined as > 70% agreement among all participants. In total 822 surgeons cast their vote on the key statements and recommendations during the four plenary consensus meetings or via the web survey. Consensus was reached on 34 out of 39 (87%) recommendations, and on six out of seven (86%) statements. No consensus was reached on the use of light versus heavy-weight meshes (69%), superior cost-effectiveness of day-case laparo-endoscopic repair (69%), omitting prophylactic antibiotics in hernia repair, general or local versus regional anesthesia in elderly patients (55%) and re-operation in case of immediate postoperative pain (59%). Globally, there is 87% consensus regarding the diagnosis and management of groin hernias. This provides a solid basis for standardizing the care path of patients with groin hernias.


The use of iron-fortified wheat flour to reduce anemia among the estate population in Sri Lanka.
The use of flour fortified with 66 mg/kg of electrolytic or reduced iron to reduce the prevalence of anemia was determined in a two-year, double-blind, controlled trial. The trial was conducted in Sri Lanka among preschoolers between 9 and 71 months old, primary schoolers 6 to 11 years old, and nonpregnant women. At baseline, 18.4% of the preschoolers had low hemoglobin (Hb) concentrations. Neither electrolytic nor reduced iron had an effect on Hb concentration among preschoolers. Only 7% of the primary schoolers were anemic at the start of the trial and, again, fortification had no effect on Hb concentration. Twenty-nine percent of women had a low Hb at outset and there was no evidence that fortification had an effect on Hb in this group. The findings from this study suggest that fortification of flour with electrolytic iron or reduced iron was not beneficial in reducing anemia in this population. This was probably due to the low prevalence of anemia and low bioavailability of the fortificant iron. Fortification with either iron fortificant was acceptable.


Using Clinical Indicators to Reduce Perianesthesia Recovery Time Following Outpatient Tonsillectomy.
To determine whether we could reduce the time that patients undergoing tonsillectomy are observed postoperatively without decreasing the quality of care, which would eliminate the unnecessary use of resources to monitor those patients. Prospective cohort. Patients undergoing tonsillectomy were recruited for the study prior to their operation. Each patient was then monitored in perianesthesia recovery until clinical indicators for discharge readiness were met (baseline respiratory function, afebrile, ambulation per age, adequate consciousness, absence of nausea/vomiting, adequate pain control, no active bleeding, fluid toleration). Patients were then contacted by phone approximately 24 to 72 hours after discharge to determine if they experienced any postoperative complications. Data analyzed included general demographics and surgical case information such as surgical duration, medications, and timeframes during recovery. Data from 93 patients (age range, 3-34 years) were analyzed. Clinical indicators were met in a mean time of 253.36 (SD ± 79.0) minutes, an average of 93.2 (SD ± 63.4) minutes sooner than average total post-anesthesia recovery time (346.63 minutes). Eight patients experienced minor complications overall (3 in perianesthesia recovery, 5 at home). This study demonstrates that using clinical indicators as discharge criteria is both safe and efficient, with a low rate of postoperative complications.


Interventions for treating chronic ankle instability.
Chronic lateral ankle instability occurs in 10% to 20% of people after an acute ankle sprain. Initial treatment is conservative but if this fails and ligament laxity is present, surgical intervention is considered. To compare different treatments, conservative or surgical, for chronic lateral ankle instability. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and reference lists of articles, all to February 2010. All identified randomised and quasi-randomised controlled trials of interventions for chronic lateral ankle instability were included. Two review authors independently assessed risk of bias and extracted data from each study. Where appropriate, results of comparable studies were pooled. Ten randomised controlled trials were included. Limitations in the design, conduct and reporting of these trials resulted in unclear or high risk of bias assessments relating to allocation concealment, assessor blinding, incomplete and selective outcome reporting. Only limited pooling of the data was possible.Neuromuscular training was the basis of conservative treatment evaluated in four trials. Neuromuscular training compared with no training resulted in better ankle function scores at the end of four weeks training (Ankle Joint Functional Assessment Tool (AJFAT): mean difference (MD) 3.00, 95% CI 0.3 to 5.70; 1 trial, 19 participants; Foot and Ankle Disability Index (FADI) data: MD 8.83, 95% CI 4.46 to 13.20; 2 trials, 56 participants). The fourth trial (19 participants) found no significant difference in the functional outcome after six weeks training programme on a cyclo-ergometer with a bi-directional compared with a traditional uni-directional pedal. Longer-term follow-up data were not available for these four trials.Four studies compared surgical procedures for chronic ankle instability. One trial (40 participants) found more nerve injuries after tenodesis than anatomical reconstruction (risk ratio (RR) 5.50, 95% CI 1.39 to 21.71). One trial (99 participants) comparing dynamic versus static tenodesis excluded 17 patients allocated dynamic tenodesis because their tendons were too thin. The same trial found that dynamic tenodesis resulted in higher numbers of people with unsatisfactory function (RR 8.62, 95% CI 1.97 to 37.77, 82 participants). One trial comparing techniques of lateral ankle ligament reconstruction (60 participants) found that operating time was shorter using the reinsertion technique than the imbrication method (MD -9.00 minutes, 95% CI -13.48 to -4.52). Two trials (70 participants) compared functional mobilisation with immobilisation after surgery. These found early mobilisation led to earlier return to work (MD -2.00 weeks, 95% CI -3.06 to -0.94; 1 trial) and to sports (MD -3.00 weeks, 95% CI -4.49 to -1.51; 1 trial). Neuromuscular training alone appears effective in the short term but whether this advantage would persist on longer-term follow-up is not known. While there is insufficient evidence to support any one surgical intervention over another surgical intervention for chronic ankle instability, it is likely that there are limitations to the use of dynamic tenodesis. After surgical reconstruction, early functional rehabilitation appears to be superior to six weeks immobilisation in restoring early function.


Expression of bacterial Rho factor in yeast identifies new factors involved in the functional interplay between transcription and mRNP biogenesis.
In eukaryotic cells, the nascent pre-mRNA molecule is coated sequentially with a large set of processing and binding proteins that mediate its transformation into an export-competent ribonucleoprotein particle (mRNP) that is ready for translation in the cytoplasm. We have implemented an original assay that monitors the dynamic interplay between transcription and mRNP biogenesis and that allows the screening for new factors linking mRNA synthesis to translation in Saccharomyces cerevisiae. The assay is based on the perturbation of gene expression induced by the bacterial Rho factor, an RNA-dependent helicase/translocase that acts as a competitor at one or several steps of mRNP biogenesis in yeast. We show that the expression of Rho in yeast leads to a dose-dependent growth defect that stems from its action on RNA polymerase II-mediated transcription. Rho expression induces the production of aberrant transcripts that are degraded by the nuclear exosome. A screen for dosage suppressors of the Rho-induced growth defect identified several genes that are involved in the different steps of mRNP biogenesis and export, as well as other genes with both known functions in transcription regulation and unknown functions. Our results provide evidence for an extensive cross talk between transcription, mRNP biogenesis, and export. They also uncover new factors that potentially are involved in these interconnected events.


Immunotherapy for High-Risk Neuroblastoma: Management of Side Effects and Complications.
Despite more intensive therapy, high-risk neuroblastoma continues to be a challenging disease to treat. Postconsolidation immunotherapy has been studied for many years and has proven to be effective in clinical trials. Immunotherapy has become the standard of care for patients with high-risk disease, and many institutions across the country are providing this therapy. The care of these patients is complex and often associated with many side effects. The purpose of this article is to review the most common side effects seen in clinical practice and examine their management. Furthermore, this article will discuss the need for a consistent and educated multidisciplinary front-line team to care for these patients, with advanced practitioners playing a lead role to provide the care and attention needed for this patient population.


Salmonella adhesion, invasion and cellular immune responses are differentially affected by iron concentrations in a combined in vitro gut fermentation-cell model.
In regions with a high infectious disease burden, concerns have been raised about the safety of iron supplementation because higher iron concentrations in the gut lumen may increase risk of enteropathogen infection. The aim of this study was to investigate interactions of the enteropathogen Salmonella enterica ssp. enterica Typhimurium with intestinal cells under different iron concentrations encountered in the gut lumen during iron deficiency and supplementation using an in vitro colonic fermentation system inoculated with immobilized child gut microbiota combined with Caco-2/HT29-MTX co-culture monolayers. Colonic fermentation effluents obtained during normal, low (chelation by 2,2'-dipyridyl) and high iron (26.5 mg iron/L) fermentation conditions containing Salmonella or pure Salmonella cultures with similar iron conditions were applied to cellular monolayers. Salmonella adhesion and invasion capacity, cellular integrity and immune response were assessed. Under high iron conditions in pure culture, Salmonella adhesion was 8-fold increased compared to normal iron conditions while invasion was not affected leading to decreased invasion efficiency (-86%). Moreover, cellular cytokines IL-1β, IL-6, IL-8 and TNF-α secretion as well as NF-κB activation in THP-1 cells were attenuated under high iron conditions. Low iron conditions in pure culture increased Salmonella invasion correlating with an increase in IL-8 release. In fermentation effluents, Salmonella adhesion was 12-fold and invasion was 428-fold reduced compared to pure culture. Salmonella in high iron fermentation effluents had decreased invasion efficiency (-77.1%) and cellular TNF-α release compared to normal iron effluent. The presence of commensal microbiota and bacterial metabolites in fermentation effluents reduced adhesion and invasion of Salmonella compared to pure culture highlighting the importance of the gut microbiota as a barrier during pathogen invasion. High iron concentrations as encountered in the gut lumen during iron supplementation attenuated Salmonella invasion efficiency and cellular immune response suggesting that high iron concentrations alone may not lead to an increased Salmonella invasion.


Genetically encoding a light switch in an ionotropic glutamate receptor reveals subunit-specific interfaces.
Reprogramming receptors to artificially respond to light has strong potential for molecular studies and interrogation of biological functions. Here, we design a light-controlled ionotropic glutamate receptor by genetically encoding a photoreactive unnatural amino acid (UAA). The photo-cross-linker p-azido-L-phenylalanine (AzF) was encoded in NMDA receptors (NMDARs), a class of glutamate-gated ion channels that play key roles in neuronal development and plasticity. AzF incorporation in the obligatory GluN1 subunit at the GluN1/GluN2B N-terminal domain (NTD) upper lobe dimer interface leads to an irreversible allosteric inhibition of channel activity upon UV illumination. In contrast, when pairing the UAA-containing GluN1 subunit with the GluN2A subunit, light-dependent inactivation is completely absent. By combining electrophysiological and biochemical analyses, we identify subunit-specific structural determinants at the GluN1/GluN2 NTD dimer interfaces that critically dictate UV-controlled inactivation. Our work reveals that the two major NMDAR subtypes differ in their ectodomain-subunit interactions, in particular their electrostatic contacts, resulting in GluN1 NTD coupling more tightly to the GluN2B NTD than to the GluN2A NTD. It also paves the way for engineering light-sensitive ligand-gated ion channels with subtype specificity through the genetic code expansion.


A New Perspective on Dry Eye Classification: Proposal by the Asia Dry Eye Society.
The 2017 consensus report of the Asia Dry Eye Society (ADES) on the definition and diagnosis of dry eyes described dry eye disease as "Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage." The report emphasized the instability of tear film and the importance of visual dysfunction in association with dry eyes, highlighting the importance of the evaluation of tear film stability. This report also discussed the concept of tear film-oriented therapy, which stemmed from the definition, and which is centered on provision of insufficient components in each tear film layer and ocular surface epithelium. The current ADES report proposes a simple classification of dry eyes based on the concept of tear film-oriented diagnosis and suggests that there are three types of dry eye: aqueous-deficient, decreased wettability, and increased evaporation. It is suggested that these three types respectively coincide with the problems of each layer: aqueous, membrane-associated mucins, and lipid/secretory mucin. Although each component cannot be quantitatively evaluated with the current technology, a practical diagnosis based on the patterns of fluorescein breakup is recommended. The Asia Dry Eye Society classification report suggests that for a practical use of the definition, diagnostic criteria and classification system should be integrated and be simple to use. The classification system proposed by ADES is a straightforward tool and simple to use, only through use of fluorescein, which is available even to non-dry eye specialists, and which is believed to contribute to an effective diagnosis and treatment of dry eyes.


Peripheral neuromodulation via posterior tibial nerve stimulation - a potential treatment for faecal incontinence?
Faecal incontinence is a prevalent and important condition, with a range of treatment options. Neuromodulation via sacral nerve stimulators is efficacious, but expensive and associated with complications due to device implantation. Peripheral neuromodulation via posterior tibial nerve stimulation (PTNS) has been assessed in urinary incontinence, but there is minimal evidence for its use in faecal incontinence and no literature from the UK. This retrospective review aimed to assess the efficacy of PTNS in faecal incontinence. Thirteen consecutive female patients with faecal incontinence of various causes (9 idiopathic, 3 obstetric, 1 surgery) underwent PTNS at a UK hospital. All were investigated with colonic imaging, anorectal physiology and endo-anal ultrasound. Prior treatments included physiotherapy (13), sphincteroplasty (3) biofeedback (3) and PTQ implants (1). PTNS was performed for 30 min, weekly for 12 weeks. Median monthly episodes of incontinence of wind, liquid and solid reduced from 6, 10 and 18 respectively to 0 with 12 weeks' treatment (P < 0.05). Significant improvements in quality of life indices were also seen. At 1-month follow up, a sustained reduction in incontinence of wind was seen (0 episodes), with non-significant reductions of liquid and solid stool. PTNS is a potentially efficacious, technically simple and minimally invasive alternative treatment modality for faecal incontinence. These early results are encouraging, but we await medium- and long-term follow-up, and a larger randomised trial comparing PTNS with alternative treatments and placebo.


Elements of the fruitless locus regulate development of the muscle of Lawrence, a male-specific structure in the abdomen of Drosophila melanogaster adults.
A genetically defined element of the fruitless (fru) locus in Drosophila melanogaster regulates the development of a male-specific muscle spanning the fifth abdominal segment in adult males, the 'muscle of Lawrence' (MOL). The region is defined by two cytological deletions, each with a breakpoint that co-maps with previously described mutant courtship phenotypes at cytogenetic interval 91B on the third chromosome. Flies that carry both of these deletions are viable, and males express abnormalities of courtship similar to those caused by the fru inversion breakpoint at 91B. In addition, these double-deletion males show the complete absence of the MOL, suggesting that they have little or no gene expression of a postulated MOL determinant; the musculature in the fifth abdominal segment of these mutants to indistinguishable from that of a normal female. Other mutant combinations that produce fruitless courtship phenotypes--including deletion and inversion breakpoints, and a marked transposon inserted at 91B--produce intermediate forms of the MOL. A new genetic variant, induced by imprecise excision of the marked transposon, is homozygous lethal and disrupts fru functions related to courtship and the MOL. The MOL is shown to be dispensable for fertility and is therefore not the causative factor of fru-induced behavioral sterility. These genetic variants and their phenotypic results are discussed with regard to a model for the organization of the fru locus.


Subcutaneous Panniculitis-like T Cell Lymphoma Mimicking Early-Onset Nodular Panniculitis.
Subcutaneous panniculitis-like T cell lymphoma is a very uncommon subtype of cutaneous T cell lymphoma. The manifestations of this rare disease are atypical at onset, and may mimic some rheumatic or dermatologic diseases, which causes the delay of diagnosis and treatment. We report a 24-year-old man suffering from intermittent fever and skin nodules on the left anterior chest wall, who was initially misdiagnosed with nodular panniculitis and finally diagnosed with subcutaneous panniculitis-like T cell lymphoma through repeat examination of biopsy of the skin nodule. Positron emission tomography revealed extracutaneous adipose tissue involvement. Subsequently, hemophagocytic syndrome occurred while under a conventional dose of glucocorticoid, but remission was induced by treatment with cyclosporine A and high doses of dexamethasone. In order to avoid the delay diagnosis and inappropriate treatment of subcutaneous panniculitis-like T cell lymphoma, in addition to a thorough physical examination, PET-CT and disease-specific pathologic, immunophenotypic, and T cell receptor tests of the skin biopsy should be performed. Extracutaneous involvement, especially hemophagocytic syndrome, indicated worse prognosis. Even so, cyclosporine A plus high-dose corticosteroid could be an option of treatment.


Local and timely antimicrobial resistance data for local and national actions: the early implementation of an automated tool for data analysis at local hospital level in Thailand.
In low- and middle-income countries (LMICs), hospitals can rarely utilize their own antimicrobial resistance (AMR) data in a timely manner. To evaluate the utility of local AMR data generated by an automated tool in the real-world setting. From 16 December 2022 to 10 January 2023, on behalf of the Health Administration Division, Ministry of Public Health (MoPH) Thailand, we trained 26 public tertiary-care and secondary-care hospitals to utilize the AutoMated tool for Antimicrobial resistance Surveillance System (AMASS) with their own microbiology and hospital admission data files via two online meetings, one face-to-face meeting and online support. All meetings were recorded on video, and feedback was analysed. Twenty-five hospitals successfully generated and shared the AMR reports with the MoPH by 28 February 2023. In 2022, the median frequency of hospital-origin bloodstream infections (BSIs) caused by carbapenem-resistant Escherichia coli (CREC) was 129 (range 0-1204), by carbapenem-resistant Klebsiella pneumoniae (CRKP) was 1306 (range 0-5432) and by carbapenem-resistant Acinetobacter baumannii (CRAB) was 4472 (range 1460-11 968) per 100 000 patients tested for hospital-origin BSI. The median number of all-cause in-hospital deaths with hospital-origin AMR BSI caused by CREC was 1 (range 0-18), by CRKP was 10 (range 0-77) and by CRAB was 56 (range 7-148). Participating hospitals found that the data obtained could be used to support their antimicrobial stewardship and infection prevention control programmes. Local and timely AMR data are crucial for local and national actions. MoPH Thailand is inviting all 127 public tertiary-care and secondary-care hospitals to utilize the AMASS. Using any appropriate analytical software or tools, all hospitals in LMICs that have electronic data records should analyse and utilize their data for immediate actions.


Does 'no pesticide' reduce suicides?
Ingestion of pesticides is the most common method of suicide, particularly in China, Sri Lanka and India. Reported pesticide suicides in India numbered 22,000 in the year 2006. Four villages in the state of Andhra Pradesh in India that had stopped using chemical pesticides in favour of non-pesticide management (NPM) were visited to assess any change in suicide incidence before and after discontinuation of chemical pesticides. Four similar villages in the same region that continued to use chemical pesticides were used as controls for comparison. In the pesticide-free villages there were 14 suicides before introduction of NPM and only three suicides thereafter. The percentage of suicides not reported to authorities was 47%. Restriction of pesticide availability and accessibility by NPM has the potential to reduce pesticide suicides, in addition to psychosocial and health interventions.


"One Health" or Three? Publication Silos Among the One Health Disciplines.
The One Health initiative is a global effort fostering interdisciplinary collaborations to address challenges in human, animal, and environmental health. While One Health has received considerable press, its benefits remain unclear because its effects have not been quantitatively described. We systematically surveyed the published literature and used social network analysis to measure interdisciplinarity in One Health studies constructing dynamic pathogen transmission models. The number of publications fulfilling our search criteria increased by 14.6% per year, which is faster than growth rates for life sciences as a whole and for most biology subdisciplines. Surveyed publications clustered into three communities: one used by ecologists, one used by veterinarians, and a third diverse-authorship community used by population biologists, mathematicians, epidemiologists, and experts in human health. Overlap between these communities increased through time in terms of author number, diversity of co-author affiliations, and diversity of citations. However, communities continue to differ in the systems studied, questions asked, and methods employed. While the infectious disease research community has made significant progress toward integrating its participating disciplines, some segregation--especially along the veterinary/ecological research interface--remains.


Left Ventricular Hemodynamics with an Implanted Assist Device: An In Vitro Fluid Dynamics Study.
Left ventricle assist devices (VADs) aid the heart pumping blood into the systemic circulation and grant the required cardiac output (CO) when the heart itself cannot provide it. However, it is unclear how effective these devices are at restoring not only physiological CO values but also normal intraventricular hemodynamics. In this work, the modified hemodynamics due to a VAD implantation is studied in vitro using an elastic ventricle made of silicone, which is incorporated into a pulse-duplicator setup prescribing a realistic pulsatile flow. Thereafter, a continuous axial pump is connected at the ventricle apex to mimic a VAD and its effect on the ventricular hemodynamics is investigated as a function of the pump flow suction. Using particle image velocimetry (PIV), we observe that the continuous pump flow effectively provides unloading on the ventricle and yields an increased CO. Conversely, the continuous blood suction from the ventricle apex deeply alters the hemodynamics and, in addition, the VAD obstruction in the ventricle behaves as a bluff body that affects the vorticity distribution in the LV thus creating a stagnant region at the ventricle apex. This phenomenon is rationalized by measuring in a modified set-up the benefits on the hemodynamics of a flush-mounted device. Additionally, the suction operated by the VAD reduces the ventricular pressure and yields an increase in the swirling motion around the ventricle axis, in a similar fashion as the bath-tub vortex effect, thus further modifying the intraventricular hemodynamics with respect to healthy conditions.


Prevention of infections during primary immunodeficiency.
Because infectious diseases are a major source of morbidity and mortality in the majority of patients with primary immunodeficiencies (PIDs), the application of a prophylactic regimen is often necessary. However, because of the variety of PIDs and pathogens involved, and because evidence is scarce, practices are heterogeneous. To homogenize practices among centers, the French National Reference Center for PIDs aimed at elaborating recommendations for anti-infectious prophylaxis for the most common PIDs. We performed a literature review of infectious complications and prophylactic regimens associated with the most frequent PIDs. Then, a working group including different specialists systematically debated about chemoprophylaxis, immunotherapy, immunization, and recommendations for patients. Grading of prophylaxis was done using strength of recommendations (decreasing from A to D) and evidence level (decreasing from I to III). These might help infectious diseases specialists in the management of PIDs and improving the outcome of patients with PIDs.


Inhibition of advanced glycation endproduct formation by foodstuffs.
The Maillard reaction, which is generally termed nonenzymatic browning or glycation, has been implicated in accelerated aging and diabetic complications in vivo. Although the molecular basis of glycation-induced pathogenesis is not well understood, the following have been noted: (1) protein glycation leads to the formation and accumulation of toxic advanced glycation endproducts (AGEs); (2) AGEs can permanently alter the structure and function of body proteins; and (3) the interaction between AGE-modified proteins and AGE-specific receptors (RAGEs) on the cell surface induces the overproduction of reactive oxygen species (ROSs) and inflammatory mediators, which leads to cellular disorders in biological systems. To date, studies that have examined the contribution of protein glycation to disease-states have primarily focused on the deleterious effects and related mechanisms of these glycotoxins. However, it remains unknown whether phytochemicals exert protective effects against glycotoxin-induced damage. Thus, the development and investigation of AGE inhibitors, especially the natural anti-AGE agents without adverse effects, may provide a therapeutic approach for delaying and preventing premature aging and diabetic complications. In this review, we provide an outline of anti-glycation properties of foodstuffs and/or their active components, and discuss their mechanisms of action.


'It's not just about fish': Assessing the social impacts of marine protected areas on the wellbeing of coastal communities in New South Wales.
Managing Marine Protected Areas (MPAs) is about managing human behaviours, but decision-making processes have traditionally focussed on ecological aspects, treating social aspects as secondary. It is now becoming more evident that an equal focus on the ecological and social aspects is required. Without the collection of information about social aspect such as impacts and sharing this as well as ecological information with communities, MPAs are at higher risk of opposition and social acceptability problems. This paper explores the development of a wellbeing framework to understand the social aspects, including the impacts of MPAs on the wellbeing of local communities. This research investigates two case study MPAs: Cape Byron and Port Stephens-Great Lakes Marine Parks in New South Wales, Australia. The MPAs are multiple-use and were implemented in 2006 and 2007, respectively. The research began with a review of the literature, followed by fieldwork, including semi-structured qualitative interviews with community members. Through thematic coding of the interview transcripts in light of the literature on assessing the social impacts of MPAs, a community wellbeing framework of domains and associated attributes was developed to investigate social impacts. Our analysis shows; first, local perspectives are crucial to understanding social impacts. Second, understanding social impacts gives insight into the nature of trade-offs that occur in decision-making regarding MPAs. Third, the intangible social impacts experienced by local communities are just as significant as the tangible ones for understanding how MPAs operate. Fourth, governance impacts have been the most influential factor affecting the social acceptability of the case study parks. We argue that failure to address negative social impacts can undermine the legitimacy of MPAs. We propose that the framework will support policymakers to work towards more effective, equitable and socially sustainable MPAs by employing much-needed monitoring of human dimensions of conservation interventions at the community level to shape adaptive management.


Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology.
Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.


The therapeutic potential of adenosine triphosphate as an immune modulator in the treatment of HIV/AIDS: a combination approach with HAART.
Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the host's own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection.


Vincristine enhances amoeboid-like motility via GEF-H1/RhoA/ROCK/Myosin light chain signaling in MKN45 cells.
Anti-cancer drugs are widely used in cancer treatment frequently combined with surgical therapy and/or radiation therapy. Although surgery and radiation have been suggested to facilitate invasion and metastasis of tumor cells in some cases, there is so far little information about the effect of anti-cancer drugs on cellular invasive ability and metastasis. In this study, using four different anti-cancer drugs (vincristine, paclitaxel, cisplatin and etoposide), we examined whether these drugs influence the invasive ability of tumor cells. Human gastric adenocarcinoma MKN45 cells were used to evaluate the effect of anti-cancer drugs. After drug treatment, cellular invasive ability was assessed using the Matrigel invasion chamber. Cytoskeletal changes after treatment were examined microscopically with F-actin staining. In addition, we monitored cellular motility in 3D matrigel environment by time-lapse microscopic analysis. The drug-induced activation of RhoA and ROCK was evaluated by pull-down assay and Western blotting using an antibody against phosphorylated myosin light chain (MLC), respectively. Where necessary, a ROCK inhibitor Y27632 and siRNA for guanine nucleotide exchange factor-H1 (GEF-H1) were applied. Among all drugs tested, only vincristine stimulated the invasive ability of MKN45 cells. Microscopic analysis revealed that vincristine induced the formation of non-apoptotic membrane blebs and amoeboid-like motility. Vincristine significantly enhanced RhoA activity and MLC phosphorylation, suggesting the involvement of RhoA/ROCK pathway in the vincristine-induced cytoskeletal reorganization and cellular invasion. Furthermore, we found that Y27632 as well as the siRNA for GEF-H1, a RhoA-specific activator, attenuated MLC phosphorylation, the formation of membrane blebs and the invasive ability after vincristine treatment. These results indicate that vincristine activates GEF-H1/RhoA/ROCK/MLC signaling, thereby promoting amoeboid-like motility and the invasive ability of MKN45 cells.


Palladium-catalyzed vicinal amino alcohols synthesis from allyl amines by in situ tether formation and carboetherification.
Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium-catalyzed oxy-alkynylation, oxy-arylation, or oxy-vinylation of allylic amines. High regio- and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes.


Enhanced avidity maturation of antibody to human immunodeficiency virus envelope: DNA vaccination with gp120-C3d fusion proteins.
DNA vaccination can elicit both humoral and cellular immune responses and can confer protection against several pathogens. However, DNA vaccines expressing the envelope (Env) protein of human immunodeficiency virus (HIV) have been relatively ineffective at generating high titer, long-lasting, neutralizing antibodies in a variety of animal models. In this study, we report that fusion of Env and the complement component, C3d, in a DNA vaccine, enhances the titers of antibody to Env. Plasmids were generated that expressed a secreted form of Env (sgp120) from three isolates of HIV and these same forms fused to three tandem copies of the murine homologue of C3d (sgp120-3C3d). Analyses of titers and avidity maturation of the raised antibody indicated that immunizations with each of the sgp120-3C3d-expressing DNAs accelerated both the onset and the avidity maturation of antibody to Env.


Restoring function and esthetics in a patient with amelogenesis imperfecta: a case report.
Amelogenesis imperfecta is a hereditary disorder that affects enamel on primary and permanent teeth. It is a rare dental disease but represents a major restorative challenge for the dentist. A 14-year-old boy presented with sensitive, discolored, and mutilated teeth and a decreased vertical dimension of occlusion. The aim of treatment was to reduce dental sensitivity, to restore esthetics, and to correct the vertical dimension of occlusion. To modify the occlusion, and to protect the dentin from chemical and thermal attacks, nickel-chrome onlays were placed on the molars. To improve the esthetics of the incisors and premolars, resin composite restorations were applied. The patient was regularly recalled during the postoperative period. Radiographic and clinical examinations 10 months posttreatment revealed no evidence of disorders associated with the restored teeth or their supporting structures.


Cloud-point extraction of rhodamine 6G by using Triton X-100 as the non-ionic surfactant.
Cloud-point extraction (CPE) using the non-ionic surfactant Triton X-100 was used successfully to remove a highly toxic dye, rhodamine 6G (R6G), from water and wastewater. The effects of different analytical parameters such as pH, concentration of Triton X-100 (TX-100) and salts, equilibrium temperature, and incubation time on the efficiency of the extraction of R6G were studied in detail, and optimum conditions for dye extraction were obtained. Thermodynamic parameters including changes in Gibbs free energy, enthalpy, and entropy were also calculated, and these parameters indicated that the CPE of R6G was feasible, spontaneous, and endothermic in the temperature range of 75-95 degrees C. The equilibrium solubilization capacity of TX-100 was found to be 1.10 mmol/mol by using Langmuir isotherm models. No significant interference effects were observed in the presence of phenol and its derivatives, some acidic and basic dyes and most of the anions and cations. It was concluded that the CPE process described in this paper can be an alternative technique for removal of dyes and other pollutants from waters and wastewaters.


Incidence, mortality, and survival trends of ovarian cancer in Hong Kong, 1997 to 2006: a population-based study.
To assess the incidence and mortality of ovarian cancer, and the survival patterns of the invasive epithelial ovarian carcinoma in Hong Kong based on population-based cancer registry data. Historical cohort study. Hong Kong. All patients with ovarian cancer diagnosed between 1997 and 2006 were included. Patients eligible for survival analysis were followed up until 31 December 2007. Age-standardised incidence and mortality rates with their estimated annual percent changes were determined. Cumulative observed and relative survival rates were estimated using a period approach. During the study period, in Hong Kong there was a steadily increasing ovarian cancer incidence rate (1.4% annually) but a steadily decreasing mortality rate (1.9% annually). The improvement in mortality was mainly in the age-group of 50-69 years (4.7% annually). Invasive epithelial ovarian carcinoma accounted for 79.6% of the study cohort. The 2-year and 5-year relative survival rates were 75.8% and 63.1%, respectively. Those diagnosed in the period 2002 to 2006 had significantly better survival than those diagnosed in the period 1997 to 2001 (65.3% vs 60.7%; P=0.008); a significant improvement was evident for patients with stage II disease and in the age-group of 50-69 years. Multivariate analyses confirmed that age, histological subtype, FIGO stage, and the period of diagnosis were independent prognostic indicators of invasive epithelial ovarian carcinoma. In Hong Kong, invasive epithelial ovarian carcinoma showed an increasing incidence and an improving survival trend over the period 1997 to 2006. The survival data derived from this study provides a baseline from which to monitor the effectiveness of ovarian cancer treatment in Hong Kong.


Performance evaluation of an optical hybrid switch with circuit queued reservations and circuit priority preemption.
We provide here a new loss model for an optical hybrid switch that can function as an optical burst switch and/or optical circuit switch. Our model is general as it considers an implementation whereby some of the circuits have preemptive priority over bursts and others are allowed to queue their reservations. We first present an analysis based on a 3-dimension state-space Markov chain that provides exact results for the blocking probabilities of bursts and circuits, the proportion of circuits that are delayed and the mean delay of the circuits that are delayed. Because it is difficult to exactly compute the blocking probability in realistic scenarios with a large number of wavelengths, we derive computationally a scalable and accurate approximations based on reducing the 3-dimension state space into a single dimension. These scalable approximations that can produce performance results in a fraction of a second can readily enable switch dimensioning. Extensive numerical results are presented to demonstrate the accuracy and the use of the new approximations.


Time-dependence of inhibition of carnitine palmitoyltransferase I by malonyl-CoA in mitochondria isolated from livers of fed or starved rats. Evidence for transition of the enzyme between states of low and high affinity for malonyl-CoA.
The degree of inhibition of CPT I (carnitine palmitoyltransferase, EC 220.127.116.11) in isolated rat liver mitochondria by malonyl-CoA was studied by measuring the activity of the enzyme over a short period (15s) after exposure of the mitochondria to malonyl-CoA for different lengths of time. Inhibition of CPT I by malonyl-CoA was markedly time-dependent, and the increase occurred at the same rate in the presence or absence of palmitoyl-CoA (80 microM), and in the presence of carnitine, such that the time-course of acylcarnitine formation deviated markedly from linearity when CPT I activity was measured in the presence of malonyl-CoA over several minutes. The initial rate of increase in degree of inhibition with time was independent of malonyl-CoA concentration. CPT I in mitochondria from 48 h-starved rats had a lower degree of inhibition by malonyl-CoA at zero time, but was equally capable of being sensitized to malonyl-CoA, as judged by an initial rate of increase of inhibition identical with that of the enzyme in mitochondria from fed rats. Double-reciprocal plots for the degree of inhibition produced by different malonyl-CoA concentrations at zero time for the enzyme in mitochondria from fed or starved animals indicated that the enzyme in the latter mitochondria was predominantly in a state with low affinity for malonyl-CoA (concentration required to give 50% inhibition, I0.5 congruent to 10 microM), whereas that in mitochondria from fed rats displayed two distinct sets of affinities: low (congruent to 10 microM) and high (less than 0.3 microM). Plots for mitochondria after incubation for 0.5 or 1 min with malonyl-CoA indicated that the increased sensitivity observed with time was due to a gradual increase in the high-affinity state in both types of mitochondria. These results suggest that the sensitivity of CPT I in rat liver mitochondria in vitro had two components: (i) an instantaneous sensitivity inherent to the enzyme which depends on the nutritional state of the animal from which the mitochondria are isolated, and (ii) a slow, malonyl-CoA-induced, time-dependent increase in sensitivity. It is suggested that the rate of malonyl-CoA-induced sensitization of the enzyme to malonyl-CoA inhibition is limited by a slow first-order process, which occurs after the primary event of interaction of malonyl-CoA with the mitochondria.(ABSTRACT TRUNCATED AT 400 WORDS)


In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection.
We previously established long-term, 3-dimensional culture of organoids from mouse tissues (intestine, stomach, pancreas, and liver) and human intestine and pancreas. Here we describe conditions required for long-term 3-dimensional culture of human gastric stem cells. The technology can be applied to study the epithelial response to infection with Helicobacter pylori. We generated organoids from surgical samples of human gastric corpus. Culture conditions were developed based on those for the mouse gastric and human intestinal systems. We used microinjection to infect the organoids with H pylori. Epithelial responses were measured using microarray and quantitative polymerase chain reaction analyses. Human gastric cells were expanded indefinitely in 3-dimensional cultures. We cultured cells from healthy gastric tissues, single-sorted stem cells, or tumor tissues. Organoids maintained many characteristics of their respective tissues based on their histology, expression of markers, and euploidy. Organoids from healthy tissue expressed markers of 4 lineages of the stomach and self-organized into gland and pit domains. They could be directed to specifically express either lineages of the gastric gland, or the gastric pit, by addition of nicotinamide and withdrawal of WNT. Although gastric pit lineages had only marginal reactions to bacterial infection, gastric gland lineages mounted a strong inflammatory response. We developed a system to culture human gastric organoids. This system can be used to study H pylori infection and other gastric pathologies.


Overlooked Tertiary Sulci Serve as a Meso-Scale Link between Microstructural and Functional Properties of Human Lateral Prefrontal Cortex.
Understanding the relationship between neuroanatomy and function in portions of cortex that perform functions largely specific to humans such as lateral prefrontal cortex (LPFC) is of major interest in systems and cognitive neuroscience. When considering neuroanatomical-functional relationships in LPFC, shallow indentations in cortex known as tertiary sulci have been largely unexplored. Here, by implementing a multimodal approach and manually defining 936 neuroanatomical structures in 72 hemispheres (in both males and females), we show that a subset of these overlooked tertiary sulci serve as a meso-scale link between microstructural (myelin content) and functional (network connectivity) properties of human LPFC in individual participants. For example, the posterior middle frontal sulcus (pmfs) is a tertiary sulcus with three components that differ in their myelin content, resting-state connectivity profiles, and engagement across meta-analyses of 83 cognitive tasks. Further, generating microstructural profiles of myelin content across cortical depths for each pmfs component and the surrounding middle frontal gyrus (MFG) shows that both gyral and sulcal components of the MFG have greater myelin content in deeper compared with superficial layers and that the myelin content in superficial layers of the gyral components is greater than sulcal components. These findings support a classic, yet largely unconsidered theory that tertiary sulci may serve as landmarks in association cortices, as well as a modern cognitive neuroscience theory proposing a functional hierarchy in LPFC. As there is a growing need for computational tools that automatically define tertiary sulci throughout cortex, we share pmfs probabilistic sulcal maps with the field.SIGNIFICANCE STATEMENT Lateral prefrontal cortex (LPFC) is critical for functions that are thought to be specific to humans compared with other mammals. However, relationships between fine-scale neuroanatomical structures largely specific to hominoid cortex and functional properties of LPFC remain elusive. Here, we show that these structures, which have been largely unexplored throughout history, surprisingly serve as markers for anatomical and functional organization in human LPFC. These findings have theoretical, methodological, developmental, and evolutionary implications for improved understanding of neuroanatomical-functional relationships not only in LPFC, but also in association cortices more broadly. Finally, these findings ignite new questions regarding how morphological features of these neglected neuroanatomical structures contribute to functions of association cortices that are critical for human-specific aspects of cognition.


Influence of Sulfide Nanoparticles on Dissolved Mercury and Zinc Quantification by Diffusive Gradient in Thin-Film Passive Samplers.
Diffusive gradient in thin-film (DGT) passive samplers are frequently used to monitor the concentrations of metals such as mercury and zinc in sediments and other aquatic environments. The application of these samplers generally presumes that they quantify only the dissolved fraction and not particle-bound metal species that are too large to migrate into the sampler. However, metals associated with very small nanoparticles (smaller than the pore size of DGT samplers) can be abundant in certain environments, yet the implications of these nanoparticles for DGT measurements are unclear. The objective of this study was to determine how the performance of the DGT sampler is affected by the presence of nanoparticulate species of Hg and Zn. DGT samplers were exposed to solutions containing known amounts of dissolved Hg(II) and nanoparticulate HgS (or dissolved Zn(II) and nanoparticulate ZnS). The amounts of Hg and Zn accumulated onto the DGT samplers were quantified over hours to days, and the rates of diffusion of the dissolved metal (i.e., the effective diffusion coefficient D) into the sampler's diffusion layer were calculated and compared for solutions containing varying concentrations of nanoparticles. The results suggested that the nanoparticles deposited on the surface of the samplers might have acted as sorbents, slowing the migration of the dissolved species into the samplers. The consequence was that the DGT sampler data underestimated the dissolved metal concentration in the solution. In addition, X-ray absorption spectroscopy was employed to determine the speciation of the Hg accumulated on the sampler binding layer, and the results indicated that HgS nanoparticles did not appear to directly contribute to the DGT measurement. Overall, our findings suggest that the deployment of DGT samplers in settings where nanoparticles are relevant (e.g., sediments) may result in DGT data that incorrectly estimated the dissolved metal concentrations. Models for metal uptake into the sampler may need to be reconsidered.


The effect of nanometre-scale structure on interfacial energy.
Natural surfaces are often structured with nanometre-scale domains, yet a framework providing a quantitative understanding of how nanostructure affects interfacial energy, gamma(SL), is lacking. Conventional continuum thermodynamics treats gamma(SL) solely as a function of average composition, ignoring structure. Here we show that, when a surface has domains commensurate in size with solvent molecules, gamma(SL) is determined not only by its average composition but also by a structural component that causes gamma(SL) to deviate from the continuum prediction by a substantial amount, as much as 20% in our system. By contrasting surfaces coated with either molecular- (<2 nm) or larger-scale domains (>5 nm), we find that whereas the latter surfaces have the expected linear dependence of gamma(SL) on surface composition, the former show a markedly different non-monotonic trend. Molecular dynamics simulations show how the organization of the solvent molecules at the interface is controlled by the nanostructured surface, which in turn appreciably modifies gamma(SL).


Removal of indigenous coliphages and enteric viruses during riverbank filtration from highly polluted river water in Delhi (India).
Emerging countries frequently afflicted by waterborne diseases require safe and cost-efficient production of drinking water, a task that is becoming more challenging as many rivers carry a high degree of pollution. A study was conducted on the banks of the Yamuna River, Delhi, India, to ascertain if riverbank filtration (RBF) can significantly improve the quality of the highly polluted surface water in terms of virus removal (coliphages, enteric viruses). Human adenoviruses and noroviruses, both present in the Yamuna River in the range of 10(5) genomes/100 mL, were undetectable after 50 m infiltration and approximately 119 days of underground passage. Indigenous somatic coliphages, used as surrogates of human pathogenic viruses, underwent approximately 5 log10 removal after only 3.8 m of RBF. The initial removal after 1 m was 3.3 log10, and the removal between 1 and 2.4 m and between 2.4 and 3.8 m was 0.7 log10 each. RBF is therefore an excellent candidate to improve the water situation in emerging countries with respect to virus removal.


Feline cystic rete ovarii.
Cysts of the rete ovarii system from 20 cats are described. The cellular morphology of these cysts varies because the normal rete ovarii in the cat consists of three anatomically distinct parts. Cysts arise in the ovarian medulla or at the tubal extremity of the ovary, expand into ovarian stroma rather than the mesovarium , and are lined by ciliated columnar to flattened epithelium. Their functional significance is unknown.


Quantifying elongation rhythm during full-length protein synthesis.
Pauses regulate the rhythm of ribosomal protein synthesis. Mutations disrupting even minor pauses can give rise to improperly formed proteins and human disease. Such minor pauses are difficult to characterize by ensemble methods, but can be readily examined by single-molecule (sm) approaches. Here we use smFRET to carry out real-time monitoring of the expression of a full-length protein, the green fluorescent protein variant Emerald GFP. We demonstrate significant correlations between measured elongation rates and codon and isoacceptor tRNA usage, and provide a quantitative estimate of the effect on elongation rate of replacing a codon recognizing an abundant tRNA with a synonymous codon cognate to a rarer tRNA. Our results suggest that tRNA selection plays an important general role in modulating the rates and rhythms of protein synthesis, potentially influencing simultaneous co-translational processes such as folding and chemical modification.


Discovery of mosquito saliva microRNAs during CHIKV infection.
Mosquito borne pathogens are transmitted to humans via saliva during blood feeding. Mosquito saliva is a complex concoction of many secretory factors that modulate the feeding foci to enhance pathogen infection and establishment. Multiple salivary proteins/factors have been identified/characterized that enhance pathogen infection. Here, we describe, for the first time, the identification of exogenous microRNAs from mosquito saliva. MicroRNAs are short, 18-24 nucleotide, non-coding RNAs that regulate gene expression, and are generally intracellular. However, circulating miRNAs have been described from serum and saliva of humans. Exogenous miRNAs have not been reported from hematophagous arthropod saliva. We sought to identify miRNAs in the mosquito saliva and their role in Chikungunya virus (CHIKV) infection. Next generation sequencing was utilized to identify 103 exogenous miRNAs in mosquito saliva of which 31 miRNAs were previously unidentified and were designated novel. Several miRNAs that we have identified are expressed only in the CHIKV infected mosquitoes. Five of the saliva miRNAs were tested for their potential to regulated CHIKV infection, and our results demonstrate their functional role in the transmission and establishment of infection during blood feeding on the host.