The rattling sound of rattlesnakes (Crotalus viridis) as a communicative resource for ground squirrels (Spermophilus beecheyi) and burrowing owls (Athene cunicularia).
Animal communication involves very dynamic processes that can generate new uses and functions for established communicative activities. In this article, the authors describe how an aposematic signal, the rattling sound of rattlesnakes (Crotalus viridis), has been exploited by 2 ecological associates of rattlesnakes: (a) California ground squirrels (Spermophilus beecheyi) use incidental acoustic cues in rattling sounds to assess the danger posed by the rattling snake, and (b) burrowing owls (Athene cunicularia) defend themselves against mammalian predators by mimicking the sound of rattling. The remarkable similarity between the burrowing owl's defensive hiss and the rattlesnake's rattling reflects both exaptation and adaptation. Such exploitation of the rattling sound has favored alternations in both the structure and the deployment of rattling by rattlesnakes.


Stem cell-based immunomodulation in type 1 diabetes: beyond the regenerative approach.
Type 1 diabetes (T1D) is an autoimmune disease, leading to pancreatic β-cell destruction and loss of glycaemic control. Administration of exogenous insulin to diabetic patients prevents life-threatening metabolic derangement, but may fail to prevent other longterm complications, such as kidney failure or diabetic retinopathy. Islet transplantation is a low-risk surgical procedure, affording improved glucose homeostasis provided sufficient islets engraft in the liver. Here we review work on the use of stem cells to generate β- cells for islet transplantation, indicating the need for improved protocols for their derivation and full maturation. We also consider recent evidence indicating that adult stem/progenitor cells may affect islet transplantation by improving the viability of engrafted islets and controlling immune reactions to islet allo- and auto-antigens, extending stem-cell use in T1D beyond the regenerative approach.


Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment.
The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo. We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor (PPAR)gamma-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism. In this study, we determined the molecular mechanism by which cyclin D1 regulated PPARgamma function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARgamma ligand was associated with a reduction in histone deacetylase (HDAC1) activity. Cyclin D1-/- MEFs showed an increased propensity to undergo differentiation into adipocytes. Genetic deletion of cyclin D1 reduced HDAC1 activity. Reconstitution of cyclin D1 into the cyclin D1-/- MEFs increased HDAC1 activity and blocked PPARgamma-mediated adipogenesis. PPARgamma activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARgamma activity and enhanced HDAC repression of PPARgamma activity. Cyclin D1 bound HDAC in vivo and preferentially physically associated with HDAC1, HDAC2, HDAC3, and HDAC5. Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of HDAC1 and HDAC3 and histone methyltransferase SUV39H1 to the PPAR response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9. Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function.


Occupational skin diseases of the feet.
Although dermatoses account for the vast majority of occupational disease, the role played by foot disorders is uncharted. Often, protective footgear has an etiologic rather than a therapeutic effect. The environmental, chemical, physical, and biologic causes of pedal skin disease in the workplace are described, with emphasis on the need for their recognition and control.


Single amino acid substitutions in hydrophobic cores at a head-coiled coil junction region of cohesin facilitate its release of DNA during anaphase.
Cohesin holds sister chromatids together and is cleaved by separase/Cut1 to release DNA during the transition from mitotic metaphase to anaphase. The cohesin complex consists of heterodimeric structural maintenance of chromosomes (SMC) subunits (Psm1 and Psm3), which possess a head and a hinge, separated by long coiled coils. Non-SMC subunits (Rad21, Psc3 and Mis4) bind to the SMC heads. Kleisin/Rad21's N-terminal domain (Rad21-NTD) interacts with Psm3's head-coiled coil junction (Psm3-HCJ). Spontaneous mutations that rescued the cleavage defects in temperature-sensitive (ts) separase mutants were identified in the interaction interface, but the underlying mechanism is yet to be understood. Here, we performed site-directed random mutagenesis to introduce single amino acid substitutions in Psm3-HCJ and Rad21-NTD, and then identified 300 mutations that rescued the cohesin-releasing defects in a separase ts mutant. Mutational analysis indicated that the amino acids involved in hydrophobic cores (which may be in close contact) in Psm3-HCJ and Rad21-NTD are hotspots, since 80 mutations (approx. 27%) were mapped in these locations. Properties of these substitutions indicate that they destabilize the interaction between the Psm3 head and Rad21-NTD. Thus, they may facilitate sister chromatid separation in a cleavage-independent way through cohesin structural re-arrangement.


Expected Number of Fixed Points in Boolean Networks with Arbitrary Topology.
Boolean network models describe genetic, neural, and social dynamics in complex networks, where the dynamics depend generally on network topology. Fixed points in a genetic regulatory network are typically considered to correspond to cell types in an organism. We prove that the expected number of fixed points in a Boolean network, with Boolean functions drawn from probability distributions that are not required to be uniform or identical, is one, and is independent of network topology if only a feedback arc set satisfies a stochastic neutrality condition. We also demonstrate that the expected number is increased by the predominance of positive feedback in a cycle.


Improved tolerance with two radiation fractions per day for treatment of abdominal and pelvic malignancies.
When major volumes of the abdomen are the tolerable dose is frequently limited by the tolerance of the small intestine and other gastrointestinal tissues. In an attempt to increase the tolerable dose, a twice-daily, 5 day/week fractionation scheme was used. One hundred and thirty-nine patients were started on treatment for abdominal and pelvic malignancies, of whom 124 received the planned dose, usually in the prescribed time. Fifty-five hundred to 6000 rad in about 8 weeks was administered to large volumes of the pelvis and abdomen, frequently with "boost" radiation to 7500 rad to limited volumes. Ninety percent of the patients were able to complete treatment without interruption. In 90% of all cases there were no late radiation-related complications. The acute reactions and late complications have been comparable to those incurred when total doses 20-30% less are administered with one fraction per day. The survival rates of these patients indicates a probable improvement in therapeutic ratio. The physical techniques, areas treated, and time-dose sequence are described. A detailed analysis by primary organ, patient characteristics, performance status, types of complications, cause of death, and survival characteristics is presented.


Mechanisms of paradoxical rib cage motion in patients with chronic obstructive pulmonary disease.
Paradoxical motion of the rib cage is well recognized in patients with chronic obstructive pulmonary disease (COPD); most often this is seen in the lateral dimension (Hoover's sign), but paradoxical indrawing of the lower sternum during inspiration has also been described. We have examined the possible mechanisms of these abnormalities by relating rib cage motion (using magnetometers) to the changes in pleural (Ppl), abdominal (Pab), and transdiaphragmatic (Pdi) pressures in 13 patients with COPD and hyperinflation who had previously documented abnormal rib cage motion. During tidal breathing, Pab became more negative in early inspiration in 11 of the 13 patients. Paradox of the lateral rib cage was present in 11 patients, and in these, the abnormal movement related well to increasing Pdi or decreasing Ppl, but the peak distortion fitted more closely with Pdi. During attempted voluntary relaxation at full inflation, the lateral rib cage dimensions always increased as Pdi declined. Five of the 13 patients showed indrawing of the sternum in early inspiration, and in 4, the abnormal motion was confined to the lower sternum, with qualitatively normal motion at the angle of Louis. In these 4 patients, the peak distortion coincided with the nadir of Pab in early inspiration. In all 5 patients, an increase in Pab during expiration suggested expiratory muscle contraction, and this was associated with a paradoxical increase in the anteroposterior diameter of the rib cage.(ABSTRACT TRUNCATED AT 250 WORDS)


Exploring the SARS-CoV-2 structural proteins for multi-epitope vaccine development: an in-silico approach.
The ongoing life-threatening pandemic of coronavirus disease 2019 (COVID-19) has extensively affected the world. During this global health crisis, it is fundamentally crucial to find strategies to combat SARS-CoV-2. Despite several efforts in this direction and continuing clinical trials, no vaccine has been approved for it yet. To find a preventive measure, we have computationally designed a multi-epitopic subunit vaccine using immuno-informatic approaches. The structural proteins of SARS-CoV-2 involved in its survival and pathogenicity were used to predict antigenic epitopes. The antigenic epitopes were capable of eliciting a strong humoral as well as cell-mediated immune response, our predictions suggest. The final vaccine was constructed by joining the all epitopes with specific linkers and to enhance their stability and immunogenicity. The physicochemical property of the vaccine was assessed. The vaccine 3D structure prediction and validation were done and docked with the human TLR-3 receptor. Furthermore, molecular dynamics simulations of the vaccine-TLR-3 receptor complex are employed to assess its dynamic motions and binding stability in-silico. Based on this study, we strongly suggest synthesizing this vaccine, which further can be tested in-vitro and in-vivo to check its potency in a cure for COVID-19.


Nanocatalyst superior to Pt for oxygen reduction reactions: the case of core/shell Ag(Au)/CuPd nanoparticles.
Controlling the electronic structure and surface strain of a nanoparticle catalyst has become an important strategy to tune and to optimize its catalytic efficiency for a chemical reaction. Using density functional theory (DFT) calculations, we predicted that core/shell M/CuPd (M = Ag, Au) NPs with a 0.8 or 1.2 nm CuPd2 shell have similar but optimal surface strain and composition and may surpass Pt in catalyzing oxygen reduction reactions. We synthesized monodisperse M/CuPd NPs by the coreduction of palladium acetylacetonate and copper acetylacetonate in the presence of Ag (or Au) nanoparticles with controlled shell thicknesses of 0.4, 0.75, and 1.1 nm and CuPd compositions and evaluated their catalysis for the oxygen reduction reaction in 0.1 M KOH solution. As predicted, our Ag/Cu37Pd63 and Au/Cu40Pd60 catalysts with 0.75 and 1.1 nm shells were more efficient catalysts than the commercial Pt catalyst (Fuel Cells Store), with their mass activity reaching 0.20 A/mg of noble metal at -0.1 V vs Ag/AgCl (4 M KCl); this was over 3 times higher than that (0.06 A/mg Pt) from the commercial Pt. These Ag(Au)/CuPd nanoparticles are promising non-Pt catalysts for oxygen reduction reactions.


Inhibitory effect of protein kinase C inhibitor on the replication of influenza type A virus.
The growth of influenza virus A/PR/8/34 in MDCK cells was inhibited by 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H7) which is a potent inhibitor of protein kinase C, but not by an effective inhibitor of cyclic nucleotide-dependent protein kinases. Analysing the inhibitory effect of H7 during the replication cycle of influenza virus, we found that the primary transcripts were sufficiently synthesized in infected cells exposed to H7. The primary transcripts synthesized in the presence and absence of H7 were active in directing the synthesis of viral polypeptides both in a cell-free system and in the system containing H7. In the system where infected cells were exposed to H7, the viral positive-sense RNAs were also significantly amplified 6 h after infection. However, the synthesis of viral proteins other than nucleoprotein from viral primary or amplified (secondary) mRNAs was extremely restricted. The synthesis of host cellular proteins in mock-infected cells was significantly retained in the presence of H7. These results suggest that the selective inhibition of influenza virus translation following the transcription of viral mRNA was induced by H7 in infected cells.


An analysis of nicotinic and opioid processes in the medulla oblongata and nucleus ambiguus of the dog.
Effects of opioids and nicotine on blood pressure and heart rate were studied by microinjections in the region of nucleus ambiguus of acutely decerebrated dogs. Nicotine (5 micrograms/0.5 microliter) microinjected into the region of nucleus ambiguus produced hypotension accompanied by either bradycardia or tachycardia. Both types of response were antagonized by mecamylamine (10 micrograms/0.5 microliter) but not by naloxone (10 micrograms/0.5 microliter). Fentanyl (5 micrograms/0.5 microliter) and ethylketazocine (10 micrograms/0.5 microliter) decreased blood pressure and heart rate after microinjection into the nucleus ambiguus. The actions of fentanyl were antagonized by naloxone (10 micrograms/0.5 microliter) and N-allylnormetazocine (10 micrograms/0.5 microliter), but not by mecamylamine (10 micrograms/0.5 microliter). Naloxone (10 micrograms/0.5 microliter) administered after ethylketazocine elevated blood pressure and tended to increase heart rate. Naloxone, mecamylamine or N-allylnormetazocine did not produce significant effect when microinjected alone. It is concluded that, under the present experimental conditions, nicotine and opioid mu, kappa but not sigma receptors are distributed in the region of nucleus ambiguus. No evidence for an interaction between nicotine and opioids in this nucleus was obtained. Furthermore, there was no detectable endogenous opioid or cholinergic nicotinic tone in the nucleus ambiguus of the acutely decerebrated dog.


The Net Present Value and Other Economic Implications of a Medical Career.
College graduates' career choices are driven by a complex mixture of factors, one of which is economics. The author comments on the report by Marcu and colleagues in this issue, which focuses strictly on the economics of this decision. Specifically, Marcu and colleagues modeled career choices as long-term financial investments in human capital, which consists of the knowledge and clinical skills physicians gain in undergraduate and graduate medical education. They distill the numerous factors that shape the economics of career choice into a commonly used criterion for long-term financial investments of any kind-namely, the so-called net present value (NPV) of the investment. For them, that investment is the decision to pursue a medical career rather than the next best nonmedical, alternative career. This NPV calculation determines the increase or decrease in wealth, relative to that of the next best alternative career, that a college graduate is thought to experience as of the moment she or he enters medical school simply by choosing a medical career rather than the next best alternative. Marcu and colleagues use this human capital model to explore how different plans to finance a medical school education impact the NPV, all other parameters being equal. The author of this Commentary explains in layman's terms how the NPV is calculated and then raises a number of other issues concerning the economics of a medical career, including medical school tuition, residents' salaries, and investments in human capital as tax deductible.


Beef Intake Is Associated with Higher Nutrient Intake and Nutrient Adequacy in U.S. Adolescents, NHANES 2001-2018.
Nutrient adequacy among adolescents is of concern due to higher nutrient requirements for their developing bodies as well as the gap between the current nutrient intake and the recommendations. The objective of this study was to determine beef intake and assess the relationship between beef consumption and nutrient intake and nutrient adequacy in male and female adolescents, 14-18 years of age. Dietary recalls collected during the What We Eat in America (WWEIA) portion of the National Health and Nutrition Examination Survey (NHANES) cycles 2001-2018 were utilized to determine beef intake. Usual nutrient intakes were determined with the National Cancer Institute method in conjunction with day 1 and day 2 total nutrient files. Nutrient adequacy was assessed by calculating the percentage of the population below the estimated average requirement (EAR) or above the adequate intake (AI). The average beef intake of male and female adolescent beef consumers was 57.9 ± 2.4 and 46.8 ± 2.2 g with a 90th percentile of 82.3 ± 4.3 and 67.8 ± 3.5 g, respectively. Compared to non-consumers, beef consumers had a 10% or higher intake of calcium, iron, phosphorus, potassium, total choline, vitamin B12, and zinc. Over 50% of the adolescent population (regardless of beef consumption) had intakes below the EAR for calcium, magnesium, and vitamins A, C, D, and E. The percentage of the beef-consuming population below the EAR was lower for calcium, copper, folate, iron, phosphorus, zinc, and vitamins B12 and B6 as compared to non-consumers. Additionally, the portion of the population above the AI for sodium was higher in female beef consumers as compared to non-consumers. We estimate approximately 900,000 to 1,400,000, 400,000-700,000, 200,000-600,000, and 200,000-400,000 fewer adolescents to be below the EAR for zinc, phosphorus, vitamin B12, and iron, respectively if beef non-consumers were to consume beef. This study suggests beef can help increase the nutrient intake and nutrient adequacy in the diets of adolescents, helping to close important gaps for this nutritionally vulnerable population. While recommendations to reduce beef intake are widely prevalent, this could result in unintended nutritional consequences regarding under-consumed nutrients including those of public health concern important for adolescent health.


Roles for RpoS in survival of Escherichia coli during protozoan predation and in reduced moisture conditions highlight its importance in soil environments.
The soil is a complex ecosystem where interactions between biotic and abiotic factors determine the survival and fate of microbial inhabitants of the system. Having previously shown that Escherichia coli requires the general stress response regulator, RpoS, to survive long term in soil, it was important to determine what specific conditions in this environment necessitate a functional RpoS. This study investigated the susceptibility of soil-persistent E. coli to predation by the single-celled eukaryotes Acanthamoeba polyphaga and Tetrahymena pyriformis, and the role RpoS plays in resisting this predation. Strain-specific differences were observed in the predation of E. coli strains, with soil-persistent strain COB583 being the most resistant to predation by both protozoans. RpoS and curli, proteinaceous fibres used for attachment to biotic and abiotic surfaces, increased the ability of E. coli to resist predation by A. polyphaga and T. pyriformis. Furthermore, soil moisture content impacted the survival of E. coli BW25113 but wild-type COB583 had similar survival irrespective of soil moisture content. Overall, this study confirmed that RpoS contributes to the resistance of E. coli to protozoan predation and that RpoS is crucial for the increased fitness of soil-persistent E. coli against predation and reduced moisture in soil.


The antiviral signaling mediated by black carp MDA5 is positively regulated by LGP2.
Melanoma differentiation-associated gene 5 (MDA5) belongs to RIG-I like receptor (RLR) family, which detects cytosolic viral RNA component in immune response. In this study, MDA5 orthologue of black carp (Mylopharyngodon piceus) has been cloned and characterized. The full-length cDNA of black carp MDA5 (bcMDA5) comprises 3244 nucleotides and the predicted bcMDA5 protein contains 984 amino acids. The constitutive transcription of bcMDA5 was extremely low in all the tested tissues, which included gill, skin, muscle, intestine, kidney, spleen, liver and heart. However, bcMDA5 mRNA level was much enhanced in most selected tissues in response to GCRV or SVCV infection. bcMDA5 migrated around 120 KDa in immunoblot and was identified as a cytosolic protein by immunofluorescent staining in both EPC and HeLa cells. Expressing bcMDA5 in EPC cells resulted in the induction of promoter activity of zebrafish IFN3 or fathead minnow IFN. The EPC cells expressing bcMDA5 obtained improved antiviral ability against both SVCV and GCRV. When EPC cells were co-transfected with plasmids expressing bcMDA5 and bcLGP2, the induced IFN expression by bcMDA5 was obviously enhanced. EPC cells expressing both bcMDA5 and bcLGP2 owned much improved antiviral ability than those cells expressing only bcMDA5 or bcLGP2. In general, our data support the conclusion that bcMDA5 plays an important role in the antiviral innate immune response of black carp and bcLGP2 acts as a positive regulator in bcMDA5 mediated signaling.


Renal hemodynamic, fluid volume, and arterial pressure changes during hyperproteinemia.
The chronic effects of hyperproteinemia on renal hemodynamics, fluid volume, and arterial pressure were determined in six conscious dogs over a 32-day period. Plasma protein concentration was increased by intravenous infusion of approximately 300 ml/day of previously collected autologous plasma, and the responses to changes in sodium intake were studied. By the end of a 9-day period of hyperproteinemia and normal sodium intake, plasma protein concentration had increased 2.2 g/dl, plasma colloid osmotic pressure had increased 7-8 mmHg, mean arterial pressure had increased 12 mmHg, glomerular filtration rate (GFR) had increased 15%, estimated renal plasma flow (ERPF) had increased 51% primarily due to renal vasodilatation, and filtration fraction had decreased 23%. Also, sodium balance was negative, water balance was positive, sodium iothalamate space had increased, plasma sodium concentration had decreased, and the relationship between mean arterial pressure and urinary sodium excretion was shifted to the right along the arterial pressure axis. In conclusion, long-term increases of plasma protein concentration result in a marked increase in ERPF as well as significant increases in GFR, extracellular fluid volume, and arterial pressure.


Soluble klotho and autosomal dominant polycystic kidney disease.
Fibroblast growth factor 23 (FGF23) levels are elevated in patients with autosomal dominant polycystic kidney disease (ADPKD) and X-linked hypophosphatemia (XLH), but only the latter is characterized by a renal phosphate wasting phenotype. This study explored potential mechanisms underlying resistance to FGF23 in ADPKD. FGF23 and klotho levels were measured, and renal phosphate transport was evaluated by calculating the ratio of the maximum rate of tubular phosphate reabsorption to GFR (TmP/GFR) in 99 ADPKD patients, 32 CKD patients, 12 XLH patients, and 20 healthy volunteers. ADPKD and CKD patients were classified by estimated GFR (CKD stage 1, ≥90 ml/min per 1.73 m(2); CKD stage 2, 60-89 ml/min per 1.73 m(2)). ADPKD patients had 50% higher FGF23 levels than did XLH patients; TmP/GFR was near normal in most ADPKD patients and very low in XLH patients. Serum klotho levels were lowest in the ADPKD group, whereas the CKD and XLH groups and volunteers had similar levels. ADPKD patients with an apparent renal phosphate leak had two-fold higher klotho levels than those without. Serum klotho values correlated inversely with cyst volume and kidney growth. Loss of klotho might be a consequence of cyst growth and constrain the phosphaturic effect of FGF23 in most patients with ADPKD. Normal serum klotho levels were associated with normal FGF23 biologic activity in all XLH patients and a minority of ADPKD patients. Loss of klotho and FGF23 increase appear to exceed and precede the changes that can be explained by loss of GFR in patients with ADPKD.


[Infectious pathology in diabetic patients cared for in an emergency department].
We study the influence of diabetes in the incidence of infectious diseases attended in an emergency department (ED). 2,500 adult patients attended in the ED of a general hospital were examined. We value prospectively: clinical data, diagnosis in ED and rate of admissions, comparing two groups: Group A (175 diabetic patients), Group B (350 non diabetic control patients, with the same age and sex). We used the glycated Hb and the glucose levels to make a difference in A Group: patients with good control (A1 = Hb A1c < 8), patients with poor control (A2 = HbA1c > 8), patients with low glucose levels (A3 = glucose < 200 mg/dl) and high glucose levels (A4 = glucose > 200 mg/dl). Infectious disease are more frequent in diabetic patients than no diabetic (Group A = 13.1% vs Group B = 3.2%), certain amount pneumonia and urinary tract infection. Also the infectious diseases are more frequent in diabetic patients with high glucose levels (Group A4) than diabetic patients with low glucose levels (Group A3), but there were no significant differences between A1 and A2 groups. The presence of diabetes was bound up with a higher frequency of infectious diseases, above all pneumonia and urinary tract infection, in an ED. The importance of metabolic control in relation with infectious diseases is not definite in our study.


Abnormal blood microbiota profiles are associated with inflammation and immune restoration in HIV/AIDS individuals.
The characteristics of blood microbiota in HIV-infected individuals and their relevance to disease progression are still unknown, despite alterations in gut microbiota diversity and composition in HIV-infected individuals. Here, we present evidence of increased blood microbiota diversity in HIV-infected individuals, which may result from gut microbiota translocation. Also, we identify a group of microbes, Porphyromonas gingivalis, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius, which are linked to poor immunological recovery. This work provides a scientific foundation toward therapeutic strategies targeting blood microbiota for immune recovery of HIV infection.


Antifeedant and Antiviral Diterpenoids from the Fresh Roots of Euphorbia jolkinii.
The perennial herbaceous plant Euphorbia jolkinii (Euphorbiaceae) is a noxious weed widely distributed in the grasslands of northwestern Yunnan and has greatly threatened the local biodiversity. Phytochemical investigation on the fresh roots of E. jolkinii afforded six new diterpenoids 1, 2, 4-6, and 8, together with fifteen known diterpenoids. Their structures were elucidated on the basis of 1D and 2D NMR and other spectroscopic methods. Casbane, lathyrane, abietane, and ent-kaurane diterpenoids were reported from this plant for the first time. Selected compounds were evaluated for their antifeedant and anti-RSV (respiratory syncytial virus) activities. Compound 2 and ingenol (3) exhibited moderate antifeedant activity against a generalist insect herbivore, Spodoptera exigua, with EC50 values of 17.88 and 17.71 μg/cm(2) respectively. Compound 19 showed significant anti-RSV activity, with 50 % inhibition (IC50) value of 10.0 μM and selective index of 8.0. Compounds 1 and 2 were less active against RSV virus, both with IC50 value of 25 μM, and with selective indices of 1.0 and 3.2 respectively. These findings provided new evidence for the biological functions and utilization of the diversified diterpenoid metabolites in the roots of this rich but harmful plant.


A point-prevalence study for MRSA in a German university hospital to identify patients at risk and to evaluate an established admission screening procedure.
Due to the enormous increase in the number of MRSA-patients, in July 2004, an extended admission screening protocol was implemented in ICUs and surgical wards at Hannover Medical School. In 2005, a point-prevalence study (also known as a cross-sectional study) was conducted to determine the prevalence of MRSA and Panton-Valentine leukocidin (PVL) among inpatients, to identify patients at risk for MRSA colonization and to evaluate compliance with admission screening. Inpatients were screened by taking cultures from nose, throat and skin lesions. S. aureus isolates were tested for antimicrobial susceptibility and PVL. MRSA was analyzed by staphylococcal protein A (spa) typing. Of 509 inpatients, 145 (28%) were S. aureus carriers. 27 (19%) inpatients were MRSA positive, i.e., the MRSA point-prevalence was 5.3% (95% CI, 3.49; 7.70). spa type t032 was predominant in 67% of the MRSA inpatients. The PVL gene was present in one (0.2%) methicillin-susceptible strain. Comparison with data retrieved from the local hospital MRSA database showed that, the status of 37% of the MRSA had previously remained undetected (10/27). Consequently, MRSA colonization was newly identified in 2.0% (10/509) of the patients. Compliance with admission screening failed in three cases. Nosocomial acquisition was identified in three patients. Four other patients harbouring MRSA were newly identified on wards without routine screening (three neurological, one internal medicine ward). Despite extended admission screening, 37% of all MRSA-positive inpatients were missed. The neurological patients were identified as a further risk group and were included in the admission screening procedure established.


A Bayesian approach to modeling phytoplankton population dynamics from size distribution time series.
The rates of cell growth, division, and carbon loss of microbial populations are key parameters for understanding how organisms interact with their environment and how they contribute to the carbon cycle. However, the invasive nature of current analytical methods has hindered efforts to reliably quantify these parameters. In recent years, size-structured matrix population models (MPMs) have gained popularity for estimating division rates of microbial populations by mechanistically describing changes in microbial cell size distributions over time. Motivated by the mechanistic structure of these models, we employ a Bayesian approach to extend size-structured MPMs to capture additional biological processes describing the dynamics of a marine phytoplankton population over the day-night cycle. Our Bayesian framework is able to take prior scientific knowledge into account and generate biologically interpretable results. Using data from an exponentially growing laboratory culture of the cyanobacterium Prochlorococcus, we isolate respiratory and exudative carbon losses as critical parameters for the modeling of their population dynamics. The results suggest that this modeling framework can provide deeper insights into microbial population dynamics provided by size distribution time-series data.


Orbital fat preservation in lower-lid blepharoplasty.
In the last 4 years, there have been a few reports concerning unconventional management of the fat posterior to the orbital septum (intraorbital) as well as periorbital fat located superficial to the orbital septum in a plane both superficial and deep to the orbicularis oculi muscle. With reference to intraorbital fat, some reports suggest that this fat be preserved and mobilized to other areas to recontour the lower lid, while other authors suggest repositioning the fat within the bony orbit. To address these new concepts, a discussion of the theories behind these approaches is needed.


Fluorescence spectroscopy for the detection of tongue carcinoma--validation in an animal model.
The efficacy of fluorescence spectroscopy to detect squamous cell carcinoma is evaluated in an animal model following laser excitation at 442 and 532 nm. Lesions are chemically induced with a topical DMBA application at the left lateral tongue of Golden Syrian hamsters. The animals are investigated every 2 weeks after the 4th week of induction until a total of 26 weeks. The right lateral tongue of each animal is considered as a control site (normal contralateral tissue) and the induced lesions are analyzed as a set of points covering the entire clinically detectable area. Based on fluorescence spectral differences, four indices are determined to discriminate normal and carcinoma tissues, based on intraspectral analysis. The spectral data are also analyzed using a multivariate data analysis and the results are compared with histology as the diagnostic gold standard. The best result achieved is for blue excitation using the KNN (K-nearest neighbor, a interspectral analysis) algorithm with a sensitivity of 95.7% and a specificity of 91.6%. These high indices indicate that fluorescence spectroscopy may constitute a fast noninvasive auxiliary tool for diagnostic of cancer within the oral cavity.


Copper-catalyzed regioselective trans-silaboration of internal arylalkynes with stereochemical switch to cis-addition mode.
Copper-catalyzed silafunctionalization of alkynes using a silylboronic ester as a silicon source has recently progressed rapidly. Generally, the reaction affords a product with cis-stereoselectivity. We herein describe trans-selective 1,2-addition of silylboronic esters to internal arylalkynes, which was promoted efficiently by the CuOt-Bu/RCy2P/NaOt-Bu catalysts. Moreover, we report a stereochemical switch to cis-addition in the reactions of Me2(i-PrO)Si-B(pin) in hydrocarbon solvents including cyclohexane.


The effect of diabetes control status on treatment response in pulmonary tuberculosis: a prospective study.
Uncontrolled diabetes, unlike controlled diabetes, is associated with an impaired immune response. However, little is known about the impact of the status of diabetes control on clinical features and treatment outcomes in patients with pulmonary TB (PTB). We conducted this study to evaluate whether the status of diabetes control influences clinical manifestations and treatment responses in PTB. A multicentre prospective study was performed between September 2012 and September 2014. The patients were categorised into three groups according to the glycated haemoglobin (HbA1C) level: PTB without diabetes mellitus (non-DM), PTB with controlled diabetes (controlled-DM) and PTB with uncontrolled diabetes (uncontrolled-DM). The primary outcome was the sputum culture conversion rate after 2 months of intensive treatment. Among 661 patients with PTB, 157 (23.8%) had diabetes and 108 (68.8%) had uncontrolled diabetes (HbA1C≥7.0%). The uncontrolled-DM group exhibited more symptoms, positive sputum smears (p<0.001) and presence of cavities (p<0.001) than the non-DM group. Regarding treatment responses, patients with uncontrolled-DM were more likely to have a positive culture after 2 months (p=0.009) and either treatment failure (p=0.015) or death (p=0.027) compared with the non-DM group. In contrast, those with controlled-DM showed similar treatment responses to the non-DM group. In multivariable analysis, uncontrolled diabetes was an independent risk factor for a positive sputum culture after 2 months of treatment (adjusted OR, 2.11; p=0.042) and either treatment failure or death (adjusted OR, 4.11; p=0.022). Uncontrolled diabetes is an independent risk factor for poor treatment response in PTB.


Soil nitrogen dynamics and competition during plant invasion: insights from Mikania micrantha invasions in China.
Invasive plants often change a/biotic soil conditions to increase their competitiveness. We compared the microbially mediated soil nitrogen (N) cycle of invasive Mikania micrantha and two co-occurring native competitors, Persicaria chinensis and Paederia scandens. We assessed how differences in plant tissue N content, soil nutrients, N cycling rates, microbial biomass and activity, and diversity and abundance of N-cycling microbes associated with these species impact their competitiveness. Mikania micrantha outcompeted both native species by transferring more N to plant tissue (37.9-55.8% more than natives). We found total soil N to be at lowest, and available N highest, in M. micrantha rhizospheres, suggesting higher N cycling rates compared with both natives. Higher microbial biomass and enzyme activities in M. micrantha rhizospheres confirmed this, being positively correlated with soil N mineralization rates and available N. Mikania micrantha rhizospheres harbored highly diverse N-cycling microbes, including N-fixing, ammonia-oxidizing and denitrifying bacteria and ammonia-oxidizing archaea (AOA). Structural equation models indicated that M. micrantha obtained available N via AOA-mediated nitrification mainly. Field data mirrored our experimental findings. Nitrogen availability is elevated under M. micrantha invasion through enrichment of microbes that participate in N cycling, in turn increasing available N for plant growth, facilitating high interspecific competition.


Predictors of mortality over 8 years in type 2 diabetic patients: Translating Research Into Action for Diabetes (TRIAD).
To examine demographic, socioeconomic, and biological risk factors for all-cause, cardiovascular, and noncardiovascular mortality in patients with type 2 diabetes over 8 years and to construct mortality prediction equations. Beginning in 2000, survey and medical record information was obtained from 8,334 participants in Translating Research Into Action for Diabetes (TRIAD), a multicenter prospective observational study of diabetes care in managed care. The National Death Index was searched annually to obtain data on deaths over an 8-year follow-up period (2000-2007). Predictors examined included age, sex, race, education, income, smoking, age at diagnosis of diabetes, duration and treatment of diabetes, BMI, complications, comorbidities, and medication use. There were 1,616 (19%) deaths over the 8-year period. In the most parsimonious equation, the predictors of all-cause mortality included older age, male sex, white race, lower income, smoking, insulin treatment, nephropathy, history of dyslipidemia, higher LDL cholesterol, angina/myocardial infarction/other coronary disease/coronary angioplasty/bypass, congestive heart failure, aspirin, β-blocker, and diuretic use, and higher Charlson Index. Risk of death can be predicted in people with type 2 diabetes using simple demographic, socioeconomic, and biological risk factors with fair reliability. Such prediction equations are essential for computer simulation models of diabetes progression and may, with further validation, be useful for patient management.


Racial discrimination by low-prejudiced whites. Facial movements as implicit measures of attitudes related to behavior.
We investigated the relationship of implicit racial prejudice to discriminatory behavior. White university students chose the best of three applicants (two were White and one was Black) for a prestigious teaching fellowship. They then completed the Implicit Association Test (IAT), a measure of implicit racial bias. Three weeks later, participants completed a second implicit measure of racial bias by viewing photos of Whites and Blacks while facial electromyography (EMG) was recorded from sites corresponding to the muscles used in smiling and frowning. Analyses revealed that bias in cheek EMG activity was related to the race of the chosen applicant, whereas bias on the IAT was not. Motivations to control prejudiced reactions were not related to EMG activity or the race of the applicant chosen, but were related to IAT bias. The findings indicate that facial EMG can be used as an implicit measure of prejudice related to discrimination.


Of Parachutes and Participant Protection: Moving Beyond Quality to Advance Effective Research Ethics Oversight.
There are several reasons to believe that Institutional Review Boards (IRBs) and Human Research Protection Programs (HRPPs) contribute to ethical research and the protection of research participants, but there are also important reasons to interrogate this belief. Determining whether IRBs and HRPPs "work" requires empirical evaluation of whether and how well they actually achieve what they were designed to do. In other words, it is critical to examine their outcomes and not only their procedures and structures. In this response to Tsan, we argue that the concept of IRB and HRPP quality entails three dimensions: (1) effectiveness, (2) procedures and structures likely to promote effectiveness, and (3) features unrelated to effectiveness but nonetheless essential, such as efficiency, fairness, and proportionality. Because not all types of quality necessarily guarantee or entail effectiveness, we suggest that broad quality assessments, including such features as regulatory compliance and other procedural measures suggested by Tsan, are unhelpful as the first step in evaluating IRBs and HRPPs. Instead, we must start with outcomes relevant to effectiveness. To do this, we launched the Consortium to Advance Effective Research Ethics Oversight (AEREO), with a mission to define and specify ways to measure relevant outcomes for research ethics oversight, empirically evaluate whether those outcomes are achieved, test new approaches to achieving them, and ultimately, develop and implement empirically-based policy and practice to advance IRB and HRPP effectiveness. We describe several anticipated AEREO projects and call for collaboration between various stakeholders to more meaningfully evaluate IRB and HRPPs.


Conservative management of extrauterine pregnancy.
An abdominal pregnancy in a 28-year-old nulliparous woman with a fertility problem was treated conservatively. The clinical antenatal course was unremarkable. A healthy 2000-g infant was delivered at term by laparotomy. The placenta was removed at the same time. Three years later the patient had a ruptured tubal pregnancy which was treated by salpingectomy. The literature on extrauterine pregnancy is reviewed briefly.


Specific reading disability: a multiplanar view.
In the past three decades a revolution has altered the way society approaches people with disabilities. Social changes resulted in a significant increase in fundamental and applied research that seeks to improve the lives of people with disabilities by facilitating better understanding of the mechanisms, manifestations, prevention, and treatment of functional impairment. Specific Reading Disability (SRD) has benefited from this revolution. This review focuses on the evolution of SRD, new information in its neurobiology and management, and the challenges that remain. Evidence from a wide spectrum of research provides strong support for the role of phonology in Specific Reading Disability. Despite the mounting evidence, the case is far from completely established. Adults with compensated SRD read but still demonstrate disordered phonology (Felton et al. [1990] Brain Language 39:485-497). Whether poor phonology is causal or a covariant remains to be demonstrated. Of children with poor phonology, it is not known how many are poor readers. While phonology is associated with SRD, other studies have questioned the uniqueness of SRD. Challenges have been made to the method of classification, the uniqueness of phonological dysfunction as a mechanism in SRD and the response to treatment. In the final analysis all poor readers may have a common core of dysphonology, independent of whether their reading is discrepant from their IQ.


Functional responses of bone cells to thrombin.
Cells responsible for the formation and maintenance of bone express thrombin-responsive members of the protease-activated receptor family of G protein-coupled receptors. Thrombin has been shown to elicit a number of functional responses in these cells, including proliferation and cytokine production in osteoblasts. Many, but not all, of the effects of thrombin on bone cells are initiated by activation of protease-activated receptor-1. A combination of in vitro observations and results of in vivo studies in protease-activated receptor-1-null mice suggest that thrombin plays multiple roles in the early stages of bone healing.


The Role of immune and inflammatory mechanisms in ALS.
Amyotrophic lateral sclerosis (ALS) is a severe progressive neurodegenerative disease. The cause is unknown, but genetic abnormalities have been identified in subjects with familial ALS and also in subjects with sporadic ALS. Environmental factors such as occupational exposure have been shown to be risk factors for the development of ALS. Patients differ in their clinical features and differ in the clinical course of disease. Immune abnormalities have been found in the central nervous system by pathological studies and also in the blood and CSF of subjects with ALS. Inflammation and immune abnormalities are also found in animals with a model of ALS due to mutations in the SOD1 gene. Previously it has been considered that immune abnormalities might contribute to the pathogenesis of disease. However more recently it has become apparent that an immune response can occur as a response to damage to the nervous system and this can be protective.


Long-Term Longitudinal Stability of Kidney Filtration Marker Measurements: Implications for Epidemiological Studies and Clinical Care.
Establishment and improvement of glomerular filtration rate estimating equations requires accurate and precise laboratory measurement procedures (MPs) for filtration markers. The Advanced Research and Diagnostic Laboratory (ARDL) at the University of Minnesota, which has served as the central laboratory for the Chronic Kidney Disease Epidemiology Collaboration since 2009, has implemented several quality assurance measures to monitor the accuracy and stability of filtration marker assays over time. To assess longitudinal stability for filtration marker assays, a 40-sample calibration panel was created using pooled serum, divided into multiple frozen aliquots stored at -80 °C. ARDL monitored 4 markers-creatinine, cystatin C, beta-2-microglobulin (B2M) and beta-trace protein-measuring 15 calibration panel aliquots from 2009 to 2019. Initial target values were established using the mean of the first 3 measurements performed in 2009-10, and differences from target were monitored over time. New MPs for cystatin C and B2M were added in 2012, with target values established using the first measurement. The mean percentage difference from mean target values across time was <2% for all original MPs (-0.59% for creatinine; -0.94% for cystatin C; -0.82% for B2M; 1.24% for beta-trace protein). Close monitoring of filtration marker trends with a calibration panel at ARDL demonstrates remarkable long-term stability of the MPs. Routine use of a calibration panel for both research studies and clinical care is recommended for filtration markers where longitudinal monitoring is important to detect analytical biases, which can mask or confound true clinical trends in patients.


Sharp trench waveguide bends in dual mode operation with ultra-small photonic crystals for suppressing radiation.
A sharp 90 degree bend in a dual mode trench waveguide is analyzed by means of the MMP method. Through evolutionary strategy optimization, different configurations with low reflection, low radiation, low mode conversion, and therefore high transmission for the dominant mode are obtained. Three different types of bends are analyzed and compared: mirror-based structures, resonator-based structures, and structures with a small photonic crystal in the bend area. The local photonic crystal helps not only suppressing radiation but also provides solutions with fewer fabrication tolerance problems.


Providing Personalised Nutrition: Consumers' Trust and Preferences Regarding Sources of Information, Service Providers and Regulators, and Communication Channels.
Personalised nutrition has potential to revolutionise dietary health promotion if accepted by the general public. We studied trust and preferences regarding personalised nutrition services, how they influence intention to adopt these services, and cultural and social differences therein. A total of 9,381 participants were quota-sampled to be representative of each of 9 EU countries (Germany, Greece, Ireland, Poland, Portugal, Spain, the Netherlands, the UK, and Norway) and surveyed by a questionnaire assessing their intention to adopt personalised nutrition, trust in service regulators and information sources, and preferences for service providers and information channels. Trust and preferences significantly predicted intention to adopt personalised nutrition. Higher trust in the local department of health care was associated with lower intention to adopt personalised nutrition. General practitioners were the most trusted of service regulators, except in Portugal, where consumer organisations and universities were most trusted. In all countries, family doctors were the most trusted information providers. Trust in the National Health Service as service regulator and information source showed high variability across countries. Despite its highest variability across countries, personal meeting was the preferred communication channel, except in Spain, where an automated internet service was preferred. General practitioners were the preferred service providers, except in Poland, where dietitians and nutritionists were preferred. The preference for dietitians and nutritionists as service providers highly varied across countries. These results may assist in informing local initiatives to encourage acceptance and adoption of country-specific tailored personalised nutrition services, therefore benefiting individual and public health.


Nonnegative matrix factorization with the Itakura-Saito divergence: with application to music analysis.
This letter presents theoretical, algorithmic, and experimental results about nonnegative matrix factorization (NMF) with the Itakura-Saito (IS) divergence. We describe how IS-NMF is underlaid by a well-defined statistical model of superimposed gaussian components and is equivalent to maximum likelihood estimation of variance parameters. This setting can accommodate regularization constraints on the factors through Bayesian priors. In particular, inverse-gamma and gamma Markov chain priors are considered in this work. Estimation can be carried out using a space-alternating generalized expectation-maximization (SAGE) algorithm; this leads to a novel type of NMF algorithm, whose convergence to a stationary point of the IS cost function is guaranteed. We also discuss the links between the IS divergence and other cost functions used in NMF, in particular, the Euclidean distance and the generalized Kullback-Leibler (KL) divergence. As such, we describe how IS-NMF can also be performed using a gradient multiplicative algorithm (a standard algorithm structure in NMF) whose convergence is observed in practice, though not proven. Finally, we report a furnished experimental comparative study of Euclidean-NMF, KL-NMF, and IS-NMF algorithms applied to the power spectrogram of a short piano sequence recorded in real conditions, with various initializations and model orders. Then we show how IS-NMF can successfully be employed for denoising and upmix (mono to stereo conversion) of an original piece of early jazz music. These experiments indicate that IS-NMF correctly captures the semantics of audio and is better suited to the representation of music signals than NMF with the usual Euclidean and KL costs.


Motion analysis and segmentation through spatio-temporal slices processing.
This paper presents new approaches in characterizing and segmenting the content of video. These approaches are developed based upon the pattern analysis of spatio-temporal slices. While traditional approaches to motion sequence analysis tend to formulate computational methodologies on two or three adjacent frames, spatio-temporal slices provide rich visual patterns along a larger temporal scale. We first describe a motion computation method based on a structure tensor formulation. This method encodes visual patterns of spatio-temporal slices in a tensor histogram, on one hand, characterizing the temporal changes of motion over time, on the other hand, describing the motion trajectories of different moving objects. By analyzing the tensor histogram of an image sequence, we can temporally segment the sequence into several motion coherent subunits, in addition, spatially segment the sequence into various motion layers. The temporal segmentation of image sequences expeditiously facilitates the motion annotation and content representation of a video, while the spatial decomposition of image sequences leads to a prominent way of reconstructing background panoramic images and computing foreground objects.


Lemon balm and dandelion leaf extract synergistically alleviate ethanol-induced hepatotoxicity by enhancing antioxidant and anti-inflammatory activity.
We investigated the effect of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (LD) on ethanol (EtOH)-mediated liver injury and explored the underlying mechanisms. Administration of LD synergistically reduced relative liver weight and decreased the levels of serum biomarkers of hepatic injury. Histopathological and biochemical analyses indicated that LD synergistically attenuated hepatic accumulation of triacylglycerides (TGs) and restored the levels of mRNAs related to fatty acid metabolism. In addition, LD significantly reduced EtOH-induced hepatic oxidative stress by attenuating the reduction in levels of nuclear factor E2-related factor 2 (Nrf2) mRNA and enhancing antioxidant activity. Moreover, LD decreased the EtOH-mediated increase in levels of hepatic tumor necrosis factor-α (TNF-α) mRNA. In vitro, LD significantly scavenged free radicals, increased cell viability against tert-butylhydroperoxide (tBHP), and transactivated Nrf2 target genes in HepG2 cells. Furthermore, LD decreased levels of pro-inflammatory mediators in lipopolysaccharide-stimulated Raw264.7 cells. Therefore, LD shows promise for preventing EtOH-mediated liver injury. PRACTICAL APPLICATIONS: There were no approved therapeutic agents for preventing and/or treating alcoholic liver diseases. In this study, a 2:1 (w/w) mixture of lemon balm and dandelion leaf extract (DL) synergistically ameliorated EtOH-induced hepatic injury by inhibiting lipid accumulation, oxidative stress, and inflammation. Our findings will enable the development of a novel food supplement for the prevention or treatment of alcohol-mediated liver injury.


High-frequency, magnetic-field-responsive drug release from magnetic nanoparticle/organic hybrid based on hyperthermic effect.
Magnetic nanoparticles (MNPs) generate heat when a high-frequency magnetic field (HFMF) is applied to them. Induction heat is useful not only for hyperthermia treatment but also as a driving force for drug-release. beta-Cyclodextrin (CD) can act as drug container because of its inclusion properties. Drugs incorporated in the CD can thus be released through the use of induction heating, or hyperthermic effects, by applying a HFMF. In this study, we have synthesized folic acid (FA) and CD-functionalized superparamagnetic iron oxide nanoparticles, FA-CD-SPIONs, by chemically modifying SPIONs derived from iron(III) allylacetylacetonate. FA is well-known as a targeting ligand for breast cancer tumor and endows the SPIONs with cancer-targeting capability. Immobilization of FA and CD on spinel iron oxide nanoparticles was confirmed by Fourier transform IR (FTIR) and X-ray photoelectron spectroscopy (XPS). The FA-CD-SPIONs have a hydrodynamic diameter of 12.4 nm and prolonged stability in water. They are superparamagnetic with a magnetization of 51 emu g(-1) at 16 kOe. They generate heat when an alternating current (AC) magnetic field is applied to them and have a specific absorption rate (SAR) of 132 W g(-1) at 230 kHz and 100 Oe. Induction heating triggers drug release from the CD cavity on the particle - a behavior that is controlled by switching the HFMF on and off. The FA-CD-SPIONs are noncytotoxic for cells. Thus, FA-CD-SPIONs can serve as a novel device for performing drug delivery and hyperthermia simultaneously.


Evidence for dynamic and multiple roles for huntingtin in Ciona intestinalis.
Although mutations in the huntingtin gene (HTT) due to poly-Q expansion cause neuropathology in humans (Huntington's disease; HD), the normal function(s) of the gene and its protein (HTT) remain obscure. With new information from recently sequenced invertebrate genomes, the study of new animal models opens the possibility of a better understanding of HTT function and its evolution. To these ends, we studied huntingtin expression pattern and dynamics in the invertebrate chordate Ciona intestinalis. Ciona huntingtin (Ci-HTT) shows a biphasic expression pattern during larval development and prior to metamorphosis. A single form of huntingtin protein is present until the early larval stages, at which time two different mass proteins become evident in the metamorphically competent larva. An antibody against Ci-HTT labeled 50 cells in the trunk mesenchyme regions in pre-hatching and hatched larvae and probably represents the distribution of the light form of the protein. Dual labeling with anti-Ci-HTT and anti-aldoketoreductase confirmed the presence of Ci-HTT in mesenchyme cells. Suppression of Ci-HTT RNA by a morpholino oligonucleotide reduced the number and apparent mobility of Ci-HTT positive cells. In Ciona, HTT expression has a dynamic temporal and spatial expression pattern that in ontogeny precedes metamorphosis. Although our results may reflect a derived function for the protein in pre- and post-metamorphic events in Ciona, we also note that as in vertebrates, there is evidence for multiple differential temporal expression, indicating that this protein probably has multiple roles in ontogeny and cell migration.


4-hydroxy-2-nonenal-protein adducts and apoptosis in murine lung cells after acute ozone exposure.
Ozone is a photochemically generated pollutant that can cause acute pulmonary inflammation and induce cellular injury and may contribute to the development or exacerbation of chronic lung diseases. Despite extensive investigation, the mechanisms of ozone and oxidant-induced cellular injury are still uncertain. Ozone has been reported to cause the formation of aldehydes in biological fluids that could explain many of the cellular effects caused by ozone. One of the most toxic aldehydes formed during oxidant-induced lipid peroxidation is 4-hydroxy-2-nonenal (HNE). HNE reacts primarily with Cys and secondarily with Lys and His amino acids, altering protein function and forming protein adducts that can be detected using specific adducts. In this study, we investigated whether ozone could cause the formation of HNE by assaying for HNE-protein adducts in cells isolated by lung lavage from C3H/HeJ mice exposed to 2.0 and 0.25 ppm ozone for 3 hr. Since oxidative stress and HNE have been shown to cause apoptosis we also examined the lung lavage cells for evidence of apoptosis following ozone exposure. Using a specific polyclonal antibody against HNE-amino acid adducts, two principle HNE-protein adducts were detected by Western analysis in cells obtained after ozone exposure at approximately 86-90 and 32 kDa. In addition to cell necrosis, apoptosis of lung cells was significant 3 hr after ozone exposure as detected using a Cell Death ELISA procedure and confirmed with DNA ladder and morphological analysis. The apoptotic cell injury peaked at 6 hr postexposure and decreased by 24 hr. Taken together, these results demonstrate that HNE is formed in vivo following ozone exposure and HNE appears to form specific protein adducts in lung cells. Furthermore, ozone can cause lung cell injury by an apoptotic mechanism in addition to a necrotic mechanism. Since HNE is toxic to cells and is formed as a result of ozone exposure, it may contribute to the lung cell injury following ozone exposure.


Designing Decision-Support Technologies for Patient-Generated Data in Type 1 Diabetes.
People living with type 1 diabetes generate data as a byproduct of diabetes management. The development of decision support technologies can be enabled by harnessing these patient-generated data, but a major challenge is for these technologies to provide meaningful and highly personalized guidance to support individual patients' decision-making processes. In this paper, results from a year-long qualitative study were reported. Twenty-six people with type 1 diabetes were interviewed regarding the types of self-generated data they use for decision-making, their decision-making processes using self-generated data, and the difficulties they experience when attempting to use this data for decision-making. These patients' behaviors and difficulties point to new approaches to designing decision support technologies for personal use, including patient-centered and automated data entry, automated and individualized data analysis, and humanized output.


Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens.
Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab ( NCT03290950 ), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.


Systematic review and proposal of an in vivo reflectance confocal microscopy assessment tool for cutaneous lymphoma.
Reflectance confocal microscopy (RCM) is a non-invasive imaging technique that provides dynamic information and allows in vivo monitoring, with excellent histologic correlation. In the last decade, the use of RCM for cutaneous T-cell lymphomas (CTCL) has been reported. CTCL may require multiple biopsies for diagnosis due to its equivocal clinical presentation. RCM was described as a possible tool to help determine the best site for skin biopsy. This study aims to systematically review all RCM features reported in literature for CTCL. A systematic literature search concerning CTCL evaluated by RCM was performed in eight electronic databases until May 2019 following PRISMA-DTA quality assessment. Eighteen RCM features were described in patients with CTCL. The most frequent were: interface dermatitis (89%), epidermal lymphocytes (82%), epidermal architectural disarray (81%), and vesicle-like structure (Pautrier microabscess) (51%). In order to establish comparable parameters among the studies identified, we proposed descriptors for CTCL features and a grading system to quantify them. This will facilitate to define the role of RCM in the diagnosis and monitoring of CTCL patients.


[Features of microbiocenosis of colon in tumoral processes].
Microbiocenoses of 47 patients with tumor processes of colon and 18 persons of control group have been researched. The increase, in comparison with control of inoculation frequency of hemolytic Escherichia and Escherichia with lowered biochemical activity, partial replacement of the resident microflora on commensal microorganisms is registered. Isolation of opportunistic Enterobacteria (genus Citrobacter and Klebsiella) was observed more often. The increase of frequency of Bacteroides and Clostridium isolation is marked for patients of this group. Differences in specific composition of Bacteroides in patients with tumors in comparison with the control group are marked.


Lethal giant larvae 2 regulates development of the ciliated organ Kupffer's vesicle.
Motile cilia perform crucial functions during embryonic development and throughout adult life. Development of organs containing motile cilia involves regulation of cilia formation (ciliogenesis) and formation of a luminal space (lumenogenesis) in which cilia generate fluid flows. Control of ciliogenesis and lumenogenesis is not yet fully understood, and it remains unclear whether these processes are coupled. In the zebrafish embryo, lethal giant larvae 2 (lgl2) is expressed prominently in ciliated organs. Lgl proteins are involved in establishing cell polarity and have been implicated in vesicle trafficking. Here, we identified a role for Lgl2 in development of ciliated epithelia in Kupffer's vesicle, which directs left-right asymmetry of the embryo; the otic vesicles, which give rise to the inner ear; and the pronephric ducts of the kidney. Using Kupffer's vesicle as a model ciliated organ, we found that depletion of Lgl2 disrupted lumen formation and reduced cilia number and length. Immunofluorescence and time-lapse imaging of Kupffer's vesicle morphogenesis in Lgl2-deficient embryos suggested cell adhesion defects and revealed loss of the adherens junction component E-cadherin at lateral membranes. Genetic interaction experiments indicate that Lgl2 interacts with Rab11a to regulate E-cadherin and mediate lumen formation that is uncoupled from cilia formation. These results uncover new roles and interactions for Lgl2 that are crucial for both lumenogenesis and ciliogenesis and indicate that these processes are genetically separable in zebrafish.


Malformations of cerebral development and clues from the peripheral nervous system: A systematic literature review.
Clinical manifestations of malformations of cortical development (MCD) are variable and can range from mild to severe intellectual disability, cerebral palsy and drug-resistant epilepsy. Besides common clinical features, non-specific or more subtle clinical symptoms may be present in association with different types of MCD. Especially in severely affected individuals, subtle but specific underlying clinical symptoms can be overlooked or overshadowed by the global clinical presentation. To facilitate the interpretation of genetic variants detailed clinical information is indispensable. Detailed (neurological) examination can be helpful in assisting with the diagnostic trajectory, both when referring for genetic work-up as well as when interpreting data from molecular genetic testing. This systematic literature review focusses on different clues derived from the neurological examination and potential further work-up triggered by these signs and symptoms in genetically defined MCDs. A concise overview of specific neurological findings and their associations with MCD subtype and genotype are presented, easily applicable in daily clinical practice. The following pathologies will be discussed: neuropathy, myopathy, muscular dystrophies and spastic paraplegia. In the discussion section, tips and pitfalls are illustrated to improve clinical outcome in the future.


Inactivation of CHEK1 and EI24 is associated with the development of invasive cervical carcinoma: clinical and prognostic implications.
To understand the importance of frequent deletion of chromosomal 11q23.3-24.3 region in cervical carcinogenesis, alterations (deletion/methylation/mutation/expression) of the candidate genes LOH11CR2A, EI24 and CHEK1 located in the region were analyzed in 29 cervical intraepithelial neoplasia (CIN), 112 cervical carcinoma (CACX) samples and two CACX cell lines. The deletion frequency of these genes was low in CIN than in CACX [CIN: CHEK1: 28%, EI24: 21%, LOH11CR2A: 15% and CACX: CHEK1: 51%, EI24: 41%, LOH11CR2A: 36%]. Similar trend was seen in promoter methylation of these genes [CIN: CHEK1: 10%, EI24: 3%, LOH11CR2A: 3% and CACX: CHEK1: 55%, EI24: 31%, LOH11CR2A: 14%]. Mutations of the genes are a rare event. Overall alterations (deletion and methylation) of CHEK1 and EI24 were associated with progression of CACX. Quantitative mRNA expression analysis showed reduced expression of the three genes in concordance to their molecular alterations. A shorter isoform of CHEK1 lacking exon 8, hence impaired in substrate binding capacity, was found in two samples. Immunohistochemical analysis showed nuclear expression of Chek1, p-Chek1 and Ei24 in tumor tissues, whereas the cell lines exhibited both nuclear and cytoplasmic expression of Chek1 and Ei24, as is also evident from Western blot analysis suggesting differential localization of the proteins. Alterations of CHEK1 and EI24 coupled with tumor stage and early sexual debut (≤ 19 years) predicted worst prognosis. Thus, our data suggest that inactivation of EI24 and CHEK1 through two independent mechanisms contributes to the development of CACX.


BizarreParosteal Osteochondromatous Proliferation (Nora's lesion) with translocation t(1;17)(q32;q21): a case report and role of cytogenetic studies on diagnosis.
Bizarre Parosteal Osteochondromatous Proliferation (BPOP) is a benign tumor-like lesion that has recently been reported to have an association with a specific translocation t(1:17)(q32;q21)[1]. Like other reactive periosteal lesions, BPOP can be diagnostically challenging, with the ever-present possibility of a potentially devastating erroneous diagnosis of malignancy. These lesions are often clinically, radiologically and histopathologically ambiguous, with rapid but circumscribed, non-infiltrative growth patterns, and histological atypia, but without overt features of malignancy. However, recent published reports have better characterized radiological [2] as well as histological features that aid in making an accurate diagnosis. In spite of all these advances, one of the biggest challenges in making the correct diagnosis still remains the inexperience of the practicing pathologist with this lesion, simply due to its rarity. We present a case of Nora's lesion in the distal ulna of an 8 year-old girl, in which, besides the histological features, we were able to demonstrate the translocation t(1:17)(q32;q21). Thus, we would like to emphasize the utility of cytogenetic studies in the correct and rapid diagnosis of clinically and radiologically ambiguous periosteal-based lesion.


Sensors and Actuation Technologies in Exoskeletons: A Review.
Exoskeletons are robots that closely interact with humans and that are increasingly used for different purposes, such as rehabilitation, assistance in the activities of daily living (ADLs), performance augmentation or as haptic devices. In the last few decades, the research activity on these robots has grown exponentially, and sensors and actuation technologies are two fundamental research themes for their development. In this review, an in-depth study of the works related to exoskeletons and specifically to these two main aspects is carried out. A preliminary phase investigates the temporal distribution of scientific publications to capture the interest in studying and developing novel ideas, methods or solutions for exoskeleton design, actuation and sensors. The distribution of the works is also analyzed with respect to the device purpose, body part to which the device is dedicated, operation mode and design methods. Subsequently, actuation and sensing solutions for the exoskeletons described by the studies in literature are analyzed in detail, highlighting the main trends in their development and spread. The results are presented with a schematic approach, and cross analyses among taxonomies are also proposed to emphasize emerging peculiarities.


A smartphone-based system for fluorescence polarization assays.
This paper demonstrates the use of a smartphone-based sensor for fluorescence polarization (FP) analysis of biomolecules. The FP detection can rapidly sense ligand-analyte bindings by measuring molecule mobility, and thus, FP-based assays have been widely used for rapid diagnostics in clinics. Here, we implemented the FP detection apparatus using a 3D-printed compact holder and the built-in camera of a smartphone. The system offers accurate measurements of the degree of polarization by simultaneously detecting the fluorescence intensities parallel and perpendicular to the polarization of the excitation. The fluorescence signal of the sample is excited by a laser or light-emitting diode and separated by a polarization beam cube depending on the polarization. Parallel and perpendicular polarized emissions are projected onto two different regions of the sensor chip in the smartphone camera. A custom software app was developed to count the average intensity in the areas of interest and compute the degree of polarization. We validated the system by measuring the polarization of dye molecules dissolved in solutions with different viscosities. As an example of biomolecule sensing, a competitive FP immunoassay of Prostaglandin E2 was demonstrated using the developed system and exhibited the limit of detection of 1.57 ng/mL. The smartphone-based FP assay platform can also be implemented for the detection of toxins, disease biomarkers, and pathogens in resource-limited settings.


Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients.
Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.


[Analgesic quality in a postoperative pain service: continuous assessment with the cumulative sum (cusum) method].
The aim of this study was to assess the cumulative sum (cusum) method for evaluating the performance of our hospital's acute postoperative pain service. The period of analysis was 7 months. Analgesic failure was defined as a score of 3 points or more on a simple numerical scale. Acceptable failure (p0) was set at 20% of patients upon admission to the postanesthetic recovery unit and at 7% 24 hours after surgery. Unacceptable failure was set at double the p0 rate at each time (40% and 14%, respectively). The unit's patient records were used to generate a cusum graph for each evaluation. Nine hundred four records were included. The rate of failure was 31.6% upon admission to the unit and 12.1% at the 24-hour postoperative assessment. The curve rose rapidly to the value set for p0 at both evaluation times (n = 14 and n = 17, respectively), later leveled off, and began to fall after 721 and 521 cases, respectively. Our study shows the efficacy of the cusum method for monitoring a proposed quality standard. The graph also showed periods of suboptimal performance that would not have been evident from analyzing the data en block. Thus the cusum method would facilitate rapid detection of periods in which quality declines.


The mental wellbeing of current and retired professional cricketers: an observational prospective cohort study.
Scientific knowledge about symptoms of common mental disorders in professional cricket is non-existent. Consequently, the aims of the study were to determine the prevalence and the 6 months incidence of symptoms of common mental disorders (CMD: distress, anxiety/depression, sleep disturbance, adverse alcohol use) among current and former professional cricketers and to explore the association of potential stressors (significant injury, surgery, adverse life events, career dissatisfaction) and CMD. An observational prospective cohort study with a follow-up period of 6 months was conducted among current and former professional cricketers from South Africa. Using validated questionnaires to assess symptoms of common mental disorders as well as several stressors, an electronic questionnaire was set up and distributed by the South African Cricketers Association (SACA). A total of 116 participants enrolled at baseline (overall response rate of 33%) and 76 of those participants completed the 6 month follow-up (follow up rate of 66%). The prevalence of symptoms of CMD in current professional cricketers was 38% for distress, 38% for sleep disturbance, 37% for anxiety/depression and 26% for adverse alcohol use. Among former professional cricketers, baseline prevalence as was 26% for distress, 24% for anxiety/depression, 21% for sleep disturbance and 22% for adverse alcohol use. Career dissatisfaction led to an increased risk of distress, anxiety/depression and sleep disturbance in current professional cricketers. Surgeries and adverse life events led to an increase in reported symptoms of distress and anxiety/depression in current professional cricketers. It was concluded that symptoms of CMD are prevalent in both current and former professional cricketers and the association with surgery, adverse life events and cricket career dissatisfaction may provide some insight into possible mechanisms.


Intracranial Atherosclerosis Increases the Risk of Postoperative Stroke After Cardiac Surgery: A Review and Meta-Analysis.
Postoperative stroke is a devastating complication of cardiac surgery with high morbidity, mortality, and health care cost. Extracranial carotid atherosclerosis (ECAS) is a known risk factor for stroke; however, the impact of intracranial atherosclerosis (ICAS) remains unclear. To our knowledge, this is the first literature review of ICAS in cardiac surgery. We aimed to assess the prevalence, association with postoperative stroke, and perioperative management of ICAS in cardiac surgery. A search was performed to identify studies reporting rates of ICAS and stroke after cardiac surgery. Data extraction and primary outcomes for meta-analysis included the prevalence of preoperative ICAS and the association between ICAS and stroke. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled by random-effects modelling. Seventeen studies were reviewed and seven were included in the meta-analysis, comprising 4,936 patients. Prevalence of intracranial atherosclerosis (ICAS) among cardiac surgery patients was 21% (95% CI 13%-32%). Patients with ICAS were more likely to develop postoperative stroke (RR 3.61; 95% CI 2.30-5.67; p<0.001). ICAS was more closely associated with stroke than ECAS. Preoperative brain perfusion single-photon emission computed tomography with acetazolamide challenge, staged intracerebral revascularisation, or conversion to off-pump coronary artery bypass grafting are described management options for ICAS. Patients with ICAS are 3.61 times more likely to develop stroke after cardiac surgery. Known predictors for ICAS can be used to develop risk stratification screening tools. Further research with diverse cohorts is required to develop evidence-based guidelines for screening and management of ICAS in cardiac surgery.


Group testing for pathway analysis improves comparability of different microarray datasets.
The wide use of DNA microarrays for the investigation of the cell transcriptome triggered the invention of numerous methods for the processing of microarray data and lead to a growing number of microarray studies that examine the same biological conditions. However, comparisons made on the level of gene lists obtained by different statistical methods or from different datasets hardly converge. We aimed at examining such discrepancies on the level of apparently affected biologically related groups of genes, e.g. metabolic or signalling pathways. This can be achieved by group testing procedures, e.g. over-representation analysis, functional class scoring (FCS), or global tests. Three public prostate cancer datasets obtained with the same microarray platform (HGU95A/HGU95Av2) were analyzed. Each dataset was subjected to normalization by either variance stabilizing normalization (vsn) or mixed model normalization (MMN). Then, statistical analysis of microarrays was applied to the vsn-normalized data and mixed model analysis to the data normalized by MMN. For multiple testing adjustment the false discovery rate was calculated and the threshold was set to 0.05. Gene lists from the same method applied to different datasets showed overlaps between 42 and 52%, while lists from different methods applied to the same dataset had between 63 and 85% of genes in common. A number of six gene lists obtained by the two statistical methods applied to the three datasets was then subjected to group testing by Fisher's exact test. Group testing by GSEA and global test was applied to the three datasets, as well. Fisher's exact test followed by global test showed more consistent results with respect to the concordance between analyses on gene lists obtained by different methods and different datasets than the GSEA. However, all group testing methods identified pathways that had already been described to be involved in the pathogenesis of prostate cancer. Moreover, pathways recurrently identified in these analyses are more likely to be reliable than those from a single analysis on a single dataset.


Prevention and management of complications in urological laparoscopic port site placement.
To review complications associated with urological laparoscopic port-site placement and outline techniques for their prevention and management. Review of the literature using Medline. Laparoscopy now plays a key role in urological surgery. Its applications are expanding with experience and evolving data confirming equivalent long-term outcome. Although significant port-site complications are uncommon, their occurrence impacts significantly on perioperative morbidity and rate of recovery. The incidence of such complications is inversely related to surgeon experience. Ports now utilise bladeless tips to reduce the incidence of vascular and visceral injuries, and subsequently port-site herniation. Metastases occurring at the port site are preventable by adhering to certain measures. Whether performing standard or robot-assisted laparoscopy, port-site creation and maintenance is critical in ensuring minimal invasiveness in laparoscopic urological surgery. Although patient factors can be optimised perioperatively and port design continues to improve, it is clear that adequate training is central in the prevention, early recognition, and treatment of complications related to laparoscopic access.


Integrating Training in Quality Improvement and Health Equity in Graduate Medical Education: Two Curricula for the Price of One.
A recent call to address health care disparities has come from the Accreditation Council for Graduate Medical Education's (ACGME's) Clinical Learning Environment Review (CLER) program. The CLER program aspires that faculty and residents will identify the disparities among the patient populations they serve and engage in quality improvement (QI) activities designed to address them. In this Perspective, the authors provide a framework for integrating QI and health equity principles in graduate medical education to meet these ACGME expectations. The authors illustrate their four-step framework by describing a faculty development workshop that provides strategies and tools for embedding equity into existing QI educational efforts and using QI methods to address equity challenges. Using examples, the authors outline how medical educators can begin to integrate QI and equity initiatives to address health care disparities and involve their residents/fellows in the process. In addition, the authors emphasize the importance of applying an equity lens to QI interventions and of recognizing that QI initiatives will have different impacts on outcomes depending on the patient population. The authors conclude by discussing the need for institutional leadership to build capacity and training to improve data collection and reporting of quality metrics by demographic variables; provide resources to disseminate lessons learned; support faculty development to teach and mentor trainees through equity-related QI work; and prioritize time in the curriculum for learners to participate in equity improvement activities.


Hemolytic activity of Leptospira interrogans serovar canicola cultured in protein-free medium.
Hemolytic activity of the culture supernatant of Leptospira interrogans serovar canicola strain Moulton grown in protein-free medium was demonstrated. The activity began to appear in the late logarithmic phase of growth of the organism and reached a plateau after 2 weeks of cultivation. It was inactivated by the addition of dipotassium ethylenediaminetetraacetate, but was effectively restored by Mg2+. Hemolysis by the culture supernatant was stimulated by "hot-cold" incubation. Sleep erythrocytes treated with the culture supernatant of the organism were transformed into spherocytes, in which invagination was observed. A hemolysis inhibitor in rabbit serum was found to be in the chloroform-methanol soluble fraction of the serum. The hemolysin of Leptospira may be phospholipase C.


Canine leptospirosis in Puerto Rico.
Among 116 stray dogs in Puerto Rico surveyed for leptospiral agglutinins, 73 (62.9%) has significant titers to one or more leptospiral serotypes. The most common serogroup identified serologically was icterohaemorrhagiae accounting for 53 (72.6%) of the infections. Although the infection rates were comparable for male and female dogs the older were found to be more frequently infected. The significance of the canine in the epidemiology of leptospirosis in Puerto Rico is probably of paramount importance due to the extensive direct and indirect contact dogs have with rats and the human population.


ALKBH4 Functions as a Suppressor of Colorectal Cancer Metastasis via Competitively Binding to WDR5.
Epithelial-Mesenchymal Transition (EMT) is a major process in the initiation of tumor metastasis, where cancer cells lose sessile epithelial potential and gain mesenchymal phenotype. Large-scale cell identity shifts are often orchestrated on an epigenetic level and the interplay between epigenetic factors and EMT progression was still largely unknown. In this study, we tried to identify candidate epigenetic factors that involved in EMT progression. Colorectal cancer (CRC) cells were transfected with an arrayed shRNA library targeting 384 genes involved in epigenetic modification. Candidate genes were identified by real-time PCR. Western blot, RNA-seq and gene set enrichment analysis were conducted to confirm the suppressive role of ALKBH4 in EMT. The clinical relevance of ALKBH4 in CRC was investigated in two independent Renji Cohorts and a microarray dataset (GSE21510) from GEO database. In vitro transwell assay and in vivo metastatic tumor model were performed to explore the biological function of ALKBH4 in the metastasis of CRC. Co-IP (Co-Immunoprecipitation) and ChIP (Chromatin Immunoprecipitation) assays were employed to uncover the mechanism. We screened for candidate epigenetic factors that affected EMT process and identified ALKBH4 as a candidate EMT suppressor gene, which was significantly downregulated in CRC patients. Decreased level of ALKBH4 was associated with metastasis and predicted poor prognosis of CRC patients. Follow-up functional experiments illustrated overexpression of ALKBH4 inhibited the invasion ability of CRC cells in vitro, as well as their metastatic capability in vivo. Mechanistically, CO-IP and ChIP assays indicated that ALKBH4 competitively bound WDR5 (a key component of histone methyltransferase complex) and decreased H3K4me3 histone modification on the target genes including MIR21. This study illustrated that ALKBH4 may function as a novel metastasis suppressor of CRC, and inhibits H3K4me3 modification through binding WDR5 during EMT.


Vicarious Post-traumatic Growth in Professionals Exposed to Traumatogenic Material: A Systematic Literature Review.
Repeated exposure to traumatogenic material as part of work with traumatised individuals can have detrimental effects on professionals' well-being. Growing research has explored this phenomenon, known as 'vicarious traumatisation'. Nevertheless, little research has focused on the positive effects of this work on professionals, namely, 'vicarious post-traumatic growth'. This literature review aims to identify existing research demonstrating mental health professionals' experiences of growth, along with environmental and personal factors that facilitate this growth. Eight qualitative and seven quantitative articles were identified following a systematic search of six electronic databases and assessed for their quality using standardised checklists. Qualitative studies were assessed using the Quality Appraisal Checklist for Qualitative Studies (NICE, 2012), and quantitative studies were assessed using the Appraisal Tool for Cross-Sectional Studies (Downes et al., 2016). Professionals described changes in the way they view themselves, the value they place on their relationships and their appreciation for life. Important organisational factors and personal traits were identified as significant predictors for professionals' growth. Our findings have the potential to inform practical recommendations and directions for future research.


Proplast implants used in otology and in facial reconstructive surgery.
Proplast, a self-stabilising alloplastic material, was evaluated in ear surgery and in facial reconstructive surgery. Proplast implants were used on 33 patients to reconstruct the ossicular chain (total or partial ossicular replacement prosthesis), or to rebuild the mastoid cavity. The lack of extrusion over a 24-month period is encouraging. In facial reconstructive surgery 11 patients received Proplast implants to augment and restore facial contours. Contamination with saliva remains a problem, owing to the high porosity of Proplast, which could harbour infection. When Proplast was sterile when implanted, no extrusion appeared over a 12-month period. Although the patients presented here were followed up for a relatively short time, they provide reason for some optimism that the vexed question of alloplastics applied in the field of ear, nose and throat surgery may be solved.


[Home care practice in Ishigaki Island, Okinawa].
In Yaeyama district in Okinawa, despite the scarcity of health-care resources for home visit, most of the patients used to choose home care instead of in-hospital care because of their special beliefs and preference different from mainland. Since people resided in a large family and formed a tightly knit community, patients were able to receive care from their family and community members. However, together with increase in chronic care facilities and modernization of the island that have brought downsizing of the family unit and loose community, the elderly are facing difficulty in receiving home care due to lack of care-givers. In order to establish the system to support the patients who wish to receive domiciliary care and live at home in their own life style, Yaeyama Hospital is expected to provide community-based health-care services 24 hours a day. It is essential that medical and welfare professions who are in charge of home care maintain close relations in good communication and collaboration.


Intensive Care Versus Nonintensive Care Ward for Postoperative Management of Head and Neck Free Flaps: A Meta-Analysis.
Introduction: Although advances in surgical technique and medical management have drastically improved outcomes of free flap reconstructive surgery in head and neck patients, there is no clear consensus on appropriate level of postoperative care. Methods: The literature was searched systematically for all comparative studies of intensive care unit (ICU) and non-ICU admissions for head and neck patients. The primary outcomes were flap failure rate, flap complications, and hospital length of stay (LOS). Secondary outcomes included cost implications, medical complications, and rates of revision surgery, readmission, and mortality. Results: Nine articles (2510 patients) were included. Patients admitted to non-ICU wards were not significantly at increased risk for free flap failure, flap-related complications, or longer LOS. Total medical complications were found to have a pooled relative risk (RR) of 0.57 [95% confidence interval (CI) 0.40 to 0.83], favoring the non-ICU cohort. In particular, the non-ICU cohort was less likely to develop neuropsychiatric complications (RR 0.34 [95% CI 0.24 to 0.48]) and sepsis (RR 0.18 [95% CI 0.05 to 0.68]) with no difference in cardiovascular or pulmonary complications. Discussion: Patients admitted to non-ICU wards did not experience higher rates of adverse flap-related outcomes and had decreased risk of developing medical complications in the studies included in this meta-analysis.


Rapid infancy weight gain and subsequent obesity: systematic reviews and hopeful suggestions.
In a systematic review, we identified 21 separate studies with data on the association between rapid infancy weight gain, up to age 2 y, and subsequent obesity risk. Uniformly all studies reported significant positive associations. We transformed the reported effect sizes to a standard infancy weight gain exposure, and found that further differences in study design accounted for much of the variation in risk. An accompanying paper by Melinda Yeung reminds us that there are benefits of postnatal catch-up growth in certain populations, and suggests that genetic and nutritional factors could moderate the unhealthy translation of rapid infancy weight gain to visceral fat and insulin resistance. Further evidence is needed, and we will need to rigorously test the benefits and risks of any interventions. However, the concept of "healthy" rapid catch-up infancy growth is an attractive prospect. Rapid infancy weight gain is consistently associated with increased subsequent obesity risk, but the predictive ability of different weight gain cut-offs needs to be tested.


Interaction of porcine monocyte-derived dendritic cells with African swine fever viruses of diverse virulence.
African swine fever (ASF) is a devastating disease for which there is no vaccine. The ASF virus (ASFV) can infect dendritic cell (DC), but despite the critical role these cells play in induction of adaptive immunity, few studies investigated their response to ASFV infection. We characterized the in vitro interactions of porcine monocyte-derived DCs (moDC) with a virulent (22653/14), a low virulent (NH/P68) and an avirulent (BA71V) ASFV strain. At a high multiplicity of infection (MOI = 1), all three strains infected immature moDC. Maturation of moDC, with IFN-α/TNF-α, increased susceptibility to infection with 22653/14 and other virulent strains, but reduced susceptibility to NH/P68 and BA71V. The reduced moDC susceptibility to BA71V/NH/P68 was IFN-α mediated, whereas increased susceptibility to 22653/14 was induced by TNF-α. Using an MOI of 0.01, we observed that BA71V replicated less efficiently in moDC compared to the other isolates and we detected increased replication of NH/P68 compared to 22653/14. We observed that BA71V and NH/P68, but not 22653/14, downregulated expression of MHC class I on infected cells. All three strains decreased CD16 expression on moDC, whereas ASFV infection resulted in CD80/86 down-regulation and MHC class II DR up-regulation on mature moDC. None of the tested strains induced a strong cytokine response to ASFV and only modest IL-1α was released after BA71V infection. Overall our results revealed differences between strains and suggest that ASFV has evolved mechanisms to replicate covertly in inflammatory DC, which likely impairs the induction of an effective immune response.