High-throughput mapping of brain-wide activity in awake and drug-responsive vertebrates.
The reconstruction of neural activity across complete neural circuits, or brain activity mapping, has great potential in both fundamental and translational neuroscience research. Larval zebrafish, a vertebrate model, has recently been demonstrated to be amenable to whole brain activity mapping in behaving animals. Here we demonstrate a microfluidic array system ("Fish-Trap") that enables high-throughput mapping of brain-wide activity in awake larval zebrafish. Unlike the commonly practiced larva-processing methods using a rigid gel or a capillary tube, which are laborious and time-consuming, the hydrodynamic design of our microfluidic chip allows automatic, gel-free, and anesthetic-free processing of tens of larvae for microscopic imaging with single-cell resolution. Notably, this system provides the capability to directly couple pharmaceutical stimuli with real-time recording of neural activity in a large number of animals, and the local and global effects of pharmacoactive drugs on the nervous system can be directly visualized and evaluated by analyzing drug-induced functional perturbation within or across different brain regions. Using this technology, we tested a set of neurotoxin peptides and obtained new insights into how to exploit neurotoxin derivatives as therapeutic agents. The novel and versatile "Fish-Trap" technology can be readily unitized to study other stimulus (optical, acoustic, or physical) associated functional brain circuits using similar experimental strategies.


Transcription poisoning by Topoisomerase I is controlled by gene length, splice sites, and miR-142-3p.
Topoisomerase I (Top1) relaxes DNA supercoiling by forming transient cleavage complexes (Top1cc) up- and downstream of transcription complexes. Top1cc can be trapped by carcinogenic and endogenous DNA lesions and by camptothecin, resulting in transcription blocks. Here, we undertook genome-wide analysis of camptothecin-treated cells at exon resolution. RNA samples from HCT116 and MCF7 cells were analyzed with the Affy Exon Array platform, allowing high-resolution mapping along 18,537 genes. Long genes that are highly expressed were the most susceptible to downregulation, whereas short genes were preferentially upregulated. Along the body of genes, downregulation was most important toward the 3'-end and increased with the number of exon-intron junctions. Ubiquitin and RNA degradation-related pathway genes were selectively downregulated. Parallel analysis of microRNA with the Agilent miRNA microarray platform revealed that miR-142-3p was highly induced by camptothecin. More than 10% of the downregulated genes were targets of this p53-dependent microRNA. Our study shows the profound impact of Top1cc on transcription elongation, especially at intron-exon junctions and on transcript stability by microRNA miR-142-3p upregulation.


Visible ghost imaging with nonvisible light.
In this paper, we present a new scheme of thermal ghost imaging: visible ghost imaging with nonvisible light, which can overcome the disadvantages of conventional thermal imaging. For the two light beams of the thermal ghost imaging, we use the nonvisible light (i.e., infrared light) as the object beam and the visible light as the reference beam. The ghost image obtained by the nonvisible light can be directly observed. The ghost imaging with nonvisible light produces a visible and colorful ghost image, which is better than the thermal-imaging technique in color and image quality. Since the ghost imaging comes from the intensity correlations, the ghost imaging effectively overcomes the effect of the interference light. We believe that this new ghost imaging may be developed into a new night-vision technique.


Neutralization of haemorrhagic activity of viper venoms by 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile.
Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 × 10(-9) (kcal/mol) without chelating Zn(2+) in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.


Cross-Validation of Data Compatibility Between Small Angle X-ray Scattering and Cryo-Electron Microscopy.
Cryo-electron microscopy (EM) and small angle X-ray scattering (SAXS) are two different data acquisition modalities often used to glean information about the structure of large biomolecular complexes in their native states. A SAXS experiment is generally considered fast and easy but unveils the structure at very low resolution, whereas a cryo-EM experiment needs more extensive preparation and postacquisition computation to yield a three-dimensional (3D) density map at higher resolution. In certain applications, we may need to verify whether the data acquired in the SAXS and cryo-EM experiments correspond to the same structure (e.g., before reconstructing the 3D density map in EM). In this article, a simple and fast method is proposed to verify the compatibility of the SAXS and EM experimental data. The method is based on averaging the two-dimensional correlation of EM images and the Abel transform of the SAXS data. Orientational preferences are known to exist in cryo-EM experiments, and we also consider these effects on our method. The results are verified on simulations of conformational states of large biomolecular complexes.


Rare combination of familial adenomatous polyposis and gallbladder polyps.
Familial adenomatous polyposis is associated with a high incidence of malignancies in the upper gastrointestinal tract (particularly ampullary adenocarcinomas). However, few reports have described a correlation between familial adenomatous polyposis and gallbladder neoplasms. We present a case of a 60-year-old woman with familial adenomatous polyposis who presented with an elevated mass in the neck of the gallbladder (measuring 16 mm × 8 mm in diameter) and multiple small cholecystic polyps. She had undergone a total colectomy for ascending colon cancer associated with familial adenomatous polyposis 22 years previously. The patient underwent laparoscopic cholecystectomy under a preoperative diagnosis of multifocal gallbladder polyps. Pathologic examination of the resected gallbladder revealed more than 70 adenomatous lesions, a feature consistent with adenoma of the gallbladder. This case suggests a requirement for long-term surveillance of the biliary system in addition to the gastrointestinal tract in patients with familial adenomatous polyposis.


Controlled copper-mediated chlorination of phenol rings under mild conditions.
The very unusual case of copper-mediated chlorination of phenol rings under mild conditions at room temperature is reported. Reaction of the ligand 1,7-bis(2-hydroxyphenyl)-2,6-diaza-4-hydroxylheptane (H3L1) with CuCl2 in acetonitrile leads to either the formation of a tetranuclear copper(II) complex [Cu4(HL3)2(mu-Cl)2Cl2](CH3CN) (1) or a linear trinuclear complex [Cu3(HL1)2Cl2(CH3CN)2](CH3CN)2 (2), depending on the reaction conditions. Both compounds have been fully characterized, including the determination of their 3D structures by X-ray diffraction. The unprecedented tetranuclear compound 1 is constituted of a dichlorido-bridged dimer of di-mu-phenoxido-dinuclear species, whereas the trinuclear complex 2 presents a linear array of copper(II) ions, held together through di-mu-phenoxido bridges of the central and external ions. The magnetic susceptibility of the two compounds was investigated, revealing either very strong (J<-500 cm-1) or strong (J value around -370(1) cm-1) antiferromagnetic dominant interactions among the CuII ions for 1 and 2, respectively. The tetranuclear complex 1 is obtained, under dry conditions, through the in situ formation of ligand HL3 (H3L3=1,7-bis(2-hydroxy-5-chlorophenyl)-2,6-diaza-4-hydroxylheptane) by oxidative chlorination of (HL1)2-. In the presence of traces of water, 1 is partially hydroxylated at the ortho position of one of the phenyl rings. The use of trimethylorthoformate as the dehydrating agent prevents the formation of hydroxylated ligands. Several partly chlorinated/hydroxylated products (identified as H3L2) have also been obtained through slight variations of the synthetic procedures (presence or absence of water and/or triethylamine in the reaction mixtures). These partially chlorinated and/or hydroxylated coordination species are mutually isomorphous to either 1 or 2. Several "modified" ligands have been isolated and characterized by 1H NMR and MS, after reaction with sodium sulfide of the complexes formed.


Mortality study of employees with potential exposure to epichlorohydrin: a 10 year update.
A 10 year extension of follow up (up to 1993) of 863 employees who had potential exposure to epichlorohydrin at two chemical plants between May 1948 and December 1965 was conducted to further evaluate the previously reported potential association between exposure to epichlorohydrin and heart disease. The mortality observed was compared with that expected from the death rates from the local male population where these chemical plants are located. Workers were assigned to one of five exposure categories based on their job with the highest level of potential exposure. Vital status was ascertained to the end of 1993. Among diseases of particular interest, there were no excess deaths from heart disease (standardised mortality ratio (SMR) 63.3), lung cancer (SMR 63.8), or non-malignant respiratory disease (SMR 37.7) for employees with 20 or more years after first exposure. Based on the level of potential exposure to epichlorohydrin, mortality for heart disease was slightly higher (SMR 75.7, 95% confidence interval (95% CI) 51.8-106.7) in the moderate to heavy exposure group than in the none to light exposure group (SMR 59.5, 95% CI 37.7-89.3); this difference is well within the range of random variation. The SMR for heart disease was 90.4 among employees who had both probable exposure to allyl chloride and moderate to heavy exposure to epichlorohydrin, although it was 88.1 among employees who had moderate to heavy potential exposure to epichlorohydrin but no exposure to allyl chloride. This study does not support an association between exposure to epichlorohydrin and heart disease or lung cancer. There were no additional deaths from leukaemia in this update; the raised SMR for leukaemia noted in the previous study has substantially decreased from 500.0 to 161.3 (95% CI 33.2-471.0) and is not significant. The overall mortality and cancer mortality of employees potentially exposed to epichlorohydrin continued to be lower than that of the local population.


Study on performance of magnetic fluorescent nanoparticles as gene carrier and location in pig kidney cells.
We evaluated the performance of green fluorescent magnetic Fe3O4 nanoparticles (NPs) as gene carrier and location in pig kidney cells. When the mass ratio of NPs to green fluorescent protein plasmid DNA reached 1:16 or above, DNA molecules can be combined completely with NPs, which indicates that the NPs have good ability to bind negative DNA. Atomic force microscopy (AFM) experiments were carried out to investigate the binding mechanism between NPs and DNA. AFM images show that individual DNA strands come off of larger pieces of netlike agglomerations and several spherical nanoparticles are attached to each individual DNA strand and interact with each other. The pig kidney cells were labelled with membrane-specific red fluorescent dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate and nucleus-specific blue fluorescent dye 4',6-diamidino-2-phenylindole dihydrochloride. We found that green fluorescent nanoparticles can past the cell membrane and spread throughout the interior of the cell. The NPs seem to locate more frequently in the cytoplasm than in the nucleus.


Circulating pigment epithelium-derived factor levels are associated with insulin resistance and decrease after weight loss.
We aimed to study circulating pigment epithelium-derived factor (PEDF) in vivo in association with insulin resistance and in vitro in human adipocytes. Circulating PEDF (ELISA) and metabolic profile were assessed in 125 Caucasian men. PEDF levels were also assessed in an independent cohort of subjects (n = 33) to study the effects of changing insulin action. PEDF gene expression and secretion were measured during differentiation of human preadipocytes. In all subjects, PEDF was positively associated with body mass index (r = 0.326; P < 0.0001), waist-to-hip ratio (r = 0.380; P < 0.0001), HbA(1c), and fasting triglycerides and negatively with insulin sensitivity (r = -0.320; P < 0.0001). PEDF levels were significantly increased in subjects with altered glucose tolerance and type 2 diabetes. Of the inflammatory markers measured, PEDF levels were positively associated with serum soluble TNF-α receptor 1 and IL-10 in obese subjects. Interestingly, weight loss led to significantly decreased PEDF concentration from 34.8 ± 19.3 to 22.5 ± 14.2 μg/ml (P < 0.0001). Multiple linear regression analyses revealed that insulin sensitivity contributed independently to explain 14% of the variance in PEDF levels after controlling for the effects of body mass index, age, and log fasting triglycerides. Differences in PEDF observed after weight loss were related to changes in obesity, insulin resistance, and blood pressure measures. PEDF gene expression and secretion increased during differentiation of human preadipocytes. Circulating PEDF is associated with insulin sensitivity. The findings show, for the first time in humans, that PEDF concentrations decrease significantly after weight loss in association with blood pressure. PEDF seems to be involved in human adipocyte biology.


Investigation of enterohemorrhagic Escherichia coli O157:H7 adherence characteristics and invasion potential reveals a new attachment pattern shared by intestinal E. coli.
In this study, the interactions of enterohemorrhagic Escherichia coli (EHEC) O157 strains with human ileocecal (HCT-8) epithelial cells and HEp-2 cells were examined. EHEC adhered to, but did not invade, HCT-8 cells by the localized adherence mechanism and a heretofore unrecognized pattern which we called log jam. The log jam formation was (i) not observed on HEp-2 cells, (ii) independent of the EHEC eaeA gene required for localized adherence, and (iii) shared by pathogenic and nonpathogenic E. coli strains but not K-12 strains. The log jam phenotype may represent a basal means by which E. coli bacteria attach to the human intestine.


Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial.
Increases in body weight (BW) are important determinants for hospitalization in ambulatory patients with heart failure (HF), but have not yet been explored in patients hospitalized for worsening HF. We explore the relationship between change in BW after hospitalization for worsening HF and risk for repeat hospitalization and mortality in the EVEREST trial. The EVEREST trial randomized 4133 patients hospitalized for worsening HF and low ejection fraction (< or =40%) to tolvaptan, a vasopressin antagonist, or placebo. Following discharge, BW was assessed at 1, 4, and 8 weeks, and every 8 weeks thereafter. A time-dependent Cox proportional Hazard model explored the relationship between change in BW at 60, 120, and 180 days from discharge and the risks of HF hospitalization, cardiovascular (CV) hospitalization, and all-cause mortality. For subjects re-hospitalized for heart failure at 60, 120, and 180 days after discharge, mean BW increase prior to the event was 1.96, 2.07, and 1.97 kg, respectively, compared with 0.74, 0.90, and 1.04 kg in patients without re-hospitalization (P < 0.001 all groups). A similar pattern was observed with CV hospitalization. However, increases in BW were not predictive of all-cause mortality. Increases in BW after hospitalization for worsening HF was predictive of repeat hospitalization events, but not mortality in the post-discharge period.


Bibliometric analysis of global scientific research on carbapenem resistance (1986-2015).
Antimicrobial resistance is a global public health challenge and carbapenem resistance, in particular, is considered an urgent global health threat. This study was carried out to give a bibliometric overview of literature on carbapenem resistance. In specific, number of publications, top productive countries and institutes, highly cited articles, citation analysis, co-authorships, international collaboration, top active authors, and journals publishing articles on carbapenem resistance were analyzed and discussed. Specific keywords pertaining to carbapenem resistance were used in Scopus database. Quantitative and qualitative analysis of retrieved data were presented using appropriate bibliometric indicators and visualization maps. A total of 2617 journal articles were retrieved. The average number of citations per article was of 21.47. The growth of publications showed a dramatic increase from 2008 to 2015. Approximately 9 % of retrieved articles on carbapenem resistance were published in Antimicrobial Agents and Chemotherapy journal. Retrieved articles were published by 102 different countries. The United States of America (USA) contributed most with 437 (16.70 %) articles followed by China with 257 (9.82 %) articles. When productivity was stratified by population size, Greece ranked first followed by France. Greece also ranked first when data were stratified by gross domestic product (GDP). Asian countries have lesser international collaboration compared with other countries in the top ten list. Five of top ten productive institutes were Europeans (France, the UK, Greece, Italy, and Switzerland) and two were Asians (China and South Korea). Other active institutes included an Israeli and a Brazilian institute. Four of the top ten cited articles were published in Antimicrobial Agents and Chemotherapy journal and two were published in The Lancet Infectious Diseases. There was a dramatic increase in number of publications on carbapenem resistance in the past few years. These publications were produced from different world regions including Asia, Europe, Middle East, and Latin America. International collaboration needs to be encouraged particularly for researchers in Asia. Molecular biology and epidemiology dominated the theme of the top ten cited articles on carbapenem resistance. This bibliometric study will hopefully help health policy makers in planning future research and allocating funds pertaining to carbapenem resistance.


Experimental and modeling analysis of Synechocystis sp. PCC 6803 growth.
The influence of different parameters such as temperature, irradiance, nitrate concentration, pH, and an external carbon source on Synechocystis PCC 6803 growth was evaluated. 4.5-ml cuvettes containing 2 ml of culture, a high-throughput system equivalent to batch cultures, were used with gas exchange ensured by the use of a Parafilm™ cover. The effect of the different variables on maximum growth was assessed by a multi-way statistical analysis. Temperature and pH were identified as the key factors. It was observed that Synechocystis cells have a strong influence on the external pH. The optimal growth temperature was 33°C while light-saturating conditions were reached at 40 µE·m⁻²·s⁻¹. It was demonstrated that Synechocystis exhibits a marked difference in behavior between autotrophic and glucose-based mixotrophic conditions, and that nitrate concentrations did not have a significant influence, probably due to endogenous nitrogen reserves. Furthermore, a dynamic metabolic model of Synechocystis photosynthesis was developed to gain insights on the underlying mechanism enabling this cyanobacterium to control the levels of external pH. The model showed a coupled effect between the increase of the pH and ATP production which in turn allows a higher carbon fixation rate.


Insecticide susceptibility status of Phlebotomus (Paraphlebotomus) sergenti and Phlebotomus (Phlebotomus) papatasi in endemic foci of cutaneous leishmaniasis in Morocco.
In Morocco, cutaneous leishmaniasis is transmitted by Phlebotomus sergenti and Ph. papatasi. Vector control is mainly based on environmental management but indoor residual spraying with synthetic pyrethroids is applied in many foci of Leishmania tropica. However, the levels and distribution of sandfly susceptibility to insecticides currently used has not been studied yet. Hence, this study was undertaken to establish the susceptibility status of Ph. sergenti and Ph. papatasi to lambdacyhalothrin, DDT and malathion. The insecticide susceptibility status of Ph. sergenti and Ph. papatasi was assessed during 2011, following the standard WHO technique based on discriminating dosage. A series of twenty-five susceptibility tests were carried out on wild populations of Ph. sergenti and Ph. papatasi collected by CDC light traps from seven villages in six different provinces. Knockdown rates (KDT) were noted at 5 min intervals during the exposure to DDT and to lambdacyhalothrin. After one hour of exposure, sandflies were transferred to the observation tubes for 24 hours. After this period, mortality rate was calculated. Data were analyzed by Probit analysis program to determine the knockdown time 50% and 90% (KDT50 and KDT90) values. Study results showed that Ph.sergenti and Ph. papatasi were susceptible to all insecticides tested. Comparison of KDT values showed a clear difference between the insecticide knockdown effect in studied villages. This effect was lower in areas subject to high selective public health insecticide pressure in the framework of malaria or leishmaniasis control. Phlebotomus sergenti and Ph. papatasi are susceptible to the insecticides tested in the seven studied villages but they showed a low knockdown effect in Azilal, Chichaoua and Settat. Therefore, a study of insecticide susceptibility of these vectors in other foci of leishmaniasis is recommended and the level of their susceptibility should be regularly monitored.


A Prospective Open-Label Study of Combined Treatment for Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive Treatment.
The purpose of this study was to examine the effectiveness and safety of combined treatment using acupuncture and bee venom acupuncture (BVA) as an adjunctive treatment for idiopathic Parkinson's disease (PD). Eleven patients (7 men and 4 women) with idiopathic PD who had been receiving a stable dose of anti-parkinsonian medication for at least 4 weeks. Participants received conventional treatment for 12 weeks. Subsequently, they received additional treatment with acupuncture and BVA twice weekly for 12 weeks while still maintaining conventional treatment. All participants were assessed at baseline, 12 weeks, and 24 weeks by using the Unified Parkinson's Disease Rating Scale (UPDRS), the Parkinson's Disease Quality of Life Questionnaire (PDQL), the speed and number of steps required to walk 20 m, and the Beck Depression Inventory (BDI). Maximum excursion and directional control, measured by computerized dynamic posturography (Balance Master(®) System, NeuroCom, San Carlos, CA), were used to assess postural stability. Patients who underwent 12 weeks of twice-weekly combined treatment with acupuncture and BVA showed significant improvements in gait speed, PDQL score, activities of daily living (UPDRS part II), motor symptoms (UPDRS part III), and combined UPDRS part II+III scores compared with assessments after conventional treatment. Combined treatment with acupuncture and BVA showed promising results as a safe adjunctive therapy for PD.


Medication adherence assessment: high accuracy of the new Ingestible Sensor System in kidney transplants.
This open-label single-arm exploratory study evaluated the accuracy of the Ingestible Sensor System (ISS), a novel technology for directly assessing the ingestion of oral medications and treatment adherence. ISS consists of an ingestible event marker (IEM), a microsensor that becomes activated in gastric fluid, and an adhesive personal monitor (APM) that detects IEM activation. In this study, the IEM was combined to enteric-coated mycophenolate sodium (ECMPS). Twenty stable adult kidney transplants received IEM-ECMPS for a mean of 9.2 weeks totaling 1227 cumulative days. Eight patients prematurely discontinued treatment due to ECMPS gastrointestinal symptoms (n=2), skin intolerance to APM (n=2), and insufficient system usability (n=4). Rash or erythema due to APM was reported in 7 (37%) patients, all during the first month of use. No serious or severe adverse events and no rejection episode were reported. IEM detection accuracy was 100% over 34 directly observed ingestions; Taking Adherence was 99.4% over a total of 2824 prescribed IEM-ECMPS ingestions. ISS could detect accurately the ingestion of two IEM-ECMPS capsules taken at the same time (detection rate of 99.3%, n=2376). ISS is a promising new technology that provides highly reliable measurements of intake and timing of intake of drugs that are combined with the IEM.


Effective dissipation: Breaking time-reversal symmetry in driven microscopic energy transmission.
At molecular scales, fluctuations play a significant role and prevent biomolecular processes from always proceeding in a preferred direction, raising the question of how limited amounts of free energy can be dissipated to obtain directed progress. We examine the system and process characteristics that efficiently break time-reversal symmetry at fixed energy loss; in particular for a simple model of a molecular machine, an intermediate energy barrier produces unusually high asymmetry for a given dissipation. We relate the symmetry-breaking factors found in this model to recent observations of biomolecular machines.


Zika Virus Disease.
The Zika virus is an arbovirus belonging to the virus family Flaviviridae. The virus was isolated in 1947 from a rhesus monkey in the Zika Forest of Uganda. The virus causes sporadic mild human infections in Africa and later in Asia. However, by 2007 a major shift in its infection pattern was noticed and thousands of human infections were reported in the State of Yap and Federated States of Micronesia. In the last 3 years, major outbreaks have continued to occur and the virus has spread to several Pacific and American countries. These outbreaks were mostly asymptomatic; however, there were more severe clinical signs associated with the infections. Those signs included microcephaly and Guillain-Barre syndrome. It is believed that various species of mosquitoes can biologically transmit the virus. However, Aedes aegypti is most widely associated with the Zika virus. Recently, new modes of virus transmission have been reported, including mother-to-fetus, sexual, blood transfusion, animal bites, laboratory exposure and breast milk. Differential diagnosis is very important as some other arboviruses such as yellow fever virus, West Nile virus, dengue virus, and chikungunya virus have similar clinical manifestations to the Zika virus infection as well as relating serologically to some of these viruses. Established laboratory diagnostic tests to detect the Zika virus are limited, with reverse transcription polymerase chain reaction being the most widely used test. Taking into consideration the quickness of the spread of infection, size of the infected population and change of the infection severity pattern, the Zika virus infection merits collective efforts on all levels to prevent and control the disease. Limited research work and data, concurrent infection with other arboviruses, involvement of biological vectors, mass crowd events, human and trade movements and lack of vaccines are some of the challenges that we face in our efforts to prevent and control the Zika virus infection.


Stroke prevention. MATCHing therapy to the patient with TIA.
The short-term risk of stroke after transient ischemic attack (TIA) is about 10% to 20% in the first 3 months, with much of the risk front-loaded in the first week. Unfortunately, little is known about the best therapies for hyperacute stroke prevention after TIA. A recent trial referred to by the acronym MATCH (for Management of Atherothrombosis With Clopidogrel in High-risk Patients With Recent Transient Ischemic Attack or Ischemic Stroke) provides hypothesis-generating data to suggest that double antiplatelet therapy in the short term may be appropriate. Here, the authors discuss treatment considerations, outlining the current knowledge and stressing the need for formal randomized trials to definitively establish the effectiveness of preventive therapies after minor stroke or TIA.


Awareness of symptoms and risk factors of ovarian cancer in a population of women and healthcare providers.
Awareness of ovarian cancer among women and healthcare providers is understudied. An early awareness of ovarian cancer may lead to early detection and treatment of ovarian cancer. The purpose of this study was to determine the level of that awareness among a sample of women and providers. Written surveys were developed by the authors based on available literature and were administered to women (n = 857) and healthcare providers (n = 188) attending or volunteering at a community health fair. Chi-square tests for independence and z tests were used for analysis. Healthcare providers were significantly more likely to identify the symptoms and risk factors for ovarian cancer. Forty percent of women reported being at least slightly familiar with the symptoms of ovarian cancer. Women who were familiar with symptoms were significantly more likely to identify symptoms and risk factors correctly and to report symptoms immediately to a provider. Identification of symptoms among healthcare providers ranged from 59%-93%. Identification of ovarian cancer symptoms and risk factors is poor among women, and knowledge deficits are present in providers. Increasing familiarity and awareness could lead to improvements in early diagnosis.


Two new missense mutations in the protein interaction ASH domain of OCRL1 identified in patients with Lowe syndrome.
The oculocerebrorenal syndrome of Lowe is a rare X-linked disease characterized by congenital cataracts, proximal renal tubulopathy, muscular hypotonia and mental impairment. This disease is caused by mutations in the OCRL gene encoding membrane bound inositol polyphosphate 5-phosphatase OCRL1. Here, we examined the OCRL gene of two Lowe syndrome patients and report two new missense mutations that affect the ASH domain involved in protein-protein interactions. Genomic DNA was extracted from peripheral blood of two non-related patients and their relatives. Exons and flanking intronic regions of OCRL were analyzed by direct sequencing. Several bioinformatics tools were used to assess the pathogenicity of the variants. The three-dimensional structure of wild-type and mutant ASH domains was modeled using the online server SWISS-MODEL. Clinical features suggesting the diagnosis of Lowe syndrome were observed in both patients. Genetic analysis revealed two novel missense variants, c.1907T>A (p.V636E) and c.1979A>C (p.H660P) in exon 18 of the OCRL gene confirming the clinical diagnosis in both cases. Variant c.1907T>A (p.V636E) was inherited from the patient's mother, while variant c.1979A>C (p.H660P) seems to have originated de novo. Analysis with bioinformatics tools indicated that both variants are pathogenic. Both amino acid changes affect the structure of the OCRL1 ASH domain. In conclusion, the identification of two novel missense mutations located in the OCRL1 ASH domain may shed more light on the functional importance of this domain. We suggest that p.V636E and p.H660P cause Lowe syndrome by disrupting the interaction of OCRL1 with other proteins or by impairing protein stability.


Cyberbullying among adolescents: the role of affective and cognitive empathy, and gender.
The purpose of the study was to examine the association between affective empathy, cognitive empathy, and gender on cyberbullying among adolescents. Participants were 396 adolescents from Singapore with age ranging from 12 to 18 years. Adolescents responded to a survey with scales measuring both affective and cognitive empathy, and cyberbullying behavior. A three-step hierarchical multiple regression analysis was used with cyberbullying scores as the dependent variable. Gender was dummy coded and both affective and cognitive empathy were centered using the sample mean prior to creating interaction terms and entering them into the regression equations. The testing, probing and interpretation of interaction effects followed established statistical procedures. Results from hierarchical multiple regression analysis indicated a significant three-way interaction. At low affective empathy, both boys and girls who also had low cognitive empathy had higher scores on cyberbullying than those who had high cognitive empathy. This pattern of results was similarly found for boys at high affective empathy. However, for girls, high or low levels of cognitive empathy resulted in similar levels of cyberbullying. Implications of these findings include the need for empathy training and the importance of positive caregiver-child relationships in reducing cyberbullying behavior among adolescents.


Time-dependent inhibitory effect of lipopolysaccharide injection on Per1 and Per2 gene expression in the mouse heart and liver.
Lipopolysaccharide (LPS) is a pathogen-associated large molecule responsible for sepsis-related endotoxic shock, and the heart is one of the most common organs adversely affected. LPS is reported to increase serum TNFalpha levels and reduce Per1 and Per2 gene expression. Therefore, in this experiment, we determined the time-dependent effects of LPS on heart rate (HR) and circadian gene expression in the mouse heart and liver. HR of the LPS group was significantly elevated 2 and 8 h after injection compared to the control group. A significant percent increase in HR was observed at ZT6, 12, and 18. LPS increased Tnfalpha mRNA expression in the heart and liver at ZT6, 18, and 24. A time-dependent effect of LPS on reduction of Per1 and Per2 gene expression was also observed in the heart and liver. In order to examine the effect of LPS on cell damage, we examined apoptosis-related gene expression after LPS injection. Bax mRNA expression level of the LPS group was higher than that of the control group 8 and 26 h after injection. On the other hand, Bcl2 mRNA expression level of the LPS group was lower than that of the control group 2 and 26 h after injection. Dexamethasone strongly attenuated the LPS-induced increase of serum TNFalpha without significant change in Per1 and Per2 gene expression in the heart. In conclusion, the present results demonstrated that LPS exerts a time-dependent inhibitory effect on Per1 and Per2 gene expression in the heart and liver. The chronopharmacological lethal effect of LPS may be related to the time-dependent increase of serum TNFalpha level and simultaneously high level of Per2 gene expression in the heart and liver between ZT12-18. Taken together, chronopharmacological effect of LPS may be related to not only sickness behavior syndrome and mortality, but also circadian rhythm systems.


Pre-arrest predictors of failure to survive after in-hospital cardiopulmonary resuscitation: a meta-analysis.
Our objective was to perform a systematic review of pre-arrest predictors of the outcome of in-hospital cardiopulmonary resuscitation (CPR) in adults. We searched PubMed for studies published since 1985 and bibliographies of previous meta-analyses. We included studies with predominantly adult patients, limited to in-hospital arrest, using an explicit definition of cardiopulmonary arrest and CPR and reporting survival to discharge by at least one pre-arrest variable. A total of 35 studies were included in the final analysis. Inclusion criteria, design elements and results were abstracted in parallel by both investigators. Discrepancies were resolved by consensus. The rate of survival to discharge was 17.5%; we found a trend towards increasing survival in more recent studies. Metastatic malignancy [odds ratio (OR) 3.9] or haematologic malignancy (OR 3.9), age over 70, 75 or 80 years (OR 1.5, 2.8 and 2.7, respectively), black race (OR 2.1), altered mental status (OR 2.2), dependency for activities of daily living (range OR 3.2-7.0 depending on specific activity), impaired renal function (OR 1.9), hypotension on admission (OR 1.8) and admission for pneumonia (OR 1.7), trauma (OR 1.7) or medical non-cardiac diagnosis (OR 2.2) were significantly associated with failure to survive to discharge; cardiovascular diagnoses and co-morbidities were associated with improved survival (range OR 0.23-0.53). Elevated CPR risk scores predicted failure to survive but have not been validated consistently in different populations. We identified several pre-arrest variables associated with failure to survive to discharge. This information should be shared with patients as part of a shared decision-making process regarding the use of do not resuscitate orders.


Next of kin's feelings of guilt and shame in end-of-life care.
In this study the aim was to explore and describe next of kin's feelings of guilt and shame in end-of-life care via secondary analysis of 47 qualitative interviews. In the analysis categories and subcategories emerged which conveyed how the next of kin experienced guilt; not having done or talked enough, being absent at important events or making errors of judgement. Categories conveying feelings of shame were situations where the next of kin felt inferior, was ashamed on behalf of the dying person and when family conflicts became apparent. Receiving help and support in order to make the remaining period as pleasant as possible can facilitate the next of kin's sense of having fulfilled their duties and responsibilities and therein reduce feelings of guilt and shame. It is apparent that these feelings should be taken into account and the next of kin should receive support to increase their well-being during the remaining time in end-of-life care and the grieving period.


Vagal cardiovascular reflexes in young persons with syncope.
To study the neurocardiologic reflexes in young persons who have fainted under conditions of emotional stress. Case-control study. Clinical neurophysiology laboratory in Haifa, Israel. Sixty persons (41 women and 19 men), 15 to 17 years old, who were referred for study because of syncope related to an emotionally distressing event. Forty aged-matched, healthy volunteers drawn from the same population served as controls. Resting electrocardiogram, inspiratory-expiratory difference in heart rate during deep breathing, heart rate response to the Valsalva maneuver, and blood pressure during motionless standing for 5 minutes. Although individual results were within widely accepted limits of normal, patients with syncope as a group had higher vagal autonomic tone than did controls. This manifested as a slower heart rate at rest (mean, 67.8 beats/min compared with 73.2 beats/min; P = 0.005), a higher inspiratory-expiratory difference in heart rate (mean, 44.1 beats/min compared with 37.9 beats/min; P = 0.001), and a higher Valsalva ratio (1.91 compared with 1.72; P < 0.0001). No significant difference was found in the PR and QTc (QT interval corrected for rate) intervals of the electrocardiogram or in the blood pressure response to standing. Many young persons who faint under conditions of emotional distress do so because a relatively high vagal tone predisposes them to the cardioinhibitory component of the syncope. Age-related physiologic reduction in vagal cardiac responses may explain the lower incidence of this type of syncope with increasing age.


College openings in the United States increase mobility and COVID-19 incidence.
School and college reopening-closure policies are considered one of the most promising non-pharmaceutical interventions for mitigating infectious diseases. Nonetheless, the effectiveness of these policies is still debated, largely due to the lack of empirical evidence on behavior during implementation. We examined U.S. college reopenings' association with changes in human mobility within campuses and in COVID-19 incidence in the counties of the campuses over a twenty-week period around college reopenings in the Fall of 2020. We used an integrative framework, with a difference-in-differences design comparing areas with a college campus, before and after reopening, to areas without a campus and a Bayesian approach to estimate the daily reproductive number (Rt). We found that college reopenings were associated with increased campus mobility, and increased COVID-19 incidence by 4.9 cases per 100,000 (95% confidence interval [CI]: 2.9-6.9), or a 37% increase relative to the pre-period mean. This reflected our estimate of increased transmission locally after reopening. A greater increase in county COVID-19 incidence resulted from campuses that drew students from counties with high COVID-19 incidence in the weeks before reopening (χ2(2) = 8.9, p = 0.012) and those with a greater share of college students, relative to population (χ2(2) = 98.83, p < 0.001). Even by Fall of 2022, large shares of populations remained unvaccinated, increasing the relevance of understanding non-pharmaceutical decisions over an extended period of a pandemic. Our study sheds light on movement and social mixing patterns during the closure-reopening of colleges during a public health threat, and offers strategic instruments for benefit-cost analyses of school reopening/closure policies.


Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma.
Tumor-associated B7-H1 molecules inhibit antitumor immunity in some malignancies. We found that B7-H1 expression on patient myeloma cells and human myeloma cell lines (HMCLs) was upregulated by cultivating the cells with autologous stromal cells and the human stromal cell line HS-5. Among major cytokines produced by HS-5 cells, interleukin (IL)-6-induced B7-H1 expression on HMCLs. Moreover, HS-5 cell-mediated B7-H1 expression was downregulated by inhibiting IL-6. B7-H1(+) HMCLs were more proliferative and less susceptible to antimyeloma chemotherapy compared with B7-H1(-) HMCLs. Moreover, the former cells showed higher levels of Bcl-2 and FasL expression than the latter. Finally, B7-H1 molecules on HMCLs induced T-cell apoptosis and anergy of tumor-specific T cells. Consistent with these in vitro observations, patients whose myeloma cells expressed high levels of B7-H1 had higher myeloma cell percentages in the bone marrow (BM) and higher serum lactate dehydrogenase levels compared with other myeloma patients. In addition, B7-H1 expression levels were often upregulated after myeloma patients relapsed or became refractory to therapy. Our data indicate that the BM microenvironment upregulates B7-H1 expression on myeloma cells, which links to the two biological actions of inducing T-cell downregulation and enhancing aggressive myeloma-cell characteristics. Modulating the B7-H1 pathway may be worthwhile in myeloma.


Enhancing the scalability of the collaborative care model for depression using mobile technology.
The collaborative care model (CoCM) has substantial support for improving behavioral health care in primary care. However, large-scale CoCM adoption relies on addressing operational and financial implementation challenges across health care settings with varying resources. An academic medical center serving socioeconomically and racially diverse patients implemented the CoCM in seven practices. A smartphone application was introduced to facilitate CoCM care management during depression treatment (app-augmented CoCM). App features included secure texting, goal/appointment reminders, symptom monitoring, and health education material. A nonrandomized convenience patient sample (N = 807) was enrolled in app-augmented CoCM and compared with patients in standard CoCM (N = 3,975). Data were collected on clinical contact frequency, engagement, and clinical outcomes. App-augmented CoCM patients received more health care team contacts (7.9 vs. 4.9, p < .001) and shorter time to follow up compared with the standard CoCM sample (mean = 11 vs. 19 days, p < .001). App-augmented CoCM patients had clinical outcomes similar to the standard CoCM group (47% vs. 46% with ≥50% depression improvement or score <10), despite app-augmented patients having more prior depression treatment episodes. Further, the app-augmented group with greater app engagement demonstrated increased behavioral health appointment compliance, including more completed appointments and fewer no shows, and greater depression symptom improvement than those with less app engagement. App-augmented CoCM may improve patient engagement in treatment and provide opportunities to implement key CoCM elements without overburdening practice resources. CoCM sustainability and scalability in primary care may be enhanced by using this technology.


Failure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice.
Vision loss caused by photoreceptor death represents one of the first symptoms in neuronal ceroid lipofuscinosis, a condition characterized by accumulation of intracellular waste. Cln6nclf mice have a naturally occurring mutation in ceroid-lipofuscinosis neuronal (CLN) protein 6 and are a model of this disorder. In order to identify the effect intracellular waste (lipofuscin) accumulation plays in driving retinal degeneration, the time course of degeneration was carefully characterized functionally using the electroretinogram and structurally using histology. Cln6nclf and C57BL/6J, wild-type, mice were studied at postnatal day 18 (P18), P30, P60, P120, and P240, and retinal degeneration was correlated with changes in the retinal pigment epithelial (RPE) and neuronal autophagy-lysosomal pathways using super-resolution microscopy. In Cln6nclf mice there was significant loss of rod photoreceptor function at P18, prior to photoreceptor nuclei loss at P60. In contrast, cone pathway function was not affected until P240. The loss of rod photoreceptor function correlated with significant disruption of the autophagy-lysosomal degradation pathways within photoreceptors, but not in the RPE or other retinal neurons. Additionally, there was cytosolic accumulation of P62 and undigested mitochondrial-derived, ATP synthase subunit C in the photoreceptor layers of Cln6nclf mice at P30. These results suggest that rod photoreceptors have an increased sensitivity to disturbances in the autophagy-lysosomal pathway and the subsequent failure of mitochondrial turnover, relative to other retinal cells. It is likely that primary failure of the rod photoreceptors rather than the RPE or other retinal neurons underlies the early visual dysfunction that occurs in the Cln6nclf mouse model.


Optical properties of spheres containing several spherical inclusions.
The formalism that was previously devised [J. Opt. Soc. Am. A 9, 1327 (1992)] to deal with the optical properties of homogeneous spheres containing an eccentric spherical inclusion is extended to the case of several inclusions. The extinction efficiency of dielectric spheres containing two identical metallic inclusions is calculated for a few significant geometries. Extinction by a low-density dispersion of the anisotropic scatterers mentioned above is also evaluated. Our results show that the subdivision of the included material has quite visible effects that strongly depend on both the polarization of the incident light and the geometric arrangement of the inclusions.


The effect of zinc limitation on the transcriptome of Pseudomonas protegens Pf-5.
Zinc is an important nutrient but can be lacking in some soil environments, influencing the physiology of soil-dwelling bacteria. Hence, we studied the global effect of zinc limitation on the transcriptome of the rhizosphere biocontrol strain Pseudomonas protegens Pf-5 (formerly Pseudomonas fluorescens). We observed that the expression of the putative zinc uptake regulator (Zur) gene was upregulated, and we mapped putative Zur binding sites in the Pf-5 genome using bioinformatic approaches. In line with the need to regulate intracellular zinc concentrations, an array of potential zinc transporter genes was found to be zinc-regulated. To adapt to low-zinc conditions, a gene cluster encoding non-zinc-requiring paralogues of zinc-dependent proteins was also significantly upregulated. Similarly, transcription of genes encoding non-zinc-requiring paralogues of ribosomal proteins L31 and L36 was increased by zinc limitation. A strong transcriptional downregulation of the putative copper chaperone gene (copZ) was also observed, suggesting interplay between zinc and copper homeostasis. Importantly, zinc also affected biocontrol attributes in Pf-5, most notably reducing the expression of the gene cluster responsible for biosynthesis of the antibiotic 2,4-diacetylphloroglucinol (DAPG) under zinc limitation. This study clearly defines changes to the molecular physiology of Pf-5 that enable it to survive under zinc limitation.


Adopting a healthy lifestyle when pregnant and obese - an interview study three years after childbirth.
Obesity during pregnancy is increasing and is related to life-threatening and ill-health conditions in both mother and child. Initiating and maintaining a healthy lifestyle when pregnant with body mass index (BMI) ≥ 30 kg/m(2) can improve health and decrease risks during pregnancy and of long-term illness for the mother and the child. To minimise gestational weight gain women with BMI ≥ 30 kg/m(2) in early pregnancy were invited to a lifestyle intervention including advice and support on diet and physical activity in Gothenburg, Sweden. The aim of this study was to explore the experiences of women with BMI ≥ 30 kg/m(2) regarding minimising their gestational weight gain, and to assess how health professionals' care approaches are reflected in the women's narratives. Semi-structured interviews were conducted with 17 women who had participated in a lifestyle intervention for women with BMI ≥ 30 kg/m(2) during pregnancy 3 years earlier. The interviews were digitally recorded and transcribed in full. Thematic analysis was used. The meaning of changing lifestyle for minimising weight gain and of the professional's care approaches is described in four themes: the child as the main motivation for making healthy changes; a need to be seen and supported on own terms to establish healthy routines; being able to manage healthy activities and own weight; and need for additional support to maintain a healthy lifestyle. To support women with BMI ≥ 30 kg/m(2) to make healthy lifestyle changes and limit weight gain during pregnancy antenatal health care providers should 1) address women's weight in a non-judgmental way using BMI, and provide accurate and appropriate information about the benefits of limited gestational weight gain; 2) support the woman on her own terms in a collaborative relationship with the midwife; 3) work in partnership to give the woman the tools to self-manage healthy activities and 4) give continued personal support and monitoring to maintain healthy eating and regular physical activity habits after childbirth involving also the partner and family.


ABC-SysBio--approximate Bayesian computation in Python with GPU support.
The growing field of systems biology has driven demand for flexible tools to model and simulate biological systems. Two established problems in the modeling of biological processes are model selection and the estimation of associated parameters. A number of statistical approaches, both frequentist and Bayesian, have been proposed to answer these questions. Here we present a Python package, ABC-SysBio, that implements parameter inference and model selection for dynamical systems in an approximate Bayesian computation (ABC) framework. ABC-SysBio combines three algorithms: ABC rejection sampler, ABC SMC for parameter inference and ABC SMC for model selection. It is designed to work with models written in Systems Biology Markup Language (SBML). Deterministic and stochastic models can be analyzed in ABC-SysBio. http://abc-sysbio.sourceforge.net


Sustainable deployment of QTLs conferring quantitative resistance to crops: first lessons from a stochastic model.
Quantitative plant disease resistance is believed to be more durable than qualitative resistance, since it exerts less selective pressure on the pathogens. However, the process of progressive pathogen adaptation to quantitative resistance is poorly understood, which makes it difficult to predict its durability or to derive principles for its sustainable deployment. Here, we study the dynamics of pathogen adaptation in response to quantitative plant resistance affecting pathogen reproduction rate and its colonizing capacity. We developed a stochastic model for the continuous evolution of a pathogen population within a quantitatively resistant host. We assumed that pathogen can adapt to a host by the progressive restoration of reproduction rate or of colonizing capacity, or of both. Our model suggests that a combination of quantitative trait loci (QTLs) affecting distinct pathogen traits was more durable if the evolution of repressed traits was antagonistic. Otherwise, quantitative resistance that depressed only pathogen reproduction was more durable. In order to decelerate the progressive pathogen adaptation, QTLs that decrease the pathogen's maximum capacity to colonize must be combined with QTLs that decrease the spore production per lesion or the infection efficiency or that increase the latent period. Our theoretical framework can help breeders to develop principles for sustainable deployment of QTLs.


Stimulation of reproductive growth in rainbow trout (Oncorhynchus mykiss) following exposure to treated sewage effluent.
Rainbow trout (Oncorhynchus mykiss) were exposed to 1.5 and 15% v/v secondary treated sewage effluent for 32 weeks in flow-through mesocosms. The exposure encompassed the full period of reproductive development for rainbow trout. Trout did not show any evidence of a dose-dependent change in growth. Fish exposed to 15% effluent were the only group to show mortality (5%) over the duration of the experiment. Trout at the highest effluent concentration had significantly higher liver size than reference water fish. Both male and female trout in the 15% exposure group also exhibited significantly higher gonad weight than the reference group. In female trout, this gonad size increase could be explained by higher egg numbers. Female and male trout both displayed a significant increase in plasma 17 beta-estradiol levels after exposure to 15% effluent, while neither sex had dose-dependent differences in plasma testosterone. Male trout displayed elevated vitellogenin levels and reduced plasma 11-ketotestosterone concentration after exposure to 15% effluent. Chemical examination of steroidal compounds, including both estrogens and androgens, in the wastewater revealed that only estrone was detectable at a mean concentration of 4.5 ng/L. It is assumed that the effects observed in trout exposed to 15% effluent were consistent with stimulation of reproductive development due to very low levels of estrogens. Overall, long-term exposure to treated sewage effluent containing low levels of estrogen did not have significant negative implications for reproductive development in rainbow trout.


Immunogenicity of decellularized cryopreserved allografts in pediatric cardiac surgery: comparison with standard cryopreserved allografts.
Recognition of the immunogenicity of standard cryopreserved allografts has led to the development of new decellularized allografts (CryoValve SG; CryoLife, Inc, Kennesaw, Ga). This preliminary study examined the HLA antibody response to these decellularized allografts and compared it with the response to standard allograft material. We prospectively measured the frequency of panel-reactive HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DR/DQ) alloantibodies in 14 children (age 8.5 +/- 7.9 years) receiving decellularized, cryopreserved allografts, including 6 undergoing allograft patch insertion and 8 with a valved pulmonary allograft. We compared them with 20 historical control subjects (age 1.7 +/- 2.4 years) undergoing implantation of standard cryopreserved allografts, 8 with valves and 12 with allograft patch. All patients had panel-reactive antibody levels measured before and at 1, 3, and 12 months after the operation. HLA class I and class II panel-reactive antibody levels were determined with a sensitive flow cytometry technique. We found panel-reactive antibody levels in decellularized allografts to be elevated slightly from preoperative levels for both class I and class II antibodies at 1, 3, and 12 months (P >.05). The panel-reactive antibody level for both class I and class II antibodies were significantly lower for decellularized allografts as compared to standard allografts. Functionally, the allografts were similar with decellularized valved grafts showing a peak echo-determined systolic gradient of 13 +/- 15 mm Hg at 8 +/- 2.6 months postoperatively as compared to a gradient of 24 +/- 18 mm Hg measured 12 +/- 6 months postoperatively in standard allografts (P =.11). Decellularized grafts elicited significantly lower levels of class I and class II HLA antibody formation at 1, 3, and 12 months after implantation than did standard cryopreserved allografts. Early hemodynamic function of decellularized grafts was similar to that of standard cryopreserved allograft valves. Further experience is necessary to determine whether the reduced immunogenicity of decellularized allografts will truly allow tissue ingrowth and improved long-term durability in patients.


Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber's hereditary optic neuropathy.
To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families. A cohort of 1218 Han Chinese subjects with LHON and 316 control subjects underwent the clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The age at onset of optic neuropathy in these subjects ranged from 5 to 55 years, with the average of 18 years. Mutational analysis of ND6 gene identified 92 (73 known and 19 novel) variants in these subjects. These variants included 29 (9 novel and 20 known) missense mutations and 63 silence variants. A total of 94 subjects carrying one of the known T14484C, T14502C, and G14459A mutations accounted for 7.7% cases of this cohort, particularly 4.4% for T14484C mutation. Furthermore, eight putative LHON-associated ND6 mutations accounted for 1.1% case of this cohort. Thus, 106 subjects carrying one of ND6 mutations accounted for 8.7% cases of this cohort. Low penetrance of optic neuropathy in pedigrees carrying one of eight putative mutations indicated that the mutation(s) is necessary, but itself insufficient to produce a clinical phenotype. Mitochondrial DNAs in 98 probands carrying the ND6 mutation(s) were widely dispersed among 12 Eastern Asian subhaplogroups. In particular, the occurrences of haplogroups M9, M10, M11, and H2 in patients carrying the ND6 mutations were higher than those in controls. These data further support that the ND6 gene is the hot spot for mutations associated with LHON. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of LHON.


A Metabolomics Approach to the Identification of Urinary Biomarkers of Pea Intake.
A significant body of evidence demonstrates that isoflavone metabolites are good markers of soy intake, while research is lacking on specific markers of other leguminous sources such as peas. In this context, the objective of our current study was to identify biomarkers of pea intake using an untargeted metabolomics approach. A randomized cross-over acute intervention study was conducted on eleven participants who consumed peas and couscous (control food) in random order. The urine samples were collected in fasting state and postprandially at regular intervals and were further analysed by ultra-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UPLC-QTOF-MS). Multivariate statistical analysis resulted in robust Partial least squares Discriminant Analysis (PLS-DA) models obtained for comparison of fasting against the postprandial time points (0 h vs. 4 h, (R²X = 0.41, Q² = 0.4); 0 h vs. 6 h, ((R²X = 0.517, Q² = 0.495)). Variables with variable importance of projection (VIP) scores ≥1.5 obtained from the PLS-DA plot were considered discriminant between the two time points. Repeated measures analysis of variance (ANOVA) was performed to identify features with a significant time effect. Assessment of the time course profile revealed that ten features displayed a differential time course following peas consumption compared to the control food. The interesting features were tentatively identified using accurate mass data and confirmed by tandem mass spectrometry (MS using commercial spectral databases and authentic standards. 2-Isopropylmalic acid, asparaginyl valine and N-carbamoyl-2-amino-2-(4-hydroxyphenyl) acetic acid were identified as markers reflecting pea intake. The three markers also increased in a dose-dependent manner in a randomized intervention study and were further confirmed in an independent intervention study. Overall, key validation criteria were met for the successfully identified pea biomarkers. Future work will examine their use in nutritional epidemiology studies.


Ordinal linguistic personification as a variant of synesthesia.
This study examines the principles underlying ordinal linguistic personification (OLP): the involuntary and automatic tendency in certain individuals to attribute animate-like qualities such as personality and gender to sequential linguistic units (e.g., letters, numerals, days, months). This article aims to provide four types of evidence that OLP constitutes a form of synesthesia and is likely to have the same neurodevelopmental basis. We show that (a) OLP significantly co-occurs with other variants of synesthesia, (b) OLP associations (like those of synesthesia) are highly consistent over time (Experiment 1), (c) OLP associations (like those of synesthesia) have the characteristic of letter-to-word transference (i.e., they spread from initial letters throughout words) (Experiment 2), and (d) OLP associations (like those of synesthesia) are automatically generated and interfere in Stroop-type tasks (Experiment 3). We argue that these shared characteristics suggest a unified underlying behavior, and propose OLP as a subtype of synesthesia. In so doing, our study extends the range of reported phenomena that are known to be susceptible to cross-modal association.


Sjögren's syndrome: cytokine and Epstein-Barr viral gene expression within the conjunctival epithelium.
In primary Sjögren's syndrome (SS), ocular surface changes within the conjunctival epithelium include lymphocytic infiltration, squamous cell metaplasia, and a reduction in goblet cell number. These changes may be the simple result of increased mechanical abrasion secondary to dryness. Alternatively, they may represent a local response to ocular and/or systemic inflammatory processes, perhaps in response to Epstein-Barr viral (EBV) infection, an agent recently implicated in the etiology of SS. To determine whether inflammatory processes or local infection by EBV contribute to the ocular surface pathology of SS, we examined the expression of inflammatory cell surface markers, cytokines, and EBV gene products within the ocular conjunctiva of patients with SS. Ocular conjunctival tissue was isolated from patients with primary SS and nondry eye control patients by impression cytology or direct biopsy. These specimens were examined by immunofluorescence microscopy and reverse-transcriptase polymerase chain reaction (RT-PCR) for the expression of various markers. The authors found the frequency of expression of HLA-DR (P < 0.0001), ICAM-1 (P < 0.035), and IL-6 (P < 0.0001) to be significantly elevated in patients with primary SS versus nondry eye control patients. The IL-2 receptor and cytokines IL-1 beta and IL-8 were each found to be expressed with relatively high frequency in both patient populations, whereas mRNAs encoding cytokines IL-2, IFN-gamma, GM-CSF, and TGF-beta were not reproducibly detectable in either population. Messenger RNA encoding a marker for passive-latent EBV infection (EBNA-1) was detected with high frequency in both SS and normal populations. The EBV IL-10 analog BCRF-1 was expressed with low frequency in the SS population; however, these levels were not significantly different from the control population. The expression of two other markers of EBV infection, latent membrane protein (LMP, a lytic and latent marker), and BZLF-1 (putative latent-lytic switch gene) was undetectable in either study population. Based on the increased expression of the cell surface molecules HLA-DR and ICAM-1, and the inflammatory cytokine IL-6, the authors propose that local inflammatory processes contribute to the ocular surface changes and ocular surface dryness associated with primary SS.


The genome of the obligate intracellular parasite Trachipleistophora hominis: new insights into microsporidian genome dynamics and reductive evolution.
The dynamics of reductive genome evolution for eukaryotes living inside other eukaryotic cells are poorly understood compared to well-studied model systems involving obligate intracellular bacteria. Here we present 8.5 Mb of sequence from the genome of the microsporidian Trachipleistophora hominis, isolated from an HIV/AIDS patient, which is an outgroup to the smaller compacted-genome species that primarily inform ideas of evolutionary mode for these enormously successful obligate intracellular parasites. Our data provide detailed information on the gene content, genome architecture and intergenic regions of a larger microsporidian genome, while comparative analyses allowed us to infer genomic features and metabolism of the common ancestor of the species investigated. Gene length reduction and massive loss of metabolic capacity in the common ancestor was accompanied by the evolution of novel microsporidian-specific protein families, whose conservation among microsporidians, against a background of reductive evolution, suggests they may have important functions in their parasitic lifestyle. The ancestor had already lost many metabolic pathways but retained glycolysis and the pentose phosphate pathway to provide cytosolic ATP and reduced coenzymes, and it had a minimal mitochondrion (mitosome) making Fe-S clusters but not ATP. It possessed bacterial-like nucleotide transport proteins as a key innovation for stealing host-generated ATP, the machinery for RNAi, key elements of the early secretory pathway, canonical eukaryotic as well as microsporidian-specific regulatory elements, a diversity of repetitive and transposable elements, and relatively low average gene density. Microsporidian genome evolution thus appears to have proceeded in at least two major steps: an ancestral remodelling of the proteome upon transition to intracellular parasitism that involved reduction but also selective expansion, followed by a secondary compaction of genome architecture in some, but not all, lineages.


Suicidal Ideation Among Korean Elderly: Risk Factors and Population Attributable Fractions.
The objective of this study was to investigate the risk factors of suicidal ideation and their population attributable fraction (PAF) in a representative sample of the elderly population in Korea. We examined the data set from the Survey of Living Conditions and Welfare Needs of Korean Older Persons, which was conducted by the Korea Institute for Health and Social Affairs (KIHASA) in 2011. In that survey, 10,674 participants were randomly selected from those older than age 65. Simultaneous multivariate logistic regression was used to investigate the risk factors of suicidal ideation in terms of their sociodemographic and health-related variables. Subsequently, the PAF was calculated with adjustment for other risk factors. The weighted prevalences of depression and suicidal ideation were 30.3% and 11.2%, respectively. In multivariate analysis, factors significantly associated with decreased risk of suicidal ideation included old-old age (odds ratio [OR] = 0.66 for 75 to 79 years, OR = 0.52 for 80 to 84 years, OR = 0.32 for older than 85 years), economic status (OR = 0.59 for 5th quintile; more than US$25,700 per year), whereas those associated with increased risk included poor social support (OR = 1.28), currently smoking (OR = 1.42), sleep problems (OR = 1.74), chronic illness (OR = 1.40), poor subjective health (OR = 1.56), functional impairment (OR = 1.45), and depression (OR = 4.36). Depression was associated with a fully adjusted PAF of 45.7%, followed by chronic illness (19.4%), poor subjective health status (18.9%), sleep problems (14.1%), functional impairment (4.9%), poor social support (4.2%), and currently smoking (3.6%). Preventive strategies focused particularly on depression might reduce the impact of suicidal ideation in the elderly population. Also, specific mental health centers focused on the specific needs of the elderly population should be established to manage suicidal risk.


Phosphide from metorites: barringerite, a new iron-nickel mineral.
Schreibersite, (Fe,Ni)(3)P, and a higher phosphide, barringerite, occur in the Ollague pallasite. The composition of the higher phosphide, determined by electron probe microanalysis, is (Fe(0.58)Ni(0.42)Co(0.003))(1.95)P. It is hexagonal, with space group P62m and a = 5.87 +/- 0.07 angstroms and c = 3.44 +/- 0.04 angstroms. If we assume a primary origin, the new mineral indicates that troilite and schreibersite crystallized at high temperatures. The occurrence of a higher phosphide in a pallasite indicates local nonequilibria within a group of meteorites that are remarkable for their overall degree of equilibrium crystallization.


Generalized functional responses for species distributions.
Researchers employing resource selection functions (RSFs) and other related methods aim to detect correlates of space-use and mitigate against detrimental environmental change. However, an empirical model fit to data from one place or time is unlikely to capture species responses under different conditions because organisms respond nonlinearly to changes in habitat availability. This phenomenon, known as a functional response in resource selection, has been debated extensively in the RSF literature but continues to be ignored by practitioners for lack of a practical treatment. We therefore extend the RSF approach to enable it to estimate generalized functional responses (GFRs) from spatial data. GFRs employ data from several sampling instances characterized by diverse profiles of habitat availability. By modeling the regression coefficients of the underlying RSF as functions of availability, GFRs can account for environmental change and thus predict population distributions in new environments. We formulate the approach as a mixed-effects model so that it is estimable by readily available statistical software. We illustrate its application using (1) simulation and (2) wolf home-range telemetry. Our results indicate that GFRs can offer considerable improvements in estimation speed and predictive ability over existing mixed-effects approaches.


Challenges and opportunities in the care of chronic subdural haematoma: perspectives from a multi-disciplinary working group on the need for change.
A chronic subdural haematoma (cSDH) is a collection of altered blood products between the dura and brain resulting in a slowly evolving neurological deficit. It is increasingly common and, in high income countries, affects an older, multimorbid population. With changing demographics improving the care of this cohort is of increasing importance. We convened a cross-disciplinary working group (the 'Improving Care in Elderly Neurosurgery Initiative') in October 2020. This comprised experts in neurosurgical care and a range of perioperative stakeholders. An Implementation Science framework was used to structure discussions around the challenges of cSDH care within the United Kingdom. The outcomes of these discussions were recorded and summarised, before being circulated to all attendees for comment and refinement. The working group identified four key requirements for improving cSDH care: (1) data, audit, and natural history; (2) evidence-based guidelines and pathways; (3) shared decision-making; and (4) an overarching quality improvement strategy. Frequent transfers between care providers were identified as impacting on both perioperative care and presenting a barrier to effective data collection and teamworking. Improvement initiatives must be cognizant of the complex, system-wide nature of the problem, and may require a combination of targeted trials at points of clinical equipoise (such as anesthetic technique or anticoagulant management), evidence-based guideline development, and a cycle of knowledge acquisition and implementation. The care of cSDH is a growing clinical problem. Lessons may be learned from the standardised pathways of care such as those as used in hip fracture and stroke. A defined care pathway for cSDH, encompassing perioperative care and rehabilitation, could plausibly improve patient outcomes but work remains to tailor such a pathway to cSDH care. The development of such a pathway at a national level should be a priority, and the focus of future work.


A self-organizing approach to background subtraction for visual surveillance applications.
Detection of moving objects in video streams is the first relevant step of information extraction in many computer vision applications. Aside from the intrinsic usefulness of being able to segment video streams into moving and background components, detecting moving objects provides a focus of attention for recognition, classification, and activity analysis, making these later steps more efficient. We propose an approach based on self organization through artificial neural networks, widely applied in human image processing systems and more generally in cognitive science. The proposed approach can handle scenes containing moving backgrounds, gradual illumination variations and camouflage, has no bootstrapping limitations, can include into the background model shadows cast by moving objects, and achieves robust detection for different types of videos taken with stationary cameras. We compare our method with other modeling techniques and report experimental results, both in terms of detection accuracy and in terms of processing speed, for color video sequences that represent typical situations critical for video surveillance systems.


Clinical, pathological and antigenic aspects of bovine viral diarrhea virus (BVDV) type 2 isolates identified in Brazil.
Nucleotide sequencing and phylogenetic analysis of Brazilian bovine viral diarrhea virus (BVDV) field isolates identified four viruses belonging to the genotype 2. Comparison of 5' UTR sequences from these isolates to those of North American BVDV type 2 revealed genomic variations that correlated with the geographic origins of the isolates. Two of the Brazilian type 2 viruses were isolated from clinical cases of gastroenteric/respiratory disease and two were isolated from healthy bovine fetuses. The clinical cases affected young animals (8- and 18-months-old) and were characterized by diarrhea, respiratory signs, extensive oral and digestive tract erosions, conjunctival and vulvar congestion, occasional digestive bleeding and vulvar and heart petechial hemorrhage. Antigenic analysis of these isolates with a panel of 10 monoclonal antibodies revealed marked antigenic differences in the major envelope glycoprotein, gp53/E2, compared to standard laboratory and vaccine BVDV strains. In addition, virus-specific antisera raised to Brazilian BVDV type 2 viruses displayed very low serological cross-reactivity with standard BVDV type 1 strains. Differences up to 64-fold in cross-neutralization titers were observed between BVDV type 1 and Brazilian BVDV type 2 isolates. The identification of BVDV type 2 among Brazilian cattle may have important implications for epidemiological studies, diagnostic and immunization strategies. Furthermore, the low neutralizing activity of BVDV type 1 antisera against the recently identified Brazilian BVDV type 2 isolates raises the question about the degree of protection conferred by BVDV vaccines, most of them based on a single type 1 strain.


Direct comparison of time to AIDS and infectious disease death between HIV seroconverter injection drug users in Italy and the United States: results from the ALIVE and ISS studies. AIDS Link to Intravenous Experiences. Italian Seroconversion Study.
To compare the rate of HIV disease progression in a sample of polydrug injectors (AIDS Link to Intravenous Experiences [ALIVE] study) with that in a sample of predominantly opiate injectors (Italian Seroconversion Study [ISS]). Prospective cohort studies of HIV-positive individuals whose date of seroconversion (SC) is known with a good degree of precision. The ALIVE study involves a community-based cohort of injection drug users (IDU) in the United States and the ISS reports on a clinic-based cohort of seroconverters in Italy with different exposure modalities to HIV. Data from the two cohorts were combined. The date of SC was estimated as the midpoint in time between the last negative and the first positive HIV test. Time-to-event (i.e., AIDS or death from an infectious disease) statistical methods were used. Relative hazards (RH) of progression to event were adjusted by age at SC, gender, and year of SC. Of the 1003 IDUs (251 from ALIVE and 752 from ISS), 226 progressed to AIDS, and 146 died after AIDS or from an infectious disease; of these, 10 were without an AIDS diagnosis. The two groups of IDUs differed in terms of age at SC (median, 35 years for ALIVE and 25 years for ISS), proportion of women (24% versus 31%), race (7.6% versus 100% white), and year of seroconversion (i.e., ISS participants seroconverted, on average, earlier than ALIVE participants). Although the univariate analysis suggested possible differences for progression to AIDS, or to death from infectious disease between cohorts, multivariate analyses that adjusted for age showed no significant differences by cohort, gender, race, or time of seroconversion. The median time to AIDS for 25-year-old persons was 12.3 years for ALIVE and 11.8 years for ISS; for 35-year-old persons, it was 8.5 and 8.2 years, respectively. These estimates were similar to those for non-IDUs observed in the ISS and to those from large cohort of homosexual men. Our results confirm the importance of accounting for age when considering the incubation period for HIV infection. Despite differences in drug use characteristics, the similar median times to AIDS, for each age, between the two cohorts of IDUs and between the IDUs and the non-IDUs suggest a negligible effect of injection drug use on HIV progression.


Nanomedicine-Assisted Combination Therapy of NSCLC: New Platinum-Based Anticancer Drug Synergizes the Therapeutic Efficacy of Ganetespib.
Purpose: K-RAS is the most common mutated oncogene associated with Non-Small-Cell Lung Cancer (NSCLC). So far, there are no promising chemotherapies for the direct inhibition of K-RAS, and considered to be undruggable. In this work, we have introduced a new platinum-based cyanoximate complex, Pt(MCO)2, as an anti-cancer drug to enhance the therapeutic efficacy of Hsp90 inhibitor drug, ganetespib for the combination therapy of NSCLC. Methods: We have synthesized polyacrylic acid (PAA)-coated magnetic nanoparticles (MNPs) and used as drug delivery system. These MNPs were decorated with folic acid in order to target folate receptor-expressing NSCLC. The individual and combination of drugs as well as an optical dye DiI were co-encapsulated successfully inside the PAA-coating of MNPs to evaluate synergistic treatment option for NSCLC. The magnetic resonance (MR) and optical imaging modalities assisted for the monitoring drug loading and NSCLC treatment. Results: To evaluate the therapeutic efficacy of these customized MNPs, various cell-based assays including cell viability, apoptosis and necrosis, cell migration, comet and ROS experiments were performed. Results showed minimal toxicity for functional MNPs with no therapeutic drug and more than 60% cell death within 48 h of treatment, when single drug was encapsulated. Importantly, more than 90% cells were dead when both drugs were delivered. Overall, the results indicated that the Pt(MCO)2 drug enhances the therapeutic efficacy of ganetespib by more than 30% toxicity towards the targeted treatment of NSCLC, while showed minimal toxicity to the normal healthy tissues. Conclusion: We successfully developed new dual-modal magnetic nanomedicines for the rapid and controlled release of combination of drugs for the effective treatment of NSCLC. The MR and fluorescence modalities help monitoring the delivery of drugs, where the new platinum-based drug Pt(MCO)2 synergizes the therapeutic efficacy of ganetespib.


Sampling strategy optimization to increase statistical power in landscape genomics: A simulation-based approach.
An increasing number of studies are using landscape genomics to investigate local adaptation in wild and domestic populations. Implementation of this approach requires the sampling phase to consider the complexity of environmental settings and the burden of logistical constraints. These important aspects are often underestimated in the literature dedicated to sampling strategies. In this study, we computed simulated genomic data sets to run against actual environmental data in order to trial landscape genomics experiments under distinct sampling strategies. These strategies differed by design approach (to enhance environmental and/or geographical representativeness at study sites), number of sampling locations and sample sizes. We then evaluated how these elements affected statistical performances (power and false discoveries) under two antithetical demographic scenarios. Our results highlight the importance of selecting an appropriate sample size, which should be modified based on the demographic characteristics of the studied population. For species with limited dispersal, sample sizes above 200 units are generally sufficient to detect most adaptive signals, while in random mating populations this threshold should be increased to 400 units. Furthermore, we describe a design approach that maximizes both environmental and geographical representativeness of sampling sites and show how it systematically outperforms random or regular sampling schemes. Finally, we show that although having more sampling locations (between 40 and 50 sites) increase statistical power and reduce false discovery rate, similar results can be achieved with a moderate number of sites (20 sites). Overall, this study provides valuable guidelines for optimizing sampling strategies for landscape genomics experiments.


Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study.
The purposes of this study were to describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study. A single-center prospective consecutive cohort study was conducted of spontaneous ICH in children aged 1 to 18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure and King's Outcome Scale for Childhood Head Injury. ICH volumes and total brain volumes were measured by manual tracing. Twenty-two patients, median age 10.3 years (range, 4.2 to 16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At a median follow-up of 3.5 months (range, 0.3 to 7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on Pediatric Stroke Outcome Measure and King's Outcome Scale for Childhood Head Injury scores was worse in patients with ICH volume >2% of total brain volume (P=0.023) and altered mental status at presentation (P=0.005). Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.


Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients.
The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients. Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients. Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients. Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.


CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene.
Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.


Multiplexed interferometric fiber-optic sensors with digital signal processing.
A microcontroller-based digital signal processing system developed for use with fiber-optic sensors for measuring pressure in internal combustion engines is described. A single distributed feedback laser source provides optical power for four interferometric sensors. The laser current is repetitively modulated so that its optical frequency is nearly a linear function of time over most of a cycle. The interferometer phase shift is proportional to the elapsed time from the initiation of a sawtooth until the sensor output signal level crosses a threshold value proportional to the laser output power. This elapsed time, assumed to vary linearly with the combustion chamber pressure, is determined by the use of a digital timer-counter. The system has been used with fiber Fabry-Perot interferometer transducers for in-cylinder pressure measurement on a four-cylinder gasoline-powered engine.


Deregulation of type I IFN-dependent genes correlates with increased susceptibility to cytomegalovirus acute infection of dicer mutant mice.
Regulation of gene expression by microRNAs (miRNAs) is now considered as an essential mechanism for cell development and homeostasis. Indeed, numerous studies have reported that modulating their expression, maturation, or activity can affect cell survival, identity or activation. In particular, miRNAs are key players in the tight regulation of signaling cascades, and as such, they appear as perfectly suited immunomodulators. Several immune-related processes, including inflammation, have recently been demonstrated to require specific miRNAs. In addition, the discovery of herpesvirus-encoded miRNAs has reinforced this assumption. To decipher the potential roles of miRNAs in innate antiviral immune response, we developed an in vivo model based on the inoculation of mouse cytomegalovirus (MCMV) in mice. Furthermore, we exploited a mouse line carrying a hypomorphic mutation in the Dicer gene to visualize the impact of impaired miRNA biogenesis upon the anti-MCMV response. Our data indicate that miRNAs are important actors in mounting an efficient response against herpesviruses. We suggest that a rapid and transient interferon response following viral infection requires miRNA-dependent repressor release. In addition, our in vivo efforts identified several miRNA targets, thus providing a conceptual framework for future analyzes on the regulation of specific actors involved in the Type I interferon pathway.


The VPS4 component of the ESCRT machinery plays an essential role in HPV infectious entry and capsid disassembly.
Human Papillomavirus (HPV) infection involves multiple steps, from cell attachment, through endocytic trafficking towards the trans-Golgi network, and, ultimately, the entry into the nucleus during mitosis. An essential viral protein in infectious entry is the minor capsid protein L2, which engages different components of the endocytic sorting machinery during this process. The ESCRT machinery is one such component that seems to play an important role in the early stages of infection. Here we have analysed the role of specific ESCRT components in HPV infection, and we find an essential role for VPS4. Loss of VPS4 blocks infection with multiple PV types, suggesting an evolutionarily conserved critical step in infectious entry. Intriguingly, both L1 and L2 can interact with VPS4, and appear to be in complex with VPS4 during the early stages of virus infection. By using cell lines stably expressing a dominant-negative mutant form of VPS4, we also show that loss of VPS4 ATPase activity results in a marked delay in capsid uncoating, resulting in a defect in the endocytic transport of incoming PsVs. These results demonstrate that the ESCRT machinery, and in particular VPS4, plays a critical role in the early stages of PV infection.


Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy.
To determine how men infected with the human immunodeficiency virus (HIV) tolerate and respond to treatment for malignant germ cell tumors (GCTs), and how GCT histology and stage compare among HIV-infected versus non-HIV-infected men. Two hundred ninety-four cases of GCT diagnosed or treated from 1980 to 1993 were reviewed. Nine new cases among HIV-infected men were identified; these were analyzed together with six cases previously reported from our institution. Low-stage tumors (stages I and IIA) comprised 67% of HIV-infected and 63% of non-HIV-infected cases. Sixty-seven percent of HIV-infected cases were seminomas versus 51% of non-HIV-infected cases. Ten patients had AIDS at the time of GCT diagnosis. Five patients underwent radiation therapy and one patient underwent retroperitoneal lymphadenectomy without complications. Seven patients received chemotherapy with four cycles of cisplatin, etoposide, and bleomycin (PEB) or cisplatin, vinblastine, and bleomycin (PVB) without excess cytopenias or new opportunistic infections. Of seven patients treated for advanced disease, there were five complete and two partial responses. Six patients have died of AIDS at a median of 20 months after diagnosis of GCT. The median follow-up time for surviving patients has been 42 months (range, 8 to 87) and all but one remain without evidence of active disease. In no case was a patient's HIV disease classification altered by antitumor therapy. The natural history of GCTs is comparable in HIV-infected and non-HIV-infected men and standard therapy including orchiectomy, retroperitoneal lymph node dissection, radiation therapy, and chemotherapy is well tolerated.


Xylem Embolism Spreads by Single-Conduit Events in Three Dry Forest Angiosperm Stems.
Xylem cavitation resulting in air embolism is a major cause of plant death during drought, yet the spread of embolism throughout the plant water transport system is poorly understood. Our study used optical visualization and x-ray microcomputed tomography imaging to capture the spread of emboli in stems of three drought-resistant angiosperm trees: drooping she-oak (Allocasuarina verticillata), black wattle (Acacia mearnsii), and blue gum (Eucalyptus globulus). These species have similar degrees of xylem network connectivity (vessel grouping) with largely solitary vessels. The high temporal resolution of the optical vulnerability technique revealed that in current year branches, >80% of the cavitation events were discrete, temporally separated events in single vessels. This suggests that in xylem networks with low connectivity, embolism spread between conduits leading to multiple conduit cavitation events is uncommon. A. mearnsii showed both the highest number of multivessel cavitation events and the highest degree of vessel connectivity, suggesting a link between vessel arrangement and embolism spread. Knowledge of embolism spread will help us to uncover the links between xylem anatomy, arrangement, and the path of water flow in the xylem in diverse species to ultimately understand the drivers of cavitation and plant vulnerability to drought.