Generation of broadband mid-IR and UV light in gas-filled single-ring hollow-core PCF.
We report generation of an ultrafast supercontinuum extending into the mid- infrared in gas-filled single-ring hollow-core photonic crystal fiber (SR-PCF) pumped by 1.7 µm light from an optical parametric amplifier. The simple fiber structure offers shallow dispersion and flat transmission in the near and mid-infrared, enabling the generation of broadband spectra extending from 270 nm to 3.1 µm, with a total energy of a few µJ. In addition, we demonstrate the emission of ultraviolet dispersive waves whose frequency can be tuned simply by adjusting the pump wavelength. SR-PCF thus constitutes an effective means of compressing and delivering tunable ultrafast pulses in the near and mid-infrared spectral regions.


Dual Antimicrobial Effect of Medium-Chain Fatty Acids against an Italian Multidrug Resistant Brachyspira hyodysenteriae Strain.
The fastidious nature of Brachyspira hyodysenteriae limits an accurate in vitro pre-screening of conventionally used antibiotics and other candidate alternative antimicrobials. This results in a non-judicious use of antibiotics, leading to an exponential increase of the antibiotic resistance issue and a slowdown in the research for new molecules that might stop this serious phenomenon. In this study we tested four antibiotics (tylosin, lincomycin, doxycycline, and tiamulin) and medium-chain fatty acids (MCFA; hexanoic, octanoic, decanoic, and dodecanoic acid) against an Italian field strain of B. hyodysenteriae and the ATCC 27164 strain as reference. We determined the minimal inhibitory concentrations of these substances, underlining the multidrug resistance pattern of the field strain and, on the contrary, a consistent and stable inhibitory effect of the tested MCFA against both strains. Then, sub-inhibitory concentrations of antibiotics and MCFA were examined in modulating a panel of B. hyodysenteriae virulence genes (tlyA, tlyB, bhlp16, bhlp29.7, and bhmp39f). Results of gene expression analysis were variable, with up- and downregulations not properly correlated with particular substances or target genes. Decanoic and dodecanoic acid with their direct and indirect antimicrobial property were the most effective among MCFA, suggesting them as good candidates for subsequent in vivo trials.


Genetic control of startle behavior in medaka fish.
Genetic polymorphisms are thought to generate intraspecific behavioral diversities, both within and among populations. The mechanisms underlying genetic control of behavioral properties, however, remain unclear in wild-type vertebrates, including humans. To explore this issue, we used diverse inbred strains of medaka fish (Oryzias latipes) established from the same and different local populations. Medaka exhibit a startle response to a visual stimulus (extinction of illumination) by rapidly bending their bodies (C-start) 20-ms after the stimulus presentation. We measured the rates of the response to repeated stimuli (1-s interval, 40 times) among four inbred strains, HNI-I, HNI-II, HO5, and Hd-rR-II1, and quantified two properties of the startle response: sensitivity (response rate to the first stimulus) and attenuation of the response probability with repeated stimulus presentation. Among the four strains, the greatest differences in these properties were detected between HNI-II and Hd-rR-II1. HNI-II exhibited high sensitivity (approximately 80%) and no attenuation, while Hd-rR-II1 exhibited low sensitivity (approximately 50%) and almost complete attenuation after only five stimulus presentations. Our findings suggested behavioral diversity of the startle response within a local population as well as among different populations. Linkage analysis with F2 progeny between HNI-II and Hd-rR-II1 detected quantitative trait loci (QTL) highly related to attenuation, but not to sensitivity, with a maximum logarithm of odds score of 11.82 on linkage group 16. The three genotypes (homozygous for HNI-II and Hd-rR-II1 alleles, and heterozygous) at the marker nearest the QTL correlated with attenuation. Our findings are the first to suggest that a single genomic region might be sufficient to generate individual differences in startle behavior between wild-type strains. Further identification of genetic polymorphisms that define the behavioral trait will contribute to our understanding of the neural mechanisms underlying behavioral diversity, allowing us to investigate the adaptive significance of intraspecific behavioral polymorphisms of the startle response.


Intact inhibitory control processes in abstinent drug abusers (I): a functional neuroimaging study in former cocaine addicts.
Neuroimaging studies in current cocaine dependent (CD) individuals consistently reveal cortical hypoactivity across regions of the response inhibition circuit (RIC). Dysregulation of this critical executive network is hypothesized to account for the lack of inhibitory control that is a hallmark of the addictive phenotype, and chronic abuse is believed to compound the issue. A crucial question is whether deficits in this circuit persist after drug cessation, and whether recovery of this system will be seen after extended periods of abstinence, a question with implications for treatment course and outcome. Utilizing functional magnetic resonance imaging (fMRI), we examined activation in nodes of the RIC in abstinent CD individuals (n = 27) and non-using controls (n = 45) while they performed a motor response inhibition task. In contrast to current users, these abstinent individuals, despite extended histories of chronic cocaine-abuse (average duration of use = 8.2 years), performed the task just as efficiently as non-users. In line with these behavioral findings, no evidence for between-group differences in activation of the RIC was found and instead, robust activations were apparent in both groups within the well-characterized nodes of the RIC. Similarly, our complementary Electroencephalography (EEG) investigation also showed an absence of behavioral and electrophysiological deficits in abstinent drug abusers. These results are consistent with an amelioration of neurobiological deficits in inhibitory circuitry following drug cessation, and could help explain how long-term abstinence is maintained. Finally, regression analyses revealed a significant association between level of activation in the right insula with inhibition success and increased abstinence duration in the CD cohort suggesting that this region may be integral to successful recovery from cocaine addiction.


Transcranial motor evoked potentials during basilar artery aneurysm surgery: technique application for 30 consecutive patients.
Microsurgical clipping of basilar artery aneurysms carries a risk of neurological compromise resulting from midbrain or thalamic ischemia. Somatosensory evoked potential (SSEP) monitoring and electroencephalography are the standard techniques for assessing the level of cerebroprotective anesthesia and monitoring ischemia during temporary occlusion or after permanent clipping. Transcranial motor evoked potential (TcMEP) monitoring was added to determine whether this modality improved intraoperative monitoring. Combined SSEP/electroencephalographic/TcMEP monitoring was used for 30 consecutive patients with basilar artery apex aneurysms in the past 1.5 years. Voltage thresholds were recorded before, during, and after aneurysm treatment for the last 10 patients. All 30 patients underwent an orbitozygomatic craniotomy for clipping (28 patients), wrapping (1 patient), or superficial temporal artery-superior cerebellar artery bypass (1 patient). Electrophysiological changes occurred for 10 patients (33%), elicited by temporary clipping (6 patients), permanent clipping (3 patients), or retraction (1 patient). Isolated SSEP changes were observed for one patient, isolated TcMEP changes for five patients, and changes in both TcMEPs and SSEPs for four patients. Among patients with simultaneous changes, TcMEP abnormalities were more robust and occurred earlier than SSEP abnormalities. Impaired motor conduction was detected first with an increase in the voltage threshold (from 206 +/- 22 to 410 +/- 49 V, P < 0.05, n = 3) and then with loss of TcMEP responses. SSEP and TcMEP signals returned to baseline values for all patients after corrective measures were taken. TcMEP monitoring can be safely and easily added to traditional neurophysiological monitoring during basilar artery aneurysm surgery. These results suggest that TcMEPs may be more sensitive than SSEPs to basilar artery and perforating artery ischemia. This additional intraoperative information might minimize the incidence of ischemic complications attributable to prolonged temporary occlusion or inadvertent perforator occlusion.


Fine mapping of the soybean aphid-resistance genes Rag6 and Rag3c from Glycine soja 85-32.
Rag6 and Rag3c were delimited to a 49-kb interval on chromosome 8 and a 150-kb interval on chromosome 16, respectively. Structural variants in the exons of candidate genes were identified. The soybean aphid, an invasive species, has significantly threatened soybean production in North America since 2000. Host-plant resistance is known as an ideal management strategy for aphids. Two novel aphid-resistance loci, Rag6 and Rag3c, from Glycine soja 85-32, were previously detected in a 10.5-cM interval on chromosome 8 and a 7.5-cM interval on chromosome 16, respectively. Defining the exact genomic position of these two genes is critical for improving the effectiveness of marker-assisted selection for aphid resistance and for identification of the functional genes. To pinpoint the locations of Rag6 and Rag3c, four populations segregating for Rag6 and Rag3c were used to fine map these two genes. The availability of the Illumina Infinium SoySNP50K/8K iSelect BeadChip, combined with single-nucleotide polymorphism (SNP) markers discovered through the whole-genome re-sequencing of E12901, facilitated the fine mapping process. Rag6 was refined to a 49-kb interval on chromosome 8 with four candidate genes, including three clustered nucleotide-binding site leucine-rich repeat (NBS-LRR) genes and an amine oxidase encoding gene. Rag3c was refined to a 150-kb interval on chromosome 16 with 11 candidate genes, two of which are a LRR gene and a lipase gene. Moreover, by sequencing the whole-genome exome-capture of the resistant source (E12901), structural variants were identified in the exons of the candidate genes of Rag6 and Rag3c. The closely linked SNP markers and the candidate gene information presented in this study will be significant resources for integrating Rag6 and Rag3c into elite cultivars and for future functional genetics studies.


Thrombus lysis by uPA, scuPA and tPA is regulated by plasma TAFI.
The carboxypeptidase, TAFIa or CPU, is known to prolong plasma clot lysis by tissue plasminogen activator (tPA) and to have a role in thrombus stability in vivo. This current study examined lysis by urokinase (uPA) and single chain urokinase (scuPA) in addition to tPA. Further, we investigated the role of TAFIa in a model thrombus system, in which thrombi are formed under conditions of flow. We show that human thrombi, formed in vivo, and model thrombi both contain TAFI. No effect of thrombus TAFIa was observed in thrombus lysis assays, except when thrombi were bathed in plasma, in which case addition of potato tuber carboxypeptidase inhibitor (CPI) resulted in doubling of the rate of lysis. TAFIa inhibited lysis of model thrombi and plasma clots by uPA, scuPA in addition to lysis by tPA. The effect of TAFIa was more evident at high concentrations of plasminogen activator such as those used in thrombolytic therapy. Addition of plasminogen increased lysis and, in its presence, the enhancement by CPI was smaller. Thus the action of TAFIa could be partially overcome by plasminogen, whether lysis was by tPA, uPA or scuPA. This is consistent with TAFIa exerting its effect primarily through modifying the binding of plasminogen to fibrin and to a lesser extent through modification of the binding of tPA to fibrin.


Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168.
The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.


[Relationship between anthropometric measures and the prevalence of diabetes in adults of Suzhou city, Jiangsu province].
To explore the relationships between anthropometric measures as body mass index (BMI), percentage body fat, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and the risks of diabetes. We analyzed the baseline data of 53 260 participants who were aged 30-79 years and had been enrolled into the China Kadoorie Biobank (CKB) study from Suzhou city,Jiangsu province. Unconditional logistic regression analyses were conducted with adjustment for potential confounders. Overall, 5.3% of the participants had diabetes, with about a half of them being newly detected through on-site screening tests. The prevalence of diabetes increased with age, 61% higher (OR = 1.61, 95% confidence interval: 1.54-1.67) risk of diabetes, with 10 years increase of age. In both genders, all anthropometric measures were positively and significantly associated with diabetes, with the associations of measures in central adiposity stronger than those in general obesity, with WHR as the strongest. Each standard deviation (1- s) with greater WHR (<0.06 in men and 0.07 in women) was associated with 72% (61%-83%) higher risk of diabetes in men and 93% (83%-102%) in women. After adjusting for HC, each WC with 5 cm larger, showing 65% and 57% higher risks in men and women respectively. However, after adjusting for WC, every 5cm greater HC appeared and associated with respective 38% and 34% lower risks. Measures on adiposity including BMI, percentage body, WC, WHR and WHtR fat were all positively associated with the prevalence of diabetes. Measures of central obesity, particularly WHR, were more strongly associated with diabetes than measures of general obesity. When WC was under control, HC appeared inversely associated with diabetes.


Co-firing straw with coal in a swirl-stabilized dual-feed burner: modelling and experimental validation.
This paper presents a comprehensive computational fluid dynamics (CFD) modelling study of co-firing wheat straw with coal in a 150kW swirl-stabilized dual-feed burner flow reactor, in which the pulverized straw particles (mean diameter of 451microm) and coal particles (mean diameter of 110.4microm) are independently fed into the burner through two concentric injection tubes, i.e., the centre and annular tubes, respectively. Multiple simulations are performed, using three meshes, two global reaction mechanisms for homogeneous combustion, two turbulent combustion models, and two models for fuel particle conversion. It is found that for pulverized biomass particles of a few hundred microns in diameter the intra-particle heat and mass transfer is a secondary issue at most in their conversion, and the global four-step mechanism of Jones and Lindstedt may be better used in modelling volatiles combustion. The baseline CFD models show a good agreement with the measured maps of main species in the reactor. The straw particles, less affected by the swirling secondary air jet due to the large fuel/air jet momentum and large particle response time, travels in a nearly straight line and penetrate through the oxygen-lean core zone; whilst the coal particles are significantly affected by secondary air jet and swirled into the oxygen-rich outer radius with increased residence time (in average, 8.1s for coal particles vs. 5.2s for straw particles in the 3m high reactor). Therefore, a remarkable difference in the overall burnout of the two fuels is predicted: about 93% for coal char vs. 73% for straw char. As the conclusion, a reliable modelling methodology for pulverized biomass/coal co-firing and some useful co-firing design considerations are suggested.


Individual differences in bodily freezing predict emotional biases in decision making.
Instrumental decision making has long been argued to be vulnerable to emotional responses. Literature on multiple decision making systems suggests that this emotional biasing might reflect effects of a system that regulates innately specified, evolutionarily preprogrammed responses. To test this hypothesis directly, we investigated whether effects of emotional faces on instrumental action can be predicted by effects of emotional faces on bodily freezing, an innately specified response to aversive relative to appetitive cues. We tested 43 women using a novel emotional decision making task combined with posturography, which involves a force platform to detect small oscillations of the body to accurately quantify postural control in upright stance. On the platform, participants learned whole body approach-avoidance actions based on monetary feedback, while being primed by emotional faces (angry/happy). Our data evidence an emotional biasing of instrumental action. Thus, angry relative to happy faces slowed instrumental approach relative to avoidance responses. Critically, individual differences in this emotional biasing effect were predicted by individual differences in bodily freezing. This result suggests that emotional biasing of instrumental action involves interaction with a system that controls innately specified responses. Furthermore, our findings help bridge (animal and human) decision making and emotion research to advance our mechanistic understanding of decision making anomalies in daily encounters as well as in a wide range of psychopathology.


Retinoblastoma referral pattern in Kenya.
Kenya is a large country with a widely dispersed population. As retinoblastoma requires specialized treatment, we determined the referral pattern for patients with retinoblastoma in Kenya to facilitate the formulation of a national policy. A retrospective study was performed for retinoblastoma patients who presented from January 1, 2006 to December 31, 2007. Data were collected on the referral process from presenting health facility to the hospital where patient was treated. Data were also collected on the time interval when the first symptoms were noticed to the time of presentation at a health facility (lag time). For cases that could be traced to a referral hospital, the time delay due to referral (referral lag time) was recorded. There were 206 patients diagnosed with retinoblastoma in 51 Kenyan and 2 foreign healthcare facilities, and they received final treatment at a Kenyan hospital. Mean lag time was 6.8 months (±6.45). Of all patients, 18% (38/206) were treated at the hospital where they first presented and 82% (168/206) were referred elsewhere. Of those referred, 35% (58/168) were lost to follow-up. The mean referral lag time was 1.7 months (±2.5). A significant proportion of cases presented late, and either delayed seeking further treatment or were lost after initial referral. We recommend the implementation of a national strategy that emphasizes early detection, documentation and follow up of retinoblastoma patients.


Probing the size of proteins with glass nanopores.
Single molecule studies using nanopores have gained attention due to the ability to sense single molecules in aqueous solution without the need to label them. In this study, short DNA molecules and proteins were detected with glass nanopores, whose sensitivity was enhanced by electron reshaping which decreased the nanopore diameter and created geometries with a reduced sensing length. Further, proteins having molecular weights (MW) ranging from 12 kDa to 480 kDa were detected, which showed that their corresponding current peak amplitude changes according to their MW. In the case of the 12 kDa ComEA protein, its DNA-binding properties to an 800 bp long DNA molecule was investigated. Moreover, the influence of the pH on the charge of the protein was demonstrated by showing a change in the translocation direction. This work emphasizes the wide spectrum of detectable molecules using nanopores from glass nanocapillaries, which stand out because of their inexpensive, lithography-free, and rapid manufacturing process.


Alkaline side-coordination strategy for the design of nickel(II) and nickel(III) bis(1,2-diselenolene) complex based materials.
The deprotonated form of the pyrazine-2,3-diselenol (pds) ligand, pds(2-), reacts with Ni(II) inorganic salts to form the nickel compounds [Ni(II)(pds)(2)](nBu(4)N)(2) (1), [Ni(II)(pds)(2)]Na(2).2H(2)O (2), and [Ni(III)(pds)(2)](2)Na(2).4H(2)O (3), depending on the reaction conditions. They are characterized by NMR, EPR, UV-vis, and IR spectroscopies, elemental analysis, cyclic voltammetry, and X-ray crystallography. The crystal structure of compound 3 shows the formation of segregated stacks of Ni(pds)(2-) units, with a strong dimerization along the stacks. The stacked fashion of the crystal packing was expected since the supramolecular forces of the alkaline side coordination to the pyrazine moieties dominate, as happens in the recently reported analogous copper system [Cu(III)(pds)(2)]Na.2H(2)O. The structure of 2 further emphasizes the alkaline coordination as the dominating supramolecular event, and an orthogonal array of 2D layers is observed. The absence of alkaline cations in complex 1 is reflected in a crystal packing with isolated complex Ni(pds)(2)(2-) units. The dimerization found in the paramagnetic Ni(III) complex 3 promotes a very strong antiferromagnetic interaction, leading to a singlet ground state.


Bile acid metabolites control TH17 and Treg cell differentiation.
Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells.


Efficient green photoluminescence and electroluminescence of iridium complexes with high electron mobility.
Aiming to balance the injection and transport of electrons and holes, nitrogen heterocycle and 1,3,4-oxadiazole derivatives were introduced in iridium(iii) complexes to obtain organic light-emitting diodes (OLEDs) with high performances. Thus, two novel Ir(iii) complexes (Ir(tfmphpm)2(pop) and Ir(tfmppm)2(pop)) with green emissions using 2-(3,5-bis(trifluoromethyl)phenyl)pyrimidine (tfmphpm) and 2-(2,6-bis(trifluoromethyl)pyridin-4-yl)pyrimidine (tfmppm) as cyclometalating ligands, and 2-(5-phenyl-1,3,4-oxadiazol-2-yl)phenol (pop) as an ancillary ligand were synthesized. Both emitters show high photoluminescence efficiencies up to 94% and good electron mobility. The devices using two emitters with the structure of ITO (indium-tin-oxide)/MoO3 (molybdenum oxide, 5 nm)/TAPC (di-[4-(N,N-ditolyl-amino)-phenyl]cyclohexane, 30 nm)/mCP (1,3-bis(9H-carbazol-9-yl)benzene, 5 nm)/Ir(iii) complexes (6 wt%) : PPO21 (3-(diphenylphosphoryl)-9-(4-(diphenylphosphoryl)phenyl)-9H-carbazole, 10 nm)/TmPyPB (1,3,5-tri(m-pyrid-3-yl-phenyl) benzene, 40 nm)/LiF (1 nm)/Al (100 nm) display good electroluminescence performances with a maximum luminance of 48 981 cd m-2, a maximum current efficiency of 92.79 cd A-1 and a maximum external quantum efficiency up to 31.8%, respectively, and the efficiency roll-off ratio is low, suggesting that they have potential application in OLEDs.


Substitution Mapping of a Locus Responsible for Hybrid Breakdown in Populations Derived From Interspecific Introgression Line.
Hybrid breakdown, a form of postzygotic reproductive barrier, has been reported to hinder gene flow in many crosses between wild and cultivated rice. Here, the phenomenon of hybrid breakdown was observed as low-tillering (i.e., low tiller number) in some progeny of an interspecific cross produced in an attempt to introduce Oryza meridionalis Ng (W1625) chromosomal segments into Oryza sativa L. ssp. japonica "Taichung 65" (T65). Low-tillering lines were obtained in BC4-derived progeny from a cross between W1625 and "Taichung 65," but the locus for low-tillering could not be mapped in segregating populations. As a second approach to map the locus for low-tillering, we analyzed an F2 population derived from a cross between the low-tillering lines and a high-yielding indica cultivar, "Takanari." A major QTL for low-tillering, qLTN4, was detected between PCR-based markers MS10 and RM307 on the long arm of chromosome 4, with a LOD score of 15.6. The low-tillering phenotype was associated with weak growth and pale yellow phenotype; however, low-tillering plant had less reduction of grain fertility. In an F4 population (4896 plants), 563 recombinant plants were identified and the low-tillering locus was delimited to a 4.6-Mbp region between markers W1 and C5-indel3729. This region could not be further delimited because recombination is restricted in this region of qLTN4, which is near the centromere. Understanding the genetic basis of hybrid breakdown, including the low-tillering habit, will be important for improving varieties in rice breeding.


Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli.
In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, amongst them osmotic stimuli. This review will highlight findings on the TRPV subfamily, both vertebrate and invertebrate members. Out of the six mammalian TRP vanilloid (TRPV) channels, TRPV1, TRPV2, and TRPV4 were demonstrated to function in transduction of osmotic stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis in vertebrates. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic stimuli in C. elegans. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmo- and mechanosensory deficits of the TRPV mutant strain osm-9 in C. elegans, despite not more than 26% orthology of the respective proteins.


Initial Coin Offerings.
This paper examines the market for initial coin offerings (ICOs). ICOs are smart contracts based on blockchain technology that are designed for entrepreneurs to raise external finance by issuing tokens without an intermediary. Unlike existing mechanisms for early-stage finance, tokens potentially provide investors with rapid opportunities thanks to liquid trading platforms. The marketability of tokens offers novel insights into entrepreneurial finance, which I explore in this paper. First, I document that investors earn on average 8.2% on the first day of trading. However, about 40% of all ICOs destroy investor value on the first day of trading. Second, I explore the determinants of market outcomes and find that management quality and the ICO profile are positively correlated with the funding amount and returns, whereas highly visionary projects have a negative effect. Among the 21% of all tokens that get delisted from a major exchange platform, highly visionary projects are more likely to fail, which investors anticipate. Third, I explore the sensitivity of the ICO market to adverse industry events such as China's ban of ICOs, the hack of leading ledgers, and the marketing ban on FaceBook. I find that the ICO market is highly susceptible to such environmental shocks, resulting in substantial welfare losses for investors.


PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation.
Monoclonal antibodies that target the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to IL2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1-positive tumor-infiltrating lymphocytes were identified in 50% (13 of 26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P = 0.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation, and patients with these tumors may be good candidates for treatment with anti-PD-1/PD-L1 therapies.


Factors Predictive of Remission of Chronic Anterior Uveitis.
To estimate the incidence of medication-free remission of chronic anterior uveitis and identify predictors thereof. Retrospective cohort study. Patients diagnosed with anterior uveitis of longer than 3 months' duration followed up at United States tertiary uveitis care facilities. Estimation of remission incidence and identification of associated predictors used survival analysis. Incidence of medication-free remission. For the primary analysis, remission was defined as inactive uveitis while off treatment at all visits spanning an interval of at least 90 days or-for patients who did not return for follow-up after 90 days-remaining inactive without receiving suppressive medications at all of the last visits. Association of factors potentially predictive of medication-free remission was also studied. Two thousand seven hundred ninety-five eyes of 1634 patients with chronic anterior uveitis were followed up over 7936 eye-years (4676 person-years). The cumulative medication-free, person-year remission incidence within 5 years was 32.7% (95% confidence interval [CI], 30.4%-35.2%). Baseline clinical factors predictive of reduced remission incidence included longer duration of uveitis at presentation (for 2 to 5 years vs. less than 6 months: adjusted hazard ratio [aHR], 0.61; 95% CI, 0.44-0.83), bilateral uveitis (aHR, 0.75; 95% CI, 0.59-0.96), prior cataract surgery (aHR, 0.70; 95% CI 0.56-0.88), and glaucoma surgery (aHR, 0.63; 95% CI, 0.45-0.90). Two time-updated characteristics were also predictive of reduced remission incidence: keratic precipitates (aHR, 0.36; 95% CI, 0.21-0.60) and synechiae (aHR, 0.62; 95% CI, 0.41-0.93). Systemic diagnosis with juvenile idiopathic arthritis and spondyloarthropathy were also associated with reduced remission incidence. Older age at presentation was associated with higher incidence of remission (for age ≥40 years vs. <40 years: aHR, 1.29; 95% CI, 1.02-1.63). Approximately one third of patients with chronic anterior uveitis remit within 5 years. Longer duration of uveitis, younger age, bilateral uveitis, prior cataract surgery, glaucoma surgery, presence of keratic precipitates and synechiae, and systemic diagnoses of juvenile idiopathic arthritis and spondyloarthropathy predict reduced remission incidence; patients with these factors should be managed taking into account the higher probability of a longer disease course.


Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production.
Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient in FLG mutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.


Estimating serum concentrations of dioxin-like compounds in the U.S. population effective 2005-2006 and 2007-2008: A multiple imputation and trending approach incorporating NHANES pooled sample data.
Dioxin-like compounds (DLCs) are monitored in the U.S. population using data collected with the National Health and Nutrition Examination Survey (NHANES). Until recently, participants' serum samples have been analyzed individually, and summary statistics defining reference ranges by age, gender, and race/ethnicity have served as the background by which other biomonitoring data can be evaluated. In the most recent NHANES DLC data, 2005-2006 and 2007-2008, participants' sera have been physically pooled prior to laboratory analysis, introducing major challenges to their utility as a reference population: variability among individuals and relations with covariates are lost, and individual design effects cannot be applied. Further, the substantial drop in limits of detection (LODs) in pooled sample biennials prevents reliable comparisons to individual data, and has complicated estimates of change over time. In this study, we address the drawbacks introduced by pooled samples by generating U.S. population reference ranges based on individual-level data adjusted to 2005-2006 and 2007-2008 levels. Using publicly available data, multiple imputation (MI) generated four NHANES biennials (2001-2008) of individual DLC data; we then trended the change over time in each DLC by demographic stratum. NHANES 2003-2004 individuals were adjusted by the trended change over time. Population estimates of toxic equivalency (TEQ) concentrations were calculated using traditional MI survey analysis methods and reference tables provided for 2005-2006 and 2007-2008 by age, race, and gender. Demographic differences in TEQ concentrations and trended change are reported, e.g. TEQ continues to drop in young adults aged 20-39, but distributions appear stable in older adults 60+; Mexican Americans have consistently lowest dioxins, furans, and PCBs, with non-Hispanic Blacks dropping to the same levels as non-Hispanic Whites in dioxins and PCBs and significantly below non-Hispanic Whites in furans by 2007-2008. Additionally, the ratio of 95th percentile to mean in DLC distributions was found to vary by age, between dioxins, furans, and PCBs, and across mean, making a simple ratio approach impractical for describing population concentrations using pooled samples. We discuss the practical implications of the pooled sample method, the performance of this trending solution in the context of other methods, and expected effects of distribution assumptions on variability and TEQ estimates, particularly in largely undetected congeners. These updated reference populations of individuals, along with information on trending, provide a common and valid basis for interpreting other individually sampled biomonitoring data.


Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice.
With no approved pharmacological treatment, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease in Western countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here, we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic nicotinamide adenine dinucleotide (NAD(+) ) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD(+) biosynthesis, was added to the HFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1- and SIRT3-dependent mitochondrial unfolded protein response, triggering an adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 knockout mice (Sirt1(hep-/-) ), whereas apolipoprotein E-deficient mice (Apoe(-/-) ) challenged with a high-fat high-cholesterol diet affirmed the use of NR in other independent models of NAFLD. Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD.


Action potential reflection and failure at axon branch points cause stepwise changes in EPSPs in a neuron essential for learning.
In leech mechanosensory neurons, action potentials reverse direction, or reflect, at central branch points. This process enhances synaptic transmission from individual axon branches by rapidly activating synapses twice, thereby producing facilitation. At the same branch points action potentials may fail to propagate, which can reduce transmission. It is now shown that presynaptic action potential reflection and failure under physiological conditions influence transmission to the same postsynaptic neuron, the S cell. The S cell is an interneuron essential for a form of nonassociative learning, sensitization of the whole body shortening reflex. The P to S synapse has components that appear monosynaptic (termed "direct") and polysynaptic, both with glutamatergic pharmacology. Reflection at P cell branch points on average doubled transmission to the S cell, whereas action potential failure, or conduction block, at the same branch points decreased it by one-half. Each of two different branch points affected transmission, indicating that the P to S connection is spatially distributed around these branch points. This was confirmed by examining the locations of individual contacts made by the P cell with the S cell and its electrically coupled partner C cells. These results show that presynaptic neuronal morphology produces a range of transmission states at a set of synapses onto a neuron necessary for a form of learning. Reflection and conduction block are activity-dependent and are basic properties of action potential propagation that have been seen in other systems, including axons and dendrites in the mammalian brain. Individual branch points and the distribution of synapses around those branch points can substantially influence neuronal transmission and plasticity.


Supporting diversity, equity, inclusion, and belonging to strengthen and position the veterinary profession for service, sustainability, excellence, and impact.
Advancing equality and equity in society is creating positive change, and the time has come to critically evaluate veterinary medicine, which, by all metrics, lacks diversity. To keep pace with increasingly diverse demographics and recent surges in pet ownership among all racial/ethnic groups, significant efforts to enhance diversity, equity, inclusion, and belonging (DEIB) must occur in veterinary colleges and the profession. Recruiting more underrepresented students, building pipelines for diverse faculty/staff, and creating inclusive, welcoming environments where all can thrive are critical steps toward enhancing DEIB within our organizations and profession. Our goal is to share experiences and lessons learned from our intentional commitment to strengthen DEIB, with the hope that our journey will be helpful to others. Increasing diversity in the veterinary profession will be facilitated through removing barriers, creating inclusive work environments where all people feel they belong, and ensuring fair and equitable hiring and personnel management practices. These steps should in turn improve access and quality of veterinary care, ensure we are more representative of the communities we serve, increase revenue, and preserve the human-animal bond. "You cannot change any society unless you take responsibility for it, unless you see yourself belonging to it, and responsible for changing it." - Grace Lee Boggs.


Exits in order: How crowding affects particle lifetimes.
Diffusive processes are often represented using stochastic random walk frameworks. The amount of time taken for an individual in a random walk to intersect with an absorbing boundary is a fundamental property that is often referred to as the particle lifetime, or the first passage time. The mean lifetime of particles in a random walk model of diffusion is related to the amount of time required for the diffusive process to reach a steady state. Mathematical analysis describing the mean lifetime of particles in a standard model of diffusion without crowding is well known. However, the lifetime of agents in a random walk with crowding has received much less attention. Since many applications of diffusion in biology and biophysics include crowding effects, here we study a discrete model of diffusion that incorporates crowding. Using simulations, we show that crowding has a dramatic effect on agent lifetimes, and we derive an approximate expression for the mean agent lifetime that includes crowding effects. Our expression matches simulation results very well, and highlights the importance of crowding effects that are sometimes overlooked.


A semiparametric two-component "compound" mixture model and its application to estimating malaria attributable fractions.
Malaria remains a major epidemiologic problem in many developing countries. Malaria is defined as the presence of parasites and symptoms (usually fever) due to the parasites. In endemic areas, an individual may have symptoms attributable either to malaria or to other causes. From a clinical viewpoint, it is important to correctly diagnose an individual who has developed symptoms so that the appropriate treatments can be given. From an epidemiologic and economic viewpoint, it is important to determine the proportion of malaria-affected cases in individuals who have symptoms so that policies on intervention program can be developed. Once symptoms have developed in an individual, the diagnosis of malaria can be based on the analysis of the parasite levels in blood samples. However, even a blood test is not conclusive as in endemic areas many healthy individuals can have parasites in their blood slides. Therefore, data from this type of study can be viewed as coming from a mixture distribution, with the components corresponding to malaria and non-malaria cases. A unique feature in this type of data, however, is the fact that a proportion of the non-malaria cases have zero parasite levels. Therefore, one of the component distributions is itself a mixture distribution. In this article, we propose a semiparametric likelihood approach for estimating the proportion of clinical malaria using parasite-level data from a group of individuals with symptoms. Our approach assumes the density ratio for the parasite levels in clinical malaria and nonclinical malaria cases can be modeled using a logistic model. We use empirical likelihood to combine the zero and nonzero data. The maximum semiparametric likelihood estimate is more efficient than existing nonparametric estimates using only the frequencies of zero and nonzero data. On the other hand, it is more robust than a fully parametric maximum likelihood estimate that assumes a parametric model for the nonzero data. Simulation results show that the performance of the proposed method is satisfactory. The proposed method is used to analyze data from a malaria survey carried out in Tanzania.


Butterfly seed predation: effects of landscape characteristics, plant ploidy level and population structure.
Polyploidization has been suggested as one of the most common mechanisms for plant diversification. It is often associated with changes in several morphological, phenological and ecological plant traits, and therefore has the potential to alter insect-plant interactions. Nevertheless, studies evaluating the effect of plant polyploidy on interspecific interactions are still few. We investigated pre-dispersal seed predation by the butterfly Anthocharis cardamines in 195 populations of two ploidy levels of the herb Cardamine pratensis (tetraploid ssp. pratensis, 2n = 30 vs. octoploid ssp. paludosa, 2n = 56-64). We asked if differences in incidence and intensity of predation among populations were related to landscape characteristics, plant ploidy level and population structure. The incidence of the seed predator increased with increasing plant population size and decreasing distance to nearest population occupied by A. cardamines. The intensity of predation decreased with increasing plant population size and was not affected by isolation. Probability of attack decreased with increasing shading, and intensity of predation was higher in grazed than in non-grazed habitats. The attack intensity increased with increasing mean flower number of plant population, but was not affected by flowering phenology. Individuals in tetraploid populations suffered on average from higher levels of seed predation, had higher mean flower number, were less shaded and occurred more often in grazed habitats than octoploid populations. When accounting for differences in habitat preferences between ploidy levels there was no longer a difference in intensity of predation, suggesting that the observed differences in attack rates among populations of the two ploidy levels are mediated by the habitat. Overall, our results suggest that polyploidization is associated with differentiation in habitat preferences and phenotypic traits leading to differences in interspecific interaction among plant populations. This, in turn, may facilitate further divergence of ploidy levels.


Proapoptotic Activity of Achillea membranacea Essential Oil and Its Major Constituent 1,8-Cineole against A2780 Ovarian Cancer Cells.
Among the hundreds of reported Achillea species, A. membranacea (Labill.) DC. is one of the six that grow in Jordan. Many species of this genus are used in folk medicine to treat a variety of ailments and several biological and pharmacological activities have been ascribed to their essential oil (EO). For this study, the EO obtained from a specimen of A. membranacea grown in Jordan was analyzed by GC-MS. Ninety-six compounds were detected, of which oxygenated monoterpenes was the predominant class (47.9%), followed by non-terpene derivatives (27.9%), while sesquiterpenes represented 14.2% of the total composition. The most abundant compound in the EO was 1,8-cineole (21.7%). The cytotoxic activity of the EO was evaluated against three cancer cell lines (MCF7, A2780 and HT29), and one normal fibroblast cell line (MRC5) by MTT assay. Significant growth inhibition was observed in EO-exposed A2780 and HT29 cells (IC50 = 12.99 and 14.02 μg/mL, respectively), while MCF7 and MRC5 were less susceptible. The EO induced apoptosis and increased the preG1 events in A2780 cells. 1,8-Cineole, the major constituent of the EO, exhibited submicromolar cytotoxicity against A2780 cells, and was 42 times more selective against MRC5 cells. Its cytotoxicity against A2780 cells was comparable with that of doxorubicin, but 1,8-cineole was more selective for MRC5 normal cells. Interestingly, 1,8-cineole enhanced apoptosis in A2780, and caused a remarkable dose-dependent increase in preG1 events. Thus, 1,8-cineole has demonstrated promising cytotoxic and proapoptotic properties.


Leadership in Mammalian Societies: Emergence, Distribution, Power, and Payoff.
Leadership is an active area of research in both the biological and social sciences. This review provides a transdisciplinary synthesis of biological and social-science views of leadership from an evolutionary perspective, and examines patterns of leadership in a set of small-scale human and non-human mammalian societies. We review empirical and theoretical work on leadership in four domains: movement, food acquisition, within-group conflict mediation, and between-group interactions. We categorize patterns of variation in leadership in five dimensions: distribution (across individuals), emergence (achieved versus inherited), power, relative payoff to leadership, and generality (across domains). We find that human leadership exhibits commonalities with and differences from the broader mammalian pattern, raising interesting theoretical and empirical issues.


Stenting versus medical treatment for severe symptomatic intracranial stenosis.
Intracranial atherosclerosis is especially prevalent in Asians, but intracranial stent placement and medical treatment for severe intracranial stenosis are controversial. Thus, we compared long-term outcomes of these 2 therapeutic approaches in an Asian population. Patients with angiographically proved severe (≥70%) symptomatic intracranial atherosclerosis, with or without stent placement, were retrospectively reviewed at a single center between 2002 and 2009, with adjustments for age, sex, vascular risk factors, degree of baseline stenosis, and baseline functional status. Of the 114 patients followed from 3 to 36 months (mean, 17.3 months) after initial diagnosis, 53 received 56 stents in addition to medical treatment (stent-placement group), and 61 matched patients received only medical treatment (medical group). Total clinical events, including stroke, TIA, and vascular death, were 12 (22.6%) and 15 (24.6%) in the stent-placement and medical groups, respectively (P = .99). The stent-placement group had significantly better functional outcomes than the medical group (94.3% versus 78.7% for mRS scores of 0-3, P = .045). Most events in the stent-placement group occurred within the first week of the periprocedural period (17.0%) as minor embolic or perforator infarctions, and the rate of events decreased thereafter (5.7%, P = .07). Stent placement over the perforator-rich MCA and BA independently predicted periprocedural events on multivariate regression analysis. In the medical group, events increased in frequency (21.7%) and severity with time. Although the total ischemic event rate was similar in the 2 groups during a 3-year follow-up, the stent-placement group had a more favorable functional outcome despite minor periprocedural strokes.


Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current.
The expression of 15 different K+ channels in canine heart was examined, and a new K+ channel gene (Kv4.3), which encodes a rapidly inactivating K+ current, is described. The Kv4.3 channel was found to have biophysical and pharmacological properties similar to the native canine transient outward current (I(to)). The Kv4.3 gene is also expressed in human and rat heart. It is concluded that the Kv4.3 channel underlies the bulk of the I(to) in canine ventricular myocytes, and probably in human myocytes. Both the Kv4.3 and Kv4.2 channels are likely to contribute to the I(to) in rat heart, and differential expression of these two channels can account for observed differences in the kinetic properties of the I(to) in different regions of rat ventricle. There are significant differences in the pattern of K+ channel expression in canine heart, compared with rat heart, and these differences may be an adaptation to the different requirements for cardiac function in mammals of markedly different sizes. It is possible that the much longer ventricular action potential duration observed in canine heart compared with rat heart is due, in part, to the lower levels of Kv1.2, Kv2.1, and Kv4.2 gene expression in canine heart.


The polyvagal theory: new insights into adaptive reactions of the autonomic nervous system.
The polyvagal theory describes an autonomic nervous system that is influenced by the central nervous system, sensitive to afferent influences, characterized by an adaptive reactivity dependent on the phylogeny of the neural circuits, and interactive with source nuclei in the brainstem regulating the striated muscles of the face and head. The theory is dependent on accumulated knowledge describing the phylogenetic transitions in the vertebrate autonomic nervous system. Its specific focus is on the phylogenetic shift between reptiles and mammals that resulted in specific changes to the vagal pathways regulating the heart. As the source nuclei of the primary vagal efferent pathways regulating the heart shifted from the dorsal motor nucleus of the vagus in reptiles to the nucleus ambiguus in mammals, a face-heart connection evolved with emergent properties of a social engagement system that would enable social interactions to regulate visceral state.


The effect of needle tenotomy on hammer, mallet and claw toe deformities in patients with diabetes, a retrospective study.
The aim of this study was to evaluate outcomes of needle tenotomies as a treatment option for hammer, mallet and claw toes in patients with diabetes. This was a retrospective study where all patients receiving flexor tendon tenotomy by needle at our outpatient clinic were identified through the electronic patient record system. A total of 81 patients that had 106 tenotomy procedures performed were identified. The 81 included (68% male) had an average age of 65.4 years, and 27 (33%) had Type 1 diabetes. Of the 106 procedures 36 were performed due to an ulcer on the feet. Of the 36 treated ulcers, 34 (94%) healed in an average time of 28 days. Tenotomies performed to prevent impending ulcers from progressing to active ulcers, were performed 84 times in total. Of the 84 procedures 6 patients progressed to an active ulcer. No serious complications i.e. infections or amputations in relation to the procedure were registered. Needle flexor tenotomies are a relatively safe and effective treatment compared to tenotomies done by scalpel, both as treatment for ulcers and to prevent formation of new ulcers associated with hammer, mallet and claw toe deformities. As a side note, transfer lesions are avoidable if all toes on one or both feet are tenotomized in one procedure.


Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57.
Transient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers. Genome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing. We found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif. We have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.


CD4 + T cells promote renal cell carcinoma proliferation via modulating YBX1.
Renal cell carcinoma (RCC) is a common urologic tumor and the third leading cause of death among urological tumors. Recent studies demonstrate that RCC tumors are more heavily infiltrated by lymphocytes than other cancers. However, the exact roles played by CD4 + T cells in RCC proliferation remain unknown. In this study, we cocultured RCC cells with CD4 + T cells. Stable knockdown of YBX1 in RCC cells was constructed. The effects of CD4 + T cells, TGFβ1 and YBX1 on RCC cells were investigated using cell viability assays. In situ RCC nude mouse model was used to observe the tumor growth. The potential mechanisms of CD4 + T cells and YBX1 in RCC cells proliferation were explored by qRT-PCR and western blot. Expression of CD4, Foxp3 and TGFβ1 in RCC were quantified by immunohistochemical staining. The results indicated that CD4, Foxp3 and TGFβ1 were significantly up-regulated in RCC tissues. Human clinical sample and in vitro cell lines studies showed that RCC cells had better capacity than its surrounding normal kidney epithelial cells to recruit the CD4 + T cells. In vivo mouse model studies were consistent with the results by in vitro cell lines studies showing infiltrating T cells enhanced RCC cell proliferation. qRT-PCR and western blot exhibited that CD4 + T cells could enhance RCC cell proliferation via activating YBX1/HIF2α signaling pathway. Furthermore, CD4 + T cells functioned through inducing TGFβ1 expression. In a word, infiltrating CD4 + T cells promoted TGFβ1 expression in both RCC and T cells and regulated RCC cells proliferation via modulating TGFβ1/YBX1/ HIF2α signals.


Absorption and scattering by long and randomly oriented linear chains of spheres.
This paper demonstrates that the scattering cross section per unit length of randomly oriented linear chains of optically soft spheres asymptotically converges toward those of randomly oriented and infinitely long cylinders with volume-equivalent diameter as the number of spheres increases. The critical number of spheres necessary to approximate the linear chains of spheres as infinitely long cylinders decreased rapidly as the size parameter of an individual sphere increased from 0.01 to 10. On the other hand, their absorption cross section per unit length was identical to that of an infinitely long volume-equivalent cylinder for any number of spheres. However, this approximation does not apply to the angle-dependent normalized Stokes scattering matrix element ratios.


A novel irinotecan-lipiodol nanoemulsion for intravascular administration: pharmacokinetics and biodistribution in the normal and tumor bearing rat liver.
Colorectal cancer is one of the most common cancers in the United States and treatment options are limited for patients who develop liver metastases. Several chemotherapeutic regimens have been used for transvascular liver-directed therapy in the treatment of colorectal liver metastases without clear evidence of superiority of one therapy over another. We describe the development of a novel nanoemulsion through combining irinotecan (IRI), a first line systemic agent used for the treatment of colon cancer, with lipiodol, an oily contrast medium derived from poppy seed oil, and evaluated its pharmacokinetic and biodistribution profile as a function of portal venous chemoembolization (PVCE) versus transarterial chemoembolization (TACE) delivery. The Tessari technique was used to create a stable emulsion (20 mg IRI mixed with 2 mL lipiodol) with resultant particle size ranging from 28.9 nm to 56.4 nm. Pharmacokinetic profile established through venous sampling in Buffalo rats demonstrate that the area under the curve (AUC0-∞) of IRI was significantly less after PVCE with IRI-lipiodol as compared to IRI alone (131 vs. 316 µg*min/mL, p-value = .023), suggesting significantly higher amounts of IRI retention in the liver with the IRI-lipiodol nanoemulsion via first-pass extraction. Subseqent biodistribution studies in tumor-bearing WAG/Rjj rats revealed more IRI present in the tumor following TACE versus PVCE (29.19 ± 12.33 µg/g versus 3.42 ± 1.62; p-value = .0033) or IV (29.19 ± 12.33 µg/g versus 1.05 ± 0.47; p-value = .0035). The IRI-lipiodol nanoemulsion demonstrated an acceptable hepatotoxicity profile in all routes of administration. In conclusion, the IRI-lipiodol nanoemulsion via TACE showed promise and warrants further investigation as an option for the treatment of metastatic colorectal cancer.


SRP RNA remodeling by SRP68 explains its role in protein translocation.
The signal recognition particle (SRP) is central to membrane protein targeting; SRP RNA is essential for SRP assembly, elongation arrest, and activation of SRP guanosine triphosphatases. In eukaryotes, SRP function relies on the SRP68-SRP72 heterodimer. We present the crystal structures of the RNA-binding domain of SRP68 (SRP68-RBD) alone and in complex with SRP RNA and SRP19. SRP68-RBD is a tetratricopeptide-like module that binds to a RNA three-way junction, bends the RNA, and inserts an α-helical arginine-rich motif (ARM) into the major groove. The ARM opens the conserved 5f RNA loop, which in ribosome-bound SRP establishes a contact to ribosomal RNA. Our data provide the structural basis for eukaryote-specific, SRP68-driven RNA remodeling required for protein translocation.


Delayed subarachnoid hemorrhage 7 years after cerebellar infarction from traumatic vertebral artery dissection.
Vertebral artery dissection (VAD) is an important cause of ischemic stroke and subarachnoid hemorrhage (SAH). Dissections presenting with ischemia rarely cause SAH after more than a few hours, especially without radiographic evidence of pseudoaneurysm. We successfully treated a patient for persistent vessel injury presenting with SAH 7 years after presenting with extracranial subocclusive dissection of the right vertebral artery and an associated right posterior inferior cerebellar artery stroke. This is one of only three reported cases of delayed SAH occurring more than 2 weeks after an initial ischemic presentation of a VAD, and the only one without radiographic evidence of pseudoaneurysm at standard follow-up duration.


Clinical considerations for the treatment of secondary differentiated thyroid carcinoma in childhood cancer survivors.
The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.


Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder.
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20-50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.


Laparoscopic versus open gastrectomy for gastric cancer, a multicenter prospectively randomized controlled trial (LOGICA-trial).
For gastric cancer patients, surgical resection with en-bloc lymphadenectomy is the cornerstone of curative treatment. Open gastrectomy has long been the preferred surgical approach worldwide. However, this procedure is associated with considerable morbidity. Several meta-analyses have shown an advantage in short-term outcomes of laparoscopic gastrectomy compared to open procedures, with similar oncologic outcomes. However, it remains unclear whether the results of these Asian studies can be extrapolated to the Western population. In this trial from the Netherlands, patients with resectable gastric cancer will be randomized to laparoscopic or open gastrectomy. The study is a non-blinded, multicenter, prospectively randomized controlled superiority trial. Patients (≥18 years) with histologically proven, surgically resectable (cT1-4a, N0-3b, M0) gastric adenocarcinoma and European Clinical Oncology Group performance status 0, 1 or 2 are eligible to participate in the study after obtaining informed consent. Patients (n = 210) will be included in one of the ten participating Dutch centers and are randomized to either laparoscopic or open gastrectomy. The primary outcome is postoperative hospital stay (days). Secondary outcome parameters include postoperative morbidity and mortality, oncologic outcomes, readmissions, quality of life and cost-effectiveness. In this randomized controlled trial laparoscopic and open gastrectomy are compared in patients with resectable gastric cancer. It is expected that laparoscopic gastrectomy will result in a faster recovery of the patient and a shorter hospital stay. Secondly, it is expected that laparoscopic gastrectomy will be associated with a lower postoperative morbidity, less readmissions, higher cost-effectiveness, better postoperative quality of life, but with similar mortality and oncologic outcomes, compared to open gastrectomy. The study started on 1 December 2014. Inclusion and follow-up will take 3 and 5 years respectively. Short-term results will be analyzed and published after discharge of the last randomized patient. NCT02248519.


Modified Kigali combined staging predicts risk of mortality in HIV-infected adults in Lusaka, Zambia.
We assessed the utility of the modified Kigali combined (MKC) staging system for predicting survival in HIV-infected Zambian adults in a prospective, longitudinal, open cohort. From 1995 to 2004, HIV-discordant couples (one HIV-infected partner and one HIV-negative partner) were recruited from couples' voluntary counseling and testing centers in Lusaka, Zambia and followed at 3-month intervals. MKC stage, which incorporates clinical stage with erythrocyte sedimentation rate (ESR), hematocrit, and body mass index (BMI), was determined at enrollment. Kaplan-Meier survival and Cox proportional hazard methods were used to calculate median survival and relative hazards. We enrolled 1479 HIV-discordant couples with a combined 7305 person-years of follow-up. Among HIV-infected participants over the 9-year study period, there were 333 confirmed deaths. The time to 50% mortality was 8.5 years with MKC stage 1 and 2 disease compared to 3.7 years with MKC stage 4 disease at enrollment. Survival rates at 3 years were 85% with MKC stage 1 and 2 disease, 74% with MKC stage 3 disease, and 51% with MKC stage 4 disease. A total of 275 HIV-negative partners seroconverted during follow-up. In comparison, survival rates at 3 years were 94% for HIV-negative participants and 92% for participants who seroconverted during follow-up. In multivariate analysis, MKC stage 4 disease (HR = 3.7, 95% CI = 2.7-5.0) remained a strong predictor of mortality. Incorporating ESR, hematocrit, and BMI with clinical staging is a powerful, low-cost tool to identify HIV-infected adults at high risk for mortality.


Sphingolipids containing very-long-chain fatty acids define a secretory pathway for specific polar plasma membrane protein targeting in Arabidopsis.
Sphingolipids are a class of structural membrane lipids involved in membrane trafficking and cell polarity. Functional analysis of the ceramide synthase family in Arabidopsis thaliana demonstrates the existence of two activities selective for the length of the acyl chains. Very-long-acyl-chain (C > 18 carbons) but not long-chain sphingolipids are essential for plant development. Reduction of very-long-chain fatty acid sphingolipid levels leads in particular to auxin-dependent inhibition of lateral root emergence that is associated with selective aggregation of the plasma membrane auxin carriers AUX1 and PIN1 in the cytosol. Defective targeting of polar auxin carriers is characterized by specific aggregation of Rab-A2(a)- and Rab-A1(e)-labeled early endosomes along the secretory pathway. These aggregates correlate with the accumulation of membrane structures and vesicle fragmentation in the cytosol. In conclusion, sphingolipids with very long acyl chains define a trafficking pathway with specific endomembrane compartments and polar auxin transport protein cargoes.


Differential susceptibility to obesity between male, female and ovariectomized female mice.
The prevalence of obesity has increased dramatically. A direct comparison in the predisposition to obesity between males, premenopausal females, and postmenopausal females with various caloric intakes has not been made. To determine the effects of sex and ovarian hormones on the susceptibility to obesity, we conducted laboratory studies with mice. To eliminate confounders that can alter body weight gain, such as age and food consumption; we used mice with the same age and controlled the amount of calories they consumed. We determined sex-specific susceptibility to obesity between male, non-ovariectomized female, and ovariectomized female mice. To compare susceptibility to gaining body weight between males and females, animals from each sex were exposed to either a 30% calorie-restricted, low-fat (5% fat), or high-fat (35% fat) diet regimen. To establish the role of ovarian hormones in weight gain, the ovaries were surgically removed from additional female mice, and then were exposed to the diets described above. Percent body fat and percent lean mass in the mice were determined by dual energy x-ray absorptiometry (DEXA). In all three diet categories, male mice had a greater propensity of gaining body weight than female mice. However, ovariectomy eliminated the protection of female mice to gaining weight; in fact, ovariectomized female mice mimicked male mice in their susceptibility to weight gain. In summary, results show that male mice are more likely to become obese than female mice and that the protection against obesity in female mice is eliminated by ovariectomy. Understanding metabolic differences between males and females may allow the discovery of better preventive and treatment strategies for diseases associated with body weight such as cancer and cardiovascular disease.


The introduction of an interprofessional education module: students' perceptions.
The purpose of this study was to examine health science students' perceptions of an interprofessional education (IPE) module delivered by means of problem-based learning (PBL). Ninety-two students from four health science disciplines (medicine, physiotherapy, nursing and diagnostic imaging) elected to participate in this IPE PBL module. An evaluation was undertaken using a questionnaire with quantitative and qualitative components completed at the end of the module. Students were asked to evaluate aspects of the module relating to learning objectives, intellectual stimulation, resources, library information skills, work load and overall satisfaction. Open-ended questions asked students to comment on the best aspects of the module and areas for improvement. Quantitative data were analysed using SPSS version 18 and qualitative data using framework analysis methodology. Of the 92 students that participated in the module, 70 (78%) completed the questionnaire. Over 70% (n = 49) of students positively endorsed the module in terms of the statements posed. Overall satisfaction with the module was high, with 63 (91%) students reporting that they agreed or strongly agreed that they were satisfied with the module. Analysis of qualitative data revealed the following emerging themes in relation to the module: (1) collaboration (learning together with others from different professions); (2) structure (small group work, discussion, teamwork assessment procedures); and (3) content (problem diversity). The introduction of this IPE module for health science students was well received. Students valued the opportunity to work in small groups with individuals from other health science disciplines. Students highlighted module structure and content as being important elements for consideration when developing IPE. Further research is required in order to define whether improving communication and collaboration skills will ultimately lead to improved quality in patient care.


Recurrent acute pancreatitis: clinical profile and an approach to diagnosis.
Though recurrent acute pancreatitis is often seen in clinical practice, there are few comprehensive articles on this entity. The aim of this study therefore was to assess the etiological and clinical profile as well as diagnostic yield of non-invasive and invasive tests in this group of patients. All patients with recurrent acute pancreatitis seen from 2002 to 2007 were included in the study, retrospectively. Clinical information, investigation, and treatment data were collected for all patients by a standardized review of medical charts. Diagnostic tests were grouped into level one (non-invasive) and level two (invasive) tests and their yield was assessed. Comparison was made between the group with known etiology and idiopathic group to look for significant differences. A total of 188 patients with recurrent acute pancreatitis were seen during the study period. Common etiological factors were biliary disease (37%), pancreas divisum (8.5%) and alcohol (6.4%). Multiple etiologies were seen in 7% of cases, and no cause was found in 32.4%. The diagnostic yield of level-one investigation (non-invasive) was 29.3%. Level-two tests (invasive) identified presumptive etiologies in 38.3% of cases. Complications developed in 12.2% and there was no mortality. Clinical features and complications were similar in the idiopathic group and those with known etiology. Etiological diagnosis was obtained in 67.6% of patients after comprehensive diagnostic work up. Diagnosis in the majority of patients could only be reached after invasive tests (bile crystal analysis, EUS, ERCP). Early diagnosis and etiology-based therapy is the key to optimum patient outcome.


Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon.
Voltage-dependent sodium channels are uniformly distributed along unmyelinated axons, but are highly concentrated at nodes of Ranvier in myelinated axons. Here, we show that this pattern is associated with differential localization of distinct sodium channel alpha subunits to the unmyelinated and myelinated zones of the same retinal ganglion cell axons. In adult axons, Na(v)1.2 is localized to the unmyelinated zone, whereas Na(v)1.6 is specifically targeted to nodes. During development, Na(v)1.2 is expressed first and becomes clustered at immature nodes of Ranvier, but as myelination proceeds, Na(v)1.6 replaces Na(v)1.2 at nodes. In Shiverer mice, which lack compact myelin, Na(v)1.2 is found throughout adult axons, whereas little Na(v)1.6 is detected. Together, these data show that sodium channel isoforms are differentially targeted to distinct domains of the same axon in a process associated with formation of compact myelin.


Analysis of the Listeria cell wall proteome by two-dimensional nanoliquid chromatography coupled to mass spectrometry.
Genome analyses have revealed that the Gram-positive bacterial species Listeria monocytogenes and L. innocua contain a large number of genes encoding surface proteins predicted to be covalently bound to the cell wall (41 and 34, respectively). The function of most of these proteins is unknown and they have not even been identified biochemically. Here, we report the first characterization of the Listeria cell wall proteome using a nonelectrophoretic approach. The material analyzed consisted of a peptide mixture obtained from a cell wall extract insoluble in boiling 4% SDS. This extract, containing peptidoglycan (intrinsically resistant to proteases) and strongly associated proteins, was digested with trypsin in a solution with 0.01% SDS, used to favor protein digestion throughout the peptidoglycan. The resulting complex peptide mixture was fractionated and analyzed by two-dimensional nanoliquid chromatography coupled to ion-trap mass spectrometry. A total of 30 protein species were unequivocally identified in cell wall extracts of the genome strains L. monocytogenes EGD-e (19 proteins) and L. innocua CLIP11262 (11 proteins). Among them, 20 proteins bearing an LPXTG motif recognized for covalent anchoring to the peptidoglycan were identified. Other proteins detected included peptidoglycan-lytic enzymes, a penicillin-binding protein, and proteins bearing an NXZTN motif recently proposed to direct protein anchoring to the peptidoglycan. The marked sensitivity of the method makes it highly attractive in the post-genome era for defining the cell wall proteome in any bacterial species. This information will be useful to study novel protein-peptidoglycan associations and to rapidly identify new targets in the surface of important bacterial pathogens.


Genotyping and clinical factors in pediatric diarrhea caused by rotaviruses: one-year surveillance in Surabaya, Indonesia.
Rotavirus infections are a major cause of diarrhea in children in both developed and developing countries. Rotavirus genetics, patient immunity, and environmental factors are thought to be related to the severity of acute diarrhea due to rotavirus in infants and young children. The objective of this study was to provide a correlation between rotavirus genotypes, clinical factors and degree of severity of acute diarrhea in children under 5 years old in Surabaya, Indonesia. A cross-sectional study was conducted in children aged 1-60 months with acute diarrhea hospitalized in Soetomo Hospital, Surabaya, Indonesia from April to December 2013. Rotavirus in stool specimens was identified by ELISA and genotyping (G-type and P-type) using multiplex reverse transcription PCR. Severity was measured using the Ruuska and Vesikari scoring system. The clinical factors were investigated included patient's age (months), hydration, antibiotic administration, nutritional state, co-bacterial infection and co-viral infection. A total of 88 children met the criteria; 80.7% were aged 6-24 months, watery diarrhea was the most common type (77.3%) and 73.6% of the subjects were co-infected with bacteria, of which pathogenic Escherichia coli was the most common (42.5%). The predominant VP7 genotyping (G-type) was G2 (31.8%) and that of VP4 genotyping (P-type) was P[4] (31.8%). The predominant rotavirus genotype was G2P[4] (19.3%); G1P[4] and G9P[4] were uncommon with a prevalence of 4.5%. There were significant differences between the common genotype and uncommon genotype with respect to the total severity score of diarrhea (p <0.05). G3, G4 and G9 were significantly correlated with severe diarrhea (p = 0.009) in multivariate analyses and with frequency of diarrhea (>10 times a day) (p = 0.045) in univariate analyses, but there was no significant correlation between P typing and severity of diarrhea. For combination genotyping of G and P, G2P[4] was significantly correlated with severe diarrhea in multivariate analyses (p = 0.029). There is a correlation between rotavirus genotype and severity of acute diarrhea in children. Genotype G2P[4] has the highest prevalence. G3, G4, G9 and G2P[4] combination genotype were found to be associated with severe diarrhea.


Effects of Kraft Pulp and Lignin on Trametes versicolor Carbon Metabolism.
The white rot basidiomycete Trametes (Coriolus) versicolor can substantially increase the brightness and decrease the lignin content of washed, unbleached hardwood kraft pulp (HWKP). Monokaryotic strain 52J was used to study how HWKP and the lignin in HWKP affect the carbon metabolism and secretions of T. versicolor. Earlier work indicated that a biobleaching culture supernatant contained all components necessary for HWKP biobleaching and delignification, but the supernatant needed frequent contact with the fungus to maintain these activities. Thus, labile small fungal metabolites may be the vital biobleaching system components renewed or replaced by the fungus. Nearly all of the CO(2) evolved by HWKP-containing cultures came from the added glucose, indicating that HWKP is not an important source of carbon or energy during biobleaching. Carbon dioxide appeared somewhat earlier in the absence of HWKP, but the culture partial O(2) pressure was little affected by the presence of pulp. The presence of HWKP in a culture markedly increased the culture's production of a number of acidic metabolites, including 2-phenyllactate, oxalate, adipate, glyoxylate, fumarate, mandelate, and glycolate. Although the total concentration of these pulp-induced metabolites was only 4.3 mM, these compounds functioned as effective manganese-complexing agents for the manganese peroxidase-mediated oxidation of phenol red, propelling the reaction at 2.4 times the rate of 50 mM sodium malonate, the standard chelator-buffer. The presence of HWKP in a culture also markedly stimulated fungal secretion of the enzymes manganese peroxidase, cellulase, and cellobiose-quinone oxidoreductase, but not laccase (phenol oxidase) or lignin peroxidase.


Complete Genome Sequences of Three Leptospira mayottensis Strains from Tenrecs That Are Endemic in the Malagasy Region.
Leptospirosis is a zoonosis caused by Leptospira, a diversified genus containing more than 10 pathogenic species. Tenrecs are small terrestrial mammals endemic in the Malagasy region and are known to be reservoirs of the recently described species Leptospira mayottensis. We report the complete genome sequences of three L. mayottensis strains isolated from two tenrec species.


An integrated approach clarifies the cryptic diversity in Hypostomus Lacépède 1803 from the Lower La Plata Basin.
Hypostomus commersoni Valenciennes 1836, Hypostomus cordovae (Günther 1880) and Hypostomus laplatae (Eigenmann 1907) have been little studied since their original descriptions. This study shows a comprehensive review of these species from the Lower La Plata Basin, including their taxonomic history, distribution, color patterns, morphology, and ecological and molecular phylogenetic data. Morphological and phylogenetic analyses based on D-loop sequences suggested that H. commersoni can be separated into two subclades, or subgroups. Based on these results and on the non-overlapping distribution range of the two subclades, we conclude that they represent two distinct species, thereby revalidating H. spiniger. The results also suggest that H. paranensis should be considered as species inquirenda and H. cordovae as valid species. This integrated approach provides key information for assessing the conservation status and biogeographic aspects of the genus Hypostomus in the Lower La Plata Basin.


Adolescent self-harm: Parents' experiences of supporting their child and help-seeking.
Self-harm in children and adolescents is a growing public health issue. Parents are forefront in identifying, responding to and supporting their child to seek help. A sequential mixed-method study which included an online survey (N = 37) and a semi-structured interview (n = 10) was conducted to understand parents' experiences of supporting and accessing help for their child. Parents (M = 45.70 years, SD = 6.18) with a child who has engaged in self-harm behaviours (M = 16.89 years, SD = 3.91) participated. Parents sought help from a range of services and perceived psychiatrists, private psychologists and friends as the most helpful and school psychologists, paediatricians, Emergency Department (ED) and the national youth mental health organisation as the least helpful. Two themes were interpreted from the qualitative data: (1) An emotional journey into the dark unknown, and (2) The promise of psychological help. A series of recommendations for other parents in similar situations, as well as health professionals were made. Parents want health professionals to provide appropriate referrals, work collaboratively with families, meaningfully connect with and validate parents, provide practical and psychological support for families and establish parent support groups. There remains a need for widely available evidence-informed resources, information and support for parents.


Quantum crystallography.
Approximate wavefunctions can be improved by constraining them to reproduce observations derived from diffraction and scattering experiments. Conversely, charge density models, incorporating electron-density distributions, atomic positions and atomic motion, can be improved by supplementing diffraction experiments with quantum chemically calculated, tailor-made electron densities (form factors). In both cases quantum chemistry and diffraction/scattering experiments are combined into a single, integrated tool. The development of quantum crystallographic research is reviewed. Some results obtained by quantum crystallography illustrate the potential and limitations of this field.


Good practice and quality assurance in surgical oncology.
The Halstedian era of radical surgical extirpation for solid tumours dominated the first half of the 20th century. But as understanding of cancer biology increased, a paradigm shift occurred which moved the focus away from extensive surgery towards less radical procedures. Although surgery is a recognised factor in local disease control, prognosis is now believed to be predetermined at the time of diagnosis by the presence of micrometastatic deposits. Modern cancer management consists of more skilled and conservative surgery to remove the primary tumour; adjuvant therapies are also given before and after the operation to target the subclinical metastatic deposits. The most important components of high-quality care in surgical oncology are: sound clinical judgment, surgical skill, and multidisciplinary care. These prerequisites are best achieved by specialisation, but high operative volume is not essential for excision of many types of tumour. Quality assurance using several readily available tools can ensure that the process of care from presentation to outcome is constantly improved and that institutional variations in number of cases and quality of care are monitored.


Age ascription as a resource and a source of resistance - An interactional study of health professionals' castings of patients into the category 'old'.
This case study aims to give an understanding of what actions health professionals' castings of patients into the category 'old' perform on a medical and social level as well as what actions patients' interactional management of these castings perform. Particularly, this study aims to bring to the fore the negotiability of health professionals' perspectivating age ascriptions. This is done with the conversation analytic method (CA) according to which altercasting is a mutual construction performed turn by turn and shaped by the reactions of the interlocutor who can approve, resist, or modify the identity in question. The data are drawn from two Swedish television documentaries on health encounters. Three major findings are presented. Firstly, the castings of the patients into the category 'old' are in several cases embedded in metaphors that either position the patient's body in the role of a victim of old age or in the role of a machine to routinely check. Secondly, the castings with a fateful approach to old age are ambivalent; whereas they serve as resources for the health professionals' normalizing of medical projects and perspectives, they can constitute sources of problems for the patients' doctorability and/or agency. Thirdly, the health professionals' perspectivating age ascriptions are negotiable; their design facilitates resistance to them, and the patients accept, modify, interrupt or reverse them.


Delineating the psychological and behavioural factors of successful weight loss maintenance.
Overweight and obesity present alarming global health problems including detrimental health risks that call for effective interventions. Considerable research has examined behavioural and psychological factors associated with weight loss to advance the field of obesity and overweight. In line with the literature, this study aimed to develop a behavioural and psychological profile based on factors of personality, eating behaviours, emotional functioning, physical well-being, and psychopathology. The sample consisted of 105 community participants who had reduced their bodyweight by at least 10% and had either successfully maintained their weight loss for a minimum 12-month period (n = 41) or had regained their weight loss within 12 months (n = 64). Participants completed an online survey comprising demographic items and four empirical measures (Mini Marker Personality Scale, Patient Health Questionnaire, Three-Factor Eating Questionnaire-Revised, and a food screening tool). Based on significant bivariate correlations results, four factors (fat intake, restrained eating, uncontrolled eating, and emotional eating) were entered into a binary logistic regression. Restrained eating was the only factor that significantly increased the likelihood of predicting successful long-term weight loss. Findings have implications for overweight and obesity future research, which may guide the direction of obesity and overweight treatments.


Deep vein thrombosis: pathogenesis, diagnosis, and medical management.
Deep vein thrombosis (DVT) is a major preventable cause of morbidity and mortality worldwide. Venous thromboembolism (VTE), which includes DVT and pulmonary embolism (PE), affects an estimated 1 per 1,000 people and contributes to 60,000-100,000 deaths annually. Normal blood physiology hinges on a delicate balance between pro- and anti-coagulant factors. Virchow's Triad distills the multitude of risk factors for DVT into three basic elements favoring thrombus formation: venous stasis, vascular injury, and hypercoagulability. Clinical, biochemical, and radiological tests are used to increase the sensitivity and specificity for diagnosing DVT. Anticoagulation therapy is essential for the treatment of DVT. With few exceptions, the standard therapy for DVT has been vitamin K-antagonists (VKAs) such as warfarin with heparin or fractionated heparin bridging. More recently, a number of large-scale clinical trials have validated the use of direct oral anticoagulants (DOACs) in place of warfarin in select cases. In this review, we summarize the pathogenesis, diagnosis, and medical management of DVT, with particular emphasis on anticoagulation therapy and the role of DOACs in the current treatment algorithm.


Re-engineering a pharmacy work system and layout to facilitate patient counseling.
The development and evaluation of a new work system and facility design for a chain of community pharmacies are described. A new work system was developed to optimize utilization of pharmacist and technician time and allow the pharmacy to increase patient counseling without adding personnel. In the new system, pharmacists would review prescriptions, check technicians' work, and dispense prescriptions, counseling patients as needed; technicians would enter prescriptions into the pharmacy computer and fill them. The existing work system and design were evaluated in June and July of 1992 by observing, classifying, and recording activities of pharmacy personnel three days per week at six pharmacies in the chain. Pharmacy designs that would work with the new work system were created by a university design class after consultation with representatives of the pharmacy chain and the university's college of pharmacy. The pharmacy chain selected one design, and a detailed floor plan and specifications were created. To test how the new design and system would work at each of the six test pharmacies, a computer simulation program was developed and verified by using the data collected on the existing pharmacy operations. Computer simulation showed that, with the new design and system, increasing patient counseling would increase patient waiting time slightly but would not require additional personnel. The layout and work system in a chain of community pharmacies were redesigned to facilitate patient counseling and make the best use of employee time.


Tunable directly modulated fiber ring laser using a reflective semiconductor optical amplifier for WDM access networks.
We have proposed a stable, wideband, and tunable directly modulated fiber ring laser (TDMFRL) by using a reflective semiconductor optical amplifier (RSOA) and an optical tunable filter (OTF). For use in a bidirectional access network, the TDMFRL not only generates downstream data traffic but also serves as the wavelength-selecting injection light source for the Fabry-Pérot laser diode (FP-LD) located at the subscriber site. We experimentally demonstrated a bidirectional transmission at 1.25-Gb/s direct modulation over a 25-km single-mode fiber (SMF), thereby showing good performance in a wavelength division multiplexing (WDM) access network.