Engineering strategies for rational polyketide synthase design.
Covering: mid 1990s to 2018 Over the last two decades, diverse approaches have been explored to generate new polyketides by engineering polyketide synthases (PKSs). Although it has been proven possible to produce new compounds by designed PKSs, engineering strategies failed to make polyketides available via widely applicable rules and protocols. Still, organic synthetic routes have to be employed whenever new polyketides are needed for applications in medicine, agriculture, and industry. In light of the rising demand for commodity products from feedstock and for fast and cheap access to pharmaceutical compounds, the need for harnessing PKSs to produce such molecules is more urgent than ever before. In this review, we focus on a multitude of approaches to engineer modular PKSs by swapping and replacing PKS modules and domains, which we analyze in the light of recent structural and biochemical data. We conclude with an outlook on possible strategies on how to increase success rates of PKS engineering in future.


Characterization of two sets of subpolar flagella in Bradyrhizobium japonicum.
Bradyrhizobium japonicum is one of the soil bacteria that form nodules on soybean roots. The cell has two sets of flagellar systems, one thick flagellum and a few thin flagella, uniquely growing at subpolar positions. The thick flagellum appears to be semicoiled in morphology, and the thin flagella were in a tight-curly form as observed by dark-field microscopy. Flagellin genes were identified from the amino acid sequence of each flagellin. Flagellar genes for the thick flagellum are scattered into several clusters on the genome, while those genes for the thin flagellum are compactly organized in one cluster. Both types of flagella are powered by proton-driven motors. The swimming propulsion is supplied mainly by the thick flagellum. B. japonicum flagellar systems resemble the polar-lateral flagellar systems of Vibrio species but differ in several aspects.


Influence of additives and storage temperature on physicochemical and microbiological properties of eye drops containing cefazolin.
The purpose of the studies was to choose additives for eye drops containing cefazolin and the assessment of the influence of used additives and the storage temperature on the physicochemical properties and the stability of the eye drops. The drops were 1% sterile solutions of cefazolin in citrate buffer of pH 6.15-6.20. The drops were preserved with 0.002% thiomersal or 0.001% phenylmercuric borate mixed with 0.4% beta-phenylethyl alcohol. Viscosity of the eye drops was increased using polyvinyl alcohol (PVAL). The pharmaceutical compatibility test of selected additives with cefazolin showed the pharmaceutical interaction of 1% solution of cefazolin with higher than 0.003% concentration of thiomersal, 0.005% benzalkonium chloride and 0.01% chlorhexidine diacetate. The drops, protected from light, were stored at the temperature of 4 degrees C and 20 degrees C. As the criteria of the qualitative assessment of freshly prepared drops and during their storage, the following properties were considered: organoleptic analysis, sterility, pH, osmotic pressure, density, viscosity, antimicrobial activity of cefazolin and preservation efficiency of thiomersal and phenylmercuric borate in the eye drops. The studies showed that the storage temperature did not influence the physicochemical properties of the drops or the antimicrobial activity of cefazolin in the drops, which was not influenced by the used additives either. After 30 days of storage at both temperatures, cefazolin in the eye drops retained 100% of its initial activity. Phenylmercuric borate, whose antimicrobial activity in the eye drops was compatible with the preservation assay cited in the Polish Pharmacopoeia (PPh V), can be used to preserve the drops containing cefazolin.


The Possible Role of MOPr-DOPr Heteromers and Its Regulatory Protein RTP4 at Sensory Neurons in Relation to Pain Perception.
Heteromers between mu opioid receptor (MOPr) and delta opioid receptor (DOPr) (i.e., MOPr-DOPr heteromer) have been found to be expressed in different brain regions, in the spinal cord, and in dorsal root ganglia. Recent studies on this heteromer reveal its important pathophysiological function in pain regulation including neuropathic pain; this suggests a role as a novel therapeutic target in chronic pain management. In addition, receptor transporter protein 4 (RTP4) has been shown to be involved in the intracellular maturation of the MOPr-DOPr heteromers. RTP4 appears to have unique distribution in vivo being highly expressed in sensory neurons and also macrophages; the latter are effector cells of the innate immune system that phagocytose foreign substances and secrete both pro-inflammatory and antimicrobial mediators; this suggests a possible contribution of RTP4 to neuronal immune-related pathological conditions such as neuropathic pain. Although RTP4 could be considered as an important therapeutic target in the management of pain via MOPr-DOPr heteromer, a few reports have supported this. This review will summarize the possible role or functions of the MOPr-DOPr heteromer and its regulatory molecule RTP4 in pain modulation at sensory neurons.


Communalism Moderates the Association Between Racial Centrality and Emergency Department Use for Sickle Cell Disease Pain.
Sickle cell disease (SCD) is a genetic blood disorder that predominantly affects people of African descent. However, there is limited information on how social and cultural contexts affect SCD-related health care use. We explored whether communalism moderated the relation between racial centrality and emergency department use for SCD pain in a sample of 62 adults who were seen at a comprehensive clinic. Bivariate analyses showed a significant correlation between racial centrality and emergency department use (r = -.30, p = .02). Pain-adjusted regression analyses indicated a moderating effect of communalism (b = .77, p < .01) such that an inverse association between racial centrality and emergency department use was observed only at mean and low levels of communalism. Additional studies are needed to replicate these findings with larger samples. There is also a need for further studies that elucidate the role of culturally centered coping strategies on health care use in this patient group.


Educational-entertainment as an intervention with Black adolescents exposed to community violence.
Witnessing violence is one adverse childhood experience (ACE) associated with living in impoverished Black urban communities. Youth with higher violence avoidance self-efficacy and positive coping are more likely to avoid violence. This study evaluates educational entertainment (edutainment) as an intervention with Black adolescents exposed to community violence. Edutainment has shown success in increasing self-efficacy and positive coping skills in other domains. Self-administered scales were used to measure stress, anxiety, violence avoidance self-efficacy, and coping strategies. Data were collected pre- and nine days post-interventions/no intervention from 20 subjects receiving the edutainment intervention, 19 subjects participating in a group discussion about violence, and 21 subjects receiving no intervention (N = 60). Edutainment and no intervention were more effective than group discussion alone in increasing violence avoidance self-efficacy. Violence avoidance self-efficacy was found to have an intervening relationship between edutainment and the outcome of stress. This study indicates limited but positive effects for edutainment.


Experimental state tomography of itinerant single microwave photons.
A wide range of experiments studying microwave photons localized in superconducting cavities have made important contributions to our understanding of the quantum properties of radiation. Propagating microwave photons, however, have so far been studied much less intensely. Here we present measurements in which we reconstruct the quantum state of itinerant single photon Fock states and their superposition with the vacuum by analyzing moments of the measured amplitude distribution up to fourth order. Using linear amplifiers and quadrature amplitude detectors, we have developed efficient methods to separate the detected single photon signal from the noise added by the amplifier. From our measurement data we have also reconstructed the corresponding Wigner function.


Anopheles mosquitoes reveal new principles of 3D genome organization in insects.
Chromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance and evolutionary dynamics of these hierarchies are poorly defined. Here, we comprehensively profile genome organizations of five Anopheles mosquito species and show how different levels of chromatin architecture influence each other. Patterns observed on Hi-C maps are associated with known cytological structures, epigenetic profiles, and gene expression levels. Evolutionary analysis reveals conservation of chromatin architecture within synteny blocks for tens of millions of years and enrichment of synteny breakpoints in regions with increased genomic insulation. However, in-depth analysis shows a confounding effect of gene density on both insulation and distribution of synteny breakpoints, suggesting limited causal relationship between breakpoints and regions with increased genomic insulation. At the level of individual loci, we identify specific, extremely long-ranged looping interactions, conserved for ~100 million years. We demonstrate that the mechanisms underlying these looping contacts differ from previously described Polycomb-dependent interactions and clustering of active chromatin.


Disparate effects of Cu and V on structures of exohedral transition metal-doped silicon clusters: a combined far-infrared spectroscopic and computational study.
The growth mechanisms of small cationic silicon clusters containing up to 11 Si atoms, exohedrally doped by V and Cu atoms, are described. We find that as dopants, V and Cu follow two different paths: while V prefers substitution of a silicon atom in a highly coordinated position of the cationic bare silicon clusters, Cu favors adsorption to the neutral or cationic bare clusters in a lower coordination site. The different behavior of the two transition metals becomes evident in the structures of Si(n)M(+) (n = 4-11 for M = V, and n = 6-11 for M = Cu), which are investigated by density functional theory and, for several sizes, confirmed by comparison with their experimental vibrational spectra. The spectra are measured on the corresponding Si(n)M(+)·Ar complexes, which can be formed for the exohedrally doped silicon clusters. The comparison between experimental and calculated spectra indicates that the BP86 functional is suitable to predict far-infrared spectra of these clusters. In most cases, the calculated infrared spectrum of the lowest-lying isomer fits well with the experiment, even when various isomers and different electronic states are close in energy. However, in a few cases, namely Si(9)Cu(+), Si(11)Cu(+), and Si(10)V(+), the experimentally verified isomers are not the lowest in energy according to the density functional theory calculations, but their structures still follow the described growth mechanism. The different growth patterns of the two series of doped Si clusters reflect the role of the transition metal's 3d orbitals in the binding of the dopant atoms.


Unbiased MRI Analyses Identify Micropathologic Differences Between Upper Motor Neuron-Predominant ALS Phenotypes.
Amyotrophic lateral sclerosis (ALS) is an incurable and progressively fatal neurodegenerative disease that manifests with distinct clinical phenotypes, which are seen in neuroimaging, and clinical studies. T2- and proton density (PD)-weighted magnetic resonance imaging (MRI) displays hyperintense signal along the corticospinal tract (CST) in some ALS patients with upper motor neuron (UMN)-predominant signs. These patients tend to be younger and have significantly faster disease progression. We hypothesize that such ALS patients with CST hyperintensity (ALS-CST+) comprise a clinical subtype distinct from other ALS subtypes, namely patients with UMN-predominant ALS without CST hyperintensity, classic ALS, and ALS with frontotemporal dementia (FTD). Novel approaches such as fractal dimension analysis on conventional MRI (cMRI) and advanced MR techniques such as diffusion tensor imaging (DTI) reveal significant differences between ALS-CST+ and the aforementioned ALS subtypes. Our unbiased neuroimaging studies demonstrate that the ALS-CST+ group, which can be initially identified by T2-, PD-, and FLAIR-weighted cMRI, is distinctive and distinguishable from other ALS subtypes with possible differences in disease pathogenesis.


[Relation between activity volume and surgeon's results: myth or reality?].
The relationship between volume and surgical outcome seems logical, but needs to be demonstrated in the real world. A qualitative systematic review has been conducted to verify this hypothesis. Five systematic reviews and hundred original papers have been retrieved and analysed. Most of the studies were retrospective and used administrative data instead of medical charts. Moreover few studies involved a good case mix adjustment when comparing surgical units or individual surgeons. These methodological flaws do not allow any evidence based conclusions. Even though a positive relationship is suggested for surgical units, the relationship between volume and outcome was however less obvious for an individual surgeon. There is some evidence that the relationship varied greatly according to the specialty or the procedure evaluated. A new approach based on predictive scores comparing expected versus observed outcomes is mandatory and seems to be the best way to assess objectively the relationship between surgical volume and outcomes.


Broadband high-energy diode-pumped Yb:KYW multipass amplifier.
We report a diode-pumped Yb:KYW amplifier delivering up to 27 mJ pulses at a repetition rate of 100 Hz and a spectral bandwidth of 5.5 nm, centered at around 1030 nm. The system is based on a double-head multipass amplifier configuration where the pump thermal load is distributed over two relatively thin laser crystals, which permits a sufficiently large number of passes with minimal passive losses, thus maximizing the energy extraction efficiency. The amplified pulse bandwidth theoretically supports 340 fs pulses, and as a demonstration, a small fraction of the amplified pulses has been compressed to 560 fs.


Reactivity in nucleophilic vinylic substitution (S(N)V):S(N)Vπ versus S(N)Vσ mechanistic dichotomy.
The intrinsic electronic factors that determine reactivity in prototypical identity nucleophilic vinylic substitution reactions, X(-) + ViX → XVi + X(-) (Vi = vinyl), have been studied by performing quantum chemical calculations (OPBE/6-311++G(d,p)). Of the two limiting reaction types envisaged--the S(N)Vπ and S(N)Vσ mechanisms--the former is preferred for most combinations of nucleophiles and substrates, except for the combination of unactivated substrates and poor nucleophiles, as seen for the much studied reactions Cl(-) + CH2CHCl and Br(-) + CH2CHBr. It was found that periodic trends for S(N)Vπ are essentially the same as those previously reported for nucleophilic aromatic substitution, S(N)Ar, while intrinsic S(N)Vσ nucleophilicity parallels aliphatic S(N)2. It is therefore concluded that S(N)V reactivity in general can be understood in terms of this mechanistic dichotomy. Furthermore, a few representative reactions were analyzed applying two complementary schemes for energy decomposition analysis.


Recent developments in the therapy of acromegaly.
Acromegaly, a condition due to growth hormone hypersecretion usually from a benign pituitary tumour, is associated with significant morbidity and mortality. Disease control leads to normalisation of life expectancy with a reduction in signs and symptoms. Treatment modalities include surgery, radiotherapy and medical management. Surgery is the primary treatment in most of the patients, with success rates of 61-91% reported for those with microadenomas who are operated on by a specialist pituitary surgeon; however, most patients have macroadenomas and, although benefiting from surgery, are not cured and require additional medical therapy. This review will focus on emerging concepts in the medical treatment of acromegaly.


Effects of genetic strain, slow versus rapid-feathering maternal genotype, and cage density on the performance of Single Comb White Leghorns.
Two hatches involving 11,158 pullets from 22 Single Comb White Leghorn strain crosses were used in these experiments: 13 from rapid-feathering (k+/-) and 9 from slow-feathering (K/-) dams, some of which shared common genetic backgrounds; and all from 5 homozygous k+ sire types. Birds were grown intermingled within hatch, and were subsequently caged in two laying houses, one with 30.5 cm x 40.6-cm cages and the other with 40.6 cm x 30.5-cm cages, at densities of three or four birds/cage. Data were collected by cage on hen-day rate of lay from 50% production to 52 wk of age; (HD%), number of eggs produced per hen housed (EHH), percentage mortality (%M) to 52 wk of age; 35-wk BW (BW35); egg weight (EW34), specific gravity (SG34), and percentage bloodspots (BS%34) at 34 wk of age. The effects of hatches or house (H), density (D), maternal feathering type (MFT), genetic strain within MFT (GS/MFT), bank level within house (BL/H), and all possible interactions were included in the analysis model. Hatch, house, and cage type were completely confounded, so no general conclusion can be made concerning the effects of the reverse and standard cages on performance. The H effects were significant for all traits except HD%. Cage D significantly affected all traits except SG34 and BS%34. Pullets housed at three/cage weighed 26 g less, produced 5.5 more eggs that were .3 g/egg lighter, laid at a 1.7% higher hen-day rate, and had 3.6 less %M from 20 to 52 wk of age than those housed at four/cage. The MFT significantly affected all traits except %M, SG34, and BS%34. The k+/- daughters from K/- dams weighed 34 g less, produced at a 2.8% lower HD%, laid 6.9 fewer eggs, which eggs averaged .6 g/egg less than the eggs from the k+/- daughters of the k+/- dams. Interactions were in general small and nonsignificant. However, the H x GS/MFT interactions were significant for HD%, EHH, BW35, %M, and EW34 (P less than .05); their significance is suggestive of the presence of genotype x environment interactions.


Assessing the Likelihood of Gene Flow From Sugarcane (Saccharum Hybrids) to Wild Relatives in South Africa.
Pre-commercialization studies on environmental biosafety of genetically modified (GM) crops are necessary to evaluate the potential for sexual hybridization with related plant species that occur in the release area. The aim of the study was a preliminary assessment of factors that may contribute to gene flow from sugarcane (Saccharum hybrids) to indigenous relatives in the sugarcane production regions of Mpumalanga and KwaZulu-Natal provinces, South Africa. In the first instance, an assessment of Saccharum wild relatives was conducted based on existing phylogenies and literature surveys. The prevalence, spatial overlap, proximity, distribution potential, and flowering times of wild relatives in sugarcane production regions based on the above, and on herbaria records and field surveys were conducted for Imperata, Sorghum, Cleistachne, and Miscanthidium species. Eleven species were selected for spatial analyses based on their presence within the sugarcane cultivation region: four species in the Saccharinae and seven in the Sorghinae. Secondly, fragments of the nuclear internal transcribed spacer (ITS) regions of the 5.8s ribosomal gene and two chloroplast genes, ribulose-bisphosphate carboxylase (rbcL), and maturase K (matK) were sequenced or assembled from short read data to confirm relatedness between Saccharum hybrids and its wild relatives. Phylogenetic analyses of the ITS cassette showed that the closest wild relative species to commercial sugarcane were Miscanthidium capense, Miscanthidium junceum, and Narenga porphyrocoma. Sorghum was found to be more distantly related to Saccharum than previously described. Based on the phylogeny described in our study, the only species to highlight in terms of evolutionary divergence times from Saccharum are those within the genus Miscanthidium, most especially M. capense, and M. junceum which are only 3 million years divergent from Saccharum. Field assessment of pollen viability of 13 commercial sugarcane cultivars using two stains, iodine potassium iodide (IKI) and triphenyl tetrazolium chloride, showed decreasing pollen viability (from 85 to 0%) from the north to the south eastern regions of the study area. Future work will include other aspects influencing gene flow such as cytological compatibility and introgression between sugarcane and Miscanthidium species.


Sweet Modifications Modulate Plant Development.
Plant development represents a continuous process in which the plant undergoes morphological, (epi)genetic and metabolic changes. Starting from pollination, seed maturation and germination, the plant continues to grow and develops specialized organs to survive, thrive and generate offspring. The development of plants and the interplay with its environment are highly linked to glycosylation of proteins and lipids as well as metabolism and signaling of sugars. Although the involvement of these protein modifications and sugars is well-studied, there is still a long road ahead to profoundly comprehend their nature, significance, importance for plant development and the interplay with stress responses. This review, approached from the plants' perspective, aims to focus on some key findings highlighting the importance of glycosylation and sugar signaling for plant development.


Blastomycosis-like pyoderma: response to systemic retinoid therapy.
Blastomycosis-like pyoderma is a proliferative tissue response with multifactorial etiologies that may mimic other inflammatory and neoplastic skin disorders. It often occurs on sun damaged skin of immunocompromised patients. We report a case of blastomycosis-like pyoderma in a patient with underlying metastatic medullary carcinoma of the thyroid receiving treatment with sorafenib (a multikinase inhibitor). Prior treatments were unsuccessful. Our treatment with oral acitretin resulted in significant improvement.


Changing gears from chemical adhesion of cells to flat substrata toward engulfment of micro-protrusions by active mechanisms.
Microelectrode arrays increasingly serve to extracellularly record in parallel electrical activity from many excitable cells without inflicting damage to the cells by insertion of microelectrodes. Nevertheless, apart from rare cases they suffer from a low signal to noise ratio. The limiting factor for effective electrical coupling is the low seal resistance formed between the plasma membrane and the electronic device. Using transmission electron microscope analysis we recently reported that cultured Aplysia neurons engulf protruding micron size gold spines forming tight apposition which significantly improves the electrical coupling in comparison with flat electrodes (Hai et al 2009 Spine-shaped gold protrusions improve the adherence and electrical coupling of neurons with the surface of micro-electronic devices J. R. Soc. Interface 6 1153-65). However, the use of a transmission electron microscope to measure the extracellular cleft formed between the plasma membrane and the gold-spine surface may be inaccurate as chemical fixation may generate structural artifacts. Using live confocal microscope imaging we report here that cultured Aplysia neurons engulf protruding spine-shaped gold structures functionalized by an RGD-based peptide and to a significantly lesser extent by poly-l-lysine. The cytoskeletal elements actin and associated protein cortactin are shown to organize around the stalks of the engulfed gold spines in the form of rings. Neurons grown on the gold-spine matrix display varying growth patterns but maintain normal electrophysiological properties and form functioning synapses. It is concluded that the matrices of functionalized gold spines provide an improved substrate for the assembly of neuro-electronic hybrids.


Placental macrophages present distinct polarization pattern and effector functions depending on clinical onset of preeclampsia.
Hofbauer cells (HBCs) are resident macrophages of the human placenta, regulating immune tolerance and tissue homeostasis. HBCs of a normal placenta (CTR) exhibit mainly an anti-inflammatory M2 phenotype. Under exaggerated chronic inflammation during pregnancy, as in preeclampsia (PE), a phenotypic switch towards M1 polarization has been proposed. PE, defined as maternally derived syndrome can be distinguished into two different entities: early-onset (EO) preeclampsia and late-onset (LO) preeclampsia. Although the clinical presenting characteristics overlap, both can be identified by biochemical markers, heritability, and different maternal and fetal outcomes. To date, no study has specifically investigated polarization and phenotype of EO- and LO-PE HBCs and looked at possible changes in HBC functionality. Primary HBCs were isolated from CTR and PE placentae. First, in vitro morphological differences were observed between CTR and PE HBCs, with both PE groups exhibiting features of M1 macrophages alongside M2 forms. Interestingly, a different polarization pattern was observed between EO- and LO-PE HBCs. EO-PE HBCs develop a tissue remodeling M2 phenotype that is strongly shifted toward M1 polarization and showed a significant upregulation of CD86, TLR4, and HLA-DR. Furthermore, this pro-inflammatory signature is corroborated by higher expression of IRF5 and of NOS2 (p ≤ 0.05). However, their M2 characteristics is reflected by significant TGF-β secretion and ARG1 expression. In contrast, LO-PE HBCs developed a phagocytic CD209-low M2 phenotype in which the M1 pattern was not as pronounced as they downregulated the NOS2 gene, but expressed increased levels of pro-inflammatory CD80 and TLR1 (p ≤ 0.05). The enhanced phagocytosis and MMP-9 secretion alongside the increased secretion of anti-inflammatory IL -4, IL -13 and TGF-β in both EO- and LO-PE HBCs suggests their adaptive role and plasticity in resolving inflammation and tissue homeostasis.


Predicting Men's Immediate Reactions to a Simulated Date's Sexual Rejection: The Effects of Hostile Masculinity, Impersonal Sex, and Hostile Perceptions of the Woman.
Aggression is a common response to many types of social rejection. Men who respond aggressively to a woman's sexual rejection are likely to score high on risk factors associated with sexual aggression and to convince themselves that she is at fault. This study investigated how sexual dominance motivation and casual sex attitudes interact with "in the moment" hostile perceptions of the woman to predict the likelihood of an aggressive response. Male participants (N = 77) completed an online survey including self-report measures of sexual dominance motivation and casual sex attitudes. In a separate session, participants completed a laboratory study in which they interacted with a female agent in a dating simulation, allowing them to make nonsexual choices, sexual choices that were accepted, and sexual choices that were rejected. Immediate responses to sexual rejection were categorized as aggressive (n = 25) or nonaggressive (n = 52). After the simulation ended, participants answered questions about their perceptions of the situation and the woman. Moderated multiple logistic regression analyses were used to test the hypotheses. The hypothesized interactions were found such that men with high scores on sexual dominance motivation and positive attitudes about casual sex had a greater probability of responding aggressively when they formed extremely hostile perceptions of the woman who rejected them. These findings provide insight into the processes by which men respond aggressively to women's refusals, and highlight the need for training that encourages benevolent attributions and nonviolent strategies to deal with sexual rejection.


Hormonal response to LH-RH application in normal women.
The postovulatory effects of pharmacological doses of LH-RH on progesterone and LH plasma concentrations have been demonstrated. LH-RH injected on the 16th and 18th day of the menstrual cycle induces the discharge of LH; the second application results in a weaker discharge, indicating that the pituitary stores are exhausted. A LH-RH injection induces a decrease of the plasma progesterone concentration which becomes evident after a delay of 26 hours. A statistically significant correlation between LH and progesterone plasma concentrations was obtained 26 h after the administration of LH-RH.


Human genetics of intracellular infectious diseases: molecular and cellular immunity against mycobacteria and salmonellae.
The ability to develop adequate immunity to intracellular bacterial pathogens is unequally distributed among human beings. In the case of tuberculosis, for example, infection with Mycobacterium tuberculosis results in disease in 5-10% of exposed individuals, whereas the remainder control infection effectively. Similar interindividual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis, and other chronic infectious diseases, including viral infections. The outcome of infection is influenced by many factors, such as nutritional status, co-infections, exposure to environmental microbes, and previous vaccinations. It is clear, however, that genetic host factors also play an important part in controlling disease susceptibility to intracellular pathogens. Recently, patients with severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis BCG) or Salmonella spp have been identified. Many of these patients were unable to produce or respond to interferon gamma, due to deleterious mutations in genes that encode major proteins in the type 1 cytokine (interleukin 12/interleukin 23/interferon gamma) axis (interleukin 12p40/interleukin 23p40, IL12 receptor beta1/IL23 receptor beta1, interferon gamma receptors 1 and 2, or signal transducer and activator of transcription 1). This axis is a major immunoregulatory system that bridges innate and adaptive immunity. Unusual mycobacterial infections were also reported in several patients with genetic defects in inhibitor of NFkappaB kinase gamma, a key regulatory molecule in the nuclear factor kappaB pathway. New findings discussed in this review provide further and sometimes surprising insights into the role of type 1 cytokines, and into the unexpected heterogeneity seen in these syndromes.


Strategies for treatment of gait and posture associated deficits in movement disorders: the impact of deep brain stimulation.
Gait difficulties occur early in the course of Parkinson's disease (PD) as well as in generalized dystonia. Deep brain stimulation (DBS) is an effective treatment for patients with PD or dystonia. PD-associated slowness of gait improves dramatically after this procedure. Since not all gait problems can be treated with DBS, it is mandatory to assess the patient's symptoms precisely before an operation can be considered. In advanced stages of PD, postural deficits causing frequent falls are a major concern and will necessitate other strategies. In dystonia, walking may become possible only after this surgical intervention. After the implantation of DBS electrodes, rehabilitative treatment is necessary to (i) to establish new movement patterns, (ii) preserve an appropriate activity level, and (iii) treat specific disability, which resulted from secondary changes of the musculoskeletal system during pathological muscle tension in dystonia. An integrated multimodal approach, which has been adopted in our institution is presented.


Use of urinary hormone assays for evaluating endocrine patterns associated with the long-day breeding season in Eld's deer (Cervus eldi).
Reproductive seasonality and pregnancy in the endangered brow-antlered or Eld's deer (Cervus eldi) were studied by measuring urinary estrone conjugates (EC) and pregnanediol-3 alpha-glucuronide (PdG) profiles in voided urine. Based on the excretion of PdG, female Eld's deer were seasonally polyestrous, spontaneous ovulators with regular cyclic activity beginning in January to March and ending in August to October. The overall estrous cycle averaged 21.5 +/- 2.1 days (+/- SEM, n = 65); however, 2 of 13 does consistently produced prolonged cycles (30.1 +/- 4.4 days, n = 14). Behavioral estrus (approximately 12-24 h duration) was observed in 42 of 65 cycles and always occurred when PdG excretion was at nadir levels. In two does that were serially bled, preovulatory plasma LH peaks occurred coincident with estrus, and progesterone secretion paralleled PdG excretion. Mean gestation duration (n = 10) was 33.5 +/- 0.4 wk with PdG concentrations increasing markedly during pregnancy (especially the last 25 wk) before an abrupt decline coincided with parturition. Mean EC excretion remained low during much of gestation; however, significant increases in this metabolite were observed, particularly during the 4 wk immediately preceding parturition. The results are the first to demonstrate the utility of atraumatic urinary hormone monitoring for studying the endocrinology of cervids. Excreted urinary PdG accurately reflects circannual fluctuations in cyclic ovarian activity, and longitudinal increases in this metabolite are highly indicative of pregnancy. Cyclic ovarian activity cannot be clearly monitored by urinary EC concentrations, although this metabolite can be used in conjunction with elevated PdG levels to confirm pregnancy and perhaps estimate the onset of impending parturition.


Characterization of Holliday structures in FLP protein-promoted site-specific recombination.
Holliday structures are formed in the course of FLP protein-promoted site-specific recombination. Here, we demonstrate that Holliday structures are formed in reactions involving wild-type substrates and that they are kinetically competent with respect to the overall reaction rate. Together with a previous demonstration of chemical competence (L. Meyer-Leon, L.-C. Huang, S. W. Umlauf, M. M. Cox, and R. B. Inman, Mol. Cell. Biol. 8:3784-3796, 1988), Holliday structures therefore meet all criteria necessary to establish that they are obligate reaction intermediates in FLP-mediated site-specific recombination. In addition, kinetic evidence suggests that two distinct forms of the Holliday intermediate are present in the reaction pathway, interconverted in an isomerization process that is rate limiting at 0 degree C.


Assessing the Dynamics of COVID-19 Morbidity and Mortality in Response to Mass Vaccination: A Comparative Study Between Saudi Arabia and the United Kingdom.
Background Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, efforts have been in place to tackle the infection. Mass vaccination programs were regarded as the sole solution to end the pandemic. Here, we compare the differential impact of mass vaccination programs in Saudi Arabia (SA) and the United Kingdom (UK) on COVID-19 morbidity and mortality to determine whether vaccines were solely responsible for the changes observed in the disease dynamics. Methodology We retrospectively collected the number of new cases and deaths throughout 2021 in both SA and the UK. Similarly, the number of vaccine doses delivered in both countries was collected and compared. Results Through 2021, the percentage of daily COVID-19 cases was significantly less in SA than in the UK; however, the percentage of deaths was higher in SA. Interestingly, the percentage of daily cases was significantly reduced in SA upon vaccination. The vaccination coverage of both the first and second doses was higher in the UK compared to SA, and, consequently, the percentage of deaths was significantly reduced in the UK compared to SA. Conclusions The UK vaccination program succeeded in curbing the number of daily deaths compared to SA. SA had better control over the percentage of daily cases, primarily due to the restrictive measures and vaccination, such as the imposed social distancing and mandatory face masks.


T cell tumours of disparate phenotype in mice transgenic for Rbtn-2.
RBTN2 is a LIM domain protein which can be activated by the translocation t(11;14)(p13;q11) in childhood T cell acute leukaemia. Transgenic mice were examined in which rbtn2 protein is expressed in the T cell lineage. An average of 72% of these mice developed T cell tumours before 18 months of age, compared with 9% in transgenic mice expressing the related gene Rbtn-1. Rbtn2-induced tumours first appeared at 5 months of age and were clonal. They displayed a range of phenotypes, the most notable being CD3/CD45R double-positive cells. Tumours expressing either T cell receptor alpha/beta or gamma/delta heterodimers were found. Thus rbtn2 can promote tumours within a range of T cell types and maturities. The latency period before tumour development indicates that secondary events must occur before the onset of overt malignancy.


[Evidence-based midwifery practice in Scotland: a discussion of the problems].
In recent years there has been a drive to base all health care provision upon the most recent, appropriate scientific evidence. This has prompted an interest in research by midwives in clinical practice who want to ensure that they are providing the best possible care. Those midwives who do not use evidenced based practice but instead teach, support and demonstrate ritualistic practices without reference to the substantial research available, are limiting women's choice in maternity care. In a recent trial investigating whether routine suturing of perineal lacerations is required, the trial's outcome was jeopardised because of midwives' beliefs about suturing. The rationale for such ritualistic behaviour is not always easy to understand and using a framework of power and it is examined in this article to determine what concepts are influencing these practices. The article concludes by suggesting that some midwives appear to ignore the results of this trial and other research and demonstrate a paternalistic attitude towards their clients.


Expression of peptidylarginine deiminase-2 and -4, citrullinated proteins and anti-citrullinated protein antibodies in human gingiva.
The presence of citrullinated proteins, and peptidylarginine deiminase types -2 (PAD-2) and -4 (PAD-4) in periodontal tissues, determine the presence of anti-cyclic citrullinated protein antibodies (anti-CCP) in gingival crevicular fluid (GCF) and compare the expression of these proteins between inflamed and non-inflamed sites. Tissue sections were stained using antibodies against citrullinated proteins, PAD-2 and PAD-4. RT-PCR was performed to investigate PAD-2 and PAD-4 mRNA in inflamed and non-inflamed gingival tissues. Anti-CCP antibodies in gingival crevicular fluid were detected by ELISA. Citrullinated proteins, PAD-2 and PAD-4 were detected in gingiva. There was a correlation between inflammation and expression of these proteins. mRNAs for PAD-2 and PAD-4 were detected in both inflamed and non-inflamed gingival tissues. Antibodies to CCP were found mostly in the GCF of individuals with periodontitis. PAD-2 and PAD-4 (protein and mRNA) as well as citrullinated proteins are present in inflamed gingiva, and anti-CCP antibodies can be detected in the GCF of some patients. Tissue expression of citrullinated proteins and PAD increased with the severity of inflammation. The presence of anti-CCP antibodies in GCF was almost exclusive to a subset of patients with periodontitis. Increased expression of these proteins in inflamed gingiva lends support to the notion that periodontal inflammation contributes to the inflammatory burden in a similar way to rheumatoid arthritis.


Dehydroepiandrosterone Ameliorates Abnormal Mitochondrial Dynamics and Mitophagy of Cumulus Cells in Poor Ovarian Responders.
Mitochondrial dysfunction is related to reproductive decline in humans, with consequences for in vitro fertilization (IVF). We assessed whether dehydroepiandrosterone (DHEA) could regulate mitochondrial homeostasis and mitophagy of cumulus cells (CCs) in poor ovarian responders (PORs). A total of 66 women who underwent IVF treatment at the Reproductive Medicine Center of Kaohsiung Veterans General Hospital were included in this study. Twenty-eight normal ovarian responders (NOR) and 38 PORs were enrolled. PORs were assigned to receive DHEA supplementation (n = 19) or not (n = 19) before IVF cycles. DHEA prevents mitochondrial dysfunction by decreasing the activation of DNM1L and MFF, and increasing MFN1 expression. Downregulation of PINK1 and PRKN occurred after DHEA treatment, along with increased lysosome formation. DHEA not only promoted mitochondrial mass but also improved mitochondrial homeostasis and dynamics in the CCs of POR. We also observed effects of alterations in mRNAs known to regulate mitochondrial dynamics and mitophagy in the CCs of POR. DHEA may prevent mitochondrial dysfunction through regulating mitochondrial homeostasis and mitophagy.


[Nutrition intervention actions in relief situations: report on 4 experiences in Mexico].
In the last years Mexico faced several natural and human provoked disasters. We choose the Mexico City earthquake, the Chichonal volcano eruption, the Guatemala war and its refugees and the Chiapas armed movement. In all of them the INCMNSZ surveillance system proposal has been applied. To establish the intervention we classified the emergencies according to its magnitude and localization. The intervention consisted in: immediate attention of serious cases, immunizations, quimioprofilaxis, personal hygiene, environment control, nutritional assessment and diet definition. The affected population attended were: in the eruption 4.500, in the earthquake 1.000, in the Guatemala war 19.000 and in the Chiapas movement 6.940. Population damaged by the eruption and the war received mass feeding; complementary feeding (vulnerable groups) and therapeutic feeding (people with tuberculosis and serious undernutrition). In the earthquake people received first, prepared food and later they were organized to bring, plan, prepare and distribute their food. In the Chiapas armed movement people received only special baby food. In all cases, population also receive nutritional information and only with the refugees and the Chiapas damaged people the local food production was promoted. We suggest evaluating every emergency program and share experiences to afford this type of situations in a better way.


Illness perceptions and work participation: a systematic review.
Self-regulatory processes play an important role in mediating between the disease and the health outcomes, and potentially also work outcomes. This systematic review aims to explore the relationship between illness perceptions and work participation in patients with somatic diseases and complaints. The bibliographic databases Medline, PsycINFO and Embase were searched from inception to March 2008. Included were cross-sectional or longitudinal studies, patients with somatic diseases or complaints, illness perceptions based on at least four dimensions of the common sense model of self-regulation, and work participation. Two longitudinal and two cross-sectional studies selected for this review report statistically significant findings for one or more illness perception dimensions in patients with various complaints and illnesses, although some dimensions are significant in one study but not in another. Overall, non-working patients perceived more serious consequences, expected their illness to last a longer time, and reported more symptoms and more emotional responses as a result of their illness. Alternatively, working patients had a stronger belief in the controllability of their condition and a better understanding of their disease. The limited number of studies in this review suggests that illness perceptions play a role in the work participation of patients with somatic diseases or complaints, although it is not clear how strong this relationship is and which illness perception dimensions are most useful. Identifying individuals with maladaptive illness perceptions and targeting interventions toward changing these perceptions are promising developments in improving work participation.


Serum levels of toxic AGEs (TAGE) may be a promising novel biomarker in development and progression of NASH.
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), leads to fibrosis and potentially cirrhosis, liver failure, and hepatocellular carcinoma, and is one of the most common causes of liver disease worldwide. NAFLD has also been implicated in other medical conditions such as insulin resistance, obesity, metabolic syndrome, hyperlipemia, hypertension, cardiovascular disease, and diabetes. Continuous hyperglycemia has been implicated in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including the increased generation of various types of advanced glycation end-products (AGEs). We recently demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), played an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction between TAGE and the receptor for AGEs may alter intracellular signaling, gene expression, and the release of pro-inflammatory molecules and also elicits the generation of oxidative stress in numerous types of cells including hepatocytes and hepatic stellate cells. Serum levels of TAGE were significantly higher in NASH patients than in those with simple steatosis and healthy controls. Moreover, serum levels of TAGE inversely correlated with adiponectin (adiponectin is produced by adipose tissue and is an anti-inflammatory adipokine that can increase insulin sensitivity). Furthermore, immunohistochemical staining of TAGE showed intense staining in the livers of patients with NASH. Serum levels of TAGE may be a useful biomarker for discriminating NASH from simple steatosis. The administration of atorvastatin (10 mg daily) for 12 months significantly improved NASH-related metabolic parameters and significantly decreased serum levels of TAGE. The steatosis grade and NAFLD activity score were also significantly improved. These results demonstrated that atorvastatin decreased the serum levels of TAGE in NASH patients with dyslipidemia and suggest the usefulness of TAGE as a biomarker for the attenuation of NASH. Serum levels of TAGE were significantly higher in non-B or non-C hepatocellular carcinoma (NBNC-HCC) patients than in NASH subjects without HCC or control subjects. TAGE may be involved in the pathogenesis of NBNC-HCC, and could, therefore, be a biomarker that could discriminate NBNC-HCC from NASH. We propose that serum levels of TAGE are promising novel targets for the diagnosis of and therapeutic interventions against NASH.


Browsing away from rude emails: Effects of daily active and passive email incivility on employee cyberloafing.
The increasing prevalence of information communication technologies (e.g., computers, smartphones, and the internet) has made the experience of email incivility and the engagement in cyberloafing more common in the workplace. In this present study, we examined how experiencing email incivility at work can positively predict employees' cyberloafing. Based on affective events theory, we examined negative emotions as a mediator and trait prevention focus and daily workload as moderators. With daily diary data collected twice per day over 10 workdays from 113 full-time employees, we found that morning passive email incivility positively predicted afternoon cyberloafing via midday negative emotions while morning active email incivility did not. Further, trait prevention focus significantly moderated the relationship between active email incivility and negative emotions while daily workload significantly moderated the relationship between passive email incivility and negative emotions. The findings of the present study contribute to a deeper understanding of how employees' negative experiences affect their deviant behaviors in the virtual world. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Transcriptome analysis and mining of genes related to shade tolerance in foxtail millet (Setaria italica (L.) P. Beauv.).
A stereo interplanting system with foxtail millet beneath chestnut trees is an effective planting method to raise the utilization of land in chestnut orchards, increase yields and improve quality of chestnut nuts. Consequently, exploration of genes involved in shade tolerance response in foxtail millet and breeding shade-tolerant varieties have become urgent issues. In this study, RNA-seq of leaf samples from two shade-tolerant varieties and three shade-intolerant varieties of foxtail millet at the booting stage was performed. Comparisons between the varieties revealed that 70 genes were commonly differentially expressed. Moreover, the ratio of net photosynthetic rate under shaded environment to that under light environment could be used as an indicator of shade tolerance. Subsequently, weighted gene co-expression network analysis was employed to construct a co-expression network and modules were correlated with this ratio. A total of 375 genes were identified as potentially relevant to shade tolerance, among which nine genes were also present in the 70 differentially expressed genes, which implied that they were good candidates for genes involved in shade tolerance. Our results provide valuable resources for elucidation of the molecular mechanisms underlying shade tolerance and will contribute to breeding of shade-tolerant foxtail millet that are adapted to the shaded environment under chestnut trees.


Salivary and Lacrimal Gland Alterations of the Epidermal Fatty Acid-Binding Protein (E-FABP) in Non-Obese Diabetic Mice.
The purpose of this study was to investigate the changes in E-FABP in the salivary and lacrimal glands of the Sjögren syndrome (SS) model non-obese diabetic mice (NOD). Cotton thread and ocular vital staining tests were performed on 10-week NOD male mice (n = 24) and age- and sex-matched wild-type (WT) mice (n = 25). Tear and saliva samples were collected at sacrifice for E-FABP ELISA assays. Salivary and lacrimal gland specimens underwent immunohistochemistry stainings for E-FABP. Real-time RT-PCR was also performed for the quantification of mRNA expression levels in the salivary and lacrimal glands. Corneal vital staining scores in the NOD mice were significantly higher compared with those for the wild-type mice (p = 0.0001). The mean tear E-FABP level showed a significantly lower concentration in the NOD mice (p = 0.001). The mean saliva E-FABP level also showed a significantly lower concentration in the NOD mice (p = 0.04). Immunohistochemistry revealed intense E-FABP staining in the LG acinar epithelium and less intense staining in the acinar epitheliae of the SGs in the NOD mice compared to the WT mice. Real-time RT-PCR for the mRNA expression of E-FABP showed a significantly decreased expression in the SG and a significant increase in the LG of the NOD mice compared to the WT mice. In conclusion, the E-FABP showed marked alterations in the tear film, saliva, lacrimal, and salivary glands of the NOD mouse, which may help explain the ocular surface changes in relation to the dry eye disease in this SS model mouse and keratoconjunctivitis sicca in SS patients.


Approach to Very Small (< 1.5 cm) Cystic Renal Lesions: Ignore, Observe, or Treat?
This article will review the current available literature on the prevalence, behavior, and pathology of very small (< 1.5 cm) cystic renal lesions. A summary of the recommended approach to these very small lesions is provided. Limited data exist to guide the management of very small cystic renal lesions. Because most data favor benign or indolent behavior, vigorous workup of the very small cystic renal lesion seems unnecessary.


Widely wavelength switchable V-coupled-cavity semiconductor laser with ∼40 dB side-mode suppression ratio.
We report the first experimental demonstration of a single-electrode-controlled digitally wavelength switchable V-coupled-cavity laser with high side-mode-suppression-ratio (SMSR) in the 40 dB range. Sixteen-channel and twenty-six channel wavelength switchable lasers with 100 GHz spacing are demonstrated with the maximal SMSR of 40 dB and 37 dB, respectively. They do not require complex gratings, multiple epitaxial growths, or complex tuning algorithms. The device size is only 500 μm×300 μm. Such a simple, compact, and high-performance laser has great potential as a low-cost alternative to existing complex tunable lasers for wide deployment in optical networks and beyond.


Attentional window set by expected relevance of environmental signals.
The existence of an attentional window--a limited region in visual space at which attention is directed--has been invoked to explain why sudden visual onsets may or may not capture overt or covert attention. Here, we test the hypothesis that observers voluntarily control the size of this attentional window to regulate whether or not environmental signals can capture attention. We have used a novel approach to test this: participants eye-movements were tracked while they performed a search task that required dynamic gaze-shifts. During the search task, abrupt onsets were presented that cued the target positions at different levels of congruency. The participant knew these levels. We determined oculomotor capture efficiency for onsets that appeared at different viewing eccentricities. From these, we could derive the participant's attentional window size as a function of onset congruency. We find that the window was small during the presentation of low-congruency onsets, but increased monotonically in size with an increase in the expected congruency of the onsets. This indicates that the attentional window is under voluntary control and is set according to the expected relevance of environmental signals for the observer's momentary behavioral goals. Moreover, our approach provides a new and exciting method to directly measure the size of the attentional window.


The development of attachment in separated and divorced families. Effects of overnight visitation, parent and couple variables.
This study represents the first systematic investigation of the effects on infant attachment to mother and to father of the increasingly common practice of overnight visitation (time-sharing) with the father in separated and divorced families. There were 145 infants (ages 12 to 20 months) and their mothers (and 83 fathers) who participated in the study. Parents completed questionnaires, were interviewed about their relationship with the baby, and were observed with their infants in the Strange Situation. Infants in separated/divorced families who had regular overnight visits with father (n = 44) were significantly less likely to be classified as secure and more likely to be classified as disorganized or unclassifiable in their attachment to mother than infants in a married comparison group (n = 52). Attachment classification to father was unrelated to visiting (time-sharing) arrangements, but infants were significantly more likely to be classified disorganized/unclassifiable with father in the separated/divorced groups (n = 39) than in dual-parent families (n = 44). Disorganized attachment to mother in the Overnight group was associated with maternal reports of low parent communication and high parent conflict, and with low maternal psychological protection of the infant, assessed from maternal interviews. Consistent with Bowlby's and Rutter's context-sensitive views of the effects of separation, the results suggest that repeated overnight separations from the primary caregiver are associated with disruption in mother-infant attachment when the conditions of visitation are poor, i.e. when parents are unable to provide adequate psychological support to the child.


Tissue-adhesive hydrogel for multimodal drug release to immune cells in skin.
Both innate and adaptive immune systems play a crucial role in the pathology of skin diseases. To control these cells, there is a need for transdermal drug delivery systems that can target multiple cell populations at independently tunable rates. Herein, we describe a tissue-adhesive hydrogel system that contains particles capable of regulating the release of small molecule drugs at defined rates. Resiquimod (a macrophage-targeting drug) and palbociclib (a T cell-targeting drug) are encapsulated within two types of silicone particles embedded within the hydrogel. We demonstrate that drug release is mediated by the crosslink density of the particles, which is decoupled from the bulk properties of the hydrogel. We show that this system can be used to sustainably polarize macrophages toward an anti-tumor phenotype in vitro and ex vivo, and that the hydrogels can remain attached to skin explants for several days without generating toxicity. The hydrogel system is compatible with standard dermatological procedures and allows transdermal passage of drugs. The multimodal, tunable nature of this system has implications in treating a variety of skin disorders, managing infections, and delivering vaccines. STATEMENT OF SIGNIFICANCE: We describe a tissue-adhesive hydrogel that can regulate the release of drugs in a manner that is decoupled from its bulk properties. The mechanism of drug release is mediated by embedded microparticles with well-defined crosslink densities. The significance of this system is that, by encapsulating different drugs into the particles, it is possible to achieve multimodal drug release. We demonstrate this capability by releasing two immunomodulatory drugs at disparate rates. A drug that targets innate immune cells is released quickly, and a drug that targets adaptive immune cells is released slowly. This programmable system offers a direct means by which cellular responses can be enhanced through independent targeting for a variety of transdermal applications, including cancer treatment and vaccine delivery.


A generic impact-scoring system applied to alien mammals in Europe.
We present a generic scoring system that compares the impact of alien species among members of large taxonomic groups. This scoring can be used to identify the most harmful alien species so that conservation measures to ameliorate their negative effects can be prioritized. For all alien mammals in Europe, we assessed impact reports as completely as possible. Impact was classified as either environmental or economic. We subdivided each of these categories into five subcategories (environmental: impact through competition, predation, hybridization, transmission of disease, and herbivory; economic: impact on agriculture, livestock, forestry, human health, and infrastructure). We assigned all impact reports to one of these 10 categories. All categories had impact scores that ranged from zero (minimal) to five (maximal possible impact at a location). We summed all impact scores for a species to calculate "potential impact" scores. We obtained "actual impact" scores by multiplying potential impact scores by the percentage of area occupied by the respective species in Europe. Finally, we correlated species' ecological traits with the derived impact scores. Alien mammals from the orders Rodentia, Artiodactyla, and Carnivora caused the highest impact. In particular, the brown rat (Rattus norvegicus), muskrat (Ondathra zibethicus), and sika deer (Cervus nippon) had the highest overall scores. Species with a high potential environmental impact also had a strong potential economic impact. Potential impact also correlated with the distribution of a species in Europe. Ecological flexibility (measured as number of different habitats a species occupies) was strongly related to impact. The scoring system was robust to uncertainty in knowledge of impact and could be adjusted with weight scores to account for specific value systems of particular stakeholder groups (e.g., agronomists or environmentalists). Finally, the scoring system is easily applicable and adaptable to other taxonomic groups.


Factors Influencing Quality of Team Discussion: Discourse Analysis in an Undergraduate Team-Based Learning Biology Course.
Group activities as part of active-learning pedagogies are thought to be effective in promoting student learning in part because of the quality of discussion they engender in student teams. Not much is known, however, about which instructional factors are most important in achieving productive conversation or how these factors may differ among different collaborative pedagogies. We explored what provokes meaningful group discussions in a university physiology course taught using team-based learning (TBL). We were most interested in discussions that evoke explanations that go beyond statements of basic facts and into disciplinary reasoning. Using transcribed conversations of four randomly selected teams three times throughout the semester, we analyzed three distinct discursive phenomena-conceptual explanations, re-evaluations, and co-construction-that occurred in productive conversations. In this paper, we provide examples from student discussions showing the role of each of these elements in moving students toward conceptual understanding. These phenomena were more likely to occur in response to higher-order questions in Bloom's taxonomy. Preclass preparation and student accountability as part of TBL may be important factors in this finding. We share implications for practice based on our results.


Intestinal Colonization Dynamics of Vibrio cholerae.
To cause the diarrheal disease cholera, Vibrio cholerae must effectively colonize the small intestine. In order to do so, the bacterium needs to successfully travel through the stomach and withstand the presence of agents such as bile and antimicrobial peptides in the intestinal lumen and mucus. The bacterial cells penetrate the viscous mucus layer covering the epithelium and attach and proliferate on its surface. In this review, we discuss recent developments and known aspects of the early stages of V. cholerae intestinal colonization and highlight areas that remain to be fully understood. We propose mechanisms and postulate a model that covers some of the steps that are required in order for the bacterium to efficiently colonize the human host. A deeper understanding of the colonization dynamics of V. cholerae and other intestinal pathogens will provide us with a variety of novel targets and strategies to avoid the diseases caused by these organisms.


The nPYc-Toolbox, a Python module for the pre-processing, quality-control and analysis of metabolic profiling datasets.
As large-scale metabolic phenotyping studies become increasingly common, the need for systemic methods for pre-processing and quality control (QC) of analytical data prior to statistical analysis has become increasingly important, both within a study, and to allow meaningful inter-study comparisons. The nPYc-Toolbox provides software for the import, pre-processing, QC and visualization of metabolic phenotyping datasets, either interactively, or in automated pipelines. The nPYc-Toolbox is implemented in Python, and is freely available from the Python package index https://pypi.org/project/nPYc/, source is available at https://github.com/phenomecentre/nPYc-Toolbox. Full documentation can be found at http://npyc-toolbox.readthedocs.io/ and exemplar datasets and tutorials at https://github.com/phenomecentre/nPYc-toolbox-tutorials.


Blockage of transient receptor potential vanilloid 4 alleviates myocardial ischemia/reperfusion injury in mice.
Transient receptor potential vanilloid 4 (TRPV4) is a Ca2+-permeable nonselective cation channel and can be activated during ischemia/reperfusion (I/R). This study tested whether blockade of TRPV4 can alleviate myocardial I/R injury in mice. TRPV4 expression began to increase at 1 h, reached statistically at 4 h, and peaked at 24-72 h. Treatment with the selective TRPV4 antagonist HC-067047 or TRPV4 knockout markedly ameliorated myocardial I/R injury as demonstrated by reduced infarct size, decreased troponin T levels and improved cardiac function at 24 h after reperfusion. Importantly, the therapeutic window for HC-067047 lasts for at least 12 h following reperfusion. Furthermore, treatment with HC-067047 reduced apoptosis, as evidenced by the decrease in TUNEL-positive myocytes, Bax/Bcl-2 ratio, and caspase-3 activation. Meanwhile, treatment with HC-067047 attenuated the decrease in the activation of reperfusion injury salvage kinase (RISK) pathway (phosphorylation of Akt, ERK1/2, and GSK-3β), while the activation of survival activating factor enhancement (SAFE) pathway (phosphorylation of STAT3) remained unchanged. In addition, the anti-apoptotic effects of HC-067047 were abolished by the RISK pathway inhibitors. We conclude that blockade of TRPV4 reduces apoptosis via the activation of RISK pathway, and therefore might be a promising strategy to prevent myocardial I/R injury.


Innovative solutions: pharmacy and nursing collaboration on a high-risk medication project.
Banner Good Samaritan Medical Center is a 650-bed tertiary care facility in the Southwestern United States. The pharmacy and nursing departments collaborated on a multifocal project to address the educational and operational needs of the facility regarding the new JCAHO Medication Management Review Standards for high-risk and high-alert medications. The project encompassed policy creation, nursing education, identification and evaluation of HRHA medications, and facility-wide distribution of information related to high-risk and high-alert medications.


Electrostatic contributions to the binding of Ca2+ in calbindin D9k.
A set of accurate experimental data is provided for Ca2+ ion binding to calbindin D9k, a protein in the calmodulin superfamily of intracellular regulatory proteins. The study comprises both the role of protein surface charges and the effects of added electrolyte. The two macroscopic Ca2(+)-binding constants K1 and K2 are determined for the wild-type and eight mutant calbindins in 0, 0.05, 0.10, and 0.15 M KCl from titrations in the presence of Quin 2 or 5,5'-Br2BAPTA. The mutations involve replacement of surface carboxylates (of Glu17, Asp19, Glu26, and Glu60) with the corresponding amides. It is found that K1K2 may decrease by a factor of up to 2.5 x 10(5) (triple mutant in 0.15 M KCl as compared to the wild-type protein in 0 M KCl). Ca2(+)-binding constants of the individual Ca2+ sites (microscopic binding constants) have also been determined. The positive cooperativity of Ca2+ binding, previously observed at low salt concentration [Linse et al. (1987) Biochemistry 26, 6723-6735], is also present at physiological ionic strength and amounts to 5 kJ.mol-1 at 0.15 M KCl. The electrolyte concentration and some of the mutations are found to affect the cooperativity. 39K NMR studies show that K+ binds weakly to calbindin. Two-dimensional 1H NMR studies show, however, that potassium binding does not change the protein conformation, and the large effect of KCl on the Ca2+ affinity is thus of unspecific nature. Two-dimensional 1H NMR has also been used to assess the structural consequences of the mutations through assignments of the backbone NH and C alpha H resonances of six mutants.(ABSTRACT TRUNCATED AT 250 WORDS)


Design, synthesis, and evaluation of antitumor activity of novel C-6 sulfhydryl-substituted and 20-substituted derivatives of celastrol.
Celastrol has been identified as a potential candidate for anticancer drug development. In this study, 28 novel celastrol derivatives with C-6 sulfhydryl substitution and 20-substitution were designed and synthesized, and their antiproliferative activity against human cancer cells and non-malignant human cells was evaluated, with cisplatin and celastrol being used as controls. The results showed that most of the derivatives had enhanced in vitro anticancer activity compared to the parent compound celastrol. Specifically, derivative 2f demonstrated the most potent inhibitory potential and selectivity against HOS with an IC50 value of 0.82 μM. Our study provides new insights into the structure-activity relationship of celastrol and suggests that compound 2f may be a promising drug candidate for the treatment of osteosarcoma.


Synthetic versatility in C-H oxidation: a rapid approach to differentiated diols and pyrans from simple olefins.
Conventionally, C-H oxidation reactions are used to install functional groups. The use of C-H oxidation to transform simple starting materials into highly versatile intermediates, which enable rapid access to a range of complex target structures, is a new area with tremendous potential in synthesis. Herein we report a Pd(II)/sulfoxide-catalyzed allylic C-H oxidation to form anti-1,4-dioxan-2-ones from homoallylic oxygenates. These versatile building blocks are rapidly elaborated to differentiated syn-1,2-diols, stereodefined amino-polyols, and syn-pyrans, structures ubiquitous in medicinally important complex molecules found in Nature. We also demonstrate that a C-H oxidation approach to the synthesis of these motifs is orthogonal and complementary to other state-of-the-art methods.


Impact of Starch Coating Embedded with Silver Nanoparticles on Strawberry Storage Time.
The strawberry has a very short postharvest life due to its fast softening and decomposition. The goal of this research is to see how well a starch-silver nanoparticle (St-AgNPs) coating affects the physical, chemical, and microbiological qualities of strawberries during postharvest life. Additionally, the effect of washing with running water on silver concentration in coated strawberry fruit was studied by an inductively coupled plasma-optical emission spectrometer (ICP-OES). Furthermore, the shelf-life period was calculated in relation to the temperature of storage. Fourier transform infrared-attenuated total reflectance (FTIR-ATR), UV-Visible, and Transmission Electron Microscopic (TEM) were used to investigate the structure of starch-silver materials, the size and shape of AgNPs, respectively. The AgNPs were spherical, with an average size range of 12.7 nm. The coated samples had the lowest weight loss, decay, and microbial counts as compared to the uncoated sample. They had higher total acidity and anthocyanin contents as well. The washing process led to the almost complete removal of silver particles by rates ranging from 98.86 to 99.10%. Finally, the coating maintained strawberry qualities and lengthened their shelf-life from 2 to 6 days at room storage and from 8 to 16 days in cold storage.


Mechanical Properties and Toxicity Risks of Lead-Zinc Sulfide Tailing-Based Construction Materials.
The leaching residue of the lead-zinc sulfide tailing (LRT) is the only residue generated from the tailing leaching recovery process; it is a typical hazardous material for its high heavy-metal contents and high acidity. Due to the large output of LRT, and because its main components are Ca, Si, and Al, the preparation of building construction materials with LRT was studied. The results showed that when the LRT addition is less than 47%, with the ordinary Portland cement (OPC) and fly ash (FA) added and the curing conditions appropriate, the strength values of the tested specimens meet the M15 Class of the autoclaved lime sand brick standard (GB/T 16753-1997). The carbonization coefficient and drying shrinkage of the specimen were 0.79 and smaller than 0.42, respectively. As the SEM, TG, and XRD analysis have shown, the LRT can chemically react with additives to form stable minerals. The heavy metal contents that were leached out well met the limits in GB5085.3-2007. Based on the high addition of the LRT, the good strength and lower heavy metals were leached out of the prepared test specimen, and the tailing could be reused completely with the leaching recovery and the LRT reuse process. LRT can be used to replace OPC, allowing more sustainable concrete production and improved ecological properties of LRT.


3-D Multi-Component Reverse Time Migration Method for Tunnel Seismic Data.
Migration imaging is a key step in tunnel seismic data processing. Due to the limitation of tunnel space, tunnel seismic data are small-quantity, multi-component, and have a small offset. Kirchhoff migration based on the ray theory is limited to the migration aperture and has low migration imaging accuracy. Kirchhoff migration can no longer meet the requirements of high-precision migration imaging. The reverse time migration (RTM) method is used to realize cross-correlation imaging by reverse-time recursion principle of the wave equation. The 3-D RTM method cannot only overcome the effect of small offset, but also realize multi-component data imaging, which is the most accurate migration method for tunnel seismic data. In this paper, we will study the 3-D RTM method for multi-component tunnel seismic data. Combined with the modeled data and the measured data, the imaging accuracy of the 3-D Kirchhoff migration and 3-D RTM is analyzed in detail. By comparing single-component and multi-component Kirchhoff migration and RTM profile, the advantages of the multi-component RTM method are summarized. Compared with the Kirchhoff migration method, the 3-D RTM method has the following advantages: (1) it can overcome the effect of small offset and expand the range of migration imaging; (2) multi-component data can be realized to improve the energy of anomalous interface; (3) it can make full use of multiple waves to realize migration imaging and improve the resolution of the anomalous interface. The modeled data and the measured data prove the advantages of the 3-D multi-component RTM method.


The emotional, political, and analytical labor of engaged anthropology amidst violent political conflict.
Given the harsh realities that people live through in southern Philippines, where there is rife human rights violations and violent political conflict, it becomes difficult and arguably unethical for anthropologists to assume a position of neutrality. Following calls for engaged anthropology, I contend that engagement entails simultaneously an emotional, political, and analytical labor and troubles the separation of the self and other. I suggest that a way to labor through these challenges of researching suffering, and the reciprocal obligations this implicates, is to utilize feminist reflexivity and epistemic reflexivity. These necessitate an objectification of the self and one's intellectual field to achieve an epistemological break that would lead to an understanding of the other and their realities.


ent-Pimarane Diterpenes from the Aerial Parts of Siegesbeckia pubescens.
Five new ent-pimarane diterpenes (1-5) and five known analogs (6-10) were isolated from the aerial parts of Siegesbeckia pubescens. Their structures, including absolute configurations, were determined by comprehensive spectroscopic methods especially 1D and 2D NMR and quantum chemical electronic circular dichroism calculations. All the isolated compounds were evaluated for their cytotoxicity against human BT549, A549 and H157 cancer cell lines. Among them, compounds 1 and 2 showed mild cytotoxicity against lung cancer cell lines H157 with IC50 values of 16.35±2.59 and 18.86±4.83 μM, respectively.


MLVA typing of Haemophilus influenzae isolated from two Iranian university hospitals.
Different serotypes of Haemophilus influenzae is now divided into 2 divisions: encapsulated and unencapsulated. Multiple locus variable number tandem repeat analysis (MLVA) includes such specifications as the extra power of separation, ease of data interpretation, and epidemiological data accordance, which have made it an appropriate molecular device for good typing and phylogenetic analysis of bacterial pathogens. In this research, cultured samples were studied and strains identified through biochemical tests were recognized. Moreover, DNA was extracted and studied qualitatively and quantitatively. Four pairs of specialized primers related to H. influenzae variable number tandem repeats (VNTR) and preparation of PCR were designed according to the regulated program. Also, electrophoresis of PCR products was performed. Finally, the interpretation of electrophoresis gel was done with respect to the observable bands showing the presence or absence of the required sequence in the samples related to every primer. This study was the first MLVA typing of the unencapsulated H. influenzae in Iran. In this research, the VNTR sequences were tested in 30 strains without the unencapsulated H. influenzae. Among 30 mentioned strains, for which MLVA profile was obtained in this research, 25 different MLVA types were observed. Likewise, there was no repetition in VNTR sequences resulting from PCR in few H. influenzae. In all these cases, the number of repetitions in MLVA profile was determined as 0, except for one of the primers in 4 strains, which was 16%. However, this did not occur for the other VNTRs. The highest diversity of the repeats was for VNTR5 (7 types), followed by VNTR6 with 6 types of repeats, and VNTR12-1 and VNTR12-2 with 3 different types.


Recent developments in electrochemical detection for microchip capillary electrophoresis.
Significant progress in the development of miniaturized microfluidic systems has occurred since their inception over a decade ago. This is primarily due to the numerous advantages of microchip analysis, including the ability to analyze minute samples, speed of analysis, reduced cost and waste, and portability. This review focuses on recent developments in integrating electrochemical (EC) detection with microchip capillary electrophoresis (CE). These detection modes include amperometry, conductimetry, and potentiometry. EC detection is ideal for use with microchip CE systems because it can be easily miniaturized with no diminution in analytical performance. Advances in microchip format, electrode material and design, decoupling of the detector from the separation field, and integration of sample preparation, separation, and detection on-chip are discussed. Microchip CEEC applications for enzyme/immunoassays, clinical and environmental assays, as well as the detection of neurotransmitters are also described.


Effect of low frequency magnetic field on efficiency of chromosome break repair.
DNA repair is essential to maintain genome integrity. There is scientific evidence that exposure to magnetic fields (MF) can produce alterations in DNA repair without clear conclusions. This work aims to study the cellular response to and repair of a very deleterious type of DNA damage, the DNA double strand break (DSB), in S. cerevisiae, under MF exposure. In S. cerevisiae cells, pairs of DSB were induced enzymatically by HO endonuclease by plating the cells on Galactose-containing media. The repair processes took place under exposure to a 50Hz, 2.45mT sinusoidal MF during 21 days. MF was generated by a pair of Helmholtz coils. MF induced 1.29- and 1.5-fold increase in the number of colonies grown at day 21 of exposure in relation to untreated controls for Pho91 and Rmd5 strain, respectively. In relation to the kinetics of DSB repair during MF exposure, a higher increase (55.56-fold) in DNA reparation was observed at day 15 for Rmd5 strain in relation to the slight increment (1.18-fold) found for Pho91 strain. The results suggest that long-term MF exposure could increase the DNA repair activity and there may be a relationship between the position of the DSB and the distance to the centromere.


Two distinct domains in the yeast transcription factor IID and evidence for a TATA box-induced conformational change.
Transcription factor IID from Saccharomyces cerevisiae (YIID) binds the TATA box element present in most RNA polymerase II promoters. In this work, partial proteolysis was used as a biochemical probe of YIID structure. YIID consists of a protease-sensitive amino terminus and a highly stable, protease-resistant carboxy-terminal core. The cleavage sites of the predominant chymotrypsin- and trypsin-derived fragments were mapped to amino acid residues 40 to 41 and 48 to 49, respectively, by amino-terminal peptide sequencing. Removal of the amino terminus resulted in a dramatic increase in the ability of YIID to form a stable complex with DNA during gel electrophoresis mobility shift assays and a two- to fourfold increase in DNA-binding affinity, as assayed by DNase I footprinting analysis. The carboxy-terminal 190-amino-acid core was competent for transcription in vitro and was similar in activity to native YIID. DNA containing a TATA element induced hypersensitive sites in the amino-terminal domain and stabilized the core domain to further proteolytic attack. Native YIID did not bind to a TATA box at 0 degrees C, whereas the carboxy-terminal DNA-binding domain did. These results suggest that YIID undergoes a conformational change upon binding to a TATA box. Southern blotting showed that the carboxy-terminal domain is highly conserved, while the amino-terminal domain diverged rapidly in evolution, even between closely related budding yeasts.


Correlation of antemortem serum creatine kinase, creatine kinase-MB, troponin I, and troponin T with cardiac pathology.
Spurious increases in serum troponins, especially troponin T, have been reported in patients with and without acute myocardial syndromes. We studied 78 autopsied patients without clinical myocardial infarction (MI) and correlated histologic cardiac findings with antemortem serum creatine kinase (CK), its MB isoenzyme (CK-MB), cardiac troponin I (cTnI), and cardiac troponin T (cTnT). There was no significant myocardial pathology in 15 patients. Cardiac pathologies were in five groups: scarring from previous MI or patchy ventricular fibrosis (n = 9), recent MI (n = 27), healing MI (n = 7), degenerative myocyte changes consistent with congestive heart failure (CHF; n = 12), and other cardiac pathologies (n = 8). The median concentrations in the five groups were not significantly different for either CK or CK-MB. Compared with the no-pathology group, only the MI group was significantly different for cTnI, and the MI and other pathology groups were significantly different for cTnT. For patients with MI, 22%, 19%, 48%, and 65% had increased CK, CK-MB, cTnI, and cTnT, respectively; for CHF and other cardiac pathologies combined, the percentages were 28%, 17%, 22%, and 50%. For patients with increased cTnI, 72% and 28% had MI and other myocardial pathologies, respectively; patients with increased cTnT had 64% and 36%, respectively. Patients without myocardial pathology had no increases in CK-MB, cTnI, or cTnT. All patients with increased serum CK-MB, cTnI, and cTnT had significant cardiac histologic changes. The second-generation cTnT assay appears to be a more sensitive indicator of MI and other myocardial pathologies than the cTnI assay used in this study.


[The role of the high-density lipoprotein (HDL) particle in atherogenesis and potential methods to increase HDL concentrations].
The concentration of high-density lipoprotein (HDL) cholesterol has a strong inverse relationship to the incidence of cardiovascular disease. The protective effect of HDL cholesterol is due not only to its promotion of reverse cholesterol transport from the vascular wall to the liver, but also to its anti-inflammatory, antioxidative and antithrombotic effects. Patients with low HDL cholesterol concentrations are at increased risk for cardiovascular disease and may be considered for treatment with lipid-lowering drugs, such as statins, niacin and fibrates. Currently, only a limited number of HDL-increasing agents have demonstrated beneficial effects of increasing HDL in studies with intermediary endpoints. Among these drugs are apolipoprotein A-1 variants, inhibitors of the cholesterol ester transfer protein JTT-705 and torcetrapib.


Hydrodynamic study of flexibility in immunoglobulin IgG1 using Brownian dynamics and the Monte Carlo simulations of a simple model.
A simple bead model is proposed for the antibody molecule immunoglobulin IgG1. The partial flexibility of the hinge is represented by a quadratic potential associated to the angles between arms. Conformational and hydrodynamic properties are calculated using Monte Carlo (rigid-body) and Brownian dynamics simulations. Comparison of experimental and calculated values for some overall properties allows the assignment of dimensions and other model parameters. The Brownian dynamics technique is used next to simulate a rotational correlation function that is comparable with the decay of fluorescence emission anisotropy. This is done with varying flexibility at the hinge. The longest relaxation time shows a threefold decrease when going from the rigid Y-shaped conformation to the completely flexible case. The calculations are in good agreement with the decay times observed for IgG1. A flexibility analysis of the latter indicates that a variability of +/- 55 degrees (standard deviation) in the angle between the Fab arms.


Influence of ligand field stabilization energy on the elastic properties of multiferroic MOFs with the perovskite architecture.
We report the mechanical properties of four isostructural metal-organic frameworks (MOFs) that adopt the ABX(3) perovskite topology: [(CH(3))(2)NH(2)]M(HCOO)(3), where M = divalent Mn, Co, Ni, and Zn. Their Young's moduli were measured via single-crystal nanoindentation. We show that the mechanical stability of such isostructural frameworks with octahedral coordination increases with greater ligand field stabilization energy (LFSE).


The extensile rectus snip exposure in revision of total knee arthroplasty.
Revision of a total knee arthroplasty may require an extensile approach to permit a satisfactory exposure without compromising the attachment of the patellar tendon. It has been assumed that a rectus snip is a relatively benign form of release, but the effect of using this approach on function, pain and patient satisfaction is not known. From January 1997 to December 1999, 107 patients who underwent revision of total knee arthroplasty were followed up at a minimum of two years (mean 40.5 months) and assessed by the Oxford Hip Score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Short-Form (SF)-12 and patient satisfaction. Co-morbidity, surgical exposure, the Hospital for Special Surgery (HSS) knee scores and the range of movement were also used. A standard medial parapatellar approach was used in 57 patients and the rectus snip in 50. The two groups were equivalent for age, sex and co-morbidity scores. The WOMAC function, pain, stiffness and satisfaction scores demonstrated no statistical difference. The use of a rectus snip as an extensile procedure has no effect on outcome.


AlCl3-Mediated CHF2 Transfer and Cyclocondensation of Difluoromethoxy Functionalized o-Phenylenediamines to Access N-Substituted Benzimidazoles.
Herein, we report for the first time a transition-metal-free frustrated Lewis pair (FLP) catalyzed CHF2 group migration from an oxygen atom to the neighboring nitrogen atom, which led to the synthesis of N-substituted benzimidazoles at room temperature with excellent yields, broad functional group tolerance, and a short reaction time. The oxygen-attached difluoromethane acted as a C1 source in the synthesis of N-substituted benzimidazoles in the presence of AlCl3 by cleaving one C-O bond and two C-F bonds, resulting in formation of two new C-N bonds.


Understanding caseload and practice through analysis of therapeutic state transitions.
Increasing uptake of electronic medical records (EMRs) offers opportunities for analysis and quality assurance of clinical practice; but making appropriate inferences about chronic disease management is non-trivial. We propose a state-transition model for analysis of chronic disease therapy by community practices based on clinical practice guidelines. We abstract guideline recommendations to key therapeutic states, and map electronic prescribing data into a series of states and transitions, which can then be interpreted with respect to the recommendations of the guideline. By applying our approach to a patient cohort diagnosed with both hypertension and diabetes mellitus, we demonstrate that the method identifies cases at risk of suboptimal care, deserving further review by General Practitioners (GPs).


Effect of ethylenediamine on CMP performance of ruthenium in H2O2-based slurries.
With the aggressive scaling of integrated circuits, ruthenium has been proposed as the next generation barrier material to replace the conventional bilayer of tantalum and tantalum nitride due to its properties such as allowing direct copper electrodeposition. In this work, the effect of ethylenediamine (EDA) on the chemical mechanical polishing (CMP) properties of ruthenium in H2O2-based slurries was investigated. The results show that EDA or H2O2 alone has little effect, but the combined use of EDA and H2O2 significantly enhances the removal rate of ruthenium. Subsequently, the mechanism of action of ruthenium removal promoted by EDA was studied by combining CMP experiments, electrochemical experiments and surface chemical characterization methods. It is indicated that EDA molecules react with ruthenium oxide (not ruthenium metal) to generate a large number of complexes, which promotes the dissolution of ruthenium oxides and the corrosion of ruthenium. More importantly, the oxide layers on the ruthenium surface become rough and porous, and can be easily removed by mechanical action during the ruthenium CMP process. Meanwhile, the use of EDA can reduce the electrostatic repulsive force between the SiO2 particles and ruthenium surface in the CMP process, thus further accelerating the ruthenium removal. In order to obtain an adequate removal rate selectivity of ruthenium versus copper, the corrosion inhibitors for copper were added. As a consequence, the removal rate selectivity of 1.13 : 1 was obtained, while also reducing the corrosion potential difference between ruthenium and copper to 17 mV.


The impact of neoadjuvant hedgehog inhibitor therapy on the surgical treatment of extensive basal cell carcinoma.
Although hedgehog inhibitor therapy (HHIT) is offered as isolated medical treatment for extensive basal cell carcinoma (BCC), there is little evidence on the use of HHIT before definitive surgical intervention. In order to better define the utilization of HHIT for extensive BCC, we evaluated the impact of neoadjuvant HHIT on the subsequent surgical resection and reconstruction. An IRB-approved, retrospective chart review was performed of patients who received HHIT as initial treatment for extensive BCC. Patients who discontinued HHIT and underwent surgical resection were included. Evaluation included BCC tumor response to HHIT, operative data, pathological data, radiation requirements, and evidence of tumor recurrence. Six patients were identified with tumors of the face/scalp (n = 4), trunk (n = 1) and upper extremity (n = 1). Hedgehog inhibitor therapy continued until tumors became unresponsive (n = 3, mean = 71 weeks) or side effects became intolerable (n = 3, mean = 31 weeks). In each case, a less extensive surgery was performed than estimated before HHIT. In 3 cases, significant bone resection was avoided. All resected specimens contained BCC. Four specimens exhibited clear margins. Postoperative radiation was performed in cases with positive margins (n = 2), and 1 patient experienced local recurrence. Length of follow-up was 5.7 to 11.8 months (mean = 8.23 months). Although HHIT was not curative for extensive BCC, HHIT can decrease the morbidity of surgical treatment and increase the likelihood of curative resection. For patients with extensive BCC, a combined neoadjuvant use of HHIT and surgical treatment should be considered.


Patterns and Outcomes of Intensive Care on Acute Ischemic Stroke Patients in the US.
Up to 20% of acute ischemic stroke (AIS) patients may benefit from intensive care unit (ICU)-level care; however, there are few studies evaluating ICU availability for AIS. We aim to summarize the proportion of elderly AIS patients in the United States who are admitted to an ICU and assess the national availability of ICU-level care in AIS. We performed a retrospective cohort study using de-identified Medicare inpatient datasets from January 1, 2016 through December 31, 2019 for US individuals aged ≥65 years. We used validated International Classification of Diseases, Tenth Revision, Clinical Modification codes to identify AIS admission and interventions. ICU-level care was identified by revenue center code. AIS patient characteristics and interventions were stratified by receipt of ICU-level care, comparing differences through calculated standardized mean difference score due to large sample sizes. From 2016 through 2019, a total of 952 400 admissions by 850 055 individuals met criteria for hospital admission for AIS with 19.9% involving ICU-level care. Individuals were predominantly >75 years of age (58.5%) and identified as white (80.0%). Hospitals on average admitted 11.4% (SD 14.6) of AIS patients to the ICU, with the median hospital admitting 7.7% of AIS patients to the ICU. The ICU admissions were younger and more likely to receive reperfusion therapy but had more comorbid conditions and neurologic complications. Of the 5084 hospitals included, 1971 (38.8%) reported no ICU-level AIS care. Teaching hospitals (36.9% versus 1.6%, P<0.0001) with larger AIS volume (P<0.0001) or in larger metropolitan areas (P<0.0001) were more likely to have an ICU available. We found evidence of national variation in the availability of ICU-level care for AIS admissions. Since ICUs may provide comprehensive care for the most severe AIS patients, continued effort is needed to examine ICU accessibility and utility among AIS.


Necroptosis is a novel mechanism of radiation-induced cell death in anaplastic thyroid and adrenocortical cancers.
Necroptosis is a recently described mechanism of programmed cellular death. We hypothesize that necroptosis plays an important role in radiation-induced cell death in endocrine cancers. Thyroid and adrenocortical carcinoma cell lines were exposed to increasing doses of radiation in the presence of necroptosis inhibitor Nec-1 and/or apoptosis-inhibitor zVAD. H295R cells deficient in receptor interacting protein 1 (RIP1), an essential kinase for necroptosis, were used as controls. Survival curves were generated at increasing doses of radiation. Nec-1 and zVAD increased cellular survival with increasing doses of radiotherapy in 8505c, TPC-1, and SW13. Both inhibitors used together had an additive effect. At 6 Gy, 8505c, TPC-1, and SW13 cell survival was significantly increased compared to controls by 40%, 33%, and 31% with Nec-1 treatment, by 53%, 47%, and 44% with zVAD treatment, and by 80%, 70%, and 65% with both compounds, respectively (P < .05). H295R showed no change in survival with Nec-1 treatment. The radiobiologic parameter quasithreshold dose was significantly increased in 8505c, TPC-1, and SW13 cells when both Nec-1 and zVAD were used in combination to inhibit necroptosis and apoptosis together, revealing resistance to standard doses of fractionated therapeutic radiation. Necroptosis contributes to radiation-induced cell death. Future studies should investigate ways to promote the activation of necroptosis to improve radiosensitivity.


Delayed haemolysis secondary to treatment of severe malaria with intravenous artesunate: Report on the experience of a referral centre for tropical infections in Spain.
Post-artesunate delayed haemolysis is described as hemolytic anemia presenting days after malaria treatment in hyperparasitemic patients. Physiopathological mechanisms and clinical manifestations have not been thoroughly characterised. We conducted a retrospective study of hospitalised malaria patients who received artemisinin derivatives from January 1, 2010 to December 31, 2015. 21 patients were included in the study: 11 travellers, 8 travellers visiting friends and relatives and 2 immigrants. Median age was 35.5 years (IQR: 25.7-44.8) and 11 were men. Eight patients received oral and 13 received intravenous (IV) artemisinin-based drugs. Follow-up after the malaria episode was available for 15 patients (12 with IV treatment). Four patients presented with delayed haemolysis 9-14 days after artesunate treatment; all had been admitted with severe malaria, were treated IV and had hyperparasitaemia (17%-33%). Other than hyperparasitaemia, no other factors were associated with artesunate haemolysis. Patients' outcomes were favourable and the only additional therapeutic measure needed was a blood transfusion. Delayed haemolysis is a frequent complication in hyperparasitemic malaria treated with IV artesunate. Follow-up is mandatory for at least 2 weeks after treatment initiation. This condition is potentially severe but does not appear to be life threatening.


Fatigue in Kidney Transplantation: A Systematic Review and Meta-Analysis.
Fatigue is still present in up to 40-50% of kidney transplant recipients (KTR), the results of studies comparing the prevalence among patients on hemodialysis (HD) and KTR led to conflicting results. Fatigue correlates include inflammation, symptoms of depression, sleep disorders and obesity. Fatigue in KTR leads to significant functional impairment, it is common among KTR poorly adherent to immunosuppressive therapy and is associated with a serious deterioration of quality of life. The following databases were searched for relevant studies up to November 2020: Medline, PubMed, Web of Science and the Cochrane Library. Several studies have compared the prevalence and severity of fatigue between KTR and hemodialysis or healthy patients. They have shown that fatigue determines a significant functional deterioration with less chance of having a paid job and a significant change in quality of life. The aim of the review is to report methods to assess fatigue and its prevalence in KTR patients, compared to HD subjects and define the effects of fatigue on health status and daily life. There is no evidence of studies on the treatment of this symptom in KTR. Efforts to identify and treat fatigue should be a priority to improve the quality of life of KTR.