Crystal structure of Sulfolobus tokodaii Sua5 complexed with L-threonine and AMPPNP.
The hypermodified nucleoside N(6)-threonylcarbamoyladenosine resides at position 37 of tRNA molecules bearing U at position 36 and maintains translational fidelity in the three kingdoms of life. The N(6)-threonylcarbamoyl moiety is composed of L-threonine and bicarbonate, and its synthesis was genetically shown to require YrdC/Sua5. YrdC/Sua5 binds to tRNA and ATP. In this study, we analyzed the L-threonine-binding mode of Sua5 from the archaeon Sulfolobus tokodaii. Isothermal titration calorimetry measurements revealed that S. tokodaii Sua5 binds L-threonine more strongly than L-serine and glycine. The Kd values of Sua5 for L-threonine and L-serine are 9.3 μM and 2.6 mM, respectively. We determined the crystal structure of S. tokodaii Sua5, complexed with AMPPNP and L-threonine, at 1.8 Å resolution. The L-threonine is bound next to AMPPNP in the same pocket of the N-terminal domain. Thr118 and two water molecules form hydrogen bonds with AMPPNP in a unique manner for adenine-specific recognition. The carboxyl group and the side-chain hydroxyl and methyl groups of L-threonine are buried deep in the pocket, whereas the amino group faces AMPPNP. The L-threonine is located in a suitable position to react together with ATP for the synthesis of N(6)-threonylcarbamoyladenosine.


Lack of physician-patient communication as a key factor associated with malpractice litigation in neonatal brachial plexus palsy.
Perinatal disorders are prone to malpractice litigation. Neonatal brachial plexus palsy (NBPP) results from stretching the nerves in the perinatal period and may lead to paresis or paralysis and sensory loss in the affected arm. Little is known about the key factors associated with malpractice litigation by families of patients with NBPP and whether these factors reflect the practice environment or are inherent to the condition. In this study, the authors documented the percentage of families of NBPP patients at a specialty center that had filed a malpractice suit and described the key factors associated with that pursuit of legal action. The families/caregivers of 51 patients with NBPP who had presented to the University of Michigan Interdisciplinary Brachial Plexus Program participated in this study. A qualitative research design was applied using both a questionnaire to examine psychosocial factors and a dynamic tool to measure health outcomes from the patient perspective via parent proxy (Patient-Reported Outcomes Measurement Information System [PROMIS] assessment instruments). Statistical analysis included the Fisher exact test, chi-square test, and Student t-test. The study protocol was approved by the University of Michigan institutional review board. Forty-seven percent of the families pursued malpractice litigation. In comparing patient families that had pursued legal action with those that had not, significant differences were revealed in the perception that the sustained birth injury was unnecessary (p = 0.002), the information received in the perinatal period was inadequate (p = 0.003), family concerns were ignored in the perinatal period (p = 0.005), and family concerns were not adequately addressed (p < 0.001). Sixty-six percent of the families received external advice to pursue legal action. The PROMIS survey revealed significant group differences in depressive symptoms (p = 0.008), fatigue (p = 0.02), pain (p = 0.01), and anger (p = 0.004). In contrast, the extent of NBPP was not associated with malpractice litigation (p = 0.18). Age, sex, and race were not significantly different between litigation and nonlitigation groups. Physician-controllable factors, such as communication in the perinatal period, are associated with malpractice litigation in NBPP. The perceived level of global disability may affect the pursuit of malpractice litigation, whereas the isolated extent of nerve root involvement and/or upper extremity dysfunction are not significant factors in pursuing litigation. Identifying and ameliorating these factors within the practice environment may decrease the animosity between families and health care providers and improve overall outcome for patients with NBPP.


INDUCTION OF SEVERAL ADAPTIVE ENZYMES BY ACTINOMYCIN D.
Although actinomycin D has been used to prevent protein synthesis in experiments of several hours' duration, its effects on the synthesis of adaptive enzymes which are induced over a period of several days have received less attention. Treatment of young rats with doses of actinomycin D, which permitted survival for a period of 5 days, resulted in marked increases in the activities of four hepatic enzymes known to be induced by cortisol: alanine transaminase, tyrosine transaminase, serine dehydrase, and tryptophan pyrrolase. Actinomycin D also induced responses of two of these enzymes in adrenalectomized rats.


Comparison of psbK operon organization and group III intron content in chloroplast genomes of 12 Euglenoid species.
A novel mixed operon has been identified in the photosynthetic protist E. gracilis. The genes for psbK, ycf12, psaM, and trnR are co-transcribed. The resulting tetracistronic transcripts are processed through endonucleolytic cleavage of the intergenic spacers and intron splicing to form three mature monocistronic mRNAs and a tRNA. A group III twintron and a group III intron are located in psbK. Another group III intron is found in ycf12. The psbK operon has been cloned by PCR amplification from nine related Euglenoid species. In each species, the gene order and content of the psbK operon is conserved. The psbK operons contain phylogenetically conserved eubacterial promoter, translational, and 3' processing elements. Intron content varies significantly from species to species. Based on a comparison of the intron content with the results of phylogenetic analysis, group III intron evolution within the Euglenoid lineage is much more complex than previously believed.


[Transparency and good healthcare governance: an aid to overcoming the crisis].
Countries thrive on an economic foundation capable of facilitating the fulfillment of human potential in a society that does not renounce major achievements such as the welfare state. A necessary condition is that the "rules of the game", formal and informal institutions, make what is socially desirable individually attractive. Improving health governance, including its dimension of controlling corruption, and helping Spain out of the current economic crisis are two sides of the same coin. Characterization of health system governance in Spain and analysis of the impact of this governance on health policy, management of healthcare organizations and clinical practice allows an ambitious and feasible agenda to be drawn up of the remaining tasks that health professionals -broadly defined- and social actors should undertake with the support of citizens.


Pregnancy after catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis.
To assess the safety and efficacy of low-molecular-weight heparin (LMWH) in pregnancy and puerperium in women with previous acute iliofemoral deep venous thrombosis (DVT) treated with catheter-directed thrombolysis (CDT). Consecutive patients treated for acute iliofemoral DVT using CDT between June 1999 and June 2009 were followed yearly by colour duplex ultrasound scanning. A subgroup of these patients who became pregnant during the follow-up period, three months to 10 years after CDT, was included in the present study. During pregnancy, thromboprophylaxis using LMWH was prescribed according to individual risk assessment, and the women were regularly assessed for adverse events. Women on warfarin had this treatment discontinued before the sixth week of pregnancy in order to prevent potential teratogenic adverse effects. Administration of LMWH was started at international normalized ratio ≤ 2.0, and continued during pregnancy, delivery and puerperium. Postnatal, the anticoagulation treatment was converted back to warfarin and LMWH discontinued after a bridging period. Women, who, prior to pregnancy, had discontinued anticoagulation treatment after CDT, were prescribed anticoagulation treatment using LMWH as early in pregnancy as practical. LMWH was continued during pregnancy, delivery and for six weeks postpartum. All women were prescribed graduated compression stockings. A total of 33 women completed 45 pregnancies, 44 singletons and 1 gemelli. In 24 (53%) of the cases, the mother had been treated with adjunctive stenting immediately following the CDT. In nine (21%) of the pregnancies, the mother had been on long-time anticoagulation treatment using warfarin prior to conception due to permanent severe risk factors. Thrombophilia was demonstrated in 31 (69%) of the pregnancies, and in 29 (64%) of the patients, the previous DVT was oestrogen-related. Thromboprophylaxis using tinzaparin was given in 41 (91%) and using dalteparin in four (9%) of the pregnancies. Doses of LMWH during pregnancy were adjusted according to risk assessment. One pregnancy was terminated by induced delivery at week 22 due to fetal malformations, and two of the pregnancies (4%) were complicated by intrauterine fetal death, one in week 39 due to severe fetal infection and one in week 23 due to intrauterine fetal growth restriction caused by severe antiphospholipid syndrome. All but one of the pregnancies was carried out without recurrence of DVT or maternal pulmonary embolism and the mother remained having patent deep veins postnatal. The mother with the antiphospholipid syndrome had a recurrent DVT complicated by iliac stent occlusion. This mother was prior to pregnancy on long-time treatment using warfarin. During pregnancy, she was erroneously treated with LMWH in standard prophylaxis doses instead of therapeutic doses and without adding aspirin. After CDT for acute iliofemoral DVT including adjunctive stenting, pregnancy can be carried out almost uneventful even in women at high risk of thromboembolism. Thromboprophylaxis during pregnancy, using LMWH in a dosage adjusted to individual risk assessment, is essential.


Introduction and Differential Diagnosis of Monkeypox in Argentina, 2022.
We report detection of cases of monkeypox virus infection in Argentina in the context of a marked increase in confounding cases of atypical hand-foot-and-mouth syndrome caused by enterovirus coxsackie A6. We recommend performing an accurate differential virological diagnosis for exanthematous disease in suspected monkeypox cases.


Development of preimplantation genetic testing for monogenic diseases in China.
Preimplantation genetic testing for monogenic diseases (PGT-M) can effectively interrupt the transmission of genetic diseases from parents to the offspring before pregnancy. In China, there are over ten million individuals afflicted with monogenic disorders. This literature review summarizes the development of PGT-M in China for the past 24 years, covering the general steps such as the indications and contraindications, genetic and reproductive counselling, biopsy methods, detecting techniques and strategies during PGT-M application in China. The ethical considerations of PGT-M are also be emphasized, including sexual selection, transferring for mosaic embryos, the three-parent baby, and the different opinions for serious adult-onset conditions. Some key policies of the Chinese government for the application of PGT-M are also considered. Methods for regulation of this technique, as well as specific management to increase the accuracy and reliability of PGT-M, are regarded as priority issues in China. The third-generation sequencing and variants testing from RNA level, and non-invasive preimplantation genetic testing using blastocoel fluid and free DNA particles within spent blastocyst medium might be potential techniques and strategies for PGT-M in future.


Evaluating the Impact of Oncology Care Model Reporting Requirements on Biomarker Testing and Treatment.
The Oncology Care Model (OCM) is Medicare's first alternative payment model program for patients with cancer. As of October 2017, participating practices were required to report biomarker testing of patients with advanced non-small-cell lung cancer (aNSCLC). Our objective was to evaluate the effect of this OCM reporting requirement on quality of care. We selected patients with aNSCLC receiving care in practices in a nationwide de-identified electronic health record-derived database. We used an adjusted difference-in-differences (DID) logistic regression model to compare changes in biomarker testing rates (EGFR, ROS1, and ALK) and receipt of biomarker-guided therapy between patients in OCM versus non-OCM practices, before and after OCM implementation. The analysis included 14,048 patients from 45 OCM practices (n = 8,151) and 105 non-OCM practices (n = 5,897). The overall unadjusted rates for biomarker testing and receipt of biomarker-guided therapy increased over the study period (2011-2018) in both OCM (55.5% v 71.6%; 89.8% v 94.6%, respectively) and non-OCM (55.2% v 69.7%; 90.1% v 95.2%, respectively) practices. In the adjusted DID model, the rates of biomarker testing (odds ratio [OR], 1.09 [95% CI, 0.88 to 1.34]; P = .45) and receipt of biomarker-guided therapy (OR, 0.87 [95% CI, 0.52 to 1.45]; P = .58) were similar between OCM and non-OCM practices. OCM biomarker documentation and reporting requirements did not appear to increase the proportions of patients with aNSCLC who underwent testing or who received biomarker-guided therapy in OCM versus non-OCM practices.


Perilunate Dislocation - Case Report and Review of Literature.
Perilunate dislocations are rare injuries comprising of less than 10% of all wrist injuries. These usually occur after high-energy trauma to the wrist. One-fourth (25%) of perilunate dislocations are missed at the initial presentation. We report a case of perilunate dislocation in a patient who presented late, about two months after trauma. He underwent open reduction through a single dorsal approach and internal fixation with K-wires. Aggressive physiotherapy exercises were started after removal of K-wires. He regained near normal full range of motions at the wrist by the end of four months and showed no recurrence of the dislocation. In conclusion, perilunate dislocations should be considered as one of the important differential diagnosis in patients with history of high-energy trauma to the wrist. Early diagnosis and treatment is necessary to prevent the potential risk of avascular necrosis of lunate and scaphoid and secondary osteoarthritis. The best results can be obtained with open reduction and internal fixation with K-wires via a single dorsal approach.


Efficacy of recommended drugs against soil transmitted helminths: systematic review and network meta-analysis.
Objective To evaluate efficacies of anthelmintic drugs against soil transmitted helminths in terms of cure rates and egg reduction rates.Design Systematic review and network meta-analysis.Data Sources PubMed, ISI Web of Science, Embase, ScienceDirect, the Cochrane Central Register of Clinical Trials, and the World Health Organization library database from 1960 until 31 December 2016.Study selection Randomised controlled trials evaluating the efficacy of a single dose regimen of albendazole, mebendazole, levamisole, and pyrantel pamoate against Ascaris lumbricoides, hookworm (Necator americanus and Ancylostoma duodenale) and Trichuris trichiura. The primary outcomes included cure rates analysed by network meta-analysis with mixed logistic regression models and egg reduction rates with mixed linear models.Results 55 and 46 randomised controlled trials were included in the analysis of cure rates and egg reduction rates, respectively. All drugs were highly efficacious against A lumbricoides Albendazole showed the highest efficacy against hookworm infections with a cure rate of 79.5% (95% confidence interval 71.5% to 85.6%) and an egg reduction rate of 89.6% (81.9% to 97.3%). All drugs had low efficacy against T trichiura, with mebendazole showing the highest cure rate of 42.1% (25.9% to 60.2%) and egg reduction rate of 66.0% (54.6% to 77.3%). Estimates for the years 1995 and 2015 showed significant reductions in efficacy of albendazole against T trichiura: by 2015 the egg reduction rates fell from 72.6% (53.7% to 91.5%) to 43.4% (23.5% to 63.3%; P=0.049) and the cure rates fell from 38.6% (26.2% to 52.7%) to 16.4 (7.7% to 31.3%; P=0.027).Conclusions All four currently recommended drugs show limitations in their efficacy profile. While only albendazole showed good efficacy against hookworm infection, all drugs had low efficacy against T trichiura The decrease in efficacy of albendazole against T trichiura over the past two decades is of concern. The findings indicate the need for strengthening efforts to develop new drug treatments, with a particular focus on drugs against T trichiura.


Systematic review with meta-analysis: bariatric surgery reduces the incidence of hepatocellular carcinoma.
Obesity is a risk factor for non-alcoholic steatohepatitis (NASH) and increases the risk of several cancer types including cancers of the liver. Bariatric surgery can provide durable weight loss, but little is known about the later development of hepatocellular carcinoma (HCC) after surgery. To determine whether bariatric surgery reduces the risk of HCC. We performed a comprehensive literature search of major databases (from inception to November 2020) to identify studies which assess the incidence and risk of HCC following bariatric surgery. Pooled data were assessed using a random-effects model expressed in terms of odds ratio (OR), incidence rate ratio and 95% confidence interval (CI). Nine studies (two abstracts and seven full texts) were included for meta-analysis which involved 19 514 750 patients (18 423 546 controls and 1 091 204 bariatric patients). Pooled unadjusted odds ratio (OR) was 0.40 (95% CI: 0.28-0.57) which favoured bariatric surgery, though with high heterogeneity (I2 : 79%). Using an adjusted model derived from matched cohorts (five studies) yielded an OR of 0.63 (95% CI: 0.53-0.75) with moderate heterogeneity (I2 : 38%). The pooled rate/1000 person-years was 0.05 (95% CI: 0.02-0.07) in bariatric surgery patients and 0.34 (95% CI: 0.20-0.49) in the control group with an incidence rate ratio of 0.28 (95% CI: 0.18-0.42). Bariatric surgery is associated with a decreased risk of HCC.


Helium Isotopes Quantum Sieving through Graphtriyne Membranes.
We report accurate quantum calculations of the sieving of Helium atoms by two-dimensional (2D) graphtriyne layers with a new interaction potential. Thermal rate constants and permeances in an ample temperature range are computed and compared for both Helium isotopes. With a pore larger than graphdiyne, the most common member of the γ-graphyne family, it could be expected that the appearance of quantum effects were more limited. We find, however, a strong quantum behavior that can be attributed to the presence of selective adsorption resonances, with a pronounced effect in the low temperature regime. This effect leads to the appearance of some selectivity at very low temperatures and the possibility for the heavier isotope to cross the membrane more efficiently than the lighter, contrarily to what happened with graphdiyne membranes, where the sieving at low energy is predominantly ruled by quantum tunneling. The use of more approximate methods could be not advisable in these situations and prototypical transition state theory treatments might lead to large errors.


Primary active transport of pravastatin across the liver canalicular membrane in normal and mutant Eisai hyperbilirubinaemic rats.
We have previously demonstrated that the HMG-CoA inhibitor pravastatin is efficiently taken up by the liver via the 'multispecific anion transporter' in an active manner. To further examine the fate of pravastatin within the liver, its biliary excretion was studied in a single-pass liver perfusion system and isolated liver canalicular membrane vesicles (CMVs) using normal (Sprague-Dawley rats; SDRs) and mutant Eisai hyperbilirubinaemic rats (EHBRs). In the liver perfusion experiments, the outflowing drug concentration reached a steady state at 30 min and the extraction ratio was approximately 0.7 in both rat strains. Both the steady state biliary excretion rate and bile flow rate of the EHBR group were 40% of those of SDRS. At steady state, the fraction of unchanged drug in bile was 25-34% in both groups. The concentration ratios of unbound drug in cytosol versus that in sinusoid and of that in bile versus that in cytosol were, respectively, 11 and 87 in SDRs, and 13 and 94 in EHBRs. After correction for the membrane potential (-40 mV in cytosol), the ratios became 49 and 19 in SDR and 58 and 21 in EHBRs, respectively. The finding that all of these values were much larger than unity suggested that active transport occurred from liver to bile, as well as from plasma to liver, in both rat strains. Furthermore, ATP-dependent uptake of pravastatin was clearly observed in CMVs prepared from EHBRs as well as SDRs, whereas the stimulation by ATP of DNP-SG transport in CMVs was observed only in SDRs. It was concluded that pravastatin is excreted into bile in high concentrations and a primary active transport mechanism which is maintained in EHBRs contributes to the biliary excretion of this drug.


Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology.
Clinical investigators in oncology are increasingly interested in using molecular analysis of cancer tissue to understand the biologic bases of response or resistance to novel interventions and to develop prognostic and predictive biomarkers that will guide clinical decision making. Some scientific questions of this nature can only be addressed, or may best be addressed, through the conduct of a clinical trial in which research biopsies are obtained from all participants. However, trial designs with mandatory research biopsies have raised ethical concerns related to the risk of harm to participants, the adequacy of voluntary informed consent, and the potential for misunderstanding among research participants when access to an experimental intervention is linked to the requirement to undergo a research biopsy. In consideration of the ethical and scientific issues at stake in this debate, the Cancer and Leukemia Group B Ethics Committee proposes guidelines for clinical trials involving mandatory research biopsies. Any cancer clinical trial that requires research biopsies of participants must be well designed to address the scientific question, obtain the biopsy in a way that minimizes risk, and ensure that research participants are fully informed of the risks, rationale, and requirements of the study, as well as of treatment alternatives. Further guidelines and discussions of this issue are specified in this position paper. We feel that if these principles are respected, an informed adult with cancer can both understand and voluntarily consent to participation in a clinical trial involving mandatory research biopsy for scientific end points.


Exploring the Host Range of Rose rosette Virus among Herbaceous Annual Plants.
To study the host range of Rose rosette virus (RRV), we employed crude sap inoculum extracted from RRV-infected roses and the RRV infectious clone. We inoculated plants from the families Solanaceae, Cucurbitaceae, Leguminosae, Malvaceae, Amaranthaceae, and Brassicaceae. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect RRV in the inoculated plants throughout their growth stages. Interestingly, RRV was detected in the newly developed leaves of tomato, pepper, tobacco, cucumber, squash, zucchini, pumpkin, pea, peanut, soybean, spinach, okra, and Chenopodium spp. The speed of upward advancement of RRV within infected plants was variable between plants as it took two to three weeks for some plant species and up to five weeks in other plant species to emerge in the newest leaves. No severe symptoms were detected on most of the inoculated plants. Chenopodium spp., spinach, cucumber and Nicotiana rustica exhibited either chlorotic or necrotic lesions with variable shapes and patterns on the systemically infected leaves. Double membrane-bound particles of 80-120 nm in diameter were detected by transmission electron microscopy in the infected tissues of cucumber, pepper, and N. benthamiana plants. This finding infers the validity of mechanical inoculation for RRV on a wide range of plants that would serve as potential natural reservoirs.


Hepatic iron content and the risk of Staphylococcus aureus bacteremia in liver transplant recipients.
Iron is a critical nutrient source and contributes to staphylococcal pathogenesis. We assessed the role of hepatic explant iron overload as a risk factor for Staphylococcus aureus bacteremia in liver transplant recipients. Seven of 13 cases with S aureus bacteremia (53.8%) had hepatic explant iron concentrations that exceeded normal limits (grade > or = 2). Length of posttransplant intensive care unit stay (P= .013) and hepatocellular carcinoma as underlying liver disease (P = .04), but not hepatic explant iron concentration, correlated with a higher risk of S aureus bacteremia after transplantation. However, noncarriers (patients without S aureus nasal carriage) who developed S aureus bacteremia were more likely to have high hepatic iron content; 4 of 7 (57%) noncarriers with high-grade iron content developed S aureus bacteremia but no noncarriers with low-grade iron content did (P = .07). All noncarriers who became infected had high iron content (grade > or = 2) of the hepatic explant. A readily quantifiable assessment of hepatic iron at the time of transplantation can potentially identify patients without carriage who may be at risk for early S aureus bacteremia.


Tracing the evolution of FERM domain of Kindlins.
Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in Integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in Integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.


Assessing the inequalities in access to online delivery services and the way COVID-19 pandemic affects marginalization.
This paper discusses the importance of incorporating online home delivery services (OHDS) into the concept of accessibility and marginalization. The authors propose a method to quantify access to OHDS and assess levels of inequalities in access to OHDS using data from OHDS providers in the pharmaceutical and food sectors, as well as from transport operators delivering parcels. The Västra Götaland Region in the West coast of Sweden is used as a case study. The results show significant inequalities in access to OHDS. Moreover, there are segments of population under a compound marginalization during the COVID-19 pandemic due to (i) limited accessibility to OHDS services, (ii) high incidence of COVID-19 cases in their area that makes physical visits to a store a risk activity, and (iii) high vulnerability (e.g., high share of individuals older than 65). These results reveal a need for the public sector to prioritize innovations in services that target specific clusters of the population that are vulnerable and marginalized, but also shows the imminent risk for some of these segments during the pandemic.


Genomic characterization of a wild diploid isolate of Saccharomyces cerevisiae reveals an extensive and dynamic landscape of structural variation.
The budding yeast Saccharomyces cerevisiae has been extensively characterized for many decades and is a crucial resource for the study of numerous facets of eukaryotic biology. Recent whole genome sequence analysis of over 1000 natural isolates of S. cerevisiae has provided critical insights into the evolutionary landscape of this species by revealing a population structure comprised of numerous genomically diverse lineages. These survey-level analyses have been largely devoid of structural genomic information, mainly because short-read sequencing is not suitable for detailed characterization of genomic architecture. Consequently, we still lack a complete perspective of the genomic variation that exists within this species. Single molecule long-read sequencing technologies, such as Oxford Nanopore and PacBio, provide sequencing-based approaches with which to rigorously define the structure of a genome, and have empowered yeast geneticists to explore this poorly described realm of eukaryotic genomics. Here, we present the comprehensive genomic structural analysis of a wild diploid isolate of S. cerevisiae, YJM311. We used long-read sequence analysis to construct a haplotype-phased, telomere-to-telomere length assembly of the YJM311 genome and characterized the structural variations (SVs) therein. We discovered that the genome of YJM311 contains significant intragenomic structural variation, some of which imparts notable consequences to the genomic stability and developmental biology of the strain. Collectively, we outline a new methodology for creating accurate haplotype-phased genome assemblies and highlight how such genomic analyses can be used to define the structural architectures of natural S. cerevisiae isolates. It is our hope that continued structural characterization of S. cerevisiae genomes, such as we have reported here for YJM311, will comprehensively advance our understanding of eukaryotic genome structure-function relationships, structural genomic diversity, and evolution.


Emotion as a source of moral understanding in conservation.
Recent debates around the meaning and implications of compassionate conservation suggest that some conservationists consider emotion a false and misleading basis for moral judgment and decision making. We trace these beliefs to a long-standing, gendered sociocultural convention and argue that the disparagement of emotion as a source of moral understanding is both empirically and morally problematic. According to the current scientific and philosophical understanding, reason and emotion are better understood as partners, rather than opposites. Nonetheless, the two have historically been seen as separate, with reason elevated in association with masculinity and emotion (especially nurturing emotion) dismissed or delegitimated in association with femininity. These associations can be situated in a broader, dualistic, and hierarchical logic used to maintain power for a dominant male (White, able-bodied, upper class, heterosexual) human class. We argue that emotion should be affirmed by conservationists for the novel and essential insights it contributes to conservation ethics. We consider the specific example of compassion and characterize it as an emotional experience of interdependence and shared vulnerability. This experience highlights conservationists' responsibilities to individual beings, enhancing established and widely accepted beliefs that conservationists have a duty to protect populations, species, and ecosystems (or biodiversity). We argue compassion, thus understood, should be embraced as a core virtue of conservation.


[Simple method of embedding in paraffin under vacuum].
A method of embedding into paraffin under vacuum is proposed. Pieces of tissues are placed into a glass jar containing melted paraffin from which the air is pumped out. The jar is permanently placed into TC-80 thermostate. The air-removing hose is placed inside the thermostate through the opening in its upper wall meant for the control thermometer. The air is pumped out by any vacuum pump with electric drive. The proposed method is simple, provides for a good saturation with paraffin, shortens the time of tissue contact with melted paraffin, and gives thin sections of good quality.


Rapid enzymatic activity model (REAM) to decipher the toxic action of per- and polyfluoroalkyl substances.
Per- and polyfluoroalkyl substances (PFAS) have been identified as emerging contaminants and human exposure to these substances is a rising public health concern. We have developed a rapid enzymatic activity model (REAM), which can serve as a cell-free screening tool that elucidates possible mechanisms of toxic action inexpensively and quickly for these and other environmentally relevant chemicals.


[Fluorescent probe 4-dimethylaminochalcone: mechanism of fluorescence quenching in nonpolar media].
The reasons for the high sensitivity of the fluorescent probe 4-dimethylaminochalcone (DMC) to nonpolar environment were explored. It was shown that, at room temperature, the fluorescence quantum yield in nonpolar media at 20 degrees C is lower than 0.01 (0.001 in methylcyclohexane). However, as temperature was lowered to -196 degrees C, the yield in methylcyclohexane increased more than 200 times. At the same time, the oscillator strength of absorption transition increased, and the absorption spectrum was shifted to red. These results, together with quantum chemistry calculations suggest that, for fluorescence quenching to occur, some barrier in the DMC molecule, probably the barrier of rotation about C-C bonds, should be overcome. In other words, the quenching is associated with the transition of DMC molecules from a flat conformation (energy minimum) to other, nonflat conformations through rotations about C-C bonds. The phosphorescence of DMC at low temperatures was detected. This suggests that fluorescence quenching is caused by radiationless transitions from the excited singlet level to the ground and triplet levels, and rotation about bonds facilitates these transitions.


The theory of evolution - a jewish perspective.
All possible pro and con arguments regarding the theory of evolution have been discussed and debated in the vast literature-scientific, religious, and lay-in the past 150 years. There is usually great zealotry in all debating parties, with mutual intolerance of ideas and concepts, disrespect toward opposing opinions and positions, and usage of very harsh language. This prejudiced approach usually does not allow for a reasonable debate. It is important to look at the facts, assumptions, and beliefs of the theory of evolution in a more calm and humble way. In this article a comparative analysis is offered between the scientific aspects of the theory of evolution and a Judaic approach to these aspects. The two sets of human thought-religion and science-are fundamentally different in their aims and purposes, in their methods of operation, in their scope of interest and issues, and in their origin and ramifications. Whenever science surpasses its limits, or religion exceeds its boundaries, it actually is a form of an abuse of both. This has happened to the theory of evolution in a more powerful mode than any other interaction between science and religion. The agenda of many scientists who promote the theory of evolution is to achieve the goal of understanding the existence of the universe as a random, purposeless, natural development, evolved slowly over billions of years from a common ancestor by way of natural selection, devoid of any supernatural metaphysical power. JEWISH FAITH PERCEIVES THE DEVELOPMENT OF THE UNIVERSE IN A DIFFERENT WAY: God created the world, with a purpose known to Him; He established natural laws that govern the world; and He imposed a moral-religious set of requirements upon Man. The discussion and comparative analysis in this article is based upon the current neo-Darwinian theory, although it seems almost certain that even the new and modern assumptions and speculations will continue to be challenged, changed, and revised as new scientific information will be discovered. The theory of evolution is based upon certain facts, many assumptions, speculations, and interpretations, and some fundamental non-evidence-based beliefs. Judaism accepts all experimentally proven facts and observations of the theory of evolution. Judaism accepts some of the assumptions and interpretations embedded in the theory of evolution, but rejects other assumptions and speculations which contradict fundamental Jewish beliefs, and which are anyway not scientifically proven; to those Judaism offers different interpretations. Judaism strongly rejects all the extensions of the theory of evolution beyond natural sciences, which endorse the biological assumption of the "survival of the fittest" in commerce and human societies as a whole by justifying claims of social inequality, sexism, racism, Nazism, eugenics, and other moral-social deviations as "laws of nature".


Acinar cell carcinoma with PRKAR1A and PTEN alterations and paraneoplastic panniculitis.
Pancreatic acinar cell carcinoma is a rare type of pancreatic malignancy, which can be confused with pancreatic neuroendocrine neoplasm. Here, we describe a woman in her 80s who presented with abdominal pain and bilateral lower extremity panniculitis. She underwent surgery for a presumed diagnosis of neuroendocrine tumour with PTEN and PRKAR1A alterations; 19 months, later, a recurrence of her pancreatic malignancy was discovered. The patient underwent repeat resection and this time immunohistochemical staining confirmed the diagnosis of acinar cell carcinoma. Staining for acinar cell carcinoma should be prompted based on clinical suspicion in context of PTEN or PRKAR1A mutation when appropriate.


Methodological and conceptual issues regarding occupational psychosocial coronary heart disease epidemiology.
Overview Psychosocial occupational epidemiology has mainly focused on the demand-control and, to a much lesser extent, the effort-reward-imbalance (ERI) models. These models and the strong focus on them raise some conceptual and methodological issues we will address in the following letter. The conceptual issues include the empirical confirmation of the assumptions of these models, the extent to which the focus on the demand-control and ERI models is warranted, and whether the sub-dimensions of the scales in these models have common health effects. We argue that there is a lack of empirical approval of (i) the assumptions behind both models and (ii) the focus on these models. The methodological issues include how exposure to job strain is categorized, how ERI previously has been measured, and the validity of self-reports of job strain. We argue that (i) a population independent definition of job strain is lacking, (ii) the older measurements of ERI mix exposure and effect, and (iii) we know little regarding the validity of the measurement of the psychosocial working environment. Finally, we suggest that analyses of monitoring data with a broader focus on the psychosocial working environment can be used to shed light to some of the issues raised above. Introduction In the last three decades (1, 2), psychosocial occupational epidemiology related to coronary heart disease (CHD) has mainly focused on the job-strain model, also referred to as the demand-control model (3, 4). In this model, two aspects of work are deemed relevant: demands and control. Negative consequences to health are to be expected when high demands are simultaneously present with low control. This combination has been termed job strain (3, 4). Recently, there has also been increased interest in the ERI model (5, 6) which considers the level of effort relative to rewards at work: an imbalance is present when the efforts outweigh the rewards (5, 6). In longitudinal studies of CHD, there has been only a limited focus on investigating occupational psychosocial factors outside of these two models (1, 2). In this letter, we would like to raise some conceptual and methodological issues which are inherent to these two stress models but also which arise from the heavy emphasis placed on them. Conceptual issues The conceptual issues we discuss below are empirical confirmation of the assumptions of these models and to what extent the focus on the demand-control and ERI models is warranted. Investigating the assumptions of the models Both the demand-control and the ERI models are based on assumptions which have only been tested empirically to a limited extent (1, 2). We pose three specific questions: (i) Does the interaction of demands and control constitute a risk factor for CHD? (ii) Does the imbalance between effort and reward explain more variance in CHD risk than high effort and low reward alone? (iii) Do the sub-dimensions of the scales in these models have common health effects? Regarding the interaction of demands and control. The concept of the demand-control model is useful when the health risk of being exposed to job strain (simultaneous high demands and low control) differs greatly from the sum of individual health risks of being exposed solely to high demands and low control. If this interaction were not present, it would be warranted to look separately at high demands and low control. This would for instance counteract overlooking those persons exposed to low control but not high demands (known as "passive work"; 3, 4). It should be emphasized that the interaction of demands and control has only been tested in very few - underpowered - cases (1, 2). Initial support for an interaction within the demand-control model can be tentatively derived from the work of the IPD-Work Consortium (7): In a reanalysis of an earlier study (8), it was shown that while neither demands nor job control alone (appendix to 8) predicted CHD, job strain did when controlling for sex, age and socioeconomic status (SES) (9). This indicates that an interaction takes place. Controlling for SES is of high relevance - otherwise, the results point in a different direction (10). However, a formal test of interaction was not performed on the IPD-Work Consortium data. Even the IPD study itself might not have sufficient statistical power to analyze a possible interaction directly: this requires many more observations than simply looking at the main effects (2). If one is interested in investigating an interaction, more incident outcomes are often required (11). Regarding effort-reward imbalance. Similarly to the combined effect of demands and control described above, focusing on the ERI model makes sense only if the imbalance of effort and reward explains the risk of CHD over and above the effect of high efforts and low rewards. To our knowledge, this has not been verified in any longitudinal study of CHD (1, 2). Regarding the effect of sub-dimensions. Finally, using the scales of the two models (demands and control or efforts and rewards) is meaningful only if the sub-dimensions of the scales all have about equal effect sizes and signs. For example, the scale psychological demands covers the sub-dimensions work pace, role conflict and work amount while control covers both influence (decision authority) and opportunities for development (skill discretion). Do these dimensions predict the risk of CHD to equal amounts within their respective scales? For now, this has not been tested elaborately to our knowledge (1, 2, 12). Consequently, it is possible that certain risk factors in the psychosocial work environment may be overlooked due to different risk factors being merged into one scale. Is the focus on the demand-control and ERI models warranted? In the past, longitudinal epidemiological research on psychosocial work characteristics and their association with the risk of CHD has mainly focused on the demand-control and - to a much lesser extent - ERI models (1). For example, in a recent review (2) covering 44 papers and including 170 analyses, 70% percent of those dealt with these models or sub-dimensions thereof. Interestingly, the demand-control model alone accounted for 66% of the analyses and ERI only 4%. A further 11% of the analyses dealt with working hours, 9% with social support, 5% with job insecurity, 3% with leadership and the remaining 3% covered conflicts, justice or predictability. Maintaining the currently high degree of focus on the DC and ERI models requires evidence that job strain and ERI are by far the most important risk factors for CHD. The review by Pejtersen et al (2) has additionally pointed out that of the 44 studies mentioned above, only two - an IPD-Work Consortium study (8) and a Swedish case-control study (13) - contained analyses with sufficient statistical power to detect an elevated CHD risk of 20%. These two sufficiently powered studies available as of April 2013 have led to the following conclusions: (i) job strain was found to be predictive of CHD in the IPD-Work Consortium study (8); and (ii) both low control and low social support predicted CHD in the Swedish study (13). Recently, a well-powered study on working hours (14) indicated that long working hours constitute a risk factor for CHD. Additionally, a recently published large study on job insecurity (15) is worth mentioning. While there was not sufficient power to detect a 20% increased risk due the relatively low prevalence of job insecurity, the study did have sufficient power to find a risk of 1.32 - which is the value actually found empirically (15). Summarizing the small number of well-powered studies available at this time indicates that both model dimensions (job strain) as well as non-model dimensions (social support and working hours) predict CHD (8, 13-15). In this context, one should bear in mind that the variety of possible dimensions that can be considered as constituting "psychosocial work environment" is large. The latter is exemplified by a recent analysis of the psychosocial content of seven European work environment monitoring questionnaires which showed that there are 34 distinct dimensions of the psychosocial work environment (16). Around half of these dimensions are not found in either the demand-control or ERI models (16). These include for instance emotional demands, demands on hiding emotions, sensorial demands, meaning of work, commitment to the workplace, organizational influence, trust, social community at work, quality of leadership, predictability, role clarity, restructuring, safety culture, work life balance, and negative acts (eg, violence, bullying). Little is currently known on the health effects of these "non-model" dimensions. Research on their possible effects might show that they are small - and that the DC and ERI dimensions are indeed the main psychosocial risk factors for CHD. However, results may also point to the importance of the non-model dimensions. To date, this remains to be investigated. Methodological issues In addition to the conceptual issues discussed above, we would like to highlight some methodological issues related to one or both of these models. The three main points address: (i) how exposure to job strain is categorized; (ii) how ERI has been measured up to now; and (iii) the validity of self-reports of job strain. Practical definition of job strain Job strain is usually operationalized as a median split of the two dimensions demands and control in the population investigated (3, 17). Hence, whether a certain worker experiences job strain or not depends on which other workers are part of the sample (18). This poses a problem when the distributions of demands and control differ between populations. Comparisons between Denmark and Spain and across Europe suggest that such differences exist (19, 20), rendering it at the least a challenge to combine populations in meta-analyses. (ABSTRACT TRUNCATED)


Activation domain requirements for disruption of Epstein-Barr virus latency by ZEBRA.
Latent infection of B lymphocytes by Epstein-Barr virus (EBV) can be disrupted by expression of the EBV ZEBRA protein. ZEBRA, a transcriptional activator, initiates the EBV lytic cascade by activating viral gene expression. ZEBRA is also indispensable for viral replication and binds directly to the EBV lytic origin of replication. The studies described herein demonstrate that the activation domain. ZEBRA activation can be replaced by a heterologous acidic, proline-rich, or glutamine-rich activation domain. ZEBRA activation domain swap constructs retain ZEBRA's native abilities to activate specific EBV promoters, to disrupt EBV latency, and to stimulate replication at the EBV lytic origin. Additional work, employing sequential and internal deletions of ZEBRA's N-terminal activation domain, indicates that its separate activities are not attributable to specific subdomains but are spread throughout its N terminus and therefore cannot be inactivated by deleting localized regions.


Prevalence of Loneliness and Related Factors Among Older Adults in Taiwan: Evidence From a Nationally Representative Survey.
Loneliness is a common problem among older populations, and very few studies have examined loneliness among older adults in Taiwan. This study aimed to understand the prevalence of loneliness and factors associated with it among older adults in Taiwan. Data from the Taiwan Longitudinal Study of Aging collected in 2015 were analyzed and involved 4588 participants aged ≥65 years. The outcome variable was a self-reported loneliness question, and independent variables included demographic characteristics, a self-reported health status, physical function, number of comorbidities, cognitive function, and social support. A multivariate logistic regression was used to identify predictors of loneliness. The prevalence of loneliness among older adults in Taiwan was 10.5%. The multivariate logistic regression showed that old persons who were male, lived alone, perceived that they had a poor health condition, had no spouse, had no job, and had poor emotional support had higher likelihood of feeling lonely. This study investigated loneliness in a nationally representative sample of older adults and revealed that one-tenth of this older population might experience loneliness which requires immediate action. Special attention should be given to the aforesaid factors in older adults to identify problems and provide interventions as early as possible in order to prevent loneliness and thus reduce the resultant negative effects on physical and mental conditions. Appropriate interventions should be developed to prevent or ameliorate feelings of loneliness among older populations using rigorous research designs such as randomized controlled trials.


Blood meals of mosquito vectors of filariasis in Guizhou Province, China.
The blood meals of mosquito vectors of W. bancrofti and B. malayi were determined by performing CIEP of the eluant of crushed mosquitoes in filter paper against rabbit anti-human, cow and pig sera. The mosquitoes were collected from houses, cowsheds and pigpens in two counties in Guizhou Province. It was shown that all three species fed on blood from humans, cows and pigs with different preference. While An sinensis fed more on cows, Cx. fatigans and An. lesteri fed on the hosts that were nearby, i.e., Cx. fatigans caught from households fed more on humans, and those collected from cowsheds or pigpens fed more on cows and pigs, respectively.


Organic dust exposures from compost handling: case presentation and respiratory exposure assessment.
Inhalation of dust from contaminated organic materials may result in acute respiratory tract illness. Possible mechanisms include toxic and cellular reactions to microbial and other organic products or immunologic responses after prior sensitization to an antigen. A case is presented of a 52 year old male who developed fever, myalgia, and marked dyspnea 12 hr after shoveling composted wood chips and leaves. Inspiratory crackles, hypoxemia, and bilateral patchy pulmonary infiltrates were seen. Precipitating antibody tests for the usual antigens were inconclusive. He improved over 3 days. In order to assess the environmental conditions the patient had experienced, we returned to the site to reproduce and measure respiratory exposures during hand loading of the compost. Visible clouds of fine particulate were easily generated during handling activities. Microscopic examination of these dusts indicated a predominance of spores. Endotoxin concentrations from inspirable and respirable dust samples ranged from 636 to 16,300 endotoxin units/m3. Levels of contaminants found were consistent with those associated with respiratory illness in other agricultural settings. Two respiratory disorders, hypersensitivity pneumonitis (HP) and organic dust toxic syndrome (ODTS), may occur after exposure to organic dusts containing fungal spores and endotoxins. Despite extensive clinical and environmental investigations, we were unable to differentiate these two disorders, and suggest they may represent parts of a spectrum of responses to complex organic dusts, rather than completely distinct clinical entities.


Inhibitory effect of alkylating modulators on the function of P-glycoprotein.
Modulators of P-glycoprotein (P-gp) are often themselves transported out of cells, thereby limiting their effectiveness. It may be possible to develop more effective modulators of multidrug resistance by designing drugs that irreversibly block the function of P-gp. Therefore, we studied the effect of the mustard derivatives of fluphenazine (FPN) and trans-flupenthixol (FPT) on P-gp function. Both fluphenazine-mustard (FPN-M) and trans-flupenthixol-mustard (FPT-M) possessed alkylating activity, as assayed using 4-(p-nitrobenzyl) pyridine. Multidrug-resistant MCF-7/AdrR cells were incubated with FPN or FPN-M, or FPT or FPT-M for 1 h, washed for varying number of times in phosphate-buffered saline (PBS), then resuspended in medium containing [3H]vinblastine (VBL), and assayed for steady-state accumulation of the drug. Washing had far less of an effect on the ability of FPN-M and FPT-M to increase VBL accumulation compared to their parent compounds. After eight washes in excess PBS, the cells initially exposed to FPN or FPT accumulated only 30% and 50% of the initially accumulated drug, whereas the FPN-M- or FPT-M-treated cells accumulated approximately 75% and 90% of the control, respectively. FPN-M and FPT-M also increased the uptake and decreased the efflux of VBL from MDR cells despite repeated washing. We also examined the effects of these modulators on sensitivity of MDR cells to cytotoxic agents. FPN-M and FPT-M sensitized MCF-7/AdrR cells to VBL and doxorubicin to a greater extent than their parent compounds. These studies point out the potential of "irreversible" P-gp modulators to produce prolonged chemosensitization.


Acute hepatitis B in two patients transmitted from an e antigen negative cardiothoracic surgeon.
Hepatitis B virus (HBV) infection was transmitted by a locum cardiothoracic surgeon to two patients during coronary artery bypass surgery. Both patients presented 12 weeks after surgery and developed serious clinical illness. The surgeon was known to be hepatitis B surface antigen (HBsAg) positive, hepatitis B e antigen (HBeAg) negative, and to have antibodies to HBeAg (anti-HBe). Sequences of regions of the HBV surface and core genes from the patients and surgeon were indistinguishable. An exercise was undertaken to notify all patients on whom the surgeon had operated while employed at the hospital where the transmissions occurred. One hundred and twenty-three out of 126 patients were tested. No evidence of transmission to any other patient was found. Revised recommendations by the UK Health Departments as to which health care workers should be permitted to perform exposure prone procedures have recently been published.


The next frontier in the molecular biology of the opioid system. The opioid receptors.
The analgesic and euphoric properties of some plant alkaloids such as morphine have been known and exploited for centuries. In contrast, only during the last twenty years have we begun to unravel the molecular basis by which opiates exert their effects, mechanisms important to our general understanding of the nervous system. The analgesic response to opiates is the result of a cascade of biochemical events that are triggered by the interaction of the opiate with specific macromolecular components found on the membranes of nervous system tissues, the opioid receptors. The endogenous ligands of these receptors are small peptides, the opioid peptides. Although much has been learned about the structures and the mode of synthesis of the opioid peptides, little is understood about the structure of their receptors. The application of molecular genetic techniques was of great importance to the studies of the opioid peptides. It is now expected that this same technology will unravel the physical mysteries of the opioid receptors.


Associations between self-reported sleep, overnight memory consolidation, and emotion perception: A large-scale online study in the general population.
Experimental studies suggest that short or disrupted sleep impairs memory consolidation, mood, and perception of emotional stimuli. However, studies have chiefly relied on laboratory-based study designs and small sample sizes. The aim of this fully online and pre-registered study was to investigate the association between sleep and overnight memory consolidation, emotion perception, and affect in a large, self-selected UK sample. A total of 1646 participants (473 completed) took part in an online study, where they completed a declarative (word-pairs) memory task, emotion perception task (valence ratings of images), and rated their affect within 2 h of bed-time. The following morning, participants reported on their state affect, sleep for the previous night, completed a cued recall task for the previously presented word-pairs, rated the valence of previously viewed images, and completed a surprise recognition task. Demographic data and habitual sleep quality and duration (sleep traits) were also recorded. Habitual sleep traits were associated with immediate recall for the word-pairs task, while self-reported sleep parameters for the specific night were not associated with overnight memory consolidation. Neither habitual sleep traits, nor nightly sleep parameters were associated with unpleasantness ratings to negative stimuli or overnight habituation. Habitual poor sleep was associated with less positive and more negative affect, and morning affect was predicted by the specific night's sleep. This study suggests that overnight emotional processing and declarative memory may not be associated with self-reported sleep across individuals. More work is needed to understand how findings from laboratory-based studies extrapolate to real-world samples and contexts.


Prevalence and mental health correlates of harassment and discrimination in the workplace: results from a national study.
This study describes past-year prevalence and effects on mental health and drinking outcomes for harassment and discrimination in the workplace (HDW) in a nationally representative random digit dial phone survey conducted in 2003-2004 (n = 2,151). HDW measures included experiences and perceptions of sexual harassment (SH) and generalized workplace harassment (GWH), and perceived harassment or discrimination because of race or ethnicity. Prevalence was examined by sex, race, age, occupation, marital status, and education. Effects of HDW were assessed controlling for demo-graphics and job and life stressors. Experiencing multiple types of HDW was common. SH was more prevalent among women, and Blacks and those of other or mixed race or ethnicity experienced the highest levels of HDW overall. HDW variables explained additional variance in problem drinking and mental health beyond life and job stressors, particularly for women. This study demonstrates that HDW is a prevalent problem associated with poor mental health and problem drinking in the U.S. workforce.


Neuronal dynamics in HfOx/AlOy-based homeothermic synaptic memristors with low-power and homogeneous resistive switching.
We studied the pseudo-homeothermic synaptic behaviors by integrating complimentary metal-oxide-semiconductor-compatible materials (hafnium oxide, aluminum oxide, and silicon substrate). A wide range of temperatures, from 25 °C up to 145 °C, in neuronal dynamics was achieved owing to the homeothermic properties and the possibility of spike-induced synaptic behaviors was demonstrated, both presenting critical milestones for the use of emerging memristor-type neuromorphic computing systems in the near future. Biological synaptic behaviors, such as long-term potentiation, long-term depression, and spike-timing-dependent plasticity, are developed systematically, and comprehensive neural network analysis is used for temperature changes and to conform spike-induced neuronal dynamics, providing a new research regime of neurocomputing for potentially harsh environments to overcome the self-heating issue in neuromorphic chips.


Reconfiguration of Brain Network Architectures between Resting-State and Complexity-Dependent Cognitive Reasoning.
Our capacity for higher cognitive reasoning has a measurable limit. This limit is thought to arise from the brain's capacity to flexibly reconfigure interactions between spatially distributed networks. Recent work, however, has suggested that reconfigurations of task-related networks are modest when compared with intrinsic "resting-state" network architecture. Here we combined resting-state and task-driven functional magnetic resonance imaging to examine how flexible, task-specific reconfigurations associated with increasing reasoning demands are integrated within a stable intrinsic brain topology. Human participants (21 males and 28 females) underwent an initial resting-state scan, followed by a cognitive reasoning task involving different levels of complexity, followed by a second resting-state scan. The reasoning task required participants to deduce the identity of a missing element in a 4 × 4 matrix, and item difficulty was scaled parametrically as determined by relational complexity theory. Analyses revealed that external task engagement was characterized by a significant change in functional brain modules. Specifically, resting-state and null-task demand conditions were associated with more segregated brain-network topology, whereas increases in reasoning complexity resulted in merging of resting-state modules. Further increments in task complexity did not change the established modular architecture, but affected selective patterns of connectivity between frontoparietal, subcortical, cingulo-opercular, and default-mode networks. Larger increases in network efficiency within the newly established task modules were associated with higher reasoning accuracy. Our results shed light on the network architectures that underlie external task engagement, and highlight selective changes in brain connectivity supporting increases in task complexity.SIGNIFICANCE STATEMENT Humans have clear limits in their ability to solve complex reasoning problems. It is thought that such limitations arise from flexible, moment-to-moment reconfigurations of functional brain networks. It is less clear how such task-driven adaptive changes in connectivity relate to stable, intrinsic networks of the brain and behavioral performance. We found that increased reasoning demands rely on selective patterns of connectivity within cortical networks that emerged in addition to a more general, task-induced modular architecture. This task-driven architecture reverted to a more segregated resting-state architecture both immediately before and after the task. These findings reveal how flexibility in human brain networks is integral to achieving successful reasoning performance across different levels of cognitive demand.


A comparison of selected diversity, similarity, and biotic indices for detecting changes in benthic-invertebrate community structure and stream quality.
Implementation of advanced wastewater treatment at the two municipal wastewater-treatment plants for Indianapolis, Indiana, resulted in substantial improvement in the quality of the receiving stream and significant changes in the benthic-invertebrate community. Diversity, similarity, and biotic indices were compared to determine which indices best reflected changes in the composition of the biota in the river. None of the indices perfectly reflected the changes in river quality or community structure. Similarity indices, especially percentage similarity, exhibit the most promise of the three classes of indices. Diversity indices were least useful, wrongly indicating that water quality deteriorated after the upgrade of the wastewater-treatment plants. The most descriptive tool in analyzing the data was the percentage of Ephemeroptera, Plecoptera, and Trichoptera (EPT) taxa present. Using a mixture of indices and other analytical tools, such as EPT, in the analysis of biological data will ensure the most effective investigations of water quality.


Electrically neutral Na+-H+ exchange in endosomes obtained from rabbit renal cortex.
Endocytotic vesicles (i.e., endosomes) were prepared from rabbit renal cortex following the intravenous injection of horseradish peroxidase. The endosomal population was derived from a 100,000-g pellet and was found at equilibrium in the lightest area of a sucrose density gradient. This population was separate from other organelles as determined by enzyme markers and had a 2.5-fold enrichment of horseradish peroxidase specific activity compared with the homogenate specific activity corrected for soluble horseradish peroxidase activity. The endosomes contain an oligomycin-insensitive, electrogenic H+-translocating ATPase. They also contain an electroneutral Na+-H+ exchanger. This exchanger is not inhibited by amiloride, and lithium is not a substrate for the exchanger. Lithium does inhibit the Na+-H+ exchanger when added prior to the addition of sodium. The Michaelis constant for sodium of the endosomal Na+-H+ exchanger was found to be 10.0 mM. These data indicate that a population of endosomes from rabbit renal cortex contain an electrogenic H+-ATPase and an electroneutral Na+-H+ exchanger and that the exchanger is distinct from the brush-border membrane Na+-H+ antiporter.


Historical context and the roots of Jenner's discovery.
May 2016 marks the 220th anniversary of Edward Jenner's first experimental vaccination using cowpox to protect against smallpox. Jenner's discovery, and its rapid adoption around the world, launched a medical revolution that continues to shape how we approach disease prevention. The historical roots of vaccination are found in the popularization of smallpox inoculation during the 18th century, part of an Enlightenment culture that fostered scientific inquiry and the global circulation of knowledge. Jenner was part of that culture and his study of cowpox stemmed from his varied interests as a natural historian, his contacts with leading savants in London, and his medical practice in a flourishing dairy area of England. The amazingly quick spread of vaccination resulted from organized hospital trials in major cities, the severe smallpox epidemic at the turn of the century, disease environment, and policies of European colonial powers.


Two-color RESOLFT nanoscopy with green and red fluorescent photochromic proteins.
Up to now, all demonstrations of reversible saturable optical fluorescence transitions (RESOLFT) superresolution microscopy of living cells have relied on the use of reversibly switchable fluorescent proteins (RSFP) emitting in the green spectral range. Here we show RESOLFT imaging with rsCherryRev1.4, a new red-emitting RSFP enabling a spatial resolution up to four times higher than the diffraction barrier. By co-expressing green and red RSFPs in living cells we demonstrate two-color RESOLFT imaging both for single ("donut") beam scanning and for parallelized versions of RESOLFT nanoscopy where an array of >23,000 "donut-like" minima are scanned simultaneously.


Characterizing Artificial Intelligence Applications in Cancer Research: A Latent Dirichlet Allocation Analysis.
Artificial intelligence (AI)-based therapeutics, devices, and systems are vital innovations in cancer control; particularly, they allow for diagnosis, screening, precise estimation of survival, informing therapy selection, and scaling up treatment services in a timely manner. The aim of this study was to analyze the global trends, patterns, and development of interdisciplinary landscapes in AI and cancer research. An exploratory factor analysis was conducted to identify research domains emerging from abstract contents. The Jaccard similarity index was utilized to identify the most frequently co-occurring terms. Latent Dirichlet Allocation was used for classifying papers into corresponding topics. From 1991 to 2018, the number of studies examining the application of AI in cancer care has grown to 3555 papers covering therapeutics, capacities, and factors associated with outcomes. Topics with the highest volume of publications include (1) machine learning, (2) comparative effectiveness evaluation of AI-assisted medical therapies, and (3) AI-based prediction. Noticeably, this classification has revealed topics examining the incremental effectiveness of AI applications, the quality of life, and functioning of patients receiving these innovations. The growing research productivity and expansion of multidisciplinary approaches are largely driven by machine learning, artificial neural networks, and AI in various clinical practices. The research landscapes show that the development of AI in cancer care is focused on not only improving prediction in cancer screening and AI-assisted therapeutics but also on improving other corresponding areas such as precision and personalized medicine and patient-reported outcomes.


Alterations in lipid metabolism due to a protein-restricted diet in rats during gestation and/or lactation.
Perinatal malnutrition affects not only fetal and neonatal growth, but also the health of offspring in adulthood, as suggested by the concept of metabolic programming. The impact of maternal protein malnutrition on the metabolism of offspring is demonstrated with the current data. One group of pregnant/lactating female rats was fed with an isocaloric diet having normal protein content. Three other groups were provided 50% of this protein level during pregnancy and/or lactation. The growth and metabolic state of the offspring was monitored. The expression of genes regulating lipid metabolism was determined, including SREBP-1c and SIRT-1 in liver and retroperitoneal adipose tissue. Blood cholesterol and triglycerides were higher in the adult offspring (at 110 days of age) fed a protein-restricted diet than in the adult offspring fed a normal diet. Protein restriction likely leads to inadequate detection of glucose levels, as suggested by the reduced expression of the gene for GCK, the sensor of glucose in the liver. The effects of a protein-restricted diet were highly dependent on the window in which this limitation occurred. There was a more adverse effect when the rats underwent protein restriction during gestation than lactation, leading to lower body weight and alterations in lipid metabolism in adult offspring.


Hematological and lipid profile evaluation of a hexane fraction of Costus afer leaves in arthritic rats.
Costus afer Ker Gawl. (Costaceae) is an ethnomedical plant used as therapy against inflammatory disorders. The objective of this study was to evaluate the hematological and lipid profile analysis of hexane fraction of C. afer leaves (CAHLF) in arthritic rats. Male albino rats were randomly distributed into seven groups of six rats each. Rats were induced with arthritis using formaldehyde and Complete Freund's Adjuvant (CFA) for 7 and 21 d, respectively. The animals were administered orally with 50, 100, and 250 mg/kg CAHLF, 10 mg/kg diclofenac and prednisolone, 0.9% NaCl (control), and 0.9% NaCl (normal). At the end of treatment periods, blood samples were withdrawn and subjected to hematological and biochemical analysis using auto-analyzer and spectrophotometric methods. Hematological analysis revealed that in formaldehyde- and CFA-induced arthritic rat models, 250 mg/kg CAHLF-treated groups had significantly reduced (p < 0.05) hematocrit counts (HC) (30.98 ± 1.59% and 33.55 ± 1.10%), white blood cell counts (WBC) (5.50 ± 0.35 and 4.15 ± 0.82 × 10(9)/L), and platelet counts (PC) (401.50 ± 48.94 and 246.33 ± 5.54 × 10(9)/L) compared with control HC (46.90 ± 1.92 and 41.88 ± 2.19%), WBC (11.09 ± 0.26 and 7.37 ± 0.34 × 10(9)/L), and PC (783.67 ± 59.51 and 593.83 ± 36.3 × 10(9)/L). Furthermore, blood analysis showed that CAHLF-treated groups had reduced total cholesterol, low-density lipoprotein cholesterol, and triglycerides while they had an elevated high-density lipoprotein compared with the control group. Findings from this study indicated that CAHLF could possess immunomodulatory and hypolipidemic properties in arthritic rats. CAHLF could be considered as a source of biopharmaceutical agents in anti-arthritis drug discovery process.


Use of In-Office Preparations by Dermatologists for the Diagnosis of Cutaneous Fungal Infections
Cutaneous fungal infections account for millions of office visits per year, yet their varied presentations often lead to misdiagnosis. If dermatology clinics are Clinical Laboratory Improvement Amendment (CLIA) certified, direct microscopy with potassium hydroxide or other stains can be used to inexpensively and rapidly diagnose fungal infections. In this survey, we examined dermatologists' perceptions of fungal preparations and CLIA certification to identify barriers that prevent the use of these bedside diagnostics. The response rate was 13% (n=308, based on the number of emails opened). When a cutaneous fungal infection is suspected, 20.94% rarely/never and 19.86% sometimes perform fungal preparations, often because they think clinical diagnosis is adequate or that preparations take too long. 21.32% reported not having CLIA certification, most frequently because the process requires too much work, or they do not know how to apply. Of providers with CLIA certification, over 25% thought it was difficult to obtain. Our results demonstrate that numerous barriers prevent the common use of fungal preparations, including the perception that clinical diagnosis is sufficient and the lack of required CLIA certification. These barriers emphasize the need for additional education about cutaneous fungal infections and use of bedside diagnostics. Additionally, policy-based interventions are necessary to ease the process of CLIA certification.


Phonon-Fluid Coupling Enhanced Water Desalination in Flexible Two-Dimensional Porous Membranes.
Water purification using 2D nanoporous membranes has been drawing significant attention for over a decade because of fast water transport in ultrathin membranes. We perform a comprehensive study using molecular dynamics (MD) simulations on water desalination using 2D flexible membranes where the coupling between the fluid dynamics and mechanics of the membrane plays an important role. We observe that a considerable deformation and fluctuation in the 2D membrane results in an enhanced water permeability (up to 122%) along with a slight decrease in the salt rejection rate (less than 11%). Simulations on harmonically vibrating membranes indicate that the vibrational match at the membrane-water interface can significantly increase the permeance. We conduct mechanical stability tests and discuss the maximum endurable pressure of 2D porous membranes for water desalination. These findings will contribute to advances in applications using ultrathin membranes, such as energy harvesting and molecular separation.


Homing in pigeons: the role of the hippocampal formation in the representation of landmarks used for navigation.
When given repeated training from a location, homing pigeons acquire the ability to use familiar landmarks to navigate home. Both control and hippocampal-lesioned pigeons succeed in learning to use familiar landmarks for homing. However, the landmark representations that guide navigation are strikingly different. Control and hippocampal-lesioned pigeons were initially given repeated training flights from two locations. On subsequent test days from the two training locations, all pigeons were rendered anosmic to eliminate use of their navigational map and were phase- or clock-shifted to examine the extent to which their learned landmark representations were dependent on the use of the sun as a compass. We show that control pigeons acquire a landmark representation that allows them to directly use landmarks without reference to the sun to guide their flight home, called "pilotage". Hippocampal-lesioned birds only learn to use familiar landmarks at the training location to recall the compass direction home, based on the sun, flown during training, called "site-specific compass orientation." The results demonstrate that for navigation of 20 km or more in a natural field setting, the hippocampal formation is necessary if homing pigeons are to learn a spatial representation based on numerous independent landmark elements that can be used to directly guide their return home.


Trends in continuing education in the United States.
Developments in continuing education are closely related to professional and societal trends, developments in medicine and other health professions, scientific advancement, the state of the economy, and other factors. It is safe to predict that in the future, increasing recognition will be given to continuing education as a necessity for professional practice.


Gastric Adenocarcinoma in a 16-Year-Old Female.
Primary gastric adenocarcinoma commonly occurs in the elderly in the sixth to seventh decade of life but is exceedingly rare in children and adolescents, accounting for only 0.05% of pediatric gastrointestinal malignancies. Because of the nonspecific clinical presentation, gastric adenocarcinomas in children and adolescents are often metastatic when they are discovered. We describe a case of gastric adenocarcinoma in a 16-year-old female who was diagnosed early and successfully treated with surgery and chemoradiation by volumetric modulated arc technique. The possibility of gastric adenocarcinoma should be considered in children and adolescents with persistent nonspecific symptoms of vomiting and upper abdominal pain so that the diagnosis can be made at early stages and radical treatment can be offered.


Functional roles of benzothiazole motif in antiepileptic drug research.
Benzothiazoles are promising candidates for the design of novel antiepileptic drugs. The endocyclic sulphur and nitrogen functions present in this heterocyclic nucleus have been shown to be critical for the anticonvulsant activity. The present review outlines the rational design and anticonvulsant potential of promising benzothiazole lead molecules. Particular focus has been placed on the structure activity relationship of different benzothiazole derivatives giving selected examples of molecules with significant activity being that these molecules may serve as prototypes for the development of more active antiepileptic drugs.


Capillary supply in relation to myosin heavy chain fibre composition of human intrinsic tongue muscles.
The capillary supply and myosin heavy chain (MyHC) composition of three different intrinsic tongue muscles was analysed in the anterior and posterior regions of the human tongue with biochemical and immunohistochemical techniques. Mean capillary density for the whole tongue was 796 ± 82 cap/mm², without regional differences. The overall number of capillaries around each fibre (CAF) was higher in the posterior than in the anterior region (2.5 vs. 2.1, p = 0.009). However, correcting for regional differences in fibre size, CAF per fibre area was higher in the anterior region (4.3 vs. 3.0, p < 0.001). Muscle fibres containing fast MyHCs predominated in the anterior region (78.7%), consisting of MyHCIIa (58.5%), MyHCIIx (1.0%), MyHCIIa+MyHCIIx (11.3%) and MyHCI+MyHCIIa (7.9%). Fibres containing slow MyHC predominated in the posterior region (65.2%), consisting of MyHCI (45.5%) and MyHCI+MyHCIIa (19.7%). A minor fibre population (<2%) contained unusual MyHC isoforms, namely MyHC foetal, MyHC slow-tonic, MyHC α-cardiac or MyHC embryonic. The microvascularization of the human tongue was twice as high as in human limb muscles. Regional similarities in capillary supply, but differences in fibre phenotype composition, suggest that human tongue muscle fibres are fatigue resistant independently of MyHC content. High frequency of hybrid fibres, that is fibres co-expressing two or more MyHC isoforms, indicates a wider spectrum of fibre contractile properties than in limb muscles. In conclusion, human intrinsic tongue muscles showed internal specialization in distribution of MyHC isoforms and capillary supply, but not in the expression of unusual MyHCs.


Magnetic resonance imaging and ultrasound evaluation of "healthy" joints in young subjects with severe haemophilia A.
Magnetic resonance imaging (MRI) and ultrasonography (US) are increasingly used in haemophilia A (HA) to detect early joint changes. A total of 40 clinically asymptomatic joints, never involved by bleeding events ["healthy joints" (HJ)], were evaluated by MRI and, in parallel, by US in 20 young subjects with severe HA (22.45 ± 2.72 years old; no history of arthritides, of viral infections or of inhibitors against factor VIII). The same joints were evaluated in 20 matched non-haemophilic (no-HA) subjects (mean age 23.90 ± 2.31 years, P = 0.078 vs. HA subjects). US images were obtained with specific probe positions according to validated procedures. A validated US score and progressive (P-MRI) and additive (A-MRI) MRI scores were employed for data collection and analysis. The US score was higher in HA than in no-HA subjects (3.40 ± 1.72 vs. 0.80 ± 1.10, P < 0.001). Taking into account only moderate/severe alterations, joint effusion was found in 55% of HA and in 5% of no-HA joints (P < 0.001); synovial hypertrophy was found in 20% of HA and in none of the no-HA joints; cartilage erosion was found in 30% of HA and in none of no-HA joints. MRI examinations confirmed these findings and the US score correlated with the A-MRI (r = 0.732, P < 0.001) and with the P-MRI (r = 0.598, P < 0.001) scores. MRI and US data significantly correlated as to effusion (r = 0.819, P = 0.002), synovial hypertrophy (r = 0.633, P = 0.036) and cartilage erosion (r = 0.734, P = 0.010). Despite inherent limitations, joint US examination identified subclinical abnormalities of HJ in young subjects with severe HA.


Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of NIV (13 participants). We contacted the trial authors, who were not able to provide the missing data. The conclusions of the review were therefore based on a single study of 41 participants comparing NIV with standard care. Lack of (or uncertain) blinding represented a risk of bias for participant- and clinician-assessed outcomes such as quality of life, but it was otherwise a well-conducted study with a low risk of bias.The study provided moderate-quality evidence that overall median survival was significantly different between the group treated with NIV and the standard care group. The median survival in the NIV group was 48 days longer (219 days compared to 171 days for the standard care group (estimated 95% confidence interval 12 to 91 days, P = 0.0062)). This survival benefit was accompanied by an enhanced quality of life. On subgroup analysis, in the subgroup with normal to moderately impaired bulbar function (20 participants), median survival was 205 days longer (216 days in the NIV group versus 11 days in the standard care group, P = 0.0059), and quality of life measures were better than with standard care (low-quality evidence). In the participants with poor bulbar function (21 participants), NIV did not prolong survival or improve quality of life, although there was significant improvement in the mean symptoms domain of the Sleep Apnea Quality of Life Index by some measures. Neither trial reported clinical data on intervention-related adverse effects. Moderate-quality evidence from a single RCT of NIV in 41 participants suggests that it significantly prolongs survival, and low-quality evidence indicates that it improves or maintains quality of life in people with ALS. Survival and quality of life were significantly improved in the subgroup of people with better bulbar function, but not in those with severe bulbar impairment. Adverse effects related to NIV should be systematically reported, as at present there is little information on this subject. More RCT evidence to support the use of NIV in ALS will be difficult to generate, as not offering NIV to the control group is no longer ethically justifiable. Future studies should examine the benefits of early intervention with NIV and establish the most appropriate timing for initiating NIV in order to obtain its maximum benefit. The effect of adding cough augmentation techniques to NIV also needs to be investigated in an RCT. Future studies should examine the health economics of NIV. Access to NIV remains restricted in many parts of the world, including Europe and North America. We need to understand the factors, personal and socioeconomic, that determine access to NIV.


First-line combination chemotherapy for advanced non-small cell lung cancer: the Eastern Cooperative Oncology Group and Southwest Oncology Group experience.
Over the past 15 to 20 years we have seen small but significant improvements in the treatment of patients with advanced or metastatic non-small cell lung cancer. By the late 1980s the median survival had increased from approximately 4 months in the untreated patient to approximately 7 to 8 months with traditional cisplatin-based chemotherapy combinations. In the early 1990s several new agents, including the taxanes paclitaxel and docetaxel, gemcitabine, irinotecan, and vinorelbine, demonstrated activity in metastatic non-small cell lung cancer. The combination of cisplatin with some of these newer agents such as vinorelbine or paclitaxel in recent phase II trials resulted in median survivals of approximately 9 to 10 months. Some of these results have been confirmed in large multicenter phase III trials conducted by two US Cooperative groups; the Southwest Oncology Group and the Eastern Cooperative Oncology Group. Their contribution to progress in the treatment of non-small cell lung cancer is discussed.


Blockade of the renin-angiotensin-aldosterone system prevents growth hormone-induced fluid retention in humans.
To test if the renin-angiotensin-aldosterone system (RAAS) is involved in growth hormone (GH)-associated fluid retention, we examined the effect of GH administration in the presence or absence of RAAS blockade at different levels on body fluid homeostasis. Eight subjects were examined in a controlled, randomized double-blinded trial. During four 6-day periods they received subcutaneous GH (6 IU-m-2) or placebo injections and tablets as follows: 1) placebo and placebo, 2) GH and placebo, 3) GH and captopril, and 4) GH and spironolactone. GH increased extracellular volume (liters; placebo 18.87 +/- 0.85; GH + placebo 20.43 +/- 1.01) but this effect was abolished by captopril (GH + captopril 18.82 +/- 0.67) and spironolactone (GH + spironolactone 18.99 +/- 0.85). Correspondingly, the GH-induced reduction in bioimpedance was blocked by captopril and spironolactone. Plasma renin and angiotensin II concentrations increased during all three GH treatment regimens, whereas plasma aldosterone was increased only after GH plus spironolactone. The data demonstrate that GH activates the RAAS and that blockade of the RAAS by two separate mechanisms prevents fluid retention normally encountered after GH exposure. These observations suggest that the RAAS plays a key role in GH-induced regulation of fluid homeostasis.


Developing a Conversational Agent's Capability to Identify Structural Wrongness in Arguments Based on Toulmin's Model of Arguments.
This article discusses the usefulness of Toulmin's model of arguments as structuring an assessment of different types of wrongness in an argument. We discuss the usability of the model within a conversational agent that aims to support users to develop a good argument. Within the article, we present a study and the development of classifiers that identify the existence of structural components in a good argument, namely a claim, a warrant (underlying understanding), and evidence. Based on a dataset (three sub-datasets with 100, 1,026, 211 responses in each) in which users argue about the intelligence or non-intelligence of entities, we have developed classifiers for these components: The existence and direction (positive/negative) of claims can be detected a weighted average F1 score over all classes (positive/negative/unknown) of 0.91. The existence of a warrant (with warrant/without warrant) can be detected with a weighted F1 score over all classes of 0.88. The existence of evidence (with evidence/without evidence) can be detected with a weighted average F1 score of 0.80. We argue that these scores are high enough to be of use within a conditional dialogue structure based on Bloom's taxonomy of learning; and show by argument an example conditional dialogue structure that allows us to conduct coherent learning conversations. While in our described experiments, we show how Toulmin's model of arguments can be used to identify structural problems with argumentation, we also discuss how Toulmin's model of arguments could be used in conjunction with content-wise assessment of the correctness especially of the evidence component to identify more complex types of wrongness in arguments, where argument components are not well aligned. Owing to having progress in argument mining and conversational agents, the next challenges could be the developing agents that support learning argumentation. These agents could identify more complex type of wrongness in arguments that result from wrong connections between argumentation components.


Combining the Pulmonary Rehabilitation Decisional Score with the Bode Index and Clinical Opinion in Assigning Priority for Pulmonary Rehabilitation.
Combining objective tools with clinical decision (CD) may help clinicians identify the priority for pulmonary rehabilitation (PR) in patients with COPD. We aimed to assess the specificity, sensitivity and efficiency of a new tool, the Pulmonary Rehabilitation Decisional Score (PRDS), and its correlation with the BODE index (BI) and CD in assigning PR priority. We retrospectively compared the three methods (CD vs. PRDS vs. BI) in 124 patients. We assigned low priority (LP), high priority (HP) and very high priority (VHP) to PR based on a priori scores of PRDS (LP = 0-10; HP = 11-17; VHP ≥18) and BI (LP = 0-2; HP = 3-5; VHP ≥6) and compared these with CD. PR priority assigned by the different methods was similar among groups, but did not often refer to the same subjects. PRDS and BI showed very high concordance with CD in defining VHP (97.8% and 95.6% for PRDS and BI, respectively), but were less concordant with CD in assigning LP and HP. Both PRDS and BI differently evaluated 38/124 cases compared to CD (PRDS underprescribed 18 and overprescribed 20; BI underprescribed 19 and overprescribed 19). However, a direct comparison between PRDS and BI showed that the discordance decreased to 8 underprescriptions and 10 overprescriptions (efficiency ∼85%). An objective instrument such as the PRDS can enhance CD with additional information on new aspects such as disability and fragility. PRDS and BI are nonetheless equally efficient at detecting discrepancies versus CD alone, especially when the priority for PR is defined as low or very high.


[Mechanism of disorders in neurotrophic regulation of the level of striated skeletal muscle polarization by botulinum toxin].
Muscle reinnervation was studied in experiments on rats given intramuscular injection of sublethal doses of botulinum toxin. It has been established that botulinum toxin not influencing the formation of functioning myoneural synapses leads to long-term persistence of depolarization of reinnervated muscle cells without changes in passive biophysical properties of their sarcoplasmatic membranes.


Behavioral flexibility impairment with negative feedback in refractory temporal lobe epileptic patients with unilateral amygdala and hippocampal resection.
Patients with amygdala dysfunction generally have behavioral impairment. Temporal lobe surgery might be a model of study of unilateral amygdala resection. The objective of this study was to evaluate behavioral flexibility in epileptic patients who undergo amygdala resection for epilepsy surgery and evaluate its relationship with their neuropsychiatric symptoms. Ten epileptic patients who underwent amygdala and hippocampal resection (6 left and 4 right) matched by age and educational level with 10 healthy controls were tested with an extensive neuropsychological and neuropsychiatric battery. Psychiatric symptomatology was measured with the positive and negative syndrome scale (PANSS) and the Beck depression inventory. To assess behavioral flexibility the emotion-related visual reversal-learning task (O'Doherty et al., 2001) and the gambling task (Bechara et al., 1994) were used. Patient's mean scores were: Beck: 8 +/- 1.5; PANSS positive: 10 +/- 1.3, and negative: 14.4 +/- 2.2; intellectual quotient (IQ): 101.4 +/- 6.3; category number in Wisconsin card sorting test: 4.6 +/- 2.4. The emotion-related visual reversal-learning task showed significance differences in the number of reversion: healthy controls: 9.3; epileptic patients: 4.23 (p < 0.001); in the number of trials to the first reversion: healthy controls: 5; epileptic patients: 23.42 (p < 0.05). There was no correlation between reversion and depression, PANSS and IQ. Patients with epilepsy who undergo unilateral hippocampal and amygdala resection appear to have alterations in the reversion capacity with an emotional component that would explain the lack of behavior flexibility that they sometimes have and that are not related with either the isolated presence of executive alterations or low intellectual quotient.


IL-36α induces maturation of Th1-inducing human MDDC and synergises with IFN-γ to induce high surface expression of CD14 and CD11c.
We show that IL-36α induced maturation of human MDDCs and stimulated differentiation of IFN-γ producing (Type 1) CD3+ lymphocytes but was not as effective as IL-36β in doing so. For the first time, we also show that IL-36α induced expression of CD14 by MDDCs and this was highly potentiated by co-cultured with IFN-γ. In contrast, lipopolysaccharide (LPS) did not increase CD14 expression by MDDCs, suggesting that if MDDCs represent a physiologically relevant population in vivo, they need to be stimulated by relevant inflammatory cytokines prior to CD14 expression and detection of LPS, expressed by Gram negative bacteria. IFN-γ synergised with IL-36α to restore the high levels of CD11c expression by MDDCs, which was reduced by culture with these cytokines in isolation. IL-36α/IFN-γ synergy also correlated with increased binding of the opsonic complement protein (iC3b) to MDDCs. However although IL-36α increased the phagocytic capacity of MDDCs for Salmonella Typhimurium 4/74 this was not synergistically increased by IFN-γ (P>0.05). In conclusion we report the hitherto unknown effects of IL-36α on the innate cell function of human MDDCs.