bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatic resection versus transarterial chemoembolization in infiltrative hepatocellular carcinoma: A multicenter study
Authors: Wang Yuanqi , Shen Jingxian , Feng Shiting , Liang Ruiming , Lai Jiaming , Li Dongming , Peng Baogang , Wang Zaiguo , Huang Cheng , Kuang Ming
Published: April 2020

Background and Aim

Prognosis of infiltrative hepatocellular carcinoma (iHCC) is poor, and the treatments selection based on efficacy is unclear. We performed this multicenter study to compare the efficacy of hepatic resection and transarterial chemoembolization (TACE) in treating patients with iHCC.

Methods

We retrospectively analyzed the overall survivals (OS) in 319 patients with iHCC who were initially treated by hepatic resection (n = 133) or TACE (n = 186) at four tertiary centers. Fifty‐eight patients in the TACE group were assessed as resectable and compared with the hepatic resection group in subgroup analysis. A propensity score matched (PSM) analysis was performed to reduce selection bias. Cox regression was performed to identify significant factors associated with OS.

Results

The median OS time was significantly longer in the hepatic resection group than that in the TACE group, before and after PSM (before PSM, 17.5 vs 7.3 months, P < 0.0001; after PSM, 14.0 vs 7.3 months, P < 0.0001). The multivariable analysis indicated TACE as a risk factor of OS (hazard ratio = 2.233, 95% confidence interval = 1.492 to 3.341, P < 0.0001), as well as portal venous tumor thrombosis grades 3–4 and alpha fetal protein (AFP) > 400 ng/mL. In the subgroup analysis, the better efficacy of hepatic resection over TACE persisted regardless of the grade of portal venous tumor thrombosis and the level of AFP. As for resectable patients, hepatic resection still showed significant survival benefit (before PSM, 17.5 vs 11.2 months, P = 0.0013; after PSM, 14.0 vs 10.9 months, P = 0.0304).

Conclusion

Hepatic resection might be the better choice for patients with iHCC due to its better survival benefit than TACE.
Geriatric Screening, Triage Urgency, and 30‐Day Mortality in Older Emergency Department Patients
Authors: Blomaard Laura C. , Speksnijder Corianne , Lucke Jacinta A. , de Gelder Jelle , Anten Sander , Schuit Stephanie C.E. , Steyerberg Ewout W. , Gussekloo Jacobijn , de Groot Bas , Mooijaart Simon P.
Published: April 2020

BACKGROUND

Urgency triage in the emergency department (ED) is important for early identification of potentially lethal conditions and extensive resource utilization. However, in older patients, urgency triage systems could be improved by taking geriatric vulnerability into account. We investigated the association of geriatric vulnerability screening in addition to triage urgency levels with 30‐day mortality in older ED patients.

DESIGN

Secondary analysis of the observational multicenter Acutely Presenting Older Patient (APOP) study.

SETTING

EDs within four Dutch hospitals.

PARTICIPANTS

Consecutive patients, aged 70 years or older, who were prospectively included.

MEASUREMENTS

Patients were triaged using the Manchester Triage System (MTS). In addition, the APOP screener was used as a geriatric screening tool. The primary outcome was 30‐day mortality. Comparison was made between mortality within the geriatric high‐ and low‐risk screened patients in every urgency triage category. We calculated the difference in explained variance of mortality by adding the geriatric screener (APOP) to triage urgency (MTS) by calculating Nagelkerke R2.

RESULTS

We included 2,608 patients with a median age of 79 (interquartile range = 74‐84) years, of whom 521 (20.0%) patients were categorized as high risk according to geriatric screening. Patients were triaged on urgency as standard (27.2%), urgent (58.5%), and very urgent (14.3%). In total, 132 (5.1%) patients were deceased within a period of 30 days. Within every urgency triage category, 30‐day mortality was threefold higher in geriatric high‐risk compared to low‐risk patients (overall = 11.7% vs 3.4%; P < .001). The explained variance of 30‐day mortality with triage urgency was 1.0% and increased to 6.3% by adding the geriatric screener.

CONCLUSION

Combining triage urgency with geriatric screening has the potential to improve triage, which may help clinicians to deliver early appropriate care to older ED patients. J Am Geriatr Soc 68:1755‐1762, 2020.
High‐P (P = 1.5–1.8 GPa) blueschist from Elba: Implications for underthrusting and exhumation of continental units in the Northern Apennines
Authors: Papeschi Samuele , Musumeci Giovanni , Massonne Hans‐Joachim , Mazzarini Francesco , Ryan Eric James , Viola Giulio
Published: April 2020

The Acquadolce Subunit on the Island of Elba, Italy, records blueschist facies metamorphism related to the Oligocene–early Miocene stages of continental collision in the Northern Apennines. The blueschist facies metamorphism is represented by glaucophane‐ and lawsonite‐bearing metabasite associated with marble and calcschist. These rock types occur as lenses in a schistose complex representing foredeep deposits of early Oligocene age. Detailed petrological analyses on metabasic and metapelitic protoliths, involving mineral and bulk‐rock chemistry coupled with P–T and P–T–X(Fe2O3) pseudosection modelling using PERPLE_X, show that the Acquadolce Subunit recorded nearly isothermal exhumation from peak pressure–temperature conditions of 1.5–1.8 GPa and 320–370°C. During exhumation, peak lawsonite‐ and possibly carpholite‐ or stilpnomelane‐bearing assemblages were overprinted and partially obliterated by epidote‐blueschist and, subsequently, albite‐greenschist facies metamorphic assemblages. This study sheds new light on the tectonic evolution of Adria‐derived metamorphic units in the Northern Apennines, by showing (a) the deep underthrusting of continental crust during continental collision and (b) rapid exhumation along ‘cold’ and nearly isothermal paths, compatible with syn‐orogenic extrusion.
Development of a Gaussian Process – feature selection model to characterise (poly)dimethylsiloxane (Silastic®) membrane permeation
Authors: Sun Yi , Hewitt Mark , Wilkinson Simon C , Davey Neil , Adams Roderick G , Gullick Darren R , Moss Gary P
Published: April 2020

Objectives

The current study aims to determine the effect of physicochemical descriptor selection on models of polydimethylsiloxane permeation.

Methods

A total of 2942 descriptors were calculated for a data set of 77 chemicals. Data were processed to remove redundancy, single values, imbalanced and highly correlated data, yielding 1363 relevant descriptors. For four independent test sets, feature selection methods were applied and modelled via a variety of Machine Learning methods.

Key findings

Two sets of molecular descriptors which can provide improved predictions, compared to existing models, have been identified. Best permeation predictions were found with Gaussian Process methods. The molecular descriptors describe lipophilicity, partial charge and hydrogen bonding as key determinants of PDMS permeation.

Conclusions

This study highlights important considerations in the development of relevant models and in the construction and use of the data sets used in such studies, particularly that highly correlated descriptors should be removed from data sets. Predictive models are improved by the methodology adopted in this study, notably the systematic evaluation of descriptors, rather than simply using any and all available descriptors, often based empirically on in vitro experiments. Such findings also have clear relevance to a number of other fields.
Design of enamides as new selective monoamine oxidase-B inhibitors
Authors: Kavully Fathima Sahla , Oh Jong Min , Dev Sanal , Kaipakasseri Swafvan , Palakkathondi Ashique , Vengamthodi Ajeesh , Abdul Azeez Rinshana Fathima , Tondo Anna Rita , Nicolotti Orazio , Kim Hoon , Mathew Bijo
Published: April 2020

Objectives

To develop of new class of selective and reversible MAO-B inhibitors from enamides.

Methods

Syntheses of the titled derivatives (AD1–AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines.

Key findings

Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC50 values of 0.11 and 0.10 µm, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µm, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC50 values of 4.21 and 5.95 µm, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with Ki values of 0.044 ± 0.0036 and 0.039 ± 0.0047 µm, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B.

Conclusions

These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.
Training healthcare assistants working in adult acute inpatient wards in Psychological First Aid: An implementation and evaluation study
Authors: Kantaris Xenya , Radcliffe Michelle , Acott Kevin , Hughes Peter , Chambers Mary
Published: April 2020

What is known on the subject

Healthcare assistants are untrained and unregistered frontline staff but are expected to be proactive in preventing and responding to ‘untoward’ incidents quickly and efficiently when working within adult acute inpatient psychiatric settings.

Healthcare assistants should be trained to provide enhanced care to service users residing in acute psychiatric settings. To date, a training programme in Psychological First Aid has not been expended in such a setting with nonregistered staff.

What the paper adds to existing knowledge

The study demonstrates that training healthcare assistants in Psychological First Aid is useful in improving their confidence in caring for service users, therapeutic engagement with service users and ward culture in general.

What are the implications for practice

A training programme in Psychological First Aid for healthcare assistants to enhance ward culture can be implemented in different practice environments.

Psychological First Aid is harmonious with nursing values and provides healthcare assistants with a relevant, useful and easily understood toolkit to apply in acute psychiatric settings.

Introduction

Healthcare assistants working within adult acute inpatient psychiatric settings are untrained and unregistered, however, they can contribute to quality service if they receive some training. Psychological First Aid training has never been expended in these settings, so this study intends to fill this gap in the existing evidence with this category of healthcare personnel.

Aim

The aim of this study was to introduce and evaluate first aid training for healthcare assistants.

Method

A pre/post design was adopted to gather data using questionnaires and interviews. The groups of participants included 16 healthcare assistants trained in Psychological First Aid, a sample of service users and four ward managers.

Results

Post‐training, (a) healthcare assistants and service users ranked the therapeutic milieu of the ward more favourably, (b) the self‐efficacy of the healthcare assistants increased, and the number of ‘untoward’ incidents decreased, and (c) health care assistants' confidence in their skills was high. The ward manager interviews post‐training revealed four themes: (a) staff utilization of new skills and renewed enthusiasm, (b) calmer atmosphere on the ward and staff togetherness, (c) confidence and reflection on practice and (d) therapeutic engagement.

Discussion

Training healthcare assistants is useful in improving staff confidence, therapeutic engagement with service users and ward culture in general.

Implications for practice

Techniques and skills learnt are relevant and useful to healthcare assistants and provide an easily understood toolkit that is harmonious with nursing values. If executed correctly, the training can enhance practice and care outcomes and the overall service user experience.
Sexual size dimorphism and sexual selection in primates
Authors: Cassini Marcelo H.
Published: April 2020

In most animals, females are larger than males. Paradoxically, sexual size dimorphism is biased towards males in most mammalian species. An accepted explanation is that sexual dimorphism in mammals evolved by intramale sexual selection. I tested this hypothesis in primates, by relating sexual size dimorphism to seven proxies of sexual selection intensity: operational sex ratio, mating system, intermale competition, group sex ratio, group size, maximum mating percentage (percentage of observed copulations involving the most successful male), and total paternity (a genetic estimate of the percentage of young sired by the most successful male).

I fitted phylogenetic generalised least squares models using sexual size dimorphism as the dependent variable and each of the seven measures of intensity of sexual selection as independent variables. I conducted this comparative analysis with data from 50 extant species of primates, including Homo sapiens, Pan troglodytes, and Gorilla spp.

Sexual dimorphism was positively related to the four measures of female monopolisation (operational sex ratio, mating system, intermale competition, and group sex ratio) and in some cases to group size, but was not associated with maximum mating percentage or total paternity. Additional regression analyses indicated that maximum mating percentage and total paternity were negatively associated with group size.

These results are predicted by reproductive skew theory: in large groups, males can lose control of the sexual behaviour of the other members of the group or can concede reproductive opportunities to others. The results are also consistent with the evolution of sexual size dimorphism before polygyny, due to the effects of natural, rather than sexual, selection. In birds, the study of molecular paternity showed that variance in male reproductive success is much higher than expected by behaviour. In mammals, recent studies have begun to show the opposite trend, i.e. that intensity of sexual selection is lower than expected by polygyny.

Results of this comparative analysis of sexual size dimorphism and sexual selection intensity in primates suggest that the use of intramale sexual selection theory to explain the evolution of polygyny and sexual dimorphism in mammals should be reviewed, and that natural selection should be considered alongside sexual selection as an evolutionary driver of sexual size dimorphism and polygyny in mammals.
Differential brain region‐specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey‐white matter variation
Authors: Pejhan S. , Siu V. M. , Ang L. C. , Del Bigio M. R. , Rastegar M.
Published: April 2020

Introduction and objectives

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic‐pattern immunolabelling, which has been interpreted as a reflection of activation‐state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region‐specific detection in relation to RTT pathophysiology.

Methods

We investigated MeCP2 and BDNF stabilities in non‐RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls.

Results

In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls.

Conclusions

Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.
Do E‐Waste Laws Create Behavioral Spillovers? Quasi‐Experimental Evidence from California
Authors: Dhanorkar Suvrat , Muthulingam Suresh
Published: April 2020

Many governing bodies have launched efforts to shape the operations of manufacturers, administration of civic entities, and behavior of individuals to limit waste generation. Typically, such efforts commence with the enactment of targeted legislations that create operational changes (e.g., recycling fees, collection centers) to the waste collection and disposal processes. For example, over 25 states in the United States have enacted legislations that aim to properly dispose used electronic and electrical goods (i.e., e‐waste) and divert such waste away from landfills. We argue that such legislations can have an impact that extends beyond just reducing e‐waste. This is because such laws may not only motivate individuals to restrict e‐waste but also induce broader behavioral spillovers that can prompt individuals to reduce waste in general. To explore this idea, we exploit a quasi‐experimental setup that arises from California's enactment of the Electronic Waste Recycling Act (EWRA). Specifically, a difference‐in‐differences analysis reveals that the introduction and implementation of the EWRA resulted in at least 4.93% reduction in municipal solid waste (MSW). A plausibility analysis illustrates that these MSW reductions are much larger than what can be attributed purely to the decline of e‐waste. Furthermore, we show that the effect of e‐waste laws is stronger when consumers have increased market access through (i) online connectivity and (ii) offline proximity. Our study informs policy makers on the effects of e‐waste legislation and the critical role of market access in enhancing the impact of such legislation.
Sports participation and sports injuries in Dutch boys with haemophilia
Authors: Versloot Olav , Timmer Merel A. , de Kleijn Piet , Schuuring Marleen , van Koppenhagen Casper F. , van der Net Janjaap , Fischer Kathelijn
Published: April 2020

Introduction

Sports participation in children with hemophilia is generally considered to be associated with increased injury risk, which is generally considered highest in severe hemophilia.

Aim

To assess sports participation according to age and severity in children with hemophilia and its association with sports injuries.

Methods

In a retrospective single‐center study, sports participation, injuries, and bleeding data from three consecutive annual clinic visits were collected for young patients with hemophilia (PWH, aged 6‐18). Sports in categories 2.5 and 3 of 3 according to the National Hemophilia Foundation classification were considered high‐risk. Groups were compared using chi‐square testing.

Results

105 PWH (median age: 13(IQR 10‐14); 53% severe; bleeding rate: 1/y) were identified; three were unable to perform sports and were excluded. The majority of PWH (77%) played sports weekly, of which 80% high‐risk sports. Sports participation (median 3.0x/wk), and the proportion of injured PWH was similar in severe (42%) and non‐severe (33%) PWH. Sports injuries were rare (65% no injuries in 3 years, median 0/y (IQR 0‐1)). Annually, PWH did not report more injuries (15%) than age‐matched boys (28%). Sports injuries were not associated with frequency and type of sports.

Discussion

This retrospective study showed high sports participation (including high‐risk sports) and low injury rates. Sports participation was similar across severities and injury rates were not higher than among the general population. Injuries were not associated with frequency or type of sports. A prospective study with objective assessment of sports participation and injuries is warranted to confirm these findings and avoid recall bias.
AtMYB92 enhances fatty acid synthesis and suberin deposition in leaves of Nicotiana benthamiana
Authors: To Alexandra , Joubès Jérôme , Thueux Jean , Kazaz Sami , Lepiniec Loïc , Baud Sébastien
Published: April 2020

Acyl lipids are important constituents of the plant cell. Depending on the cell type, requirements in acyl lipids vary greatly, implying a tight regulation of fatty acid and lipid metabolism. The discovery of the WRINKLED1 (WRI1) transcription factors, members of the AP2‐EREBP (APETALA2‐ethylene‐responsive element binding protein) family, has emphasized the importance of transcriptional regulation for adapting the rate of acyl chain production to cell requirements. Here, we describe the identification of another activator of the fatty acid biosynthetic pathway, the Arabidopsis MYB92 transcription factor. This MYB and all the members of the subgroups S10 and S24 of MYB transcription factors can directly activate the promoter of BCCP2 that encodes a component of the fatty acid biosynthetic pathway. Two adjacent MYB cis‐regulatory elements are essential for the binding and activation of the BCCP2 promoter by MYB92. Overexpression of MYB92 or WRI1 in Nicotiana benthamiana induces the expression of fatty acid biosynthetic genes but results in the accumulation of different types of acyl lipids. In the presence of WRI1, triacylglycerol biosynthetic enzymes coded by constitutively expressed genes efficiently channel the excess fatty acids toward reserve lipid accumulation. By contrast, MYB92 activates both fatty acid and suberin biosynthetic genes; hence, the remarkable increase in suberin monomers measured in leaves expressing MYB92. These results provide additional insight into the molecular mechanisms that control the biosynthesis of an important cell wall‐associated acylglycerol polymer playing critical roles in plants.
High‐density genetic variation maps reveal the correlation between asymmetric interspecific introgressions and improvement of agronomic traits in Upland and Pima cotton varieties developed in Xinjiang, China
Authors: Nie Xinhui , Wen Tianwang , Shao Panxia , Tang Binghui , Nuriman‐guli Aini , Yu Yu , Du Xiongming , You Chunyuan , Lin Zhongxu
Published: April 2020

The two new world tetraploid cottons, Gossypium hirsutum and Gossypium barbadense, are cultivated worldwide and are characterised by a high yield and superior fibre quality, respectively. Historical genetic introgression has been reported between them; however, the existence of introgression and its genetic effects on agronomic traits remain unclear with regard to independent breeding of G. hirsutum (Upland cotton) and G. barbadense (Pima cotton) elite cultivars. We collected 159 G. hirsutum and 70 G. barbadense cultivars developed in Xinjiang, China, along with 30 semi‐wild accessions of G. hirsutum, to perform interspecific introgression tests, intraspecific selection analyses and genome‐wide association studies (GWAS) with fibre quality and yield component traits in multiple environments. In total, we identified seven interspecific introgression events and 52 selective sweep loci in G. hirsutum, as well as 17 interspecific introgression events and 19 selective sweep loci in G. barbadense. Correlation tests between agronomic traits and introgressions showed that introgression loci were mutually beneficial for the improvement of fibre quality and yield traits in both species. In addition, the phenotypic effects of four interspecific introgression events could be detected by intraspecific GWAS, with Gb_INT13 significantly improving fibre yield in G. barbadense. The present study describes the landscape of genetic introgression and selection between the two species, and highlights the genetic effects of introgression among populations, which can be used for future improvement of fibre yield and quality in G. barbadense and G. hirsutum, respectively.
Is sporadic Creutzfeldt‐Jakob disease transfusion‐transmissible?
Authors: Saá Paula
Published: April 2020

See article on page 694–697, in this issue
Amyloid Beta42 oligomers up‐regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors
Authors: Marcantoni Andrea , Cerullo Maria Sabina , Buxeda Pol , Tomagra Giulia , Giustetto Maurizio , Chiantia Giuseppe , Carabelli Valentina , Carbone Emilio
Published: April 2020

Key points

NMDA receptors (NMDARs) are key molecules for controlling neuronal plasticity, learning and memory processes. Their function is impaired during Alzheimer's disease (AD) but the exact consequence on synaptic function is not yet fully identified.

An important hallmark of AD onset is represented by the neuronal accumulation of Amyloid Beta42 oligomers (Abeta42) that we have recently shown to be responsible for the increased intracellular Ca2+ concentration through ryanodine receptors (RyRs).

Here we characterized the effects of Abeta42 on NMDA synapses showing specific pre‐ and post‐synaptic functional changes that lead to a potentiation of basal and synchronous NMDA synaptic transmission.

These overall effects can be abolished by decreasing Ca2+ release from RyRs with specific inhibitors that we propose as new pharmacological tools for AD treatment.

We have recently shown that Amyloid Beta42 oligomers (Abeta42) cause calcium dysregulation in hippocampal neurons by stimulating Ca2+ release from ryanodine receptors (RyRs) and inhibiting Ca2+ entry through NMDA receptors (NMDARs). Here, we found that Abeta42 decrease the average NMDA‐activated inward current and that Ca2+ entry through NMDARs is accompanied by Ca2+ release from the stores. The overall amount of intraellular Ca2+ concentration([Ca2+]i) increase during NMDA application is 50% associated with RyR opening and 50% with NMDARs activation. Addition of Abeta42 does not change this proportion. We estimated the number of NMDARs expressed in hippocampal neurons and their unitary current. We found that Abeta42 decrease the number of NMDARs without altering their unitary current. Paradoxically, the oligomer increases the size of electrically evoked eEPSCs induced by NMDARs activation. We found that this is the consequence of the increased release probability (p) of glutamate and the number of release sites (N) of NMDA synapses, while the quantal size (q) is significantly decreased as expected from the decreased number of NMDARs. An increased number of release sites induced by Abeta42 is also supported by the increased size of the ready releasable pool (RRPsyn) and by the enhanced percentage of paired pulse depression (PPD). Interestingly, the RyRs inhibitor dantrolene prevents the increase of PPD induced by Abeta42 oligomers. In conclusion, Abeta42 up‐regulates NMDA synaptic responses with a mechanism involving RyRs that occurs during the early stages of Alzheimer's disease (AD) onset. This suggests that new selective modulators of RyRs may be useful for designing effective therapies to treat AD patients.
Kv3.1 and Kv3.3 subunits differentially contribute to Kv3 channels and action potential repolarization in principal neurons of the auditory brainstem
Authors: Choudhury Nasreen , Linley Deborah , Richardson Amy , Anderson Michelle , Robinson Susan W. , Marra Vincenzo , Ciampani Victoria , Walter Sophie M. , Kopp‐Scheinpflug Conny , Steinert Joern R. , Forsythe Ian D.
Published: April 2020

Key points

Kv3.1 and Kv3.3 subunits are highly expressed in the auditory brainstem, with little or no mRNA for Kv3.2 or Kv3.4. Changes in Kv3 currents and action potential (AP) firing were analysed from wild‐type, Kv3.1 and Kv3.3 knockout (KO) mice.

Both Kv3.1 and Kv3.3 immunostaining was present and western blots confirmed loss of subunit protein in the respective KO.

Medial nucleus of the trapezoid body (MNTB) AP repolarization utilized Kv3.1 and/or Kv3.3; while in the lateral superior olive (LSO) Kv3.3 was essential.

Voltage‐gated calcium currents were unchanged between the genotypes. But APs evoked higher [Ca2+]i in LSO than MNTB neurons; and were highest in the Kv3.3KO, consistent with longer AP durations.

High frequency stimulation increased AP failure rates and AP latency in LSO neurons from the Kv3.3KO, underlining the physiological consequences for binaural integration.

LSO neurons require Kv3.3 for functional Kv3 channels, while MNTB neurons can utilize either Kv3.1 or Kv3.3 subunits.

Kv3 voltage‐gated potassium channels mediate action potential (AP) repolarization. The relative importance of Kv3.1 and Kv3.3 subunits for assembly of functional channels in neurons of the auditory brainstem was examined from the physiological perspective that speed and precision of AP firing are crucial for sound source localization. High levels of Kv3.1 and Kv3.3 mRNA and protein were measured, with no evidence of compensation by Kv3.2 or Kv3.4 in the respective knockout (KO) mouse. Using the KOs, composition of Kv3 channels was constrained to either Kv3.1 or Kv3.3 subunits in principal neurons of the medial nucleus of the trapezoid body (MNTB) and lateral superior olive (LSO); while TEA (1 mm) was employed to block Kv3‐mediated outward potassium currents in voltage‐ and current clamp experiments. MNTB neuron APs (half‐width 0.31 ± 0.08 ms, n = 25) were fast, reliable, and showed no distinction between channels assembled from Kv3.1 or Kv3.3 subunits (in the respective KO). LSO AP half‐widths were also fast, but absolutely required Kv3.3 subunits for fast repolarization (half‐widths: 0.25 ± 0.08 ms, n = 19 wild‐type, 0.60 ± 0.17 ms, n = 21 Kv3.3KO, p = 0.0001). The longer AP duration increased LSO calcium influx and AP failure rates, and increased AP latency and jitter during high frequency repetitive firing. Both Kv3.1 and Kv3.3 subunits contribute to Kv3 channels in the MNTB (and compensate for each other in each KO); in contrast, LSO neurons require Kv3.3 subunits for fast repolarization and to sustain AP firing during high frequency stimulation. In conclusion, Kv3 channels exhibit both redundancy and Kv3.3 dominance between the brainstem nuclei involved in sound localization.
Induction and Regulation of Th1-Inducing Cytokines by Bacterial DNA, Lipopolysaccharide, and Heat-Inactivated Bacteria
Authors: Huang L.-Y. , Krieg A. M. , Eller N. , Scott D. E.
Published: April 2020

Th1 immune responses, characterized by production of gamma interferon (IFN-γ), are associated with protective immunity to viruses and intracellular bacteria. Heat-killedBrucella abortuspromotes secretion of Th1-inducing cytokines such as interleukin-12 (IL-12) and IFN-γ and has been used as a carrier to induce Th1 responses to vaccines. To explore which bacterial constituents could mediate this response and how it is regulated, murine spleen cells were cultured withB. abortusderived DNA, lipopolysaccharide (LPS), or whole killed organisms. Each constituent induced similar, substantial amounts of IL-10. However, onlyB. abortusandB. abortusDNA induced high levels of IFN-γ and IL-12.B. abortusandB. abortusDNA-stimulated IL-12 production was maximal by 6 to 18 h, while IL-10 production steadily accumulated over this time period. These kinetics suggested that IL-10 may eventually downmodulate the Th1-like cytokine response toB. abortusandB. abortusDNA, which was confirmed by using neutralizing antibody. In the absence of IL-10,B. abortusLPS induced strong IFN-γ responses, but IL-12 p70 levels were still undetectable from BALB/c spleen cells. LPS induced IL-12 if the spleen cells were primed with IFN-γ and IL-10 was neutralized, indicating that LPS can stimulate IL-12 production under the most favorable conditions. Responses toEscherichia coliLPS and DNA mirrored the responses toB. abortuscomponents, suggesting that immune effects observed with these constituents may be generalizable to many microbial species. In vivo experiments demonstrated the same hierarchy of responses for IL-12 production. These findings support the likelihood that microbial components, if used as carriers or adjuvants, can differ substantially in their ability to effect a Th1 response.
Selective Recruitment of T-Cell Subsets to the Udder during Staphylococcal and Streptococcal Mastitis: Analysis of Lymphocyte Subsets and Adhesion Molecule Expression
Authors: Soltys Jindrich , Quinn Mark T.
Published: April 2020

During bacterial infection of the bovine mammary gland, large numbers of leukocytes migrate into the udder, resulting in the establishment of a host response against the pathogen. Currently, the specific leukocyte populations mediating this immune response are not well defined. In the studies described here, we analyzed blood and milk from healthy cows and cows with naturally occurring mastitis to determine if distinct αβ and γδ T-lymphocyte subsets were involved in the response of the udder to a mastitis pathogen and if the type of mastitis pathogen influenced the subset composition of these responding leukocytes. Although blood samples from cows with confirmed staphylococcal and streptococcal mastitis were characterized by increased numbers of γδ T cells, the most dramatic changes in leukocyte distributions occurred in milk samples from these cows, with a 75% increase in αβ T-cell levels and a 100% increase in γδ T-cell levels relative to the levels in milk samples from healthy animals. Interestingly, the increase in αβ T-cell numbers observed in milk from cows with staphylococcal mastitis was primarily due to increased numbers of CD4+T cells, while the increase in αβ T-cell numbers observed in cows with streptococcal mastitis was due to a parallel increase in both CD4+and CD8+T-cell numbers. The increased numbers of γδ T cells in milk from cows with staphylococcal and streptococcal mastitis were due to a selective recruitment of a distinct γδ T-cell subset (GD3.1+), while no change in the numbers of GD197+γδ T cells was observed. We also analyzed adhesion protein expression on blood and milk leukocytes and found that, in comparison to the situation for healthy cows, L-selectin was down-regulated and CD18 was up-regulated on leukocytes from cows with mastitis. Thus, shedding of L-selectin and up-regulation of CD18 by neutrophils may provide a sensitive indicator of early inflammatory responses during bovine mastitis. Overall, these studies suggest that distinct αβ and γδ T-cell subsets are involved in the host defense of the udder against mastitis infection and that selective recruitment of these T-cell subsets depends on the infectious agent involved.
A Guide To Operating Systems Literature
Authors: Brumfield Jeffrey A.
Published: April 2020

The purpose of this guide is to introduce students who are beginning research on operating systems to the various sources of literature. This document is divided into six sections: periodicals, conferences, general texts, bibliographies, theses and dissertation, and technical reports.
Subtyping and intersection types revisited
Authors: Pfenning Frank
Published: April 2020

Church's system of simple types has proven to be remarkably robust: call-by-name, call-by-need, and call-by-value languages, with or without effects, and even logical frameworks can be based on the same typing rules. When type systems become more expressive, this unity fractures. An early example is the value restriction for parametric polymorphism which is necessary for ML but not Haskell; a later manifestation is the lack of distributivity of function types over intersections in call-by-value languages with effects.

In this talk we reexamine the logical justification for systems of subtyping and intersection types and then explore the consequences in two different settings: logical frameworks and functional programming.

In logical frameworks functions are pure and their definitions observable, but complications could arise from the presence of dependent types. We show that this is not the case, and that we can obtain soundness and completeness theorems for a certain axiomatization of subtyping. We also sketch a connection to the type-theoretic notion of proof irrelevance.

In functional programming we investigate how the encapsulation of effects in monads interacts with subtyping and intersection types, providing an updated analysis of the value restriction and related phenomena. While at present this study is far from complete, we believe that its origin in purely logical notions will give rise to a uniform theory that can easily be adapted to specific languages and their operational interpretations.
From Writer to Technician to Programmer
Authors: Bernhardt Stephen A.
Published: April 2020

That Agnew and Palmer's paper should be selected as the best paper of SIGDOC 92 suggests how much the field of documentation has changed in the last ten years. Our concerns fare increasingly centered on the technology of text, rather than on paper texts that support the user of technology. Text has become part of the machine itself, and writers are themselves not so much writers as technicians.
Optimizations in a private nursery-based garbage collector
Authors: Anderson Todd A.
Published: April 2020

This paper describes a garbage collector designed around the use of permanent, private, thread-local nurseries and is principally oriented towards functional languages. We try to maximize the cache hit rate by having threads continually reuse their individual private nurseries. These private nurseries operate in such a way that they can be garbage collected independently of other threads, which creates low collection pause times. Objects which survive thread-local collections are moved to a mature generation that can be collected either concurrently or in a stop-the-world fashion. We describe several optimizations (including two dynamic control parameter adaptation schemes) related to garbage collecting the private nurseries and to our concurrent collector, some of which are made possible when the language provides mutability information. We tested our collector against six benchmarks and saw single-threaded performance improvements in the range of 5-74%. We also saw a 10x increase (for 24 processors) in scalability for one parallel benchmark that had previously been memory-bound.
A graph theoretic approach to cache-conscious placement of data for direct mapped caches
Authors: Beg Mirza , van Beek Peter
Published: April 2020

Caches were designed to amortize the cost of memory accesses by moving copies of frequently accessed data closer to the processor. Over the years the increasing gap between processor speed and memory access latency has made the cache a bottleneck for program performance. Enhancing cache performance has been instrumental in speeding up programs. For this reason several hardware and software techniques have been proposed by researchers to optimize the cache for minimizing the number of misses. Among these are compile-time data placement techniques in memory which improve cache performance. For the purpose of this work, we concern ourselves with the problem of laying out data in memory given the sequence of accesses on a finite set of data objects such that cache-misses are minimized. The problem has been shown to be hard to solve optimally even if the sequence of data accesses is known at compile time. In this paper we show that given a direct-mapped cache, its size, and the data access sequence, it is possible to identify the instances where there are no conflict misses. We describe an algorithm that can assign the data to cache for minimal number of misses if there exists a way in which conflict misses can be avoided altogether. We also describe the implementation of a heuristic for assigning data to cache for instances where the size of the cache forces conflict misses. Experiments show that our technique results in a 30% reduction in the number of cache misses compared to the original assignment.
Book review: The leon Book by William Horton and the Discipline of Technical Communication
Authors: Pollak William
Published: April 2020

The Icon Book
by William Horton makes a valuable contribution to what might be called a
discipline
of technical communication by codifying principles for designing icons and making these principles accessible to designers of ordinary talent
. The Icon Book
has many features in common with handbooks that are used in engineering disciplines. Its focus on the needs of the practitioner supports the evolution of technical communication from an art to a normative science
.
Risks to the public in computers and related systems
Authors: Neumann Peter G.
Published: April 2020

The RISKS Forum in
Software Engineering Notes
does not limit itself just to software problems (let alone software engineering) because the risks we discuss don't either. Thus the topic demands a broad perspective.
Object-oriented programming with gradual abstraction
Authors: Nørmark Kurt , Thomsen Lone Leth , Thomsen Bent
Published: April 2020

We describe an experimental object-oriented programming language, ASL2, that supports program development by means of a series of abstraction steps. The language allows immediate object construction, and it is possible to use the constructed objects for concrete problem solving tasks. Classes and class hierarchies can be derived from the objects - via gradual abstraction steps. We introduce two levels of object classification, called weak and strong object classification. Strong object classification relies on conventional classes, whereas weak object classification is looser, and less restrictive. As a central mechanism, weakly classified objects are allowed to borrow methods from each other. ASL2 supports class generalization, as a counterpart to class specialization and inheritance in mainstream object-oriented programming languages. The final abstraction step discussed in this paper is a syntactical abstraction step that derives a source file with a syntactical class form.
Loop-aware optimizations in PyPy's tracing JIT
Authors: Ardö Håkan , Bolz Carl Friedrich , FijaBkowski Maciej
Published: April 2020

One of the nice properties of a tracing just-in-time compiler (JIT) is that many of its optimizations are simple, requiring one forward pass only. This is not true for loop-invariant code motion which is a very important optimization for code with tight kernels. Especially for dynamic languages that typically perform quite a lot of loop invariant type checking, boxed value unwrapping and virtual method lookups. In this paper we explain a scheme pioneered within the context of the LuaJIT project for making basic optimizations loop-aware by using a simple pre-processing step on the trace without changing the optimizations themselves.

We have implemented the scheme in RPython's tracing JIT compiler. PyPy's Python JIT executing simple numerical kernels can become up to two times faster, bringing the performance into the ballpark of static language compilers.
Self-optimizing AST interpreters
Authors: Würthinger Thomas , Wöß Andreas , Stadler Lukas , Duboscq Gilles , Simon Doug , Wimmer Christian
Published: April 2020

An abstract syntax tree (AST) interpreter is a simple and natural way to implement a programming language. However, it is also considered the slowest approach because of the high overhead of virtual method dispatch. Language implementers therefore define bytecodes to speed up interpretation, at the cost of introducing inflexible and hard to maintain bytecode formats. We present a novel approach to implementing AST interpreters in which the AST is modified during interpretation to incorporate type feedback. This tree rewriting is a general and powerful mechanism to optimize many constructs common in dynamic programming languages. Our system is implemented in Java and uses the static typing and primitive data types of Java elegantly to avoid the cost of boxed representations of primitive values in dynamic programming languages.
DeNovoND
Authors: Sung Hyojin , Komuravelli Rakesh , Adve Sarita V.
Published: April 2020

Recent work has shown that disciplined shared-memory programming models that provide deterministic-by-default semantics can simplify both parallel software and hardware. Specifically, the DeNovo hardware system has shown that the software guarantees of such models (e.g., data-race-freedom and explicit side-effects) can enable simpler, higher performance, and more energy-efficient hardware than the current state-of-the-art
for deterministic programs
. Many applications, however, contain non-deterministic parts; e.g., using lock synchronization. For commercial hardware to exploit the benefits of DeNovo, it is therefore necessary to extend DeNovo to support non-deterministic applications.

This paper proposes DeNovoND, a system that supports lock-based, disciplined non-determinism, with the simplicity, performance, and energy benefits of DeNovo. We use a combination of distributed queue-based locks and access signatures to implement simple memory consistency semantics for safe non-determinism, with a coherence protocol that does not require transient states, invalidation traffic, or directories, and does not incur false sharing. The resulting system is simpler, shows comparable or better execution time, and has 33% less network traffic on average (translating directly into energy savings) relative to a state-of-the-art invalidation-based protocol for 8 applications designed for lock synchronization.
InkTag
Authors: Hofmann Owen S. , Kim Sangman , Dunn Alan M. , Lee Michael Z. , Witchel Emmett
Published: April 2020

InkTag is a virtualization-based architecture that gives strong safety guarantees to high-assurance processes even in the presence of a malicious operating system. InkTag advances the state of the art in untrusted operating systems in both the design of its hypervisor and in the ability to run useful applications without trusting the operating system. We introduce
paraverification
, a technique that simplifies the InkTag hypervisor by forcing the untrusted operating system to participate in its own verification.
Attribute-based access control
allows trusted applications to create decentralized access control policies. InkTag is also the first system of its kind to ensure consistency between secure data and metadata, ensuring recoverability in the face of system crashes.
HOTL
Authors: Xiang Xiaoya , Ding Chen , Luo Hao , Bao Bin
Published: April 2020

The locality metrics are many, for example, miss ratio to test performance, data footprint to manage cache sharing, and reuse distance to analyze and optimize a program. It is unclear how different metrics are related, whether one subsumes another, and what combination may represent locality completely.

This paper first derives a set of formulas to convert between five locality metrics and gives the condition for correctness. The transformation is analogous to differentiation and integration used to convert between higher order polynomials. As a result, these metrics can be assigned an order and organized into a hierarchy.

Using the new theory, the paper then develops two techniques: one measures the locality in real time without special hardware support, and the other predicts multicore cache interference without parallel testing. The paper evaluates them using sequential and parallel programs as well as for a parallel mix of sequential programs.