bluuebunny/crossref_metadata_2025 huggingface dataset:
EVALUATION OF ELEVEN IMMUNOCHROMATOGRAPHIC ASSAYS FOR SARS-CoV-2 DETECTION: INVESTIGATING DENGUE CROSS-REACTION
Authors: Oliveira Beatriz Araujo , de Oliveira Lea Campos , de Oliveira Franciane Mendes , Pereira Geovana Maria , de Souza Regina Maia , Manuli Erika Regina , Marchini Fabricio Klerynton , Espinoza Evelyn Patrícia Sanchez , Park Marcelo , Taniguchi Leandro , Mendes Pedro Vitale , Franco Lucas Augusto Moyses , Nastri Ana Catharina , de Oliveira Maura Salaroli , Vieira Junior José Mauro , Kallas Esper Georges , Levin Anna Sara , Sabino Ester Cerdeira , Costa Silvia Figueiredo
Published: October 2020

Background

COVID-19 disease (Coronavirus disease 2019) caused by SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) is widespread worldwide, affecting more than 11 million people globally (July 6th, 2020). Diagnostic techniques have been studied in order to contain the pandemic. Immunochromatographic (IC) assays are feasible and low cost alternative for monitoring the spread of COVID-19 in the population.

Methods

Here we evaluate the sensitivity and specificity of eleven different immunochromatographic tests in 98 serum samples from confirmed cases of COVID-19 through RT-PCR and 100 negative serum samples from blood donors collected in February 2019. Considering the endemic situation of Dengue in Brazil, we also evaluated the cross-reactivity with Dengue using 20 serum samples from patients with confirmed diagnosis for Dengue collected in early 2019 through four different tests.

Results

Our results demonstrated agreement between immunochromatographic assays and RT-PCR, especially after 10 days since the onset of symptoms. The evaluation of IgG and IgM antibodies combined demonstrated a strong level of agreement (0.85) of IC assays and RT-PCR. It was observed cross-reactivity between Dengue and COVID-19 using four different IC assays for COVID-19 diagnosis. The specificity of IC assays to detected COVID-19 IgM antibodies using Dengue serum samples varied from 80% to 85%; the specificity of IgG detection was 100% and total antibody was 95%.

Conclusions

We found high sensitivity, specificity and good agreement of IC assays, especially after 10 days onset of symptoms. However, we detected cross-reactivity between Dengue and COVID-19 mainly with IgM antibodies demonstrating the need for better studies about diagnostic techniques for these diseases.

Highlights

Immunochromatographic assays demonstrated high sensitivity and specificity and good agreement with the gold-standard RT-PCR;

Increase in sensitivity and specificity of assays using samples collected after the 10th day of symptoms;

Cross-reaction with Dengue serology in evaluation of IgM.
Individual-level response adaptive crossover trial design for epilepsy: structure and simulation
Authors: Kerr Wesley T. , Zhang Xingruo , Stern John M.
Published: October 2020

Trials of antiseizure medications involve static group assignments for treatments with pre-specified durations. We propose a response-adaptive crossover design using basic statistical assumptions regarding both seizure count and duration of treatment to determine when a participant can change group assignment. We modelled seizure frequency as a Poisson process and estimated the likelihood that seizure frequency had decreased by 50% compares to baseline using both a Bayesian and maximum likelihood approach. We simulated trials to estimate the influence of this design on statistical power and observation duration with each treatment. For patients with 9 baseline seizures in 4 weeks who had no change in seizure frequency, the simulation identified non-response in a median of 16 days. The response-adaptive crossover design resulted in a modest increase in statistical power to identify an effective treatment while maximizing the time in a group producing a response. Only 8% of participants remained in the placebo group for all 90 days of the simulated trials. These example theoretical results can provide quantitative guidance regarding objective criteria to determine non-response in real-time during a controlled clinical trial without revealing the assigned treatment. Implementing a response-adaptive crossover design may both improve statistical power while minimizing participant risk.
Back to Basics: Correlates of HIV Risk in a Community Sample of Haiti
Authors: Joshi Manisha , Rahill Guitele J. , Rice Christopher , Phycien Paul , Burris Cameron , Maio Alyssa
Published: October 2020

Haiti has a 2.2 % HIV prevalence (highest in the Caribbean); this has diminished from over 12% in the past three decades (depending on sex and gender, province, and neighborhood). Preliminary studies indicate that in the Cite Soleil neighborhood of Haiti (HIV prevalence >3%) as in socioeconomically equivalent adjacent neighborhoods, over 50% of girls and women experience non-partner sexual violence (NPSV), typically perpetrated by groups of men. Rates of NPSV against men in those neighborhoods were not available. Coercive sex heightens HIV risk. Accurate HIV knowledge empowers individuals (including survivors of NPSV) to assess personal HIV risk and increases likelihood of getting tested and of determining personal HIV status; thus, accurate HIV knowledge is foundational to behavioral risk reduction for victims in future consensual relationships and to engagement in either the HIV prevention or care continuum.

Between March and July 2017, we surveyed individuals 18 years or older (210 women, 257 men), assessing experience of NPSV, HIV knowledge, history of HIV testing, knowledge of HIV status, assessment of self-risk, and sexual risk behaviors. Nearly 30% of men and 24% of women endorsed having experienced NPSV. Knowledge of HIV transmission was low: 90% endorsed HIV myths, e.g. transmission occurs via public toilets, via sharing a glass with or by being exposed to a cough or sneeze from a person living with HIV. High endorsement of these myths contrasted with low endorsement of protective behavior: Only 14.3 % used a condom during consensual sex in the past year. Only 47.9% of the respondents had ever attended an HIV awareness program; 16% of knew their HIV status, although 79% assessed their HIV risk as moderate to high. Results regressing knowledge of HIV testing on participant characteristics indicated that women (OR=2.8), individuals with a partner (OR=2.2), individuals who attended an HIV awareness class (OR=2.1), individuals who knew someone with HIV (OR=3.9), and individuals who had an HIV test (OR=33.5) were more likely to know what an HIV test is. Participants who endorsed experiencing NPSV (OR=0.33) and those who had been diagnosed with an STI (OR=0.44) were less likely to know about HIV testing.

Experience of NPSV combined with low HIV knowledge, awareness and testing heighten the HIV prevention needs of Cite Soleil residents and underscore the need to return to basics on the road to HIV eradication in that context.
Acceleration of health deficit accumulation in late-life: Evidence of terminal decline in frailty index three years before death in the US Health and Retirement study
Authors: Stolz Erwin , Mayerl Hannes , Hoogendijk Emiel O. , Armstrong Joshua J. , Roller-Wirnsberger Regina , Freidl Wolfgang
Published: October 2020

Background

Little is known about within-person frailty index (FI) changes during the last years of life. In this study, we assess whether there is a phase of accelerated health deficit accumulation (terminal health decline) in late-life.

Material and methods

23,393 observations from up to the last 21 years of life of 5,713 deceased participants of the AHEAD cohort in the Health and Retirement Study were assessed. A FI with 32 health deficits was calculated for up to 10 successive biannual assessments (1995-2014), and FI changes according to time-to-death were analyzed with a piecewise linear mixed model with random change points.

Results

The average normal (pre-terminal) health deficit accumulation rate was 0.01 per year, which increased to 0.05 per year at approximately 3 years before death. Terminal decline began earlier in women and was steeper among men. The accelerated (terminal) rate of health deficit accumulation began at a FI value of 0.29 in the total sample, 0.27 for men, and 0.30 for women.

Conclusion

We found evidence for an observable terminal health decline in the FI following declining physiological reserves and failing repair mechanisms. Our results suggest a conceptually meaningful cut-off value for the continuous FI around 0.30.
Evaluation of fully oxidized β-carotene as a feed ingredient to reduce bacterial infection and somatic cell counts in cows with subclinical mastitis
Authors: McDougall S
Published: October 2020

Aims

To assess the effect of oral supplementation with fully oxidised β-carotene (OxBC) on bacteriological cure, incidence of clinical mastitis, and somatic cell counts (SCC) in cows with subclinical intramammary infection.

Methods

Cows from four dairy herds were enrolled in early lactation if they had quarter-level SCC >200,000 cells/mL and they had a recognised bacterial intramammary pathogen in one or more quarters. They were randomly assigned to be individually fed from Day 0, for an average of 40 days, with 0.5 kg of a cereal-based supplementary feed that either contained 300 mg of OxBC (treatment; n=129 quarters) or did not (control; n=135 quarters). Quarter-milk samples were collected on Days 21 and 42 for microbiology and SCC assessment. Bacteriological cure was defined as having occurred when the bacteria present on Day 0 were not isolated from samples collected on Days 21 or 42. Clinical mastitis was diagnosed and recorded by herdowners up to Day 42.

Results

The bacteriological cure rate was greater for quarters from cows in the treatment group (13.9 (95% CI=4.1–23.7)%) than for quarters from cows in the control group (6.9 (95% CI=4.8–9.1)%; p=0.02). The prevalence of quarters that were infected on Day 42 was less in cows in the treatment group (79.9 (95% CI=62.3-97.6)%) than the control group (88.2 (95% CI=78.4-97.9)%; p=0.009). The incidence of quarters diagnosed with clinical mastitis by Day 42 was lower in cows from the treatment group (1/129 (0.78 (95% CI=0.02-4.24)%) than in cows from the control group (6/135 (4.44 (95% CI=1.65-9.42)%; p=0.03). Mean quarter-level SCC did not differ between treatment groups (p=0.34).

Conclusions and Clinical Relevance

Feeding 300 mg/cow/day of fully oxidised β-carotene resulted in a higher bacteriological cure rate, a lower prevalence of intramammary infection following 6 weeks of feeding, and a lower incidence of clinical mastitis compared to untreated controls. This offers a non-antimicrobial approach to reducing prevalence of intramammary infection in dairy cows.
The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction
Authors: Belalcazar Helen M. , Hendricks Emily L. , Zamurrad Sumaira , Liebl Faith L.W. , Secombe Julie
Published: October 2020

Mutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using theDrosophilalarval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.
Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration
Authors: Bridi Jessika C. , Bereczki Erika , Smith Saffron K. , Poças Gonçalo M. , Kottler Benjamin , Domingos Pedro M. , Elliott Christopher J. , Aarsland Dag , Hirth Frank
Published: October 2020

Alpha-synuclein (α-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson’s disease, Parkinson’s disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in aDrosophilamodel of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageingDrosophilathat occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.
Determining the efficacy of hand sanitizers against virulent nosocomial infections
Authors: Najdawi Jawad , Hubble Lester , Scarborough Alec , Watz Matthew , Watson Paul Andrew
Published: October 2020

The goal of this study was to determine the effectiveness of 0.13% benzalkonium chloride (BAC) (Steirolotion™), 100% ethanol, and 70% ethyl alcohol (Purell™) hand sanitizer in subduing the growth of nosocomial bacteria – methicillin resistant Staphylococcus  aureus  (MRSA), vancomycin resistant Enterococcus (VRE), and Pseudomonas  aeruginosa  (P.  aeruginosa ) - when plated on culture media over an extended period of time. In addition, our objective was to quantify the length of time these hand sanitizer agents remained effective, and to extrapolate their efficacy in decreasing the transmission of hospital-acquired infections. 50 microliters of either BAC, 100% ethanol, or 70% ethyl alcohol hand gel sanitizer were pipetted onto Trypticase soy agar with 5% sheep blood plates that were cultured with either MRSA, VRE, or P.  aeruginosa . The plates were then incubated at 37.0?. The zone of inhibition (ZOI) was measured daily for 5 days and additionally zones were noted whether or not regrowth recurred in areas where previous growth had initially been inhibited. BAC was found to be superior to both 100% ethanol and 70% ethyl alcohol in the inhibition of MRSA over all time points (p values < .05). BAC was found to be superior to 70% ethyl alcohol in the inhibition of VRE over all time points (p values < .05), but not statistically superior to 100% ethanol against the inhibition of VRE over any time points. BAC was found to be superior to 70% ethyl alcohol and 100% ethanol in the inhibition of pseudomonas over 72 and 24 hours, respectively (p values < .05). The results of this study demonstrate  in vitro  efficacy of BAC of preventing regrowth of common nosocomial bacteria over a prolonged period of time, especially when compared to ethyl alcohol. Further study is warranted to determine  in vivo  effectiveness of this formulation of BAC as well as the appropriate time frame of application for effectiveness against P.  aeruginosa .
Within-patient genetic diversity of SARS-CoV-2
Authors: Kuipers Jack , Batavia Aashil A , Jablonski Kim Philipp , Bayer Fritz , Borgsmüller Nico , Dondi Arthur , Drăgan Monica-Andreea , Ferreira Pedro , Jahn Katharina , Lamberti Lisa , Pirkl Martin , Posada-Céspedes Susana , Topolsky Ivan , Nissen Ina , Santacroce Natascha , Burcklen Elodie , Schär Tobias , Capece Vincenzo , Beckmann Christiane , Kobel Olivier , Noppen Christoph , Redondo Maurice , Nadeau Sarah , Seidel Sophie , Santamaria de Souza Noemie , Beisel Christian , Stadler Tanja , Beerenwinkel Niko
Published: October 2020

SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, is evolving into different genetic variants by accumulating mutations as it spreads globally. In addition to this diversity of consensus genomes across patients, RNA viruses can also display genetic diversity within individual hosts, and co-existing viral variants may affect disease progression and the success of medical interventions. To systematically examine the intra-patient genetic diversity of SARS-CoV-2, we processed a large cohort of 3939 publicly-available deeply sequenced genomes with specialised bioinformatics software, along with 749 recently sequenced samples from Switzerland. We found that the distribution of diversity across patients and across genomic loci is very unbalanced with a minority of hosts and positions accounting for much of the diversity. For example, the D614G variant in the Spike gene, which is present in the consensus sequences of 67.4% of patients, is also highly diverse within hosts, with 29.7% of the public cohort being affected by this coexistence and exhibiting different variants. We also investigated the impact of several technical and epidemiological parameters on genetic heterogeneity and found that age, which is known to be correlated with poor disease outcomes, is a significant predictor of viral genetic diversity.

Author Summary

Since it arose in late 2019, the new coronavirus (SARS-CoV-2) behind the COVID-19 pandemic has mutated and evolved during its global spread. Individual patients may host different versions, or variants, of the virus, hallmarked by different mutations. We examine the diversity of genetic variants coexisting within patients across a cohort of 3939 publicly accessible samples and 749 recently sequenced samples from Switzerland. We find that a small number of patients carry most of the diversity, and that patients with more diversity tend to be older. We also find that most of the diversity is concentrated in certain regions and positions of the virus genome. In particular, we find that a variant reported to increase infectivity is among the most diverse positions. Our study provides a large-scale survey of within-patient diversity of the SARS-CoV-2 genome.
Application of DNA barcodes and spatial analysis in conservation genetics and modeling of Iranian Salicornia genetic resources
Authors: Zeinalabedini Mehrshad , Khoshkholgh Sima Nayer Azam , Ghaffari Mohammad Reza , Ebadi Ali , Farsi Maryam
Published: October 2020

Iran is one of the origins of some Salicornia species. Nevertheless, so far, comprehensive research has not been conducted on genetic potential, distribution, selection of populations, and the economic utilization of Salicornia in Iran. In the current study, Salicornia was collected based on the previous research locations available on 26 different geographical locations of provinces in Iran. Subsequently, an accurate model was provided for identifying of Salicornia species biodiversity by performing spatial analysis and modeling of distributed areas. The results provided valuable information on the diversity of specific geographical regions, conservation status of existing species, prioritization of conservation areas, and selection of areas for Agro-Ecological, leading to the development of industrial agriculture. Further, we validated genes in the field of DNA barcoding in Salicornia plants using matK, rbcL, trnH-psbA, ycf and ITS2 identifying species groups. Together, integrating our results will provide useful information for the management and utilization of Salicornia genetic resources in Iran.
Validating Dynamicity in Resting State fMRI with Activation-Informed Temporal Segmentation
Authors: Duda Marlena , Koutra Danai , Sripada Chandra
Published: October 2020

Confirming the presence (or absence) of dynamic functional connectivity (dFC) states during rest is an important open question in the field of cognitive neuroscience. The prevailing dFC framework aims to identify dynamics directly from connectivity estimates with a sliding window approach, however this method suffers from several drawbacks including sensitivity to window size and poor test-retest reliability. We hypothesize that time-varying changes in functional connectivity are mirrored by significant temporal changes in functional activation, and that this coupling can be leveraged to study dFC without the need for a predefined sliding window. Here we introduce a straightforward data-driven dFC framework, which involves informed segmentation of fMRI time series at candidate FC state transition points estimated from changes in whole-brain functional activation, rather than a fixed-length sliding window. We show our approach reliably identifies true cognitive state change points when applied on block-design working memory task data and outperforms the standard sliding window approach in both accuracy and computational efficiency in this context. When applied to data from four resting state fMRI scanning sessions, our method consistently recovers five reliable FC states, and subject-specific features derived from these states show significant correlation with behavioral phenotypes of interest (cognitive ability, personality). Overall, these results suggest abrupt whole-brain changes in activation can be used as a marker for changes in connectivity states, and provides strong evidence for the existence of time-varying FC in rest.
Racial and ethnic imbalance in neuroscience reference lists and intersections with gender
Authors: Bertolero Maxwell A. , Dworkin Jordan D. , David Sophia U. , Lloreda Claudia López , Srivastava Pragya , Stiso Jennifer , Zhou Dale , Dzirasa Kafui , Fair Damien A. , Kaczkurkin Antonia N. , Marlin Bianca Jones , Shohamy Daphna , Uddin Lucina Q. , Zurn Perry , Bassett Danielle S.
Published: October 2020

Discrimination against racial and ethnic minority groups exists in the academy, and the associated biases impact hiring and promotion, publication rates, grant funding, and awards. Precisely how racial and ethnic bias impacts the manner in which the scientific community engages with the ideas of academics in minority groups has yet to be fully elucidated. Citations are a marker of such community engagement, as well as a currency used to attain career milestones. Here we assess the extent and drivers of racial and ethnic imbalance in the reference lists of papers published in five top neuroscience journals over the last 25 years. We find that reference lists tend to include more papers with a White person as first and last author than would be expected if race and ethnicity were unrelated to referencing. We show that this imbalance is driven largely by the citation practices of White authors, and is increasing over time even as the field diversifies. To further explain our findings, we examine co-authorship networks and find that while the network has become markedly more integrated in general, the current degree of segregation by race/ethnicity is greater now than it has been in the past. Citing further from oneself on the network is associated with greater balance, but White authors’ preferential citation of White authors remains even at high levels of network exploration. We also quantify the effects of intersecting identities, determining the relative costs of gender and race/ethnicity, and their combination in women of color. Our findings represent a call to scientists and journal editors of all disciplines to consider the ethics of citation practices, and actions to be taken in support of an equitable future.
Learning, Visualizing and Exploring 16S rRNA Structure Using an Attention-based Deep Neural Network
Authors: Zhao Zhengqiao , Woloszynek Stephen , Agbavor Felix , Mell Joshua Chang , Sokhansanj Bahrad A. , Rosen Gail
Published: October 2020

Recurrent neural networks (RNNs) with memory (e.g. LSTMs) and attention mechanisms are widely used in natural language processing because they can capture short and long term sequential information for diverse tasks. We propose an integrated deep learning model for microbial DNA sequence data, which exploits convolutional networks, recurrent neural networks, and attention mechanisms to perform sample-associated attribute prediction—phenotype prediction—and extract interesting features, such as informative taxa and predictivek-mer context. In this paper, we develop this novel deep learning approach and evaluate its application to amplicon sequences. We focus on typically short DNA reads of 16s ribosomal RNA (rRNA) marker genes, which identify the heterogeneity of a microbial community sample. Our deep learning approach enables sample-level attribute and taxonomic prediction, with the aim of aiding biological research and supporting medical diagnosis. We demonstrate that our implementation of a novel attention-based deep network architecture,Read2Pheno, achieves read-level phenotypic prediction and, in turn, that aggregating read-level information can robustly predict microbial community properties, host phenotype, and taxonomic classification, with performance comparable to conventional approaches. Most importantly, as a further result of the training process, the network architecture will encode sequences (reads) into dense, meaningful representations: learned embedded vectors output on the intermediate layer of the network model, which can provide biological insight when visualized. Finally, we demonstrate that a model with an attention layer can automatically identify informative regions in sequences/reads which are particularly informative for classification tasks. An implementation of the attention-based deep learning network is available athttps://github.com/EESI/sequence_attention.
mutSigMapper: an R package to map spectra to mutational signatures based on shot-noise modeling
Authors: Candia Julián
Published: October 2020

mutSigMapper aims to resolve a critical shortcoming of existing software for mutational signature analysis, namely that of finding parsimonious and biologically plausible exposures. By implementing a shot-noise-based model to generate spectral ensembles, this package addresses this gap and provides a quantitative, non-parametric assessment of statistical significance for the association between mutational signatures and observed spectra.

Availability and implementation

The mutSigMapper R package is available under GPLv3 license athttps://github.com/juliancandia/mutSigMapper. Its documentation provides additional details and demonstrates applications to biological datasets.
Enhanced Loading of Paclitaxel in Cationic Liposomes by Replacement of Oleoyl with Linoleoyl Lipid Tails with Benefits in Cancer Therapeutics fromIn VitroStudies
Authors: Zhen Yuhong , Ewert Kai K. , Fisher William S. , Steffes Victoria M. , Li Youli , Safinya Cyrus R.
Published: October 2020

Lipid-based carriers of the hydrophobic drug paclitaxel (PTX) are used in clinical trials as next-generation agents for cancer chemotherapy. Improving the loading capacity of these carriers requires enhanced PTX solubilization. We compared the solubility of PTX in cationic liposomes (CLs) with lipid tails containing one (oleoyl; C18:1 Δ9; DOTAP/DOPC) or two (linoleoyl; C18:2 Δ9; DLinTAP/DLinPC)cisdouble bonds with newly synthesized cationic DLinTAP (2,3-dilinoleoyloxypropyltrimethylammonium methylsufate). We used differential-interference-contrast microscopy to directly observe PTX crystal formation and generate kinetic phase diagrams representing the time-dependence of PTX solubility as a function of PTX content in the membrane. Replacing tails bearing onecisdouble bond (DO lipids) with those bearing two (DLin lipids) significantly increased PTX membrane solubility in CLs. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the membrane solubility limit which has been the focus of most previous fundamental studies and clinical trials) in DOTAP/DOPC CLs. The large increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX upon replacement of oleoyl by linoleoyl tails, rather than by the transition in membrane structure from lipid bilayers to inverse cylindrical micelles observed in small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against human prostate cancer (PC3) cells from measurements of the IC50 of PTX cytotoxicity was unaffected by changing the lipid tails, and toxicity of the CL carrier alone was negligible. Moreover, efficacy was approximately doubled against human melanoma (M21) cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. The findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading well over the typically used 3 mol% while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.
Structure of the ancestral TRPY1 channel fromSaccharomyces cerevisiaereveals mechanisms of modulation by lipids and calcium
Authors: Ahmed Tofayel , Nisler Collin R. , Fluck Edwin C. , Sotomayor Marcos , Moiseenkova-Bell Vera Y.
Published: October 2020

Transient Receptor Potential (TRP) channels have evolved in eukaryotes to control various cellular functions in response to a wide variety of chemical and physical stimuli. This large and diverse family of channels emerged in fungi as mechanosensitive osmoregulators. TheSaccharomyces cerevisiaevacuolar TRP yeast 1 (TRPY1) is the most studied TRP channel from fungi, but the molecular details of channel modulation remain elusive so far. Here, we describe the full-length cryo-electron microscopy structure of TRPY1 at 3.1 Å resolution. The structure reveals a distinctive architecture for TRPY1 among all eukaryotic TRP channels with an evolutionarily conserved and archetypical transmembrane domain, but distinct structural folds for the cytosolic N- and C-termini. We identified the inhibitory phosphatidylinositol 3-phosphate (PI(3)P) lipid binding site, which sheds light into the lipid modulation of TRPY1 in the vacuolar membrane. The structure also exhibited two Ca2+-binding sites: one in the cytosolic side, implicated in channel activation, and the other in the vacuolar lumen side, involved in channel inhibition. These findings, together with data from molecular dynamics simulations, provide structural insights into the basis of TRPY1 channel modulation by lipids and Ca2+.
The mammalian rod synaptic ribbon is essential for Cavchannel facilitation and ultrafast fusion of the readily releasable pool of vesicles
Authors: Grabner Chad Paul , Moser Tobias
Published: October 2020

Rod photoreceptors (PRs) use ribbon synapses to transmit visual information. To signal ‘no light detected’ they release glutamate continually to activate post-synaptic receptors, and when light is detected glutamate release pauses. How a rod’s individual ribbon enables this process was studied here by recording evoked changes in whole-cell membrane capacitance from wild type and ribbonless (RIBEYE-ko) rods. Wild type rods created a readily releasable pool (RRP) of 92 synaptic vesicles (SVs) that emptied as a single kinetic phase with a τ < 0.4 msec. Lowering intracellular Ca2+-buffering accelerated Cavchannel opening and facilitated release kinetics, but RRP size was unaltered. In contrast, ribbonless rods created an RRP of 24 SVs, and lacked Cavchannel facilitation; however, Ca2+channel-release coupling remained tight. The release deficits caused a sharp attenuation of rod-driven light responses measured from RIBEYE-ko mice. We conclude that the synaptic ribbon facilitates Ca2+-influx and establishes a large RRP of SVs.
Optimal design of adaptively sampled NMR experiments for measurement of methyl group dynamics with application to a ribosome-nascent chain complex
Authors: Waudby Christopher A. , Burridge Charles , Christodoulou John
Published: October 2020

NMR measurements of cross-correlated nuclear spin relaxation provide powerful probes of polypeptide dynamics and rotational diffusion, free from contributions due to chemical exchange or interactions with external spins. Here, we report on the development of a sensitivity-optimized pulse sequence for the measurement of cross-correlated relaxation in methyl spin systems by analysis of the differential relaxation of transitions within the13C multiplet. We describe the application of optimal design theory to implement a real-time ‘on-the-fly’ adaptive sampling scheme that maximizes the accuracy of the measured rate constants. The increase in sensitivity obtained using this approach enables, for the first time, quantitative measurements of rotational diffusion within folded states of translationally-arrested ribosome–nascent chain complexes of the FLN5 filamin domain, and can be used to place strong limits on interactions between the domain and the ribosome surface.
Improved protein structure prediction by deep learning irrespective of co-evolution information
Authors: Xu Jinbo , Mcpartlon Matthew , Li Jin
Published: October 2020

We describe our latest study of the deep convolutional residual neural networks (ResNet) for protein structure prediction, including deeper and wider ResNets, the efficacy of different input features, and improved 3D model building methods. Our ResNet can predict correct folds (TMscore>0.5) for 26 out of 32 CASP13 FM (template-free-modeling) targets and L/5 long-range contacts for these targets with precision over 80%, a significant improvement over the CASP13 results. Although co-evolution analysis plays an important role in the most successful structure prediction methods, we show that when co-evolution is not used, our ResNet can still predict correct folds for 18 of the 32 CASP13 FM targets including several large ones. This marks a significant improvement over the top co-evolution-based, non-deep learning methods at CASP13, and other non-coevolution-based deep learning models, such as the popular recurrent geometric network (RGN). With only primary sequence, our ResNet can also predict correct folds for all 21 human-designed proteins we tested. In contrast, RGN predicts correct folds for only 3 human-designed proteins and zero CASP13 FM target. In addition, we find that ResNet may fare better for the human-designed proteins when trained without co-evolution information than with co-evolution. These results suggest that ResNet does not simply denoise co-evolution signals, but instead is able to learn important sequence-structure relationship from experimental structures. This has important implications on protein design and engineering especially when evolutionary information is not available.
Insulin polymorphism induced by two polyphenols: new crystal forms and advances in macromolecular powder diffraction
Authors: Triandafillidis Dimitris-Panagiotis , Parthenios Nikolaos , Spiliopoulou Maria , Valmas Alexandros , Kosinas Christos , Gozzo Fabia , Reinle-Schmitt Mathilde , Beckers Detlef , Degen Thomas , Pop Mihaela , Fitch Andrew N. , Wollenhaupt Jan , Weiss Manfred S. , Karavassili Fotini , Margiolaki Irene
Published: October 2020

This study focuses on the polymorphism of human insulin (HI) upon the binding of the phenolic derivativesp-coumaric acid ortrans-resveratrol over a wide pH range. The determination of the structural behaviour of HI via X-ray powder diffraction (XRPD) and single-crystal X-ray diffraction (SCXRD) is reported. Four distinct polymorphs were identified, two of which have not been reported previously. The intermediate phase transitions are discussed. One of the novel monoclinic polymorphs displays the highest molecular packing among insulin polymorphs of the same space group to date; its structure was elucidated by SCXRD. XRPD data collection was performed using a variety of instrumental setups and a systematic comparison of the acquired data is presented. A laboratory diffractometer was used for screening prior to high-resolution XRPD data collection on the ID22 beamline at the European Synchrotron Radiation Facility. Additional measurements for the most representative samples were performed on the X04SA beamline at the Swiss Light Source (SLS) using the MYTHEN II detector, which allowed the detection of minor previously untraceable impurities and dramatically improved thed-spacing resolution even for poorly diffracting samples.
Through-grid wicking enables high-speed cryoEM specimen preparation
Authors: Tan Yong Zi , Rubinstein John L.
Published: October 2020

Blotting times for conventional cryoEM specimen preparation complicate time-resolved studies and lead to some specimens adopting preferred orientations or denaturing at the air–water interface. Here, it is shown that solution sprayed onto one side of a holey cryoEM grid can be wicked through the grid by a glass-fiber filter held against the opposite side, often called the `back', of the grid, producing a film suitable for vitrification. This process can be completed in tens of milliseconds. Ultrasonic specimen application and through-grid wicking were combined in a high-speed specimen-preparation device that was named `Back-it-up' or BIU. The high liquid-absorption capacity of the glass fiber compared with self-wicking grids makes the method relatively insensitive to the amount of sample applied. Consequently, through-grid wicking produces large areas of ice that are suitable for cryoEM for both soluble and detergent-solubilized protein complexes. The speed of the device increases the number of views for a specimen that suffers from preferred orientations.
Orchestrating internal and external resources to achieve agility and performance: the centrality of market orientation
Authors: Kurniawan Randy , Manurung Adler Haymans , Hamsal Mohammad , Kosasih Wibowo
Published: October 2020

Purpose

This study examines the collaborative impact of networking capability and balanced agile project management (APM) on firm performance through the mediating role of market orientation and business process agility of medium and large telecommunication technology providers in Indonesia.

Design/methodology/approach

Research data were collected from the executive management of telecommunication technology providers in Indonesia via a questionnaire survey to obtain 150 valid questionnaires for analysis. This study analyzed the overall model fit and causal relationship using confirmatory factor analysis (CFA) and structural equation modeling (SEM).

Findings

The results indicate that market orientation fully mediates the link between networking capability-business process agility and balanced APM-business process agility. Furthermore, business process agility mediates the relationship between market orientation and firm performance.

Research limitations/implications

This study is based on a cross-sectional nature and might fail to capture the dynamic of the studied variables over an extended period.

Originality/value

The study extends the knowledge that dynamic capabilities, represented by networking capability and balanced APM, must be framed by market orientation to create customer value and improve bargaining position. However, market orientation alone is not enough in a highly dynamic business environment. Organization also requires business process agility, responsiveness and adaptability to timely address customers' needs and requirements.
Antecedents of career self-management: home country and international careers in Kuwait
Authors: Abdalla Ikhlas , Al-Zufairi Awad
Published: October 2020

Purpose

The purpose of this paper is to examine how leadership aspiration mediates the effect of career self-efficacy on employees' engagement in career self-management (CSM; i.e. deployment of career advancement strategies concerning access to power, psychological boundaryless and self-promotion), whether self-efficacy directly influences CSM, and whether these relations are conditional upon nationality (which is a proxy for domestic and international careers in Kuwait).

Design/methodology/approach

A questionnaire was completed by 615 highly educated young Kuwaitis and self-initiated expatriates (SIEs; Arab and South Asian nationals) working in Kuwait.

Findings

The results demonstrate that self-efficacy, directly and indirectly (mediated by leadership aspiration), influences the three types of career advancement strategies. Moderated-mediation analyses suggest that SIEs and Kuwaitis engage in similar CSM behaviors when it is motivated by self-efficacy, which is mediated by leadership aspiration. Also, self-efficacy has greater direct effect on SIEs' CSM than Kuwaitis', but Kuwaitis have higher tendency for CSM behavior.

Practical implications

Interventions aiming to improve employees' engagement in CSM may focus on enhancing their psychological capital and contexts, while minding the differential effects of nationality and self-efficacy on CSM of Kuwaitis and SIEs.

Originality/value

The study provides unique information about CSM utilizing understudied populations namely, Middle-Eastern and self-initiated expatriate employees. It confirms the effects of self-efficacy and leadership aspiration on CSM and reveals different effects of nationality depending on the motivators at play.
Numerical investigation of friction laws for laminar and turbulent flow in undulated channels
Authors: Benim Ali Cemal , Maddala Sai Bhagavan
Published: October 2020

Purpose

The purpose of this paper is the numerical investigation of the friction laws for incompressible flow in undulated channels, with emphasis on the applicability of the hydraulic diameter concept. A focal point of the study is the derivation of correlations to increase the accuracy of the hydraulic diameter approach.

Design/methodology/approach

Calculations are performed for laminar and turbulent flow, for Reynolds number ranges between 10–2,000 and 5,000–100,000. For turbulent flow, the shear stress transport (SST) model is used. A simple, sawtooth-like undulation shape is considered, where the channel geometry can be described by means of three length parameters. Letting each to take three values, totally 27 geometries are analyzed.

Findings

It is observed that the hydraulic diameter concept applied via analytical or empirical expressions to obtain friction coefficients does not lead to accurate results. For laminar flow, the maximum deviations of analytical values from predicted are about 70%, while 20% deviation is observed on average. For turbulent flow, deviations of Blasius correlation from predicted ones are smaller, but still remarkable with about 20% for maximum deviation and about 10% on average.

Originality/value

Applicability of the hydraulic diameter concept to undulated channels was not computationally explored. A further original ingredient of the work is the derivation of correlations that lead to improved accuracy in calculating the friction coefficient using hydraulic diameter. For laminar flow, the maximum and average deviations of present correlations from numerical predictions are below 5% and 2%, respectively. For turbulent flow, these numbers turn out to be approximately 12% for the maximum deviation and about 2% for the average.
Hybrid nanofluid flow on a shrinking cylinder with prescribed surface heat flux
Authors: Waini Iskandar , Ishak Anuar , Pop Ioan
Published: October 2020

Purpose

This study aims to investigate the flow impinging on a stagnation point of a shrinking cylinder subjected to prescribed surface heat flux in Al2O3-Cu/water hybrid nanofluid.

Design/methodology/approach

Using similarity variables, the similarity equations are obtained and then solved using bvp4c in MATLAB. The effects of several physical parameters on the skin friction and heat transfer rate, as well as the velocity and temperature profiles are analysed and discussed.

Findings

The outcomes show that dual solutions are possible for the shrinking case, in the range

λc<λ<−1, where

λc is the bifurcation point of the solutions. Meanwhile, the solution is unique for

λ≥−1. Besides, the boundary layer is detached on the surface at

λc, where the value of

λc is affected by the hybrid nanoparticle

φhnf and the curvature parameter

γ. Moreover, the friction and the heat transfer on the surface increase with the rising values

φhnf and

γ. Finally, the temporal stability analysis shows that the first solution is stable in the long run, whereas the second solution is not.

Originality/value

The present work considers the problem of stagnation point flow impinging on a shrinking cylinder containing Al2O3-Cu/water hybrid nanofluid, with prescribed surface heat flux. This paper shows that two solutions are obtained for the shrinking case. Further analysis shows that only one of the solutions is stable as time evolves.
Influence of customer participation from the employee perspective
Authors: Yoo Jaewon , Chen Jing , Frankwick Gary L.
Published: October 2020

Purpose

To reduce costs, many banks have increased customer involvement during the creation and delivery of their products and services. Based on a job demands-resources (JD-R) model, this study tests an inverted U-shaped curvilinear relationship between perceived customer participation and employee work engagement. Customer orientation (CO) and service employee perceived fit with customers (PCF) moderate this relationship, which eventually affect both the internal and external benefits of service-employee work engagement.

Design/methodology/approach

The authors collected survey data from 518 service employees in the South Korean banking and insurance industries and analyzed the data using structural equation modeling (SEM).

Findings

The results indicate that perceived customer participation (PCP) has a significant inverted U-shape effect on work engagement. Results also suggest that CO and PCF have positive relationships with work engagement. In addition, they moderate the inverted U-shaped relationship between service employee PCP and work engagement, while work engagement positively affects organizational citizenship, job satisfaction and commitment.

Research limitations/implications

The authors empirically identify a curvilinear effect of PCP on work engagement. In doing so, the authors introduce and operationalize the new construct: PCF and suggest PCF and CO as unique job resources for service employees. The authors also examine these constructs as predictors based on a motivational process and as moderators based on a strain (energetic) process.

Practical implications

From a managerial perspective, examining the curvilinear relationships of customer participation and work engagement suggests that front-line employees’ (FLEs’) PCP does not necessarily enhance the economic benefits of productivity gains by using customers as substitutes for portions of employee labor. Another finding with managerial relevance indicates that service employees, who have more CO and PCF, showed more tolerant attitudes toward unnecessary and excessive levels of customer participation and regarded it as a job resource.

Originality/value

This study explains that researchers must consider the positive and negative sides of customer participation simultaneously because frontline employee PCP can be changed depending on the level of participation provided by customers. This study also shows that CO can be assumed as a personal resource and PCF as an environmental resource in the work engagement process.