bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved estimation of time-varying reproduction numbers at low case incidence and between epidemic waves
Authors: Parag Kris V.
Published: September 2021

We construct a recursive Bayesian smoother, termed EpiFilter, for estimating the effective reproduction number, R, from the incidence of an infectious disease in real time and retrospectively. Our approach borrows from Kalman filtering theory, is quick and easy to compute, generalisable, deterministic and unlike many current methods, requires no change-point or window size assumptions. We model R as a flexible, hidden Markov state process and exactly solve forward-backward algorithms, to derive R estimates that incorporate all available incidence information. This unifies and extends two popular methods, EpiEstim, which considers past incidence, and the Wallinga-Teunis method, which looks forward in time. We find that this combination of maximising information and minimising assumptions significantly reduces the bias and variance of R estimates. Moreover, these properties make EpiFilter more statistically robust in periods of low incidence, where several existing methods can become destabilised. As a result, EpiFilter offers improved inference of time-varying transmission patterns that are advantageous for assessing the risk of upcoming waves of infection or the influence of interventions, in real time and at various spatial scales.
A scalable Drosophila assay for clinical interpretation of human PTEN variants in suppression of PI3K/AKT induced cellular proliferation
Authors: Ganguly Payel , Madonsela Landiso , Chao Jesse T. , Loewen Christopher J. R. , O’Connor Timothy P. , Verheyen Esther M. , Allan Douglas W.
Published: September 2021

Gene variant discovery is becoming routine, but it remains difficult to usefully interpret the functional consequence or disease relevance of most variants. To fill this interpretation gap, experimental assays of variant function are becoming common place. Yet, it remains challenging to make these assays reproducible, scalable to high numbers of variants, and capable of assessing defined gene-disease mechanism for clinical interpretation aligned to the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines for ‘well-established assays’. Drosophila melanogaster offers great potential as an assay platform, but was untested for high numbers of human variants adherent to these guidelines. Here, we wished to test the utility of Drosophila as a platform for scalable well-established assays. We took a genetic interaction approach to test the function of ~100 human PTEN variants in cancer-relevant suppression of PI3K/AKT signaling in cellular growth and proliferation. We validated the assay using biochemically characterized PTEN mutants as well as 23 total known pathogenic and benign PTEN variants, all of which the assay correctly assigned into predicted functional categories. Additionally, function calls for these variants correlated very well with our recent published data from a human cell line. Finally, using these pathogenic and benign variants to calibrate the assay, we could set readout thresholds for clinical interpretation of the pathogenicity of 70 other PTEN variants. Overall, we demonstrate that Drosophila offers a powerful assay platform for clinical variant interpretation, that can be used in conjunction with other well-established assays, to increase confidence in the accurate assessment of variant function and pathogenicity.
Altering product placement to create a healthier layout in supermarkets: Outcomes on store sales, customer purchasing, and diet in a prospective matched controlled cluster study
Authors: Vogel Christina , Crozier Sarah , Penn-Newman Daniel , Ball Kylie , Moon Graham , Lord Joanne , Cooper Cyrus , Baird Janis
Published: September 2021

Background

Previous product placement trials in supermarkets are limited in scope and outcome data collected. This study assessed the effects on store-level sales, household-level purchasing, and dietary behaviours of a healthier supermarket layout.

Methods and findings

This is a prospective matched controlled cluster trial with 2 intervention components: (i) new fresh fruit and vegetable sections near store entrances (replacing smaller displays at the back) and frozen vegetables repositioned to the entrance aisle, plus (ii) the removal of confectionery from checkouts and aisle ends opposite. In this pilot study, the intervention was implemented for 6 months in 3 discount supermarkets in England. Three control stores were matched on store sales and customer profiles and neighbourhood deprivation. Women customers aged 18 to 45 years, with loyalty cards, were assigned to the intervention (n= 62) or control group (n= 88) of their primary store. The trial registration number is NCT03518151. Interrupted time series analysis showed that increases in store-level sales of fruits and vegetables were greater in intervention stores than predicted at 3 (1.71 standard deviations (SDs) (95% CI 0.45, 2.96),P= 0.01) and 6 months follow-up (2.42 SDs (0.22, 4.62),P= 0.03), equivalent to approximately 6,170 and approximately 9,820 extra portions per store, per week, respectively. The proportion of purchasing fruits and vegetables per week rose among intervention participants at 3 and 6 months compared to control participants (0.2% versus −3.0%,P= 0.22; 1.7% versus −3.5%,P= 0.05, respectively). Store sales of confectionery were lower in intervention stores than predicted at 3 (−1.05 SDs (−1.98, −0.12),P= 0.03) and 6 months (−1.37 SDs (−2.95, 0.22),P= 0.09), equivalent to approximately 1,359 and approximately 1,575 fewer portions per store, per week, respectively; no differences were observed for confectionery purchasing. Changes in dietary variables were predominantly in the expected direction for health benefit. Intervention implementation was not within control of the research team, and stores could not be randomised. It is a pilot study, and, therefore, not powered to detect an effect.

Conclusions

Healthier supermarket layouts can improve the nutrition profile of store sales and likely improve household purchasing and dietary quality. Placing fruits and vegetables near store entrances should be considered alongside policies to limit prominent placement of unhealthy foods.

Trial registration

ClinicalTrials.govNCT03518151(pre-results)
Longitudinal TprK profiling of in vivo and in vitro-propagated Treponema pallidum subsp. pallidum reveals accumulation of antigenic variants in absence of immune pressure
Authors: Lin Michelle J. , Haynes Austin M. , Addetia Amin , Lieberman Nicole A. P. , Phung Quynh , Xie Hong , Nguyen Tien V. , Molini Barbara J. , Lukehart Sheila A. , Giacani Lorenzo , Greninger Alexander L.
Published: September 2021

Immune evasion by Treponema pallidum subspecies pallidum (T. pallidum) has been attributed to antigenic variation of its putative outer-membrane protein TprK. In TprK, amino acid diversity is confined to seven variable (V) regions, and generation of sequence diversity within the V regions occurs via a non-reciprocal segmental gene conversion mechanism where donor cassettes recombine into the tprK expression site. Although previous studies have shown the significant role of immune selection in driving accumulation of TprK variants, the contribution of baseline gene conversion activity to variant diversity is less clear. Here, combining longitudinal tprK deep sequencing of near clonal Chicago C from immunocompetent and immunosuppressed rabbits along with the newly developed in vitro cultivation system for T. pallidum, we directly characterized TprK alleles in the presence and absence of immune selection. Our data confirm significantly greater sequence diversity over time within the V6 region during syphilis infection in immunocompetent rabbits compared to immunosuppressed rabbits, consistent with previous studies on the role of TprK in evasion of the host immune response. Compared to strains grown in immunocompetent rabbits, strains passaged in vitro displayed low level changes in allele frequencies of TprK variable region sequences similar to that of strains passaged in immunosuppressed rabbits. Notably, we found significantly increased rates of V6 allele generation relative to other variable regions in in vitro cultivated T, pallidum strains, illustrating that the diversity within these hypervariable regions occurs in the complete absence of immune selection. Together, our results demonstrate antigenic variation in T. pallidum can be studied in vitro and occurs even in the complete absence of immune pressure, allowing the T. pallidum population to continuously evade the immune system of the infected host.
VPS38/UVRAG and ATG14, the variant regulatory subunits of the ATG6/Beclin1-PI3K complexes, are crucial for the biogenesis of the yolk organelles and are transcriptionally regulated in the oocytes of the vector Rhodnius prolixus
Authors: Vieira Priscila H. , Benjamim Claudia F. , Atella Georgia , Ramos Isabela
Published: September 2021

In insects the reserve proteins are stored in the oocytes into endocytic-originated vesicles named yolk organelles. VPS38/UVRAG and ATG14 are the variant regulatory subunits of two class-III ATG6/Beclin1 PI3K complexes that regulate the recruitment of the endocytic (complex II) and autophagic (complex I) machineries. In a previous work from our group, we found that the silencing of ATG6/Beclin1 resulted in the formation of yolk-deficient oocytes due to defects in the endocytosis of the yolk proteins. Because ATG6/Beclin1 is present in the two above-described PI3K complexes, we could not identify the contributions of each complex to the yolk defective phenotypes. To address this, here we investigated the role of the variant subunits VPS38/UVRAG (complex II, endocytosis) and ATG14 (complex I, autophagy) in the biogenesis of the yolk organelles in the insect vector of Chagas Disease Rhodnius prolixus. Interestingly, the silencing of both genes phenocopied the silencing of ATG6/Beclin1, generating 1) accumulation of yolk proteins in the hemolymph; 2) white, smaller, and yolk-deficient oocytes; 3) abnormal yolk organelles in the oocyte cortex; and 4) unviable F1 embryos. However, we found that the similar phenotypes were the result of a specific cross-silencing effect among the PI3K subunits where the silencing of VPS38/UVRAG and ATG6/Beclin1 resulted in the specific silencing of each other, whereas the silencing of ATG14 triggered the silencing of all three PI3K components. Because the silencing of VPS38/UVRAG and ATG6/Beclin1 reproduced the yolk-deficiency phenotypes without the cross silencing of ATG14, we concluded that the VPS38/UVRAG PI3K complex II was the major contributor to the previously observed phenotypes in silenced insects.

Altogether, we found that class-III ATG6/Beclin1 PI3K complex II (VPS38/UVRAG) is essential for the yolk endocytosis and that the subunits of both complexes are under an unknown transcriptional regulatory system.
The association between socioeconomic status and pandemic influenza: Systematic review and meta-analysis
Authors: Mamelund Svenn-Erik , Shelley-Egan Clare , Rogeberg Ole
Published: September 2021

Background

The objective of this study is to document whether and to what extent there is an association between socioeconomic status (SES) and disease outcomes in the last five influenza pandemics.

Methods/principle findings

The review included studies published in English, Danish, Norwegian and Swedish. Records were identified through systematic literature searches in six databases. We summarized results narratively and through meta-analytic strategies. Only studies for the 1918 and 2009 pandemics were identified. Of 14 studies on the 2009 pandemic including data on both medical and social risk factors, after controlling for medical risk factors 8 demonstrated independent impact of SES. In the random effect analysis of 46 estimates from 35 studies we found a pooled mean odds ratio of 1.4 (95% CI: 1.2–1.7, p < 0.001), comparing the lowest to the highest SES, but with substantial effect heterogeneity across studies,–reflecting differences in outcome measures and definitions of case and control samples. Analyses by pandemic period (1918 or 2009) and by level of SES measure (individual or ecological) indicated no differences along these dimensions. Studies using healthy controls tended to document that low SES was associated with worse influenza outcome, and studies using infected controls find low SES associated with more severe outcomes. A few studies compared severe outcomes (ICU or death) to hospital admissions but these did not find significant SES associations in any direction. Studies with more unusual comparisons (e.g., pandemic vs seasonal influenza, seasonal influenza vs other patient groups) reported no or negative non-significant associations.

Conclusions/significance

We found that SES was significantly associated with pandemic influenza outcomes with people of lower SES having the highest disease burden in both 1918 and 2009. To prepare for future pandemics, we must consider social vulnerability. The protocol for this study has been registered in PROSPERO (ref. no 87922) and has been published Mamelund et al. (2019).
Evaluation of the whole auditory pathway using high-resolution and functional MRI at 7T parallel-transmit
Authors: Da Costa Sandra , Clément Jérémie , Gruetter Rolf , Ipek Özlem
Published: September 2021

Purpose

The aim of the present study is to show a MR procedure for the evaluation of simultaneous left and right auditory functions with functional MRI, and high-resolution acquisition of anatomical auditory pathway using parallel-transmit (pTx) methods at 7T.

Methods

The time-efficient MR acquisition included two steps: RF weights were optimized for the regions-of-interest and high-resolution MR images of the inner-ear were acquired for the first 30 min (400 μm-iso resolution) followed by functional MRI acquisitions along the whole auditory pathway during the next 20 minutes. Data was processed with a linear cross-correlation analysis to define frequency preferences for each voxel in the auditory relays.

Results

Tonotopic maps revealed ordered bilateral frequency gradients in the auditory relays whereas at the level of the cochlear nuclei and superior olivary complexes the frequency gradients were less evident. A 21% increase in transmit-field efficiency was achieved over the left/right inner-ear regions and thus its main structures were clearly discernible using the pTx methods, compared to a single transmit RF coil.

Conclusion

Using 7T pTx allows a fast (less than 60 min in total) and qualitative evaluation of the simultaneous left and right auditory response along the entire auditory pathway, together with high-resolution anatomical images of the inner-ear. This could be further used for patient examination at 7T.
Pentosan polysulfate sodium prevents functional decline in chikungunya infected mice by modulating growth factor signalling and lymphocyte activation
Authors: Rudd Penny A. , Lim Elisa X. Y. , Stapledon Catherine J. M. , Krishnan Ravi , Herrero Lara J.
Published: September 2021

Chikungunya virus (CHIKV) is an arthropod-borne virus that causes large outbreaks world-wide leaving millions of people with severe and debilitating arthritis. Interestingly, clinical presentation of CHIKV arthritides have many overlapping features with rheumatoid arthritis including cellular and cytokine pathways that lead to disease development and progression. Currently, there are no specific treatments or vaccines available to treat CHIKV infections therefore advocating the need for the development of novel therapeutic strategies to treat CHIKV rheumatic disease. Herein, we provide an in-depth analysis of an efficacious new treatment for CHIKV arthritis with a semi-synthetic sulphated polysaccharide, Pentosan Polysulfate Sodium (PPS). Mice treated with PPS showed significant functional improvement as measured by grip strength and a reduction in hind limb foot swelling. Histological analysis of the affected joint showed local inflammation was reduced as seen by a decreased number of infiltrating immune cells. Additionally, joint cartilage was protected as demonstrated by increased proteoglycan staining. Using a multiplex-immunoassay system, we also showed that at peak disease, PPS treatment led to a systemic reduction of the chemokines CXCL1, CCL2 (MCP-1), CCL7 (MCP-3) and CCL12 (MCP-5) which may be associated with the reduction in cellular infiltrates. Further characterisation of the local effect of PPS in its action to reduce joint and muscle inflammation was performed using NanoString™ technology. Results showed that PPS altered the local expression of key functional genes characterised for their involvement in growth factor signalling and lymphocyte activation. Overall, this study shows that PPS is a promising treatment for alphaviral arthritis by reducing inflammation and protecting joint integrity.
The properties of hot household hygroscopic materials and their potential use for non-medical facemask decontamination
Authors: Andreola Marie-Line , Becquart Fréderic , Jomaa Wahbi , Verhoeven Paul O. , Baldacchino Gérard , Hemour Simon ,   D-Mask consortium
Published: September 2021

The widespread use of facemasks throughout the population is recommended by the WHO to reduce transmission of the SARS-CoV-2 virus. As some regions of the world are facing mask shortages, reuse may be necessary. However, used masks are considered as a potential hazard that may spread and transmit disease if they are not decontaminated correctly and systematically before reuse. As a result, the inappropriate decontamination practices that are commonly witnessed in the general public are challenging management of the epidemic at a large scale. To achieve public acceptance and implementation, decontamination procedures need to be low-cost and simple. We propose the use of hot hygroscopic materials to decontaminate non-medical facemasks in household settings. We report on the inactivation of a viral load on a facial mask exposed to hot hygroscopic materials for 15 minutes. As opposed to recent academic studies whereby decontamination is achieved by maintaining heat and humidity above a given value, a more flexible procedure is proposed here using a slow decaying pattern, which is both effective and easier to implement, suggesting straightforward public deployment and hence reliable implementation by the population.
Exogenous corticosterone and melanin-based coloration explain variation in juvenile dispersal behaviour in the barn owl (Tyto alba)
Authors: Almasi Bettina , Massa Carolina , Jenni Lukas , Roulin Alexandre
Published: September 2021

Natal dispersal affects many processes such as population dynamics. So far, most studies have examined the intrinsic and extrinsic factors that determine the distance between the place of birth and of first breeding. In contrast, few researchers followed the first steps of dispersal soon after fledging. To study this gap, we radio-tracked 95 barn owl nestlings (Tyto alba) to locate their diurnal roost sites from the fledging stage until December. This was used to test whether the age of nest departure, post-fledging movements and dispersal distance were related to melanin-based coloration, which is correlated to fitness-related traits, as well as to corticosterone, a hormone that mediates a number of life history trade-offs and the physiological and behavioural responses to stressful situations. We found that the artificial administration of corticosterone delayed the age when juveniles left their parental home-range in females but not in males. During the first few months after fledging, longer dispersal distances were reached by females compared to males, by individuals marked with larger black feather spots compared to individuals with smaller spots, by larger individuals and by those experimentally treated with corticosterone. We conclude that the onset and magnitude of dispersal is sensitive to the stress hormone corticosterone, melanin-based coloration and body size.
Raman spectroscopy on blood serum samples of patients with end-stage liver disease
Authors: Staritzbichler René , Hunold Pascal , Estrela-Lopis Irina , Hildebrand Peter Werner , Isermann Berend , Kaiser Thorsten
Published: September 2021

Raman spectroscopy has shown to be a promising method for the examination of biomedical samples. However, until now, its efficacy has not been established in clinical diagnostics. In this study, Raman spectroscopy’s potential application in medical laboratories is evaluated for a large variety (38) of biomarkers. Given 234 serum samples from a cohort of patients with different stages of liver disease, we performed Raman spectroscopy at 780nm excitation wavelength. The Raman spectra were analyzed in combination with the results of routine diagnostics using specifically developed complex mathematical algorithms, including fluorescence filtering, frequency subset selection and several overfitting circumventing strategies, such as independent validation. With the results of this cohort, which were validated in 328 independent samples, a significant proof-of-concept study was completed. This study highlights the need to prevent overfitting and to use independent data for validation. The results reveal that Raman spectroscopy has high potential for use in medical laboratory diagnostics to simultaneously quantify multiple biomarkers.
Monitoring adherence to pharmacological therapy and follow-up examinations among patients with type 2 diabetes in community pharmacies. Results from an experience in Italy
Authors: Spadea Teresa , Onorati Roberta , Baratta Francesca , Pignata Irene , Parente Marco , Pannacci Lavinia , Ancona Domenica , Ribecco Paola , Costa Giuseppe , Gnavi Roberto , Brusa Paola
Published: September 2021

Introduction

Type 2 diabetes is an important public health issue, yet adherence to drugs and regular clinical follow-up is still suboptimal. This study aims to evaluate a community pharmacy programme for monitoring and enhancing adherence to prescribed pharmacological therapies and recommended examinations among patients with confirmed diabetes.

Methods

The intervention was conducted in different Italian areas between April 2017 and January 2018. All adult patients who entered a pharmacy with a personal prescription for any antidiabetic drug and agreed to participate, were interviewed. Those found to be non-adherent received counselling from the pharmacists. All patients were invited for a follow-up interview after 3 months.

Results

Overall, 930 patients were enrolled and completed the baseline interview. We found low rates of non-adherence, ranging from 8% to 13% for prescribed pharmacological therapies, and 11–29% for the recommended clinical examinations. Non-adherence to oral therapies was higher among younger and recently diagnosed patients; that to clinical examinations was higher in men, those with an intermediate duration of diabetes and less educated patients. Large geographical differences persisted after the adjustment for individual factors. Only 306 patients (32.9%) returned for the follow-up interview, most of whom were already adherent at baseline.

Conclusions

Poor adherence to drugs or clinical examinations is not easy to identify in the usual operating setting of community pharmacies. Furthermore, the majority of patients did not return for follow-up, making it impossible to evaluate the efficacy of the pharmacists’ counselling. It might be more effective to plan interventions addressed to specific subgroups of patients or areas.
Higher education and science popularization: Can they achieve coordinated growth?
Authors: Geng Yuqing , Yan Yan
Published: September 2021

This study aims to explore whether higher education and science popularization can achieve coordinated growth with temporal and spatial characteristics. Selecting the provincial regions of the Yangtze River Economic Belt in China as cases with data from the national statistics administrations (such as China Statistical Yearbook), this study uses entropy weight analysis, TOPSIS, GM(1,1) gray prediction methods and coupling coordination degree model to evaluate the coordinated growth status. The key findings are: (1) the annual budget per student, and the number of science and technology museums affect both systems more obviously; (2) the overall performances of science popularization fluctuate more obviously than those of higher education; (3) the coordinated growth performances of the two systems in most regions remain mild fluctuations and keep relatively stable coordinated status, however, temporal and spatial variation tendencies do exist among regions. Therefore, corresponding countermeasures should be implemented: generally, national authority needs to involve in coordination activities among regions; the regions with satisfactory coordinated growth performances need more creative approaches to maintain the coordinated growth interactions; the regions at the transitioning status need to prevent the grade decline and upgrade the performances; the regions with lagging performances need to stop the decline and reduce the gaps with others. The novelties include analyzing the coordinated growth interaction mechanism between the two, selecting indices to assess the abstract interaction mechanism precisely, proposing suggestions based on temporal and spatial comparisons of the coordinated growth performances, etc.
Random forest-integrated analysis in AD and LATE brain transcriptome-wide data to identify disease-specific gene expression
Authors: Wu Xinxing , Peng Chong , Nelson Peter T. , Cheng Qiang
Published: September 2021

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects thinking, memory, and behavior. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently identified common neurodegenerative disease that mimics the clinical symptoms of AD. The development of drugs to prevent or treat these neurodegenerative diseases has been slow, partly because the genes associated with these diseases are incompletely understood. A notable hindrance from data analysis perspective is that, usually, the clinical samples for patients and controls are highly imbalanced, thus rendering it challenging to apply most existing machine learning algorithms to directly analyze such datasets. Meeting this data analysis challenge is critical, as more specific disease-associated gene identification may enable new insights into underlying disease-driving mechanisms and help find biomarkers and, in turn, improve prospects for effective treatment strategies. In order to detect disease-associated genes based on imbalanced transcriptome-wide data, we proposed an integrated multiple random forests (IMRF) algorithm. IMRF is effective in differentiating putative genes associated with subjects having LATE and/or AD from controls based on transcriptome-wide data, thereby enabling effective discrimination between these samples. Various forms of validations, such as cross-domain verification of our method over other datasets, improved and competitive classification performance by using identified genes, effectiveness of testing data with a classifier that is completely independent from decision trees and random forests, and relationships with prior AD and LATE studies on the genes linked to neurodegeneration, all testify to the effectiveness of IMRF in identifying genes with altered expression in LATE and/or AD. We conclude that IMRF, as an effective feature selection algorithm for imbalanced data, is promising to facilitate the development of new gene biomarkers as well as targets for effective strategies of disease prevention and treatment.
Microbiota composition and mucosal immunity in patients with asymptomatic diverticulosis and controls
Authors: van Rossen Tessel M. , Ooijevaar Rogier E. , Kuyvenhoven Johan Ph. , Eck Anat , Bril Herman , Buijsman René , Boermeester Marja A. , Stockmann Hein B. A. C. , de Korte Niels , Budding Andries E.
Published: September 2021

Introduction

The etiology of diverticulosis is still poorly understood. However, in patients with diverticulitis, markers of mucosal inflammation and microbiota alterations have been found. The aim of this study was to evaluate potential differences of the gut microbiota composition and mucosal immunity between patients with asymptomatic diverticulosis and controls.

Methods

We performed a prospective study on patients who underwent routine colonoscopy for causes not related to diverticular disease or inflammatory bowel disease. Participants were grouped based on the presence or absence of diverticula. Mucosal biopsies were obtained from the sigmoid and transverse colon. Microbiota composition was analyzed with IS-pro, a 16S-23S based bacterial profiling technique. To predict if patients belonged to the asymptomatic diverticulosis or control group a partial least squares discriminant analysis (PLS-DA) regression model was used. Inflammation was assessed by neutrophil and lymphocyte counts within the taken biopsies.

Results

Forty-three patients were enrolled. Intestinal microbiota profiles were highly similar within individuals for all phyla. Between individuals, microbiota profiles differed substantially but regardless of the presence (n = 19) of absence (n = 24) of diverticula. Microbiota diversity in both sigmoid and transverse colon was similar in all participants. We were not able to differentiate between diverticulosis patients and controls with a PLS-DA model. Mucosal lymphocyte counts were comparable among both groups; no neutrophils were detected in any of the studied biopsies.

Conclusions

Microbiota composition and inflammatory markers were comparable among asymptomatic diverticulosis patients and controls. This suggests that the gut microbiota and mucosal inflammation do not play a major role in the pathogenesis of diverticula formation.
Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells
Authors: von Beek Christopher , Alriksson Linnéa , Palle Josefine , Gustafson Ann-Marie , Grujic Mirjana , Melo Fabio Rabelo , Sellin Mikael E. , Pejler Gunnar
Published: September 2021

Current chemotherapy for treatment of pediatric acute leukemia, although generally successful, is still a matter of concern due to treatment resistance, relapses and life-long side effects for a subset of patients. Inhibition of dynamin, a GTPase involved in clathrin-mediated endocytosis and regulation of the cell cycle, has been proposed as a potential anti-cancer regimen, but the effects of dynamin inhibition on leukemia cells has not been extensively addressed. Here we adopted single cell and whole-population analysis by flow cytometry and live imaging, to assess the effect of dynamin inhibition (Dynasore, Dyngo-4a, MitMAB) on pediatric acute leukemia cell lines (CCRF-CEM and THP-1), human bone marrow biopsies from patients diagnosed with acute lymphoblastic leukemia (ALL), as well as in a model of lymphoma (EL4)-induced tumor growth in mice. All inhibitors suppressed proliferation and induced pronounced caspase-dependent apoptotic cell death in CCRF-CEM and THP-1 cell lines. However, the inhibitors showed no effect on bone marrow biopsies, and did not prevent EL4-induced tumor formation in mice. We conclude that dynamin inhibition affects highly proliferating human leukemia cells. These findings form a basis for evaluation of the potential, and constraints, of employing dynamin inhibition in treatment strategies against leukemia and other malignancies.
Effect of TSH stimulation protocols on adequacy of low-iodine diet for radioiodine administration
Authors: Lee Hwanhee , Paeng Jin Chul , Choi Hongyoon , Cho Sun Wook , Park Young Joo , Park Do Joon , Lee Young Ah , Chung June-Key , Kang Keon Wook , Cheon Gi Jeong
Published: September 2021

Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of thyroid stimulating hormone (TSH) stimulation protocols and other clinical factors on LID adequacy. Thyroid cancer patients who underwent LID for RAI scan or treatment were retrospectively analyzed. Patients were guided to have LID for 2 weeks before RAI administration and urine iodine/creatinine ratio (UICR, μg/g Cr) was measured. TSH stimulation was conducted using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) injection. Adequacy of LID was classified by UICR as ‘excellent (< 50)’, ‘adequate (50–100)’, ‘inadequate (101–250)’ and ‘poor (> 250)’. A total of 1715 UICR measurements from 1054 patients were analyzed. UICR was significantly higher in case of rhTSH use than THW (72.4 ± 48.1 vs. 29.9 ± 45.8 μg/g Cr,P< 0.001). In patients who underwent LID twice using both TSH stimulation protocols alternately, UICR was higher in case of rhTSH than THW regardless of the order of method. Among clinical factors, female, old-age, and the first LID were significant factors to show higher UICR. Although the adequacy of LID was ‘adequate’ or ‘excellent’ in most patients, multivariate analysis demonstrated that THW method, male, young age, and prior LID-experience were significant determinants for achieving ‘excellent’ adequacy of LID. In conclusion, UICR was higher and the proportion of ‘excellent’ LID adequacy was lower with rhTSH than with THW. UICR was higher also in women, old-age, and LID-naïve patients. Further researches are required to suggest effective methods to reduce body iodine pool in case of rhTSH use and to validate the efficacy of such methods on outcomes of RAI treatment.
Health system efficiency and democracy: A public choice perspective
Authors: Roessler Martin , Schmitt Jochen
Published: September 2021

Due to increasing demand and scarce financial resources for healthcare, health system efficiency has become a major topic in political and scientific debates. While previous studies investigating determinants of health system efficiency focused primarily on economic and social influence factors, the role of the political regime has been neglected. In addition, there is a lack of formal theoretical work on this specific topic, which ensures transparency and logical consistency of arguments and implications. Using a public choice approach, this paper provides a rigorous theoretical and empirical investigation of the relationships between health system efficiency and political institutions. We develop a simple principal-agent model describing the behavior of a government with respect to investments in population health under different political regimes. The main implication of the theoretical model is that governments under more democratic regimes put more effort in reducing embezzlement of health expenditure than non-democratic regimes. Accordingly, democratic countries are predicted to have more efficient health systems than non-democratic countries. We test this hypothesis based on a broad dataset including 158 countries over the period 1995-2015. The empirical results clearly support the implications of the theoretical model and withstand several robustness checks, including the use of alternative indicators for population health and democracy and estimations accounting for endogeneity. The empirical results also indicate that the effect of democracy on health system efficiency is more pronounced in countries with higher income levels. From a policy perspective, we discuss the implications of our findings in the context of health development assistance.
Beyond identity: Understanding the contribution of the 5’ nucleotide of the antisense strand to RNAi activity
Authors: Yang Peizhen , Havecker Ericka , Bauer Matthew , Diehl Carl , Hendrix Bill , Hoffer Paul , Boyle Timothy , Bradley John , Caruano-Yzermans Amy , Deikman Jill
Published: September 2021

In both the pharmaceutical and agricultural fields, RNA-based products have capitalized upon the mechanism of RNA interference for targeted reduction of gene expression to improve phenotypes and traits. Reduction in gene expression by RNAi is the result of a small interfering RNA (siRNA) molecule binding to an ARGONAUTE (AGO) protein and directing the effector complex to a homologous region of a target gene’s mRNA. siRNAs properties that govern RNA-AGO association have been studied in detail. The siRNA 5’ nucleotide (nt) identity has been demonstrated in plants to be an important property responsible for directing association of endogenous small RNAs with different AGO effector proteins. However, it has not been investigated whether the 5’ nt identity is an efficacious determinant for topically-applied chemically synthesized siRNAs. In this study, we employed a sandpaper abrasion method to study the silencing efficacies of topically-applied 21 base-pair siRNA duplexes. TheMAGNESIUM CHELATASEandGREEN FLUORESCENT PROTEINgenes were selected as endogenous and transgenic gene targets, respectively, to assess the molecular and phenotypic effects of gene silencing. Collections of siRNA variants with different 5’ nt identities and different pairing states between the 5’ antisense nt and its match in the sense strand of the siRNA duplex were tested for their silencing efficacy. Our results suggest a flexibility in the 5’ nt requirement for topically applied siRNA duplexesin plantaand highlight the similarity of 5’ thermodynamic rules governing topical siRNA efficacy across plants and animals.
Small-scale urban agriculture: Drivers of growing produce at home and in community gardens in Detroit
Authors: Grebitus Carola
Published: September 2021

The desire for fresh, local food has increased interest in alternative food production approaches, such as private small-scale agriculture, wherein households grow their own food. Accordingly, it is worth investigating private agricultural production, especially in urban areas, given that an increasing share of the world’s population is living in cities. This study analyzed the growth of produce at people’s homes and in community gardens, focusing on behavioral and socio-demographic factors. Data were collected through an online survey in Detroit, Michigan; 420 citizens were interviewed. The results revealed that trust, attitude, and knowledge affect the growing of produce at home. Involvement and personality are also drivers of community gardening. Regarding socio-demographics, household size affects the growing of produce at home, while gender, age, and income affect community gardening. The findings have valuable implications for stakeholders who wish to foster private small-scale urban agriculture, for example, through city planning and nutrition education.
Translation of human Δ133p53 mRNA and its targeting by antisense oligonucleotides complementary to the 5′-terminal region of this mRNA
Authors: Żydowicz-Machtel Paulina , Dutkiewicz Mariola , Swiatkowska Agata , Gurda-Woźna Dorota , Ciesiołka Jerzy
Published: September 2021

The p53 protein is expressed as at least twelve protein isoforms. Within intron 4 of the human TP53 gene, a P2 transcription initiation site is located and this transcript encodes two p53 isoforms: Δ133p53 and Δ160p53. Here, the secondary structure of the 5′-terminal region of P2-initiated mRNA was characterized by means of the SHAPE and Pb2+-induced cleavage methods and for the first time, a secondary structure model of this region was proposed. Surprisingly, only Δ133p53 isoform was synthetized in vitro from the P2-initiated p53 mRNA while translation from both initiation codons occurred after the transfection of vector-encoded model mRNA to HCT116 cells. Interestingly, translation performed in the presence of the cap analogue suggested that the cap-independent process contributes to the translation of P2-initiated p53 mRNA. Subsequently, several antisense oligonucleotides targeting the 5′-terminal region of P2-initiated p53 mRNA were designed. The selected oligomers were applied in in vitro translation assays as well as in cell lines and their impact on the Δ133p53 synthesis and on cell viability was investigated. The results show that these oligomers are attractive tools in the modulation of the translation of P2-initiated p53 mRNA through attacking the 5′ terminus of the transcript. Since cell proliferation is also reduced by antisense oligomers that lower the level of Δ133p53, this demonstrates an involvement of this isoform in tumorigenesis.
A comparison of the effects of monotherapy with rosuvastatin, atorvastatin or ezetimibe versus combination treatment with rosuvastatin-ezetimibe and atorvastatin-ezetimibe on the integrity of vascular endothelial cells damaged by oxidized cholesterol
Authors: Niedzielski Mateusz , Broncel Marlena , Gorzelak-Pabiś Paulina , Woźniak Ewelina
Published: September 2021

Dyslipidemia, atherosclerosis, and cardiovascular events can be prevented, or treated, using statins, alone or in combination with ezetimibe. The aim of the study was to compare the direct pleiotropic effects of two commonly-used statins (atorvastatin, rosuvastatin), ezetimibe and their combinations on endothelial cells damaged by oxidized cholesterol. HUVEC cultures were stimulated for 20 hours with atorvastatin (5 μM; 2793 ng/mL), rosuvastatin (10 μM; 4815 ng/mL), ezetimibe (1.22 μM; 500 ng/mL), atorvastatin plus ezetimibe (5 μM + 1.22 μM; 2793 ng/mL + 500 ng/mL) and rosuvastatin plus ezetimibe (10 μM + 1.22 μM; 4815 ng/mL + 500ng/mL) in separate groups, with or without 25-hydroxycholesterol pre-incubation (24.83 μM; 10 μg/mL; four hours then washout). HUVEC integrity was measured in the RTCA-DP xCELLigence system. The mRNA expression and protein levels of ZO-1, OCLN, ICAM-1 were analyzed by real-time PCR and ELISA. Pre-incubation with 25-OHC resulted in decreased endothelial cell integrity (p<0.001), decreased expression of ZO-1 mRNA (p<0.05) and protein levels (p<0.05), OCLN mRNA (p<0.05) and protein levels (p<0.05) and increased ICAM-1 mRNA (p<0.001) and protein levels (p<0.001) compared to the control group. Incubation with rosuvastatin (12h p<0.01; 24h p<0.001) and atorvastatin (only 12h p<0.05) restored HUVEC integrity. Subsequent incubation with rosuvastatin increased ZO-1 mRNA (p<0.001) and protein (p<0.001) levels. Subsequent addition of ezetimibe increased ZO-1 mRNA level (p<0.001) but not protein level. Furthermore, only incubation with rosuvastatin increased OCLN mRNA (p<0.05) and protein (p<0.05) levels. In each drug-stimulated group, both ICAM-1 mRNA and protein levels were reduced after initial incubation with oxysterol (p<0.05). 25-hydroxycholesterol disrupts endothelial integrity, decreases the mRNA and protein levels of tight junction, and increases those of intercellular adhesion molecules. Both rosuvastatin and atorvastatin can improve endothelial integrity, but only rosuvastatin can completely abolish the effect of oxysterol. The combination of statins with ezetimibe has less direct effect on the endothelial barrier than the statins alone.
Fishing trip cost modeling using generalized linear model and machine learning methods – A case study with longline fisheries in the Pacific and an application in Regulatory Impact Analysis
Authors: Chan Hing Ling , Pan Minling
Published: September 2021

Fishing trip cost is an important element in evaluating economic performance of fisheries, assessing economic effects from fisheries management alternatives, and serving as input for ecosystem and bioeconomic modeling. However, many fisheries have limited trip-level data due to low observer coverage. This article introduces a generalized linear model (GLM) utilizing machine learning (ML) techniques to develop a modeling approach to estimate the functional forms and predict the fishing trip costs of unsampled trips. GLM with Lasso regularization and ML cross-validation of model are done simultaneously for predictor selection and evaluation of the predictive power of a model. This modeling approach is applied to estimate the trip-level fishing costs using the empirical sampled trip costs and the associated trip-level fishing operational data and vessel characteristics in the Hawaii and American Samoa longline fisheries. Using this approach to build models is particularly important when there is no strong theoretical guideline on predictor selection. Also, the modeling approach addresses the issue of skewed trip cost data and provides predictive power measurement, compared with the previous modeling efforts in trip cost estimation for the Hawaii longline fishery. As a result, fishing trip costs for all trips in the fishery can be estimated. Lastly, this study applies the estimated trip cost model to conduct an empirical analysis to evaluate the impacts on trip costs due to spatial regulations in the Hawaii longline fishery. The results show that closing the Western and Central Pacific Ocean (WCPO) could induce an average 14% increase in fishing trip costs, while the trip cost impacts of the Eastern Pacific Ocean (EPO) closures could be lower.
Adaptive capacity and flexibility of the Neanderthals at Heidenschmiede (Swabian Jura) with regard to core reduction strategies
Authors: Çep Berrin , Schürch Benjamin , Münzel Susanne C. , Frick Jens Axel
Published: September 2021

The branched reduction system at the Heidenschmiede described here is hitherto exceptional for the Middle Paleolithic of the Swabian Jura. By means of refits and supporting objects, we are able to describe a superordinate reduction system that combines several individual reduction concepts, such as Levallois and blade production, within one volume. In the Middle Paleolithic of the Swabian Jura, blade technology has thus far played a rather minor role. On the one hand, it is possible to split a selected volume (nodule) into three parts, which are reduced separately according to individual concepts. On the other hand, it is also possible to reduce parts of a volume with one concept first and then with another. The hypothetical reduction system can be branched or linear, thus emphasizing the technological flexibility in core reduction, which requires a high degree of cognitive skills of three-dimensional imagination.
Novel Drexlerviridae bacteriophage KMI8 with specific lytic activity against Klebsiella michiganensis and its biofilms
Authors: Ku Heng , Kabwe Mwila , Chan Hiu Tat , Stanton Cassandra , Petrovski Steve , Batinovic Steven , Tucci Joseph
Published: September 2021

The bacterial genus Klebsiella includes the closely related species K. michiganensis, K. oxytoca and K. pneumoniae, which are capable of causing severe disease in humans. In this report we describe the isolation, genomic and functional characterisation of the lytic bacteriophage KMI8 specific for K. michiganensis. KMI8 belongs to the family Drexlerviridae, and has a novel genome which shares very little homology (71.89% identity over a query cover of only 8%) with that of its closest related bacteriophages (Klebsiella bacteriophage LF20 (MW417503.1); Klebsiella bacteriophage 066039 (MW042802.1). KMI8, which possess a putative endosialidase (depolymerase) enzyme, was shown to be capable of degrading mono-biofilms of a strain of K. michiganensis that carried the polysaccharide capsule KL70 locus. This is the first report of a lytic bacteriophage for K. michiganensis, which is capable of breaking down a biofilm of this species.