bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep sequencing of the HIV-1 polymerase gene for characterisation of cytotoxic T-lymphocyte epitopes during early and chronic disease stages
Authors: Nkone Paballo , Loubser Shayne , Quinn Thomas C. , Redd Andrew D. , Ismail Arshad , Tiemessen Caroline T. , Mayaphi Simnikiwe H.
Published: March 2022

Background

Despite multiple attempts, there is still no effective HIV-1 vaccine available. The HIV-1 polymerase (pol) gene is highly conserved and encodes cytotoxic T-lymphocyte (CTL) epitopes. The aim of the study was to characterise HIV-1 Pol CTL epitopes in mostly sample pairs obtained during early and chronic stages of infection.

Methods

Illumina deep sequencing was performed for all samples while Sanger sequencing was only performed on baseline samples. Codons under immune selection pressure were assessed by computing nonsynonymous to synonymous mutation ratios using MEGA. Minority CTL epitope variants occurring at $$\ge$$
≥
5% were detected using low-frequency variant tool in CLC Genomics. Los Alamos HIV database was used for mapping mutations to known HIV-1 CTL epitopes.

Results

Fifty-two participants were enrolled in the study. Their median age was 28 years (interquartile range: 24–32 years) and majority of participants (92.3%) were female. Illumina minority variant analysis identified a significantly higher number of CTL epitopes (n = 65) compared to epitopes (n = 8) identified through Sanger sequencing. Most of the identified epitopes mapped to reverse transcriptase (RT) and integrase (IN) regardless of sequencing method. There was a significantly higher proportion of minority variant epitopes in RT (n = 39, 60.0%) compared to IN (n = 17, 26.2%) and PR (n = 9, 13.8%), p = 0.002 and < 0.0001, respectively. However, no significant difference was observed between the proportion of minority variant epitopes in IN versus PR, p = 0.06. Some epitopes were detected in either early or chronic HIV-1 infection whereas others were detected in both stages. Different distribution patterns of minority variant epitopes were observed in sample pairs; with some increasing or decreasing over time, while others remained constant. Some of the identified epitopes have not been previously reported for HIV-1 subtype C. There were also variants that could not be mapped to reported CTL epitopes in the Los Alamos HIV database.

Conclusion

Deep sequencing revealed many Pol CTL epitopes, including some not previously reported for HIV-1 subtype C. The findings of this study support the inclusion of RT and IN epitopes in HIV-1 vaccine candidates as these proteins harbour many CTL epitopes.
HBx inhibits DNA sensing signaling pathway via ubiquitination and autophagy of cGAS
Authors: Chen Hong , Jiang Linshan , Chen Shu , Hu Qin , Huang Ying , Wu Ying , Chen Weixian
Published: March 2022

Background

Cyclic GMP-AMP synthase (cGAS) is a crucial DNA sensor and plays an important role in host antiviral innate immune responses. During hepatitis B virus (HBV) infection, the cGAS signaling pathway can suppress HBV replication. As an important regulatory protein of HBV, hepatitis B virus X protein (HBx) may serve as an antagonistic character to the cGAS/STING signaling pathway. In this study, we aim to investigate the functional role of HBx in the cGAS/STING signaling pathway.

Methods

The effects of HBx on IFN-β promoter activity were measured by Dual-luciferase reporter assays. Ubiquitination and autophagy were analyzed by Western-blot and Co-immunoprecipitation assays.

Results

Our results show that HBx down-regulates IFN-I production by directly promoting ubiquitination and autophagy degradation of cGAS.

Conclusions

HBV can antagonize host cGAS DNA sensing to promote HBV replication and provide novel insights to develop novel approaches against HBV infection.
Occupational injury and associated factors among cement factories workers in central Ethiopia
Authors: Fresenbet Demissu Seyoum , Olana Ararso Tafese , Tulu Abera Shibiru , Danusa Kababa Temesgen
Published: March 2022

Background

The cement industry experiences accident rate is high compared to other manufacturing industries. Hence, this study was aimed to assess the occupational injury and associated factors among cement factories workers in West Shoa Zone, Oromia regional state, Ethiopia 2020.

Methods

An institution-based cross-sectional study design was employed. A total of 374 study participants were selected by using a systematic random sampling technique with K-interval. The collected data were entered into Epi-Info version 7 and analyzed by using SPSS version 21. Bivariate and multivariable binary logistic regression was used to identify the magnitude of occupational injury and the factor associated. A statistically significant association was declared at a 95% confidence interval and p-value<0.05.

Results

The study revealed that the magnitude of occupational injury among workers of cement factories was 183(48.9%). Workers found in an engineering department were 3.7 times more likely to be injured than those who were working in a clinker department [AOR: 3.72, 95% CI: 1.35-10.18]. Those workers who were working room did not have danger signs were 2.9 times more likely to be injured than their counterparts [AOR 2.99, 95% CI: 1.79-4.98). Those workers who did not use personal protective equipment were 3.7 times more likely to be injured than those who were used Personal Protective Equipments [AOR: 3.78, 95% CI: 1.76 - 8.12].

Conclusion

The magnitude of occupational injury in cement factories in the study area was high. The factories’ managers must provide adequate and quality safety materials in a timely and supervise their appropriate use and put danger signs where it is required.
MultipleXLab: A high-throughput portable live-imaging root phenotyping platform using deep learning and computer vision
Authors: Lube Vinicius , Noyan Mehmet Alican , Przybysz Alexander , Salama Khaled , Blilou Ikram
Published: March 2022

Background

Profiling the plant root architecture is vital for selecting resilient crops that can efficiently take up water and nutrients. The high-performance imaging tools available to study root-growth dynamics with the optimal resolution are costly and stationary. In addition, performing nondestructive high-throughput phenotyping to extract the structural and morphological features of roots remains challenging.

Results

We developed the MultipleXLab: a modular, mobile, and cost-effective setup to tackle these limitations. The system can continuously monitor thousands of seeds from germination to root development based on a conventional camera attached to a motorized multiaxis-rotational stage and custom-built 3D-printed plate holder with integrated light-emitting diode lighting. We also developed an image segmentation model based on deep learning that allows the users to analyze the data automatically. We tested the MultipleXLab to monitor seed germination and root growth of Arabidopsis developmental, cell cycle, and auxin transport mutants non-invasively at high-throughput and showed that the system provides robust data and allows precise evaluation of germination index and hourly growth rate between mutants.

Conclusion

MultipleXLab provides a flexible and user-friendly root phenotyping platform that is an attractive mobile alternative to high-end imaging platforms and stationary growth chambers. It can be used in numerous applications by plant biologists, the seed industry, crop scientists, and breeding companies.
Installation and imaging of thousands of minirhizotrons to phenotype root systems of field-grown plants
Authors: Rajurkar Ashish B. , McCoy Scott M. , Ruhter Jeremy , Mulcrone Jessica , Freyfogle Luke , Leakey Andrew D. B.
Published: March 2022

Background

Roots are vital to plant performance because they acquire resources from the soil and provide anchorage. However, it remains difficult to assess root system size and distribution because roots are inaccessible in the soil. Existing methods to phenotype entire root systems range from slow, often destructive, methods applied to relatively small numbers of plants in the field to rapid methods that can be applied to large numbers of plants in controlled environment conditions. Much has been learned recently by extensive sampling of the root crown portion of field-grown plants. But, information on large-scale genetic and environmental variation in the size and distribution of root systems in the field remains a key knowledge gap. Minirhizotrons are the only established, non-destructive technology that can address this need in a standard field trial. Prior experiments have used only modest numbers of minirhizotrons, which has limited testing to small numbers of genotypes or environmental conditions. This study addressed the need for methods to install and collect images from thousands of minirhizotrons and thereby help break the phenotyping bottleneck in the field.

Results

Over three growing seasons, methods were developed and refined to install and collect images from up to 3038 minirhizotrons per experiment. Modifications were made to four tractors and hydraulic soil corers mounted to them. High quality installation was achieved at an average rate of up to 84.4 minirhizotron tubes per tractor per day. A set of four commercially available minirhizotron camera systems were each transported by wheelbarrow to allow collection of images of mature maize root systems at an average rate of up to 65.3 tubes per day per camera. This resulted in over 300,000 images being collected in as little as 11 days for a single experiment.

Conclusion

The scale of minirhizotron installation was increased by two orders of magnitude by simultaneously using four tractor-mounted, hydraulic soil corers with modifications to ensure high quality, rapid operation. Image collection can be achieved at the corresponding scale using commercially available minirhizotron camera systems. Along with recent advances in image analysis, these advances will allow use of minirhizotrons at unprecedented scale to address key knowledge gaps regarding genetic and environmental effects on root system size and distribution in the field.
Dosimetric and radiobiological comparison of simultaneous integrated boost radiotherapy for early stage right side breast cancer between three techniques: IMRT, hybrid IMRT and hybrid VMAT
Authors: Bi Suyan , Zhu Rui , Dai Zhitao
Published: March 2022

Purpose

This study aimed at evaluating the clinical impact of full intensity-modulated radiotherapy (IMRT), hybrid IMRT (H-IMRT) and hybrid volumetric-modulated arc therapy (H-VMAT) for early-stage breast cancer with simultaneous integrated boost (SIB), in terms of plan quality and second cancer risk (SCR).

Methods

Three different plans were designed in full IMRT, hybrid IMRT, and hybrid VMAT for each of twenty patients with early-stage breast cancer. Target quality, organs at risk (OARs) sparing, and SCR were compared among the three plans for each case.

Results

In compared with H-IMRT, IMRT plans showed deterioration in terms of D2% of SIB, V10 of ipsilateral lung, and excess absolute risk (EAR) to contralateral lung (C-Lung) and esophagus. D2% and the homogeneity index (HI) of SIB, V5 of ipsilateral lung (I-Lung), the Dmean of the esophagus, the EAR to C-Lung and the esophagus with hybrid VMAT dramatically increased by 0.63%, 10%, 17.99%, 149.27%, 230.41%, and 135.29%, respectively (p = 0.024; 0.025; 0.046; 0.011; 0.000; 0.014). Dmean of the heart, the EAR to contralateral breast (C-Breast) and C-Lung by full IMRT was significantly decreased in comparison to the H-VMAT (4.67%, p = 0.033, 26.76%, p = 0.018; 48.05%, p = 0.036).

Conclusion

The results confirmed that H-IMRT could achieve better target quality and OARs sparing than IMRT and H-VMAT for SIB radiotherapy of early-stage right breast cancer. H-IMRT was the best treatment option, while H-VMAT performed the worst among the three plans in terms of SCR to peripheral OARs.
Chemoradiotherapy is an alternative choice for patients with primary mediastinal seminoma
Authors: Zhai Yirui , Chen Bo , Feng Xiaoli , Liu Kan , Wang Shulian , Hui Zhouguang , Feng Qinfu , Li Junling , Xiao Zefen , Lv Jima , Gao Yushun , Liu Yueping , Fang Hui , Wang Jianyang , Deng Lei , Liu Wenyang , Wang Wenqing , Zhou Zongmei , Li Ye-Xiong
Published: March 2022

Background

The low incidence of primary mediastinal seminomas has precluded the development of clinical trials on mediastinal seminomas. We investigated the clinicopathologic characteristics, prognosis of patients with primary mediastinal seminomas as well as the efficiency of nonsurgical treatments compared with treatments containing surgery.

Methods

We retrospectively collected data on the clinicopathologic characteristics, treatments, toxicities, and survival of 27 patients from a single center between 2000 and 2018. Patients were divided into two groups according to whether they received operation. Survivals were assessed using the Kaplan–Meier method. Univariate analysis was performed using the log-rank test.

Results

The median age was 28 (13–63) years. The most common symptoms were chest pain (29.6%), cough (25.9%), and dyspnea (22.2%). There were 13 and 14 patients in surgery and non-surgery group. Patients in the non-surgical group were more likely to be with poor performance scores (100% vs. 76.9%) and disease invaded to adjacent structures (100% vs. 76.9%) especially great vessels (100% vs. 46.2%).The median follow-up period was 32.23 (2.7–198.2) months. There was no significant difference of overall survival (5-year 100% vs. 100%), cancer-specific survival (5-year 100% vs. 100%), local regional survival (5-year 91.7% vs. 90.0%, p = 0.948), distant metastasis survival (5-year 90.9% vs. 100.0%, p = 0.340) and progression-free survival (82.5% vs. 90.0%, p = 0.245) between patients with and without surgery.

Conclusions

Primary mediastinal seminoma was with favorable prognosis, even though frequently invasion into adjacent structures brings difficulties to surgery administration. Chemoradiotherapy is an alternative treatment with both efficacy and safety.
MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial
Authors: Hoegen P. , Zhang K. S. , Tonndorf-Martini E. , Weykamp F. , Regnery S. , Naumann P. , Lang K. , Ristau J. , Körber S. A. , Dreher C. , Buchele C. , Rippke C. , Renkamp C. K. , Paul K. M. , König L. , Büsch C. , Krisam J. , Sedlaczek O. , Schlemmer H.-P. , Niyazi M. , Corradini S. , Debus J. , Klüter S. , Hörner-Rieber J.
Published: March 2022

Background

Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach.

Methods

This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1–3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/β = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated.

Discussion

MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs.

Trial registration

The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, “Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)”, NCT05027711.
Sequential damage assessment of the posterolateral complex of the knee joint: a finite element study
Authors: Wu Cong-Cong , Ye Li-Mei , Li Xiao-Fei , Shi Lin-Jun
Published: March 2022

Background

The posterolateral complex (PLC), which consists of the popliteus tendon (PT), lateral collateral ligament (LCL), and popliteofibular ligament (PFL), is an indispensable structure of the knee joint. The aim of this study was to explore the functionality of the PLC by determining the specific role of each component in maintaining posterolateral knee stability.

Methods

A finite element (FE) model was generated based on previous material property data and magnetic resonance imaging of a volunteer’s knee joint. The injury order of the PLC was set as LCL, PFL, and PT. A combined compressive load of 1150 N and an anterior tibial load of 134 N was applied to the tibia to investigate tibial displacement (TD). Tibial external rotation (TER) and tibial varus angulation (TVA) were measured under bending motions of 5 and 10 Nm. The instantaneous axis of rotation (IAR) of the knee joint under different rotation motions was also recorded.

Results

The TD of the intact knee under a combined compressive load of 1150 N and an anterior tibial load of 134 N matched the values determined in previous studies. Our model showed consistent increases in TD, TVA, and TER after sequential damage of the PLC. In addition, sequential disruption caused the IAR to shift superiorly and laterally during varus rotation and medially and anteriorly during external rotation. In the dynamic damage of the PLC, LCL injury had the largest effect on TD, TVA, TER, and IAR.

Conclusions

Sequential injury of the PLC caused considerable loss of stability of the knee joint according to an FE model. The most significant structure of the PLC was the LCL.
Coronary artery bypass grafting in a patient with situs inversus totalis: a case report
Authors: Oi Atsushi , Tatsuishi Wataru , Mohara Jun , Yamamoto Toshikuni , Abe Tomonobu
Published: March 2022

Background

Coronary artery bypass grafting in situs inversus totalis patients has been seldom reported in the literature.

Case presentation

A 76-year-old woman visited our hospital for chest pain and dyspnea that had started about 5 years earlier. Coronary angiography revealed triple-vessel disease, and computed tomography showed situs inversus totalis. Coronary artery bypass grafting was performed. In this case, the main operating surgeon stood on the right side of the patient until cardiopulmonary bypass was established and then switched positions to the left side of the patient for anastomosis.

Conclusion

CABG was successfully completed in a patient with situs inversus totalis. The position shift helped improve the safety and ease of the surgery.
Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease
Authors: Duan Ruoyu , Ji Haoran , Yan Huifang , Wang Junyu , Zhang Yu , Zhang Qian , Li Dongxiao , Cao Binbin , Gu Qiang , Wu Ye , Jiang Yuwu , Li Ming , Wang Jingmin
Published: March 2022

Background

The natural history and genotype–phenotype correlation of Pelizaeus–Merzbacher disease (PMD) of Chinese patients has been rarely reported.

Method

Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype–phenotype correlations were analyzed.

Result

A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group (p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age.

Conclusion

PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.
Qualitative interviews with adults with Classic Galactosemia and their caregivers: disease burden and challenges with daily living
Authors: Randall Jason A. , Sutter Carolyn , Wang Stella , Bailey Evan , Raither Lydia , Perfetti Riccardo , Shendelman Shoshana , Burbridge Claire
Published: March 2022

Background

Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Newborn screening and timely galactose-restricted diet can resolve acute symptoms and decrease fatalities. However, despite this, significant chronic, progressive morbidities remain which have a real impact upon daily life. To better understand the burden of disease, 20 in-depth qualitative interviews were undertaken with adult patients (n = 12), and their caregivers (n = 8), enrolled in the ACTION-Galactosemia trial, part of a clinical program designed to investigate the safety and efficacy of AT-007 (govorestat) in reducing toxic galactitol and long-term clinical outcomes in Classic Galactosemia.

Results

Interviews revealed the substantial burden of Classic Galactosemia on patients and families. Most adults were not able to live independently, and all required support with day-to-day activities. Short- and long-term memory difficulties and tremors were identified as the most frequently experienced and challenging symptoms. Other difficulties such as fine motor skills and slow/slurred speech contribute to the significant impact on daily activities, affecting ability to communicate and interact with others. Symptoms were first noticed in early childhood and worsened with age. Classic Galactosemia impacted all areas of daily functioning and quality of life, leading to social isolation, anxiety, anger/frustration and depression. This demonstrates the significant burden of disease and challenges associated with Classic Galactosemia.

Conclusions

The impact on both patients and caregivers underscores the severity of the unmet medical need and the importance of pharmacological intervention to halt or prevent disease progression. Any treatment that could reduce symptoms or slow functional decline would ease the burden of this condition on patients and caregivers.
Intersections between COVID-19 and socio-economic mental health stressors in the lives of South African adolescent girls and young women
Authors: Duby Zoe , Bunce Brittany , Fowler Chantal , Bergh Kate , Jonas Kim , Dietrich Janan Janine , Govindasamy Darshini , Kuo Caroline , Mathews Catherine
Published: March 2022

Background

In contexts where poverty and mental health stressors already interact to negatively impact the most vulnerable populations, COVID-19 is likely to have worsened these impacts. Before the COVID-19 pandemic, adolescent girls and young women (AGYW) in South Africa already faced intersecting mental health stressors and vulnerabilities. It is critical to understand how additional challenges brought on by COVID-19 have intersected with existing vulnerabilities and mental health risks AGYW faced, particularly given the intersections between psychological distress and increased risk behaviours that impact sexual and reproductive health. We aimed to examine socio-economic and mental health impacts of COVID-19 on South African AGYW in order to understand how additional challenges brought on by COVID-19 have intersected with existing challenges, compounding AGYW vulnerabilities.

Methods

Using qualitative and quantitative methods, framed by the syndemic theory, we examined the intersections between mental health and the COVID-19 epidemic amongst AGYW in six districts of South Africa characterised by high rates of HIV, teenage pregnancy and socio-economic hardship. Between November 2020 and March 2021 we conducted a cross-sectional telephone survey with 515 AGYW, and in-depth interviews with 50 AGYW, aged 15 to 24 years.

Results

Our findings reveal how COVID-19 restrictions led to increased experiences of stress and anxiety. Poor mental health was compounded by strained family relationships, increased fear of domestic violence, household unemployment, economic stress and food insecurity. Respondents described feelings of boredom, frustration, isolation, loneliness, fear and hopelessness. However, despite the multitude of challenges, some AGYW articulated emotional resilience, describing ways in which they coped and retained hope.

Conclusion

Various psycho-social risk factors already disproportionally affect the mental health of AGYW in these communities; the COVID-19 pandemic intersects with these pre-existing social and environmental factors. Understanding strategies AGYW have used to positively cope with the uncertainty of COVID-19 amongst an array of pre-existing mental health stressors, is key in informing efforts to respond to their needs. Multisectoral interventions are needed to address the drivers of poor mental health among AGYW, and bolster healthy coping mechanisms; interventions seeking to mitigate the mental health impacts on this vulnerable population need to be responsive to the unpredictable pandemic environment.
Direct interaction of TrkA/CD44v3 is essential for NGF-promoted aggressiveness of breast cancer cells
Authors: Trouvilliez Sarah , Cicero Julien , Lévêque Romain , Aubert Léo , Corbet Cyril , Van Outryve Alexandre , Streule Karolin , Angrand Pierre-Olivier , Völkel Pamela , Magnez Romain , Brysbaert Guillaume , Mysiorek Caroline , Gosselet Fabien , Bourette Roland , Adriaenssens Eric , Thuru Xavier , Lagadec Chann , de Ruyck Jérôme , Orian-Rousseau Véronique , Le Bourhis Xuefen , Toillon Robert-Alain
Published: March 2022

Background

CD44 is a multifunctional membrane glycoprotein. Through its heparan sulfate chain, CD44 presents growth factors to their receptors. We have shown that CD44 and Tropomyosin kinase A (TrkA) form a complex following nerve growth factor (NGF) induction. Our study aimed to understand how CD44 and TrkA interact and the consequences of inhibiting this interaction regarding the pro-tumoral effect of NGF in breast cancer.

Methods

After determining which CD44 isoforms (variants) are involved in forming the TrkA/CD44 complex using proximity ligation assays, we investigated the molecular determinants of this interaction. By molecular modeling, we isolated the amino acids involved and confirmed their involvement using mutations. A CD44v3 mimetic peptide was then synthesized to block the TrkA/CD44v3 interaction. The effects of this peptide on the growth, migration and invasion of xenografted triple-negative breast cancer cells were assessed. Finally, we investigated the correlations between the expression of the TrkA/CD44v3 complex in tumors and histo-pronostic parameters.

Results

We demonstrated that isoform v3 (CD44v3), but not v6, binds to TrkA in response to NGF stimulation. The final 10 amino acids of exon v3 and the TrkA H112 residue are necessary for the association of CD44v3 with TrkA. Functionally, the CD44v3 mimetic peptide impairs not only NGF-induced RhoA activation, clonogenicity, and migration/invasion of breast cancer cells in vitro but also tumor growth and metastasis in a xenograft mouse model. We also detected TrkA/CD44v3 only in cancerous cells, not in normal adjacent tissues.

Conclusion

Collectively, our results suggest that blocking the CD44v3/TrkA interaction can be a new therapeutic option for triple-negative breast cancers.
Commentary: Demystifying Doppler – revisiting a vital diagnostic tool
Authors: Tehan Peta , Sommerset Jill , Rounsley Richard , Fox Martin
Published: March 2022

Doppler is the most commonly utilised vascular assessment tool by podiatrists in Australia and the United Kingdom. Doppler is a key component of many international guidelines for vascular assessment. Used alongside pressure measurements such as ankle and toe‐brachial indices, Doppler assists podiatrists to diagnose, triage and subsequently manage patients with peripheral arterial disease. This commentary aims to clarify the importance, technique, and interpretation of continuous wave handheld Doppler in podiatry practice. This commentary presents discussion on the equipment and optimal test conditions for use of Doppler, and guidance on the technique required in podiatry clinical practice. Furthermore, there is a focus on interpretation of the output from Doppler including both audio and visual output. There is in depth discussion about identifying pathology and integration into the clinical management plan.
SHOOT: phylogenetic gene search and ortholog inference
Authors: Emms David Mark , Kelly Steven
Published: March 2022

Determining the evolutionary relationships between genes is fundamental to comparative biological research. Here, we present SHOOT. SHOOT searches a user query sequence against a database of phylogenetic trees and returns a tree with the query sequence correctly placed within it. We show that SHOOT performs this analysis with comparable speed to a BLAST search. We demonstrate that SHOOT phylogenetic placements are as accurate as conventional tree inference, and it can identify orthologs with high accuracy. In summary, SHOOT is a fast and accurate tool for phylogenetic analyses of novel query sequences. It is available online at www.shoot.bio.
Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: a study protocol for a multicentre adaptive randomised controlled trial
Authors: Earwaker Melissa , Villar Sofia , Fox-Rushby Julia , Duckworth Melissa , Dawson Sarah , Steele Jo , Chiu Yi-da , Litton Edward , Kunst Gudrun , Murphy Gavin , Martinez Guillermo , Zochios Vasileios , Brown Val , Brown Geoff , Klein Andrew
Published: March 2022

Background

High-flow nasal therapy is a non-invasive form of respiratory support that delivers low-level, flow dependent positive airway pressure. The device can be better tolerated by patients than alternatives such as continuous positive airway pressure. The primary objective is to determine if prophylactic high-flow nasal therapy after tracheal extubation can result in an increase in the number of days alive and at home within the first 90 days after surgery, when compared with standard oxygen therapy. The co-primary objective is to estimate the incremental cost-effectiveness and cost-utility of high-flow nasal therapy vs standard oxygen therapy at 90 days, from the view-point of the public sector, the health service and patients.

Methods

This is an adaptive, multicentre, international parallel-group, randomised controlled trial with embedded cost-effectiveness analysis comparing the use of high-flow nasal therapy with control in patients at high risk of respiratory complications following cardiac surgery. Participants will be randomised before tracheal extubation and allocated either high-flow nasal therapy or standard oxygen therapy for a minimum of 16 h immediately post extubation. Participants will be followed up until 90 days after surgery. The total sample size needed to detect a 2-day increase in DAH90 with 90% power with an intention to treat analysis is 850 patients. The adaptive design includes an interim sample size re-estimation which will provide protection against deviations from the original sample size assumptions made from the single-centre pilot study and will allow for a maximum sample size increase to 1152 patients.

Discussion

Evidence to support routine use of high-flow nasal therapy will inform the development of effective enhanced recovery care bundles. Reducing complications should reduce length of stay and re-admission to hospital and provide an important focus for cost reduction. However; high-quality studies evaluating the clinical and cost effectiveness of high-flow nasal therapy after cardiothoracic surgery are lacking.

Trial registration

The study has been registered with ISRCTN (ISRCTN14092678, 13/05/2020)

Clinicaltrials.gov Registration Pending
Synthesis of metal anthranilate complexes: catalytic and antipathogenic studies
Authors: Nawaz Muhammad , Abbasi Muhammad Waseem , Tariq Marium , Graham John Patrick , Al-Hagri Abdul-Rahman Saleh , Elkarim Ahmed Awad , Mohamed Muayad Elsiddig , Nissapatorn Veeranoot , Taha Muhammad , Hisaindee Soleiman
Published: March 2022

Background

Anthranilic acid is an active compound with diverse biological activities such as anti-inflammatory, antineoplastic, anti-malarial and α-glucosidase inhibitory properties. It can also chelate transition metals to form complexes with applications as antipathogens, photoluminescent materials, corrosion inhibitors, and catalysts.

Results

Anthranilic acid complexes (1–10) of Zn(II), Bi(III), Ag(I), Fe(II), Co(II), Cu(II), Mn(II), Al, Ni(II), and Cr(III) were synthesized and characterized using thermogravimetric (TGA), elemental analysis, FT-IR, UV–vis spectrometry, mass spectrometry and magnetic susceptibility. The morphology and size of metal complex (1–10) particles were determined by scanning electron microscope (SEM) and the surface area was determined by BET analysis. TGA and CHN analysis data indicated that the stoichiometries of complexes were 1:2 metal/ligand except for Ag(I), Al and Bi. Furthermore, DFT study was performed to optimize the structure of selected complexes. The complexes (1–10) were evaluated for their catalytic activity in the reduction of 4-nitrophenol (4-NP), antibacterial activity against S. aureus, P. aeroginosa and E. coli as well as their antifungal activity against F. solani and A. niger. The complexes were also tested against the second-stage juveniles (J2) root-knot nematodes.

Conclusion

Co(II) complex 5 and Cu(II) complex 6 showed high catalytic activity for the reduction of 4-NP to 4-aminophenol (4-AP). Ag(I) complex 3 showed the best activity against the pathogens that were tested namely clinically important bacteria S. aureus, P. aeroginosa and E. coli, commercially important fungi F. solani and A. niger and J2 root-knot nematodes M. javanica.
A pilot study: the relationship between salivary MCP-1 and IgA, and exercise performance in long-distance runners and sprinters
Authors: Uchida Masataka , Suga Tadashi , Terada Masafumi , Isaka Tadao
Published: March 2022

Objective

It remains unclear that the relationship between sprint and/or endurance performance and salivary immunological factors and stress hormones in athletes. The aim of this study was to investigate if salivary immunological factors and stress hormones are related to sprint and endurance performance in sprinters and long-distance runners. Fourteen male sprinters provided 100-m record and 22 male long-distance runners provided 5000-m record. Salivary IgA, MCP-1, interleukin-8, and cortisol levels in sprinters and long-distance runners were measured by ELISA assay.

Results

No significant differences were found in all salivary parameters between sprinters and long-distance runners. In long-distance runners, the salivary IgA and MCP-1 concentrations and secretory rate significantly correlated with their personal best 5000-m times (r = 0.534, P = 0.011; r = 0.567, P = 0.006; r = 0.452, P = 0.035, respectively). In sprinters, the salivary IgA concentration, MCP-1 concentration, and MCP-1 secretory rate did not correlate with personal best 100-m sprint times (r = − 0.260, P = 0.369; r = 0.128, P = 0.663; r = 0.122, P = 0.677, respectively). Therefore, the present study is the first to determine that immunological factors such as IgA and MCP1 may be related to endurance performance in long-distance runners.
Integrative analysis of DNA methylation and gene expression reveals key molecular signatures in acute myocardial infarction
Authors: Luo Xiaoli , Hu Yi , Shen Junwei , Liu Xinwen , Wang Tao , Li Li , Li Jue
Published: March 2022

Backgrounds

Acute myocardial infarction (AMI) has been one of the most fatal diseases among all types of heart diseases due to its rapid onset and high rates of fatality. Understanding accurately how multi-omics molecular features change at the early stage of AMI is crucial for its treatment. Currently, the changes involved in DNA methylation modification and gene expression of multiple genes have remained unexplored.

Results

We used the RNA-seq and MeDIP-seq on heart tissues from AMI mouse models at series of time points (Sham, AMI 10-min, 1-h, 6-h, 24-h and 72-h), to comprehensively describe the transcriptome and genome-wide DNA methylation changes at above time points. We identified 18814, 18614, 23587, 26018 and 33788 differential methylation positions (DMPs) and 123, 135, 731, 1419 and 2779 differentially expressed genes (DEGs) at 10-min, 1-h, 6-h, 24-h and 72-h AMI, respectively, compared with the sham group. Remarkably, the 6-h AMI with the drastic changes of DEGs and a large number of enriched functional pathways in KEGG may be the most critical stage of AMI process. The 4, 9, 40, 26, and 183 genes were further identified at each time point, based on the negative correlation (P < 0.05) between the differential mRNA expression and the differential DNA methylation. The mRNA and the promoter methylation expressions of five genes (Ptpn6, Csf1r, Col6a1, Cyba, and Map3k14) were validated by qRT-PCR and BSP methods, and the mRNA expressions were further confirmed to be regulated by DNA methylation in cardiomyocytes in vitro.

Conclusions

Our findings profiled the molecular variations from the perspective of DNA methylation in the early stage of AMI and provided promising epigenetic-based biomarkers for the early clinical diagnosis and therapeutic targets of AMI.
Epithelioid hemangioendothelioma of the spine: an analysis of imaging findings
Authors: Chen Yongye , Xing Xiaoying , Zhang Enlong , Zhang Jiahui , Yuan Huishu , Lang Ning
Published: March 2022

Background

Epithelioid hemangioendothelioma (EHE) is a low-grade malignant vascular neoplasm with the potential to metastasize. Primary EHE of the spine is very rare and an accurate diagnosis is crucial to treatment planning. We aim to investigate the imaging and clinical data of spinal EHE to improve the understanding of the disease.

Methods

We retrospectively analyzed the imaging manifestations and clinical data of 12 cases with pathologically confirmed spinal EHE. The imaging features analyzed included number, locations, size, border, density, signal, majority of the lesions, expansile osteolysis, residual bone trabeculae, sclerotic rim, vertebral compression, enhancement.

Results

Patients included 5 female and 7 male patients (mean age: 43.0 ± 19.6 years; range 15–73 years). Multiple lesions were noted in 1 case and single lesion was noted in 11 cases. The lesions were located in the thoracic, cervical, lumbar, and sacral vertebrae in 7, 3, 1, and 1 cases, respectively. They were centered in the vertebral body and posterior elements in 9 and 3 cases, respectively. Residual bone trabeculae, no sclerotic margin, and surrounding soft-tissue mass were noted in 11 cases, each, and mild expansile osteolysis and vertebral compression were noted in 10 and 6 cases, respectively. MRI was performed for 11 patients, all of whom showed isointensity on T1WI, hyperintensity or slight hyperintensity on T2WI, and hyperintensity on fat-suppressed T2WI. A marked enhancement pattern was noted in 10 cases.

Conclusion

Spinal EHE tend to develop in the thoracic vertebrae. EHE should be considered when residual bone trabeculae can be seen in the bone destruction area, accompanied by pathological compression fracture, no sclerotic rim, and high signal intensity for a vascular tumor on T2WI.
On some Volterra–Fredholm and Hermite–Hadamard-type fractional integral inequalities
Authors: Doubbi Bounoua Mohamed , Tang Jianhua
Published: March 2022

The main aim of this paper is establishing some new Volterra–Fredholm and Hermite–Hadamard-type fractional integral inequalities, which can be used as auxiliary tools in the study of solutions to fractional differential equations and fractional integral equations. Applications are also given to explicate the availability of our results.
Vaccination as an alternative to non-drug interventions to prevent local resurgence of COVID-19
Authors: Pan Jinhua , Zhu Wenlong , Tian Jie , Liu Zhixi , Xu Ao , Yao Ye , Wang Weibing
Published: March 2022

Background

While a COVID-19 vaccine protects people from serious illness and death, it remains a concern when and how to lift the high-cost and strict non-pharmaceutical interventions (NPIs). This study examined the joint effect of vaccine coverage and NPIs on the control of local and sporadic resurgence of COVID-19 cases.

Methods

Between July 2021 and January 2022, we collected the large-scale testing information and case number of imported COVID-19 patients from the website of the National Health Commission of China. A compartment model was developed to identify the level of vaccine coverage that would allow safe relaxation of NPIs, and vaccination strategies that can best achieve this level of coverage. We applied Monte Carlo simulation 50 000 times to remove random fluctuation effects and obtain fitted/predicted epidemic curve based on various parameters with 95% confidence interval at each time point.

Results

We found that a vaccination coverage of 50.4% was needed for the safe relaxation of NPIs, if the vaccine effectiveness was 79.3%. The total number of incidence cases under the key groups firstly strategy was 103 times higher than that of accelerated vaccination strategy. It needed 35 months to fully relax NPIs if the key groups firstly strategy was implemented, and 27 months were needed with the accelerated vaccination strategy. If combined the two strategies, only 8 months are needed to achieve the vaccine coverage threshold for the fully relaxation of NPIs. Sensitivity analyses results shown that the higher the transmission rate of the virus and the lower annual vaccine supply, the more difficult the epidemic could be under control. When the transmission rate increased 25% or the vaccination effectiveness rate decreased 20%, 33 months were needed to reduce the number of total incidence cases below 1000.

Conclusions

As vaccine coverage improves, the NPIs can be gradually relaxed. Until that threshold is reached, however, strict NPIs are still needed to control the epidemic. The more transmissible SARS-CoV-2 variant led to higher resurgence probability, which indicates the importance of accelerated vaccination and achieving the vaccine coverage earlier.

Graphical Abstract
Technological disruption and democracy in the twenty-first century
Authors: Arocena Felipe , Sansone Sebastián , Alvarez Nicolás
Published: March 2022

In 2019, sociologist Manuel Castells categorically stated that liberal democracy has exhausted its historical trajectory and, quoting some verses by Octavio Paz, expressed: “Not what it could have been:/it is what it was./And what it was is dead.” In this paper, we will reflect on this diagnosis based on five interrelated questions. To what extent is liberal democracy being affected by the current informational technological acceleration? Is there really a democratic crisis? What lessons can be learned from the Cambridge Analytica event? Will it be possible to manipulate feelings: hacking humans? What are the paths available for the future?
IDC: quantitative evaluation benchmark of interpretation methods for deep text classification models
Authors: Khaleel Mohammed , Qi Lei , Tavanapong Wallapak , Wong Johnny , Sukul Adisak , Peterson David A. M.
Published: March 2022

Recent advances in deep neural networks have achieved outstanding success in natural language processing tasks. Interpretation methods that provide insight into the decision-making process of these models have received an influx of research attention because of the success and the black-box nature of the deep text classification models. Evaluation of these methods has been based on changes in classification accuracy or prediction confidence when removing important words identified by these methods. There are no measurements of the actual difference between the predicted important words and humans’ interpretation of ground truth because of the lack of interpretation ground truth. A large publicly available interpretation ground truth has the potential to advance the development of interpretation methods. Manual labeling important words for each document to create a large interpretation ground truth is very time-consuming. This paper presents (1) IDC, a new benchmark for quantitative evaluation of interpretation methods for deep text classification models, and (2) evaluation of six interpretation methods using the benchmark. The IDC benchmark consists of: (1) Three methods that generate three pseudo-interpretation ground truth datasets. (2) Three performance metrics: interpretation recall, interpretation precision, and Cohen’s kappa inter-agreement. Findings: IDC-generated interpretation ground truth agrees with human annotators on sampled movie reviews. IDC identifies Layer-wise Relevance Propagation and the gradient-by-input methods as the winning interpretation methods in this study.
Why COVID vaccines for young children (5–11 years) are not essential at this moment in time?
Authors: Merchant Hamid A.
Published: March 2022

The Joint Committee on Vaccination and Immunisation (JCVI) in UK has recently advised that COVID vaccines in 5–11-year-old children is non-essential. This has created an outrage among some healthcare professionals who believed a mandatory vaccination program for all ages would be more beneficial. The JCVI decision sounds strange to many public health professionals in light of the existing practices with regards to other children’s vaccines, for instance flu jabs. The child immunisation should help reduce suffering in children, prevent virus spread in communities, reduce school off days, prevent the loss of quality of life in children and the sufferings from a preventable infection. Therefore, why not support essential COVID vaccines for young children like we do for the flu? This article explains the underlying mechanisms of currently deployed COVID vaccines, the cellular, humoral and mucosal immunity. The article explains why we should not rush mass-immunising young children and a delayed immunisation can be beneficial in offering a more suitable vaccine formulation for children, such as the nasal COVID vaccine, that is going to be available soon and will provide the sought-after protection against infection and transmission,  the public health benefit from the mass immunisation program in children.