bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of amphibian SLC26A5 using RNA-Seq
Authors: Wang Zhongying , Wang Qixuan , Wu Hao , Huang Zhiwu
Published: July 2021

Background

Prestin (SLC26A5) is responsible for acute sensitivity and frequency selectivity in the vertebrate auditory system. Limited knowledge of prestin is from experiments using site-directed mutagenesis or domain-swapping techniques after the amino acid residues were identified by comparing the sequence of prestin to those of its paralogs and orthologs. Frog prestin is the only representative in amphibian lineage and the studies of it were quite rare with only one species identified.

Results

Here we report a new coding sequence of SLC26A5 for a frog species, Rana catesbeiana (the American bullfrog). In our study, the SLC26A5 gene of Rana has been mapped, sequenced and cloned successively using RNA-Seq. We measured the nonlinear capacitance (NLC) of prestin both in the hair cells of Rana’s inner ear and HEK293T cells transfected with this new coding gene. HEK293T cells expressing Rana prestin showed electrophysiological features similar to that of hair cells from its inner ear. Comparative studies of zebrafish, chick, Rana and an ancient frog species showed that chick and zebrafish prestin lacked NLC. Ancient frog’s prestin was functionally different from Rana.

Conclusions

We mapped and sequenced the SLC26A5 of the Rana catesbeiana from its inner ear cDNA using RNA-Seq. The Rana SLC26A5 cDNA was 2292 bp long, encoding a polypeptide of 763 amino acid residues, with 40% identity to mammals. This new coding gene could encode a functionally active protein conferring NLC to both frog HCs and the mammalian cell line. While comparing to its orthologs, the amphibian prestin has been evolutionarily changing its function and becomes more advanced than avian and teleost prestin.
Single nucleotide replacement in the Atlantic salmon genome using CRISPR/Cas9 and asymmetrical oligonucleotide donors
Authors: Straume Anne Hege , Kjærner-Semb Erik , Skaftnesmo Kai Ove , Güralp Hilal , Lillico Simon , Wargelius Anna , Edvardsen Rolf Brudvik
Published: July 2021

Background

New breeding technologies (NBT) using CRISPR/Cas9-induced homology directed repair (HDR) has the potential to expedite genetic improvement in aquaculture. The long generation time in Atlantic salmon makes breeding an unattractive solution to obtain homozygous mutants and improving the rates of perfect HDR in founder (F0) fish is thus required. Genome editing can represent small DNA changes down to single nucleotide replacements (SNR). This enables edits such as premature stop codons or single amino acid changes and may be used to obtain fish with traits favorable to aquaculture, e.g. disease resistance. A method for SNR has not yet been demonstrated in salmon.

Results

Using CRISPR/Cas9 and asymmetrical ODNs, we were able to perform precise SNR and introduce a premature stop codon in dnd in F0 salmon. Deep sequencing demonstrated up to 59.2% efficiency in single embryos. In addition, using the same asymmetrical ODN design, we inserted a FLAG element into slc45a2 and dnd, showing high individual perfect HDR efficiencies (up to 36.7 and 32.7%, respectively).

Conclusions

In this work, we demonstrate that precise SNR and knock-in (KI) can be performed in F0 salmon embryos using asymmetrical oligonucleotide (ODN) donors. We suggest that HDR-induced SNR can be applied as a powerful NBT, allowing efficient introgression of favorable alleles and bypassing challenges associated with traditional selective breeding.
Prevalence of human leukocyte antigen HLA-B*57:01 in individuals with HIV in West and Central Africa
Authors: Kolou Malewe , Poda Armel , Diallo Zelica , Konou Esther , Dokpomiwa Tatiana , Zoungrana Jacques , Salou Mounerou , Mba-Tchounga Lionèle , Bigot André , Ouedraogo Abdoul-Salam , Bouyout-Akoutet Marielle , Ekouevi Didier K. , Eholie Serge P.
Published: July 2021

Background

The presence of the human leukocyte antigen HLA-B*57:01 is associated with the development of a hypersensitivity reaction to abacavir (ABC). Limited data exist on HLA-B*57:01 prevalence in individuals with HIV-1 in Africa. This study aimed to estimate HLA-B*57:01 prevalence in individuals with HIV-1 in West and Central Africa.

Methods

A cross-sectional study was conducted in four countries in West and central Africa (Burkina-Faso, Côte d’Ivoire, Gabon, and Togo) from January 2016 to February 2020 to determine the status of HLA-B*57:01 in adults with HIV-1. The presence of HLA-B*57:01 was determined by using Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) in blood samples. Prevalence rates were stratified based on country.

Results

A total of 4016 (69.8% women) individuals with HIV were enrolled. Their median age was 45, and the interquartile range was 38–52. We included 500 (12.4%) patients in Burkina-Faso, 1453 (36.2%) in Côte d’Ivoire, 951 (23.7%) in Gabon, and 1112 (27.7%) in Togo. The overall HLA-B*57:01 prevalence was 0.1% [95% CI: 0.0–0.2%]. The prevalence of HLA-B*57:01 was similar according to the four countries. Only one case was reported in each country except Togo, with no cases.

Conclusions

HLA-B*57:01 prevalence is low in individuals with HIV in West and central Africa, and there is no difference among countries. This study does not confirm the utility of HLA-B*57:01 allele testing for abacavir use in this region.
Putative mobilized colistin resistance genes in the human gut microbiome
Authors: Andrade Bruno G. N. , Goris Tobias , Afli Haithem , Coutinho Felipe H. , Dávila Alberto M. R. , Cuadrat Rafael R. C.
Published: July 2021

Background

The high incidence of bacterial genes that confer resistance to last-resort antibiotics, such as colistin, caused by mobilized colistin resistance (mcr) genes, poses an unprecedented threat to human health. Understanding the spread, evolution, and distribution of such genes among human populations will help in the development of strategies to diminish their occurrence. To tackle this problem, we investigated the distribution and prevalence of potential mcr genes in the human gut microbiome using a set of bioinformatics tools to screen the Unified Human Gastrointestinal Genome (UHGG) collection for the presence, synteny and phylogeny of putative mcr genes, and co-located antibiotic resistance genes.

Results

A total of 2079 antibiotic resistance genes (ARGs) were classified as mcr genes in 2046 metagenome assembled genomes (MAGs), distributed across 1596 individuals from 41 countries, of which 215 were identified in plasmidial contigs. The genera that presented the largest number of mcr-like genes were Suterella and Parasuterella. Other potential pathogens carrying mcr genes belonged to the genus Vibrio, Escherichia and Campylobacter. Finally, we identified a total of 22,746 ARGs belonging to 21 different classes in the same 2046 MAGs, suggesting multi-resistance potential in the corresponding bacterial strains, increasing the concern of ARGs impact in the clinical settings.

Conclusion

This study uncovers the diversity of mcr-like genes in the human gut microbiome. We demonstrated the cosmopolitan distribution of these genes in individuals worldwide and the co-presence of other antibiotic resistance genes, including Extended-spectrum Beta-Lactamases (ESBL). Also, we described mcr-like genes fused to a PAP2-like domain in S. wadsworthensis. These novel sequences increase our knowledge about the diversity and evolution of mcr-like genes. Future research should focus on activity, genetic mobility and a potential colistin resistance in the corresponding strains to experimentally validate those findings.
Identification of tomato accessions as source of new genes for improving heat tolerance: from controlled experiments to field
Authors: Gonzalo María José , Nájera Inmaculada , Baixauli Carlos , Gil David , Montoro Teresa , Soriano Vicky , Olivieri Fabrizio , Rigano Maria Manuela , Ganeva Daniela , Grozeva-Tileva Stanislava , Pevicharova Galina , Barone Amalia , Granell Antonio , Monforte Antonio José
Published: July 2021

Background

Due to global warming, the search for new sources for heat tolerance and the identification of genes involved in this process has become an important challenge as of today. The main objective of the current research was to verify whether the heat tolerance determined in controlled greenhouse experiments could be a good predictor of the agronomic performance in field cultivation under climatic high temperature stress.

Results

Tomato accessions were grown in greenhouse under three temperature regimes: control (T1), moderate (T2) and extreme heat stress (T3). Reproductive traits (flower and fruit number and fruit set) were used to define heat tolerance. In a first screening, heat tolerance was evaluated in 219 tomato accessions. A total of 51 accessions were identified as being potentially heat tolerant. Among those, 28 accessions, together with 10 accessions from Italy (7) and Bulgaria (3), selected for their heat tolerance in the field in parallel experiments, were re-evaluated at three temperature treatments. Sixteen tomato accessions showed a significant heat tolerance at T3, including five wild species, two traditional cultivars and four commercial varieties, one accession from Bulgaria and four from Italy. The 15 most promising accessions for heat tolerance were assayed in field trials in Italy and Bulgaria, confirming the good performance of most of them at high temperatures.

Finally, a differential gene expression analysis in pre-anthesis (ovary) and post-anthesis (developing fruit) under heat stress among pairs of contrasting genotypes (tolerant and sensitive from traditional and modern groups) showed that the major differential responses were produced in post-anthesis fruit. The response of the sensitive genotypes included the induction of HSP genes, whereas the tolerant genotype response included the induction of genes involved in the regulation of hormones or enzymes such as abscisic acid and transferases.

Conclusions

The high temperature tolerance of fifteen tomato accessions observed in controlled greenhouse experiments were confirmed in agronomic field experiments providing new sources of heat tolerance that could be incorporated into breeding programs.

A DEG analysis showed the complex response of tomato to heat and deciphered the different mechanisms activated in sensitive and tolerant tomato accessions under heat stress.
Primary care management of chronic insomnia: a qualitative analysis of the attitudes and experiences of Australian general practitioners
Authors: Haycock Jenny , Grivell Nicole , Redman Anne , Saini Bandana , Vakulin Andrew , Lack Leon , Lovato Nicole , Sweetman Alexander , Zwar Nicholas , Stocks Nigel , Frank Oliver , Mukherjee Sutapa , Adams Robert , McEvoy R. Doug , Hoon Elizabeth
Published: July 2021

Background

Chronic insomnia is a highly prevalent disorder, with ten to thirty percent of Australian adults reporting chronic difficulties falling asleep and/or staying asleep such that it causes significant daytime impairment. Current Australian general practice guidelines recommend cognitive behavioural therapy for insomnia (CBTi) as first line treatment for insomnia, however research suggests that most general practice consultations for insomnia result in a prescription for hypnotic or sedative medicines. Although the first point of contact for patients experiencing symptoms of insomnia is often general practice, little is known about the current role, experiences and capacity of Australian general practitioners to manage insomnia. This study aimed to address that gap by exploring the attitudes and opinions of general practitioners regarding insomnia management, to inform the development and implementation of new models of best practice insomnia care within general practice.

Methods

A descriptive, pragmatic qualitative study. Purposive sampling was used to recruit practising Australian general practitioners, varying in age, years of experience and geographic location. Semi-structured interviews were conducted, and data analysed using thematic analysis. 

Results

Twenty-eight general practitioners participated in the study. Three major themes were identified: 1) Responsibility for insomnia care; 2) Complexities in managing insomnia; and 3) Navigating treatment pathways. Whilst general practitioners readily accepted responsibility for the management of insomnia, provision of care was often demanding and difficult within the funding and time constraints of general practice. Patients presenting with comorbid mental health conditions and insomnia, and decision-making regarding long-term use of benzodiazepines presented challenges for general practitioners. Whilst general practitioners confidently provided sleep hygiene education to patients, their knowledge and experience of CBTi, and access and understanding of specialised referral pathways for insomnia was limited. 

Conclusions

General practitioners report that whilst assessing and managing insomnia can be demanding, it is an integral part of general practice. Insomnia presents complexities for general practitioners. Greater clarity about funding options, targeted education about effective insomnia treatments, and referral pathways to specialist services, such as benzodiazepine withdrawal support and psychologists, would benefit insomnia management within general practice.
Transcriptome sequencing and multi-plex imaging of prostate cancer microenvironment reveals a dominant role for monocytic cells in progression
Authors: Mangiola Stefano , McCoy Patrick , Modrak Martin , Souza-Fonseca-Guimaraes Fernando , Blashki Daniel , Stuchbery Ryan , Keam Simon P. , Kerger Michael , Chow Ken , Nasa Chayanica , Le Page Melanie , Lister Natalie , Monard Simon , Peters Justin , Dundee Phil , Williams Scott G. , Costello Anthony J. , Neeson Paul J. , Pal Bhupinder , Huntington Nicholas D. , Corcoran Niall M. , Papenfuss Anthony T. , Hovens Christopher M.
Published: July 2021

Background

Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities.

Results

In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry.

Conclusions

This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
The effect of the universal two-child policy on medical insurance funds with a rapidly ageing population: evidence from China’s urban and rural residents’ medical insurance
Authors: Zhang Xinjie , Huang Jingru , Luo Ying
Published: July 2021

Background

With the rapid growth of the ageing population, the operating burden of China’s basic medical insurance fund is becoming increasingly heavy. To counter rapid population ageing and ameliorate a series of problems, China has adjusted its fertility policies several times. On January 1, 2016, the universal two-child policy was implemented. This study analysed the impacts of the adjustment to the fertility policy and potential improvements in fertility intention on the insured population and medical insurance fund sustainability.

Methods

We used an actuarial science method and took the urban and rural residents’ basic medical insurance (URRBMI) of China, which covers most urban and rural residents, as an example to build a dynamic forecast model of population growth and a dynamic actuarial model of medical insurance funds.

Results

Compared with the original policy, under the current fertility intention (40%) with the universal two-child policy, the ageing of the population structure of URRBMI participants will decline significantly after 2026, and individuals aged 65 and over will account for only 19.01% of the total participants in 2050. The occurrence of the current deficit and accumulated deficit of the URRBMI fund will be postponed for one year to 2022 and 2028, respectively. If fertility intentions continue to rise, the ageing degree of the population structure will decrease, and the deficit would be further delayed.

Conclusions

The universal two-child policy is conducive to improving the degree of overall population ageing, delaying the occurrence of a URRBMI fund deficit, and improving the sustainability of URRBMI funds. If fertility intention increases, the effects would be stronger. However, since the adjustment of the universal two-child policy has a certain time lag, it will take time to demonstrate this impact. Therefore, while actively promoting the universal two-child policy, other measures should be taken, such as improving the fertility desire among couples of childbearing age and reforming medical insurance payment methods.
Lung function, COPD and cognitive function: a multivariable and two sample Mendelian randomization study
Authors: Higbee Daniel H. , Granell Raquel , Hemani Gibran , Smith George Davey , Dodd James W.
Published: July 2021

Background

Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).

Methods

Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.

Results

We found only weak evidence that reduced lung function (Beta − 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (− 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV1 and FVC do cause lower cognitive function, but that after conditioning for height (− 0.03 (0.03), p-value 0.29 and − 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (− 0.03 (0.03) p-value 0.33 and − 0.01 (0.02), p-value 0.35) the evidence became weak.

Conclusion

We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
Effectiveness of zinc chloride mouthwashes on oral mucositis and weight of patients with cancer undergoing chemotherapy
Authors: Oshvandi Khodayar , Vafaei Seyed Yaser , Kamallan Seyed Ramesh , Khazaei Salman , Ranjbar Hossein , Mohammadi Fateme
Published: July 2021

Background

Oral mucositis is one of the most emerging and debilitating complications of chemotherapy during the treatment period, which strongly affects the nutritional status and physical and mental condition of these patients. Zinc increased protein synthesis and improved cell membrane stability so passible effective in prevent and treat oral mucositis and promote oral health. Therefore, this study aimed to evaluate the effect of zinc chloride mouthwash on the prevention, incidence, and severity of oral mucositis in cancer patients undergoing chemotherapy.

Methods

The present study was a randomized control trial study. 96 patients with a cancer diagnosis selected from one oncology clinic in the west of Iran. Then they assigned randomly to the zinc chloride group and placebo group. The patients in each group should rinse their mouths every 8 h two times and each time 2 min with 7.5 ml from mouthwash. The severity of mucositis and weight loss examined blindly at the baseline and 3-week follow-up.

Results

The incidence and severity of oral mucositis between groups were significant higher at the end of the second (p < 0.002) and third (p < 0.001) week. The mucositis severity decreased well during the third weeks in the zinc chloride group. The difference in the weight loss was significant higher between the zinc chloride and the placebo group (p < 0.01).

Conclusion

Zinc chloride mouthwash was effective in preventing and reducing the severity of oral mucositis and improving weight in patients undergoing chemotherapy.

Trial registration We can therefore recommend more studies examine the effects zinc chloride as preventive care at the beginning of chemotherapy to improve oral health and subsequently preventing weight loss in these patients.
Longitudinal team training program in a Norwegian surgical ward: a qualitative study of nurses’ and physicians’ experiences with implementation
Authors: Ballangrud Randi , Aase Karina , Vifladt Anne
Published: July 2021

Background

Team training interventions to improve team effectiveness within healthcare are widely used. However, in-depth knowledge of how healthcare professionals experience such team training curricula and their implementation processes, as well as how contextual factors impact implementation, is currently missing. The aim of this study is therefore to describe healthcare professionals’ experiences with the implementation of a longitudinal interprofessional team training program in a surgical ward.

Methods

A descriptive design was applied based on qualitative semi-structured focus group interviews with 11 healthcare professionals. A convenience sample of physicians (n = 4), registered nurses (n = 4), and certified nursing assistants (n = 3) was divided into three professionally based focus groups, which were interviewed at three time intervals over a period of 1 year.

Intervention

The validated and evidence-based team training program Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) was implemented in a surgical ward at a hospital between January 2016 and June 2017. The team training program included three phases: 1) assessment and planning, 2) training and implementation, and 3) sustainment.

Results

Healthcare professionals’ experiences with the content of the team training program varied from valuing the different elements of it to seeing the challenges in implementing the elements in clinical practice. A one-day training course was found to be especially beneficial for interprofessional collaboration at the ward. Over time, the nursing staff seemed to maintain their motivation for the implementation of the tools and strategies, while the physicians became less actively involved. Contextual ward factors influenced the adoption and utilization of the tools and strategies of the program both positively and negatively. The healthcare professionals’ experienced the implementation of the team training program as positive for the patient safety culture at the ward in the forms of increased awareness of teamwork and open communication.

Conclusions

The study suggests that the implementation of a team training program in a surgical ward is dependent on a set of factors related to content, process, context, and impact. Knowledge on how and why a team training program work supports the transferability to clinical practice in further planning of team training measures.

Trial registration

The study is part of a larger research project with a study protocol that was registered retrospectively on 05.30.17, with the trial registration numberISRCTN13997367.
Variability of multi-omics profiles in a population-based child cohort
Authors: Gallego-Paüls Marta , Hernández-Ferrer Carles , Bustamante Mariona , Basagaña Xavier , Barrera-Gómez Jose , Lau Chung-Ho E. , Siskos Alexandros P. , Vives-Usano Marta , Ruiz-Arenas Carlos , Wright John , Slama Remy , Heude Barbara , Casas Maribel , Grazuleviciene Regina , Chatzi Leda , Borràs Eva , Sabidó Eduard , Carracedo Ángel , Estivill Xavier , Urquiza Jose , Coen Muireann , Keun Hector C. , González Juan R. , Vrijheid Martine , Maitre Léa
Published: July 2021

Background

Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood.

Methods

We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability.

Results

All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability.

Conclusions

Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both.
Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study
Authors: Kovacheva Ekaterina , Gerach Tobias , Schuler Steffen , Ochs Marco , Dössel Olaf , Loewe Axel
Published: July 2021

Background

Hypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements.

Methods

We conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally.

Results

Hypertrophy of the LV affected the course of strain, strain rate, and wall thickening—the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA.

Conclusions

This study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.
Chiral nanomaterials for tumor therapy: autophagy, apoptosis, and photothermal ablation
Authors: Peng Zaihui , Yuan Long , XuHong Juncheng , Tian Hao , Zhang Yi , Deng Jun , Qi Xiaowei
Published: July 2021

Chirality is a fundamental characteristic of natural molecules and a crucial factor in the biochemical reactions of living cells and organisms. Recently, researchers have successfully introduced chiral molecules to the surfaces of nanomaterials, creating chiral nanomaterials that exhibit an upscaling of chiral behavior from the molecular scale to the nanoscale. These chiral nanomaterials can selectively induce autophagy, apoptosis, and photothermal ablation in tumor cells based on their chirality, making them promising for application in anti-tumor therapy. However, these interesting and important phenomena have hitherto received little attention. Accordingly, we herein present a review of recent research progress in the field of chiral nanomaterials for tumor therapy along with brief looks at the mechanistic details of their actions. Finally, the current challenges and future perspectives of chiral nanomaterials in terms of maximizing their potential in tumor therapy are discussed. Thus, this review provides a helpful introduction to the design of chiral nanomaterials and will hopefully highlight the importance of chirality in tumor therapy.
Cellular dynamics of EMT: lessons from live in vivo imaging of embryonic development
Authors: Amack Jeffrey D.
Published: July 2021

Epithelial-mesenchymal transition (EMT) refers to a process in which epithelial cells lose apical-basal polarity and loosen cell–cell junctions to take on mesenchymal cell morphologies and invasive properties that facilitate migration through extracellular matrix. EMT—and the reverse mesenchymal-epithelial transition (MET)—are evolutionarily conserved processes that are used throughout embryonic development to drive tissue morphogenesis. During adult life, EMT is activated to close wounds after injury, but also can be used by cancers to promote metastasis. EMT is controlled by several mechanisms that depend on context. In response to cell–cell signaling and/or interactions with the local environment, cells undergoing EMT make rapid changes in kinase and adaptor proteins, adhesion and extracellular matrix molecules, and gene expression. Many of these changes modulate localization, activity, or expression of cytoskeletal proteins that mediate cell shape changes and cell motility. Since cellular changes during EMT are highly dynamic and context-dependent, it is ideal to analyze this process in situ in living organisms. Embryonic development of model organisms is amenable to live time-lapse microscopy, which provides an opportunity to watch EMT as it happens. Here, with a focus on functions of the actin cytoskeleton, I review recent examples of how live in vivo imaging of embryonic development has led to new insights into mechanisms of EMT. At the same time, I highlight specific developmental processes in model embryos—gastrulation in fly and mouse embryos, and neural crest cell development in zebrafish and frog embryos—that provide in vivo platforms for visualizing cellular dynamics during EMT. In addition, I introduce Kupffer’s vesicle in the zebrafish embryo as a new model system to investigate EMT and MET. I discuss how these systems have provided insights into the dynamics of adherens junction remodeling, planar cell polarity signaling, cadherin functions, and cytoskeletal organization during EMT, which are not only important for understanding development, but also cancer progression. These findings shed light on mechanisms of actin cytoskeletal dynamics during EMT, and feature live in vivo imaging strategies that can be exploited in future work to identify new mechanisms of EMT and MET.
Conflict and COVID-19 in Yemen: beyond the humanitarian crisis
Authors: Alsabri Mohammed , Alhadheri Ayman , Alsakkaf Luai M. , Cole Jennifer
Published: July 2021

Background

Yemen has been left in shambles and almost destroyed by its devastating civil war, and is now having to deal with the spread of coronavirus. The Yemeni people have been left to fend for themselves and faced many problems such as hunger, the ongoing war, infections, diseases and lack of equipment even before the COVID-19 pandemic. All together it is a humanitarian crisis. Only around 50% of the hospitals and healthcare facilities are in full working condition, and even those that are functioning are operating at nowhere near full potential. Healthcare staff and facilities lack necessary essential equipment and money.

Conclusion

As, sadly, is common in conflict-affected regions, the violence has brought with it a secondary disaster of infectious disease outbreaks. Yemen is not only battling COVID-19 amid a catastrophic war, but also has to deal with other diseases such as cholera, diphtheria and measles. A number of key measures are needed to support the current efforts against this deadly epidemic and its potential subsequent waves as well as to prevent further epidemics in Yemen.
The combined prevalence of classified rare rheumatic diseases is almost double that of ankylosing spondylitis
Authors: Leyens Judith , Bender Tim Th. A. , Mücke Martin , Stieber Christiane , Kravchenko Dmitrij , Dernbach Christian , Seidel Matthias F.
Published: July 2021

Background

Rare diseases (RDs) affect less than 5/10,000 people in Europe and fewer than 200,000 individuals in the United States. In rheumatology, RDs are heterogeneous and lack systemic classification. Clinical courses involve a variety of diverse symptoms, and patients may be misdiagnosed and not receive appropriate treatment. The objective of this study was to identify and classify some of the most important RDs in rheumatology. We also attempted to determine their combined prevalence to more precisely define this area of rheumatology and increase awareness of RDs in healthcare systems. We conducted a comprehensive literature search and analyzed each disease for the specified criteria, such as clinical symptoms, treatment regimens, prognoses, and point prevalences. If no epidemiological data were available, we estimated the prevalence as 1/1,000,000. The total point prevalence for all RDs in rheumatology was estimated as the sum of the individually determined prevalences.

Results

A total of 76 syndromes and diseases were identified, including vasculitis/vasculopathy (n = 15), arthritis/arthropathy (n = 11), autoinflammatory syndromes (n = 11), myositis (n = 9), bone disorders (n = 11), connective tissue diseases (n = 8), overgrowth syndromes (n = 3), and others (n = 8). Out of the 76 diseases, 61 (80%) are classified as chronic, with a remitting-relapsing course in 27 cases (35%) upon adequate treatment. Another 34 (45%) diseases were predominantly progressive and difficult to control. Corticosteroids are a therapeutic option in 49 (64%) syndromes. Mortality is variable and could not be determined precisely. Epidemiological studies and prevalence data were available for 33 syndromes and diseases. For an additional eight diseases, only incidence data were accessible. The summed prevalence of all RDs was 28.8/10,000.

Conclusions

RDs in rheumatology are frequently chronic, progressive, and present variable symptoms. Treatment options are often restricted to corticosteroids, presumably because of the scarcity of randomized controlled trials. The estimated combined prevalence is significant and almost double that of ankylosing spondylitis (18/10,000). Thus, healthcare systems should assign RDs similar importance as any other common disease in rheumatology.
Metabolic landscapes in sarcomas
Authors: Miallot Richard , Galland Franck , Millet Virginie , Blay Jean-Yves , Naquet Philippe
Published: July 2021

Metabolic rewiring offers novel therapeutic opportunities in cancer. Until recently, there was scant information regarding soft tissue sarcomas, due to their heterogeneous tissue origin, histological definition and underlying genetic history. Novel large-scale genomic and metabolomics approaches are now helping stratify their physiopathology. In this review, we show how various genetic alterations skew activation pathways and orient metabolic rewiring in sarcomas. We provide an update on the contribution of newly described mechanisms of metabolic regulation. We underscore mechanisms that are relevant to sarcomagenesis or shared with other cancers. We then discuss how diverse metabolic landscapes condition the tumor microenvironment, anti-sarcoma immune responses and prognosis. Finally, we review current attempts to control sarcoma growth using metabolite-targeting drugs.
Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors
Authors: Agnello Lisa , Tortorella Silvia , d’Argenio Annachiara , Carbone Clarissa , Camorani Simona , Locatelli Erica , Auletta Luigi , Sorrentino Domenico , Fedele Monica , Zannetti Antonella , Franchini Mauro Comes , Cerchia Laura
Published: July 2021

Background

Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC.

Methods

Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses.

Results

We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs.

Conclusions

Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.
A review of Dynamin 2 involvement in cancers highlights a promising therapeutic target
Authors: Trochet Delphine , Bitoun Marc
Published: July 2021

Dynamin 2 (DNM2) is an ubiquitously expressed large GTPase well known for its role in vesicle formation in endocytosis and intracellular membrane trafficking also acting as a regulator of cytoskeletons. During the last two decades, DNM2 involvement, through mutations or overexpression, emerged in an increasing number of cancers and often associated with poor prognosis. A wide panel of DNM2-dependent processes was described in cancer cells which explains DNM2 contribution to cancer pathomechanisms. First, DNM2 dysfunction may promote cell migration, invasion and metastasis. Second, DNM2 acts on intracellular signaling pathways fostering tumor cell proliferation and survival. Relative to these roles, DNM2 was demonstrated as a therapeutic target able to reduce cell proliferation, induce apoptosis, and reduce the invasive phenotype in a wide range of cancer cells in vitro. Moreover, proofs of concept of therapy by modulation of DNM2 expression was also achieved in vivo in several animal models. Consequently, DNM2 appears as a promising molecular target for the development of anti-invasive agents and the already provided proofs of concept in animal models represent an important step of preclinical development.
Advancing collaborations in health research and clinical trials in Sub-Saharan Africa: development and implementation of a biostatistical collaboration module in the Masters in Biostatistics Program at Stellenbosch University
Authors: Esterhuizen Tonya M. , Li Guowei , Young Taryn , Zeng Jie , Machekano Rhoderick , Thabane Lehana
Published: July 2021

Background

Sub-Saharan Africa continues to carry a high burden of communicable diseases such as TB and HIV and non-communicable diseases such as hypertension and other cardiovascular conditions. Although investment in research has led to advances in improvements in outcomes, a lot still remains to be done to build research capacity in health. Like many other regions in the world, Sub-Saharan Africa suffers from a critical shortage of biostatisticians and clinical trial methodologists.

Methods

Funded through a Fogarty Global Health Training Program grant, the Faculty of Medicine and Health Sciences at Stellenbosch University in South Africa established a new Masters Program in Biostatistics which was launched in January 2017. In this paper, we describe the development of a biostatistical and clinical trials collaboration Module, adapted from a similar course offered in the Health Research Methodology program at McMaster University.

Discussion

Guided by three core principles (experiential learning; multi-/inter-disciplinary approach; and formal mentorship), the Module aims to advance biostatistical collaboration skills of the trainees by facilitating learning in how to systematically apply fundamental statistical and trial methodological knowledge in practice while strengthening some soft skills which are necessary for effective collaborations with other healthcare researchers to solve health problems. We also share some preliminary findings from the first four cohorts that took the Module in January–November 2018 to 2021. We expect that this Module can provide an example of how to improve biostatistical and clinical trial collaborations and accelerate research capacity building in low-resource settings.

Funding source

Fogarty International Center of the National Institutes of Health.
Mental health and resilience among Eritrean refugees at arrival and one-year post-registration in Switzerland: a cohort study
Authors: Chernet Afona , Probst-Hensch Nicole , Sydow Véronique , Paris Daniel H. , Labhardt Niklaus D.
Published: July 2021

Objective

Eritrea is the most frequent country of origin among asylum seekers in Switzerland. On their journey through the desert and across the Mediterranean Sea, Eritrea refugees are often exposed to traumatizing experiences. The aim of this study is to assess the mental health status and resilience of Eritrean migrants in Switzerland upon arrival and one-year post-arrival, using standardized mental health screening and resilience assessment tools.

Results

At baseline, 107 refugees (11.2% female, median age 25) were interviewed: 52 (48.6%) screened positive for Post-Traumatic Stress Disorder (score ≥ 30), 10.3% for anxiety (≥ 10) and 15.0% for depression (≥ 10); 17.8% scored as risk/hazardous drinkers (≥ 8). The majority (94.4%) had a high resilience score (≥ 65). For one-year follow-up, 48 asylum seekers could be reached. In interviews 18 (38%) of these reported imprisonment in a transit country and 28 (58%) that they had witnessed the death of a close person along the migration route. At the one year assessment, rates of risky/hazardous alcohol use remained unchanged, rates of positive PTSD screening tended to be lower (50.0% (24/48) at baseline vs 25.0% (12/48) at follow-up), as were rates of positive screening for anxiety (8.3% vs 4.2%) and depression (14.6 vs 6.3%).
CD8+ Tregs ameliorate inflammatory reactions in a murine model of allergic rhinitis
Authors: Lin Lin , Dai Fei , Wei Jinjin , Chen Zheng
Published: July 2021

Background

CD8+CD25+fork-head box transcription factor (Foxp3)+regulatory T cells (CD8+Tregs) play a role in immune tolerance. However, the role of these cells in allergic rhinitis (AR) has not been elucidated. The study aimed to evaluate influences of CD8+Tregs on inflammatory conditions in a murine model of AR.

Methods

A murine model of AR was established. CD8+Tregs were isolated from mice nasal mucosa and cultured in vitro. We examined interleukin (IL)-10 and transforming growth factor (TGF)-β in cell cultures. Then, we administered CD8+Tregs into mice nasal mucosal cultures, and examined eosinophil cation protein (ECP), IL-4, IL-5 and IL-13 in these cultures. Finally, we adoptively transferred CD8+Tregs into mice models, and evaluated percentages of CD8+Tregs, numbers of sneezing and nasal rubbing, and counts of eosinophils and contents of ECP, IL-4, IL-5, IL-13, IL-10 and TGF-β in nasal lavage fluid (NLF) in mice.

Results

The percentage of CD8+Tregs from AR mice was reduced. IL-10 and TGF-β were increased in cell cultures from AR mice. ECP, IL-4, IL-5 and IL-13 were decreased after the AR mice CD8+Tregs administration in mucosal cultures. However, their contents were not changed after normal CD8+Tregs treatment. Additionally, the adoptive transfer of AR CD8+Tregs enhanced the percentage of CD8+Tregs and levels of IL-10 and TGF-β in NLF, reduced numbers of sneezing and nasal rubbing, and counts of eosinophils and concentrations of ECP, IL-4, IL-5 and IL-13 in NLF. However, normal CD8+Tregs could not change above parameters.

Conclusion

These findings show that CD8+Tregs may inhibit inflammatory responses in the AR condition.