bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic impairment and blunted transcriptional response to Mycobacterium tuberculosis of alveolar macrophages from persons living with HIV
Authors: Correa-Macedo Wilian , Fava Vinicius M. , Orlova Marianna , Cassart Pauline , Olivenstein Ron , Sanz Joaquín , Dumaine Anne , Sindeaux Renata H.M. , Yotova Vania , Pacis Alain , Girouard Josée , Kalsdorf Barbara , Lange Christoph , Routy Jean-Pierre , Barreiro Luis B. , Schurr Erwin
Published: January 2021

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (Mtb) followed by rapid progression to disease. Alveolar macrophages (AM) are the first cells of the innate immune system that engage Mtb, but how HIV and antiretroviral therapy (ART) impact on the anti-mycobacterial response of AM is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AM to Mtb, we obtained AM by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as pre-exposure prophylaxis (PrEP) to prevent HIV infection.

Following in-vitro challenge with Mtb, AM from each group displayed overlapping but distinct profiles of significantly up- and down-regulated genes in response to Mtb. Compared to HC subjects, AM isolated from PLWH and PrEP subjects presented a substantially weaker transcriptional response. Further investigation of chromatin structure revealed that AM from control subjects challenged with Mtb responded with pronounced accessibility changes in over ten thousand regions. In stark contrast, AM obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state in response to Mtb. Collectively, these results revealed a previously unknown adverse effect of ART on the epigenetic landscape and transcriptional responsiveness of AM.
Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia
Authors: Feleke Sindew M. , Reichert Emily N. , Mohammed Hussein , Brhane Bokretsion G. , Mekete Kalkidan , Mamo Hassen , Petros Beyene , Solomon Hiwot , Abate Ebba , Hennelly Chris , Denton Madeline , Keeler Corinna , Hathaway Nicholas J. , Juliano Jonathan J. , Bailey Jeffrey A. , Rogier Eric , Cunningham Jane , Aydemir Ozkan , Parr Jonathan B.
Published: January 2021

Malaria diagnostic testing in Africa is threatened by Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes. Among 12,572 subjects enrolled along Ethiopia’s borders with Eritrea, Sudan, and South Sudan and using multiple assays, we estimate HRP2-based rapid diagnostic tests would miss 9.7% (95% CI 8.5-11.1) of falciparum malaria cases due to pfhrp2 deletion. Established and novel genomic tools reveal distinct subtelomeric deletion patterns, well-established pfhrp3 deletions, and recent expansion of pfhrp2 deletion. Current diagnostic strategies need to be urgently reconsidered in Ethiopia, and expanded surveillance is needed throughout the Horn of Africa.
Noninvasive Detection of Fetal Genetic Variations through Polymorphic Sites Sequencing of Maternal Plasma DNA
Authors: Gao Song
Published: January 2021

Non-invasive prenatal testing (NIPT) for common fetal aneuploidies using circulating cell free DNA in maternal plasma has been widely adopted in clinical practice for its sensitivity and accuracy. However, the detection of subchromosomal abnormalities or monogenetic variations showed no cost-effectiveness or satisfactory accuracy. Here we developed an assay, the goodness-of-fit and graphical analysis of polymorphic sites based non-invasive prenatal testing (GGAP-NIPT), to simultaneously detect fetal chromosomal/subchromosomal and nucleotide level abnormalities. In each sample, fetal fraction was estimated using allelic counts of reference polymorphic sites and a robust linear regression model. Then the genotype of each polymorphic site was estimated using allelic goodness of fit test. Finally, monogenic mutations were detected using allelic wildtype and mutant counts of each target site, and chromosomal/subchromosomal abnormalities were identified by collective analysis of all target polymorphic sites. Such an analytic approach was highly accurate for detecting aneuploidies, microdeletions or microduplications and monogenic mutations for simulated samples with different fetal fractions and sequencing depths. Moreover, more than 93% of fetal monogenic mutations were correctly identified for target hotspot sites amplified using circulating or barcode-enabled single-molecule assays. With the aid of sample replicates, higher detection accuracy was observed. Through target polymorphic sites sequencing, all chromosomal/subchromosomal and monogenic abnormalities could be detected simultaneously, facilitating the extension of NIPT to an expanded panel of genetic disorders in a cost-effective manner.
Disentangling the association of hydroxychloroquine treatment with mortality in Covid-19 hospitalized patients through Hierarchical Clustering
Authors: Iacoviello Licia ,   The COVID-19 RISK and Treatments (CORIST) Collaboration
Published: January 2021

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and intervention studies reporting contrasting results.

To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ.

We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster*HCQ interaction (p<0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome.

These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute clarifying the current controversy on HCQ efficacy in Covid-19 treatment.
Post-Mendelian genetic model in COVID-19
Authors: Picchiotti Nicola , Benetti Elisa , Fallerini Chiara , Daga Sergio , Baldassarri Margherita , Fava Francesca , Zguro Kristina , Valentino Floriana , Doddato Gabriella , Giliberti Annarita , Tita Rossella , Amitrano Sara , Bruttini Mirella , Sarno Laura Di , Iuso Nicola , Alaverdian Diana , Beligni Giada , Croci Susanna , Meloni Ilaria , Pinto Anna Maria , Gabbi Chiara , Ceri Stefano , Esposito Antonio , Pinoli Pietro , Crawley Francis P. , Frullanti Elisa , Mari Francesca ,   GEN-COVID Multicenter Study, Gori Marco , Renieri Alessandra , Furini Simone
Published: January 2021

Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical “threshold model”. Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc).

The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity − nmildness) + F (mseverity − mmildness)

where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model “post-Mendelian”. The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.
Efficacy and safety of tocilizumab in the management of COVID-19: A systematic review and meta-analysis of observational studies
Authors: Viswanatha Gollapalle L , Male CH K V L S N Anjana , Shylaja Hanumanthappa
Published: January 2021

Background

This systematic review and meta-analysis was aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19).

Methods

The electronic search was performed using PubMed, Scopus, CENTRAL, and Google scholar to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020. Participants were hospitalized COVID-19 patients. Interventions included tocilizumab versus placebo/standard of care. The comparison will be between TCZ versus standard of care (SOC)/placebo. Inconsistency between the studies was evaluated with I2 and quality of the evidences were evaluated by Newcastle-Ottawa scale.

Results

Based on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (M-H,RE-OR −0.11(−0.18 to −0.04) 95% CI, p =0.001, I2 =88%) and increased the incidences of super-infections (M-H, RE-OR 1.49(1.13 to 1.96) 95% CI, p=0.004, I2=47%). However, there is no significant difference in ICU admissions rate (M-H, RE-OR −0.06(−0.23 to 0.12), I2=93%), need of MV (M-H, RE-OR of 0.00(−0.06 to 0.07), I = 74%), LOS (IV −2.86(−0.91 to 3.38), I2=100%), LOS-ICU (IV: −3.93(−12.35 to 4.48), I2=100%), and incidences of pulmonary thrombosis (M-H, RE-OR 1.01 (0.45 to 2.26), I2=0%) compared to SOC/control.

Conclusion

Based on cumulative low to moderate certainty evidence shows that TCZ could reduce the risk of mortality in hospitalized patients. However, there is no statistically significant difference observed between the TCZ and SOC/control groups in other parameters.
Multidimensional analysis of immune response identified biomarkers of recentMycobacterium tuberculosisinfection
Authors: Lloyd Tessa , Steigler Pia , Mpande Cheleka A.M. , Rozot Virginie , Mosito Boitumelo , Shreuder Constance , Reid Timothy D. , Hatherill Mark , Scriba Thomas J. , Little Francesca , Nemes Elisa ,   the ACS Study Team
Published: January 2021

The risk of tuberculosis (TB) disease is higher in individuals with recentMycobacterium tuberculosis(M.tb) infection compared to individuals with more remote, established infection. We aimed to define blood-based biomarkers to distinguish between recent and remote infection, which would allow targeting of recently infected individuals for preventive TB treatment. We hypothesized that integration of multiple immune measurements would outperform the diagnostic performance of a single biomarker. Analysis was performed on different components of the immune system, including adaptive and innate responses to my-cobacteria, measured on recently and remotelyM.tbinfected adolescents. The datasets were standardized using variance stabilizing (vast) scaling and missing values were imputed using a multiple factor analysis-based approach. For data integration, we compared the performance of a Multiple Tuning Parameter Elastic Net (MTP-EN) to a standard EN model, which was built to the single datasets. Biomarkers with non-zero coefficients from the optimal single data EN models were then isolated to build logistic regression models. A decision tree and random forest model were used for statistical validation. We found no difference in the predictive performances of the optimal MTP-EN model and the EN model [average area under the receiver operating curve (AUROC)=0.93]. EN models built to the integrated dataset and the adaptive dataset yielded identically high AUROC values (average AUROC=0.91), while the innate data EN model performed poorly (average AUROC=0.62). Results also indicated that integration of adaptive and innate biomarkers did not outperform the adaptive biomarkers alone (Likelihood Ratio Testχ2=6.09, p=0.808). From a total of 193 variables, the level of HLA-DR on ESAT6/CFP10-specific Th1 cytokine-expressing CD4 cells was the strongest biomarker for recentM.tbinfection. The discriminatory ability of this variable was confirmed in both tree-based models.

A single biomarker measuringM.tb-specific T cell activation yielded excellent diagnostic potential to distinguish between recent and remoteM.tbinfection.
Identification and characterization of a biphasic/bidirectional wound-inducibleRHA3Bgene promoter fromArabidopsis thaliana
Authors: Rao Venkateswara , Virupapuram Vijaybhaskar
Published: January 2021

Conditional promoters such as wound inducible are important tools for plant biotechnology to selectively express agronomically important genes. From a set of Enhancer trap (DsE-uidA) transposant lines we identified wound inducible ET1075 line by injuring leaf blade and screening for Ds linked GUS gene expression. Earliest GUS stain detected at petiolar region at 2hrs post injury with a progressive attainment of maximum visual intensity between 12 and 24hrs wherein, the transcript expression induced in a bidirectional manner. DsE was found to be inserted in the intergenic region betweenAT4G35480andAT4G35490. To find the essential transcriptional regulatory region, deletion constructs comprising upstream sequences of pRHA3Bfused to GUS reporter gene were functionally tested in Arabidopsis plants by generating stable transgenics. A 481 bp of upstream sequence from ATG is found to be sufficient to promote wound inducible gene expression. Sequence analysis revealed the presence of several regulatory elements implicated in wound inducible gene expression. Comparative analysis with similar wound inducible promoters revealed the presence of commoncis-regulatory elements. This promoter can essentially be used in pest control and in molecular pharming to conditionally express agronomically/commercially important genes in plants.

Highlights

DsE enhancer trap transposant lines were generated.

Identified a novel wound inducible promoter line ET1075.

Wound inducible promoter pRHA3Bis bidirectional and induces the expression ofRHA3BandMRPL11genes.

Wound responsive key cis-elements WRKY, W-box, FORCAare present in the pRHA3Bpromoter.
2,2,3,3,4,4,5,5-Octafluorohexane-1,6-diol. Corrigendum
Authors: Feightner Kylie , Powell Douglas R. , Burba Christopher M.
Published: January 2021

In the paper by Feightner et al. [IUCrData (2020), 5, x200445], there was an error in the name of the title compound.
(Nitrato-κO)(2,2′:6′,2′′-terpyridine-κ3
N,N′,N′′)palladium(II) nitrate
Authors: Ha Kwang
Published: January 2021

The title complex, [Pd(NO3)(C15H11N3)]NO3, comprises a cationic PdII complex and a nitrate anion. In the complex, the PdII cation is four-coordinated in a distorted square-planar coordination geometry defined by the three N atoms of the tridentate 2,2′:6′,2′′-terpyridine ligand and one O atom from the NO3
− anion. In the crystal, the complex molecules are stacked in columns along the a axis being connected by π–π stacking [closest inter-centroid separation between pyridyl rings = 3.878 (3) Å]. The connections between columns and anions to sustain a three-dimensional architecture are C—H...O hydrogen bonds.
Di-μ2-chlorido-bis{chlorido[2,4,6-tris(pyridin-2-yl)-1,3,5-triazine-κ3
N
2,N
1,N
6]nickel(II)}
Authors: Ha Kwang
Published: January 2021

In the title compound, [Ni2Cl4(C18H12N6)2], the NiII ions are hexa-coordinated in a distorted octahedral coordination environment defined by three N atoms of the tridentate 2,4,6-tri-2-pyridyl-1,3,5-triazine ligand and three Cl− anions in a meridional geometry. The two NiII ions are bridged by two Cl anionic ligands, thereby forming a dinuclear complex. A crystallographic centre of inversion is located at the centroid of the Ni2Cl2 ring.
Regional anaesthesia for rib fractures: A pilot study of serratus anterior plane block
Authors: Schnekenburger Marc , Mathew Joseph , Fitzgerald Mark , Hendel Simon , Sekandarzad Mir Wais , Mitra Biswadev
Published: January 2021

Objective

Rib fractures are not only painful but are associated with morbidity and mortality, especially in older patients. The serratus anterior plane block (SAPB) is a plane block distant from major neurovascular bundles and may provide anaesthesia to a substantial area of the hemithorax. This pilot study was designed to assess if the SAPB can be safely and efficiently incorporated to the trauma reception workflow of an adult, level 1 trauma centre.

Methods

A convenience sample of 20 adult patients with at least two or more unilateral rib fractures received a SAPB performed by an emergency physician in addition to their standard analgesic regime. Time to perform the procedure, the number of attempts and complications were recorded as feasibility measures. Secondary outcome was the safety of the block. Numerical pain scores at pre‐determined time points over 4 h, the diagnosis of hospital‐acquired pneumonia, hospital length of stay and mortality at hospital discharge were collected to provide pilot data on effectiveness.

Results

The median time to perform the procedure was 5.5 (interquartile range 4.6–10) mins with a range of 2–10.5 min. Most (16; 80%) SAPBs were completed in a single attempt. There were no documented complications. Median pain scores reduced from 6.5 (6–8) and were maintained at 3 (2–5) at 4 h after the SAPB.

Conclusions

The present study demonstrated the feasibility of ultrasound‐guided SAPB among patients with multiple rib fractures in the ED. No complications were observed. Further prospective evaluation of analgesic effects in a larger cohort is indicated.
Baseline carotid intima‐media thickness is associated with cardiovascular morbidity and mortality in peritoneal dialysis patients
Authors: Asicioglu Ebru , Velioglu Arzu , Arikan Hakki , Koc Mehmet , Tuglular Serhan , Ozener Cetin
Published: January 2021

Carotid intima‐media thickness (CIMT) is an early marker of atherosclerosis and is increased in peritoneal dialysis (PD) patients. Association of CIMT with cardiovascular disease (CVD) or mortality is less clear. Fibroblast growth factor‐23 (FGF‐23) is a hormone associated with vascular calcification, atherosclerosis, and mortality in the hemodialysis population. We investigated whether baseline CIMT and FGF‐23 are associated with CVD and mortality in PD patients. Fifty‐five PD patients were included. CVD was defined as ischemic heart disease, stroke, or peripheral artery disease. Intact FGF‐23 was measured in plasma. CIMT was measured by ultrasonography. Twenty‐one patients developed CVD and 12 died over 47.1 ± 33.8 months. Patients with CVD were older (55.9 ± 10.5 vs. 42.5 ± 12.9 years, P < .01), had lower albumin (3.8 ± 0.5 vs. 4.2 ± 0.3 g/dL, P < .01) and higher CIMT (0.87 ± 0.22 vs. 0.61 ± 0.11 mm, P < .01). Patients with mortality were also older (53.5 ± 11.5 vs. 45.8 ± 13.8 years, P = .05), had lower albumin (3.7 ± 0.6 vs. 4.1 ± 0.3 g/dL, P < .01), higher CRP (15.0 ± 8.5 vs. 7.6 ± 8.4 mg/L, P < .01) and CIMT (0.9 ± 0.3 vs. 0.6 ± 0.1 mm, P < .01). Albumin and CIMT were associated with CVD and CIMT >  0.75 mm was associated with cardiovascular mortality. FGF‐23 did not show any correlations. CIMT at baseline is associated with CVD and mortality in PD patients.
The role of intestinal mast cell infiltration in irritable bowel syndrome
Authors: Cheng Li , Luo Qing Qing , Chen Sheng Liang
Published: January 2021

As an essential part of the immune system, mast cells (MCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Accumulating evidence has identified altered MC count and density in intestinal mucosa of patients with IBS; however, conflicting findings yield inconsistent conclusions. Currently, most studies have suggested intestinal MC infiltration in IBS patients. Considering the pivotal role of MCs in IBS, it is necessary to achieve a better understanding about the pathological changes in the intestine. The risk factors for IBS, including dietary habits, psychological factors, infection, and dysbiosis, are implicated to induce intestinal MC infiltration. Mechanistically, food may trigger immune‐related allergic reactions and affect the intestinal microbiota activity. Some exogenous pathogens and altered profile of commensal bacteria promote intestinal MC recruitment through promoted release of chemokines from epithelial cells or direct activation of the immune system. In addition, psychological factors may affect the microenvironment where MCs live. MCs have been proven to interact with the enteric neurons and other immunocytes, evidenced by the close proximity of MCs to neurons and regional altered immune system components. A variety of mediators released by the enteric neurons, immunocytes, and MCs per se, such as neurotrophins, neuropeptides, cytokines, and chemokines, may have stimulant effects on MCs by modulating the survival, proliferation, and recruitment process of MCs in the intestine. In this review, the associations between IBS and intestinal MC density and the underlying mechanisms are discussed.
Cadmium sulfide nanoparticle biomineralization and biofilm formation mediate cadmium resistance of the deep‐sea bacterium Pseudoalteromonas sp. MT33b
Authors: Ma Ning , Sun Chaomin
Published: January 2021

Cadmium (Cd) is a common toxic heavy metal in the environment, and bacteria have evolved different strategies to deal with Cd toxicity. Here, a bacterium designated Pseudoalteromonas sp. MT33b possessing strong Cd resistance was isolated from the Mariana Trench sediments. Supplement of cysteine significantly increased bacterial Cd resistance and removal rate. Biofilm formation was demonstrated to play a positive role toward bacterial Cd resistance. Transcriptome analysis showed the supplement of cysteine effectively prevented Cd2+ from entering bacterial cells, promoted saccharide metabolism and thereby facilitating energy production, which consists well with bacterial growth trend analysed under the same conditions. Notably, the expressions of many biofilm formation related genes including flagellar assembly, signal transduction, bacterial secretion and TonB‐dependent transfer system were significantly upregulated when facing Cd stress, indicating their important roles in determining bacterial biofilm formation and enhancing Cd resistance. Overall, this study indicates the formation of insoluble CdS precipitates and massive biofilm is the major strategy adopted by Pseudoalteromonas sp. MT33b to eliminate Cd stress. Our results provide a good model to investigate how heavy metals impact biofilm formation in the deep‐sea ecosystems, which may facilitate a deeper understanding of microbial environmental adaptability and better utilization of these microbes for bioremediation purposes in the future.
The Enlarged Global Financial Safety Net
Authors: Vinokurov Evgeny , Levenkov Artem
Published: January 2021

The institutions and instruments of the Global Financial Safety Net (GFSN) represent the part of the global financial architecture that is responsible for providing an anti‐crisis and stabilization support to the countries in need. We argue that the standard understanding of the GFSN as a system consisting of four layers – national reserves, bilateral swaps, regional financing arrangements and the IMF – demands rethinking. We suggest the concept of an enlarged GFSN, namely its expansion by two additional elements – multilateral development banks and bilateral financial support. Both elements of the international financial architecture are partly involved in providing an anti‐crisis and macroeconomic stabilization support at concessional terms. We demonstrate how the enlarged GFSN functions, including at the time of the COVID‐19 crisis.
A systemic review of intravenous immunoglobulin G treatment in women with recurrent implantation failures and recurrent pregnancy losses
Authors: Saab Wael , Seshadri Srividya , Huang Changsheng , Alsubki Lujain , Sung Nayoung , Kwak‐Kim Joanne
Published: January 2021

Over the last few decades, the advancement in reproductive technologies and protocols to improve embryo quality through culture techniques and genetic testing to eliminate chromosomally abnormal embryos resulted in better pregnancy rates and outcomes after fertility treatments. Unfortunately, some patients still struggle with recurrent implantation failures (RIFs) and recurrent pregnancy losses (RPLs). Immune etiologies have been attributed to play an important role in some of those patients. Maintaining a pre‐conceptional anti‐inflammatory environment for implantation and pregnancy continuation yields superior results. Intravenous immunoglobulin G (IVIG) treatment has been reported to enhance reproductive outcome in patients with RIF and RPL with immune dysregulations. In this systemic review, we analyzed outcomes of IVIG trials for RIF and RPL, its mechanism of action, dosing, administration, side‐effects, and evidence for its use in women with RIF and RPL.
The potential of individualized dosing of ravulizumab to improve patient‐friendliness of paroxysmal nocturnal haemoglobinuria treatment at reduced costs
Authors: ter Avest Mendy , Langemeijer Saskia M.C. , Schols Saskia E.M. , Burger David M. , van de Kar Nicole C.A.J. , Blijlevens Nicole M.A. , Kievit Wietske , ter Heine Rob
Published: January 2021

Ravulizumab is a very expensive complement C5‐inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria, with a fixed‐dosing interval of 8 weeks. For lifelong treatment, a cost‐effective and patient‐friendly dosing strategy is preferred. We therefore explored alternative ravulizumab dosing regimens in silico based on the thorough dose‐finding studies of the manufacturer. Extending the interval to 10 weeks or individually extending the interval to a mean of 12.8 weeks based on pharmacokinetic monitoring resulted in noninferior efficacy in terms of lactate dehydrogenase normalization, with drug cost savings up to 37%. We here show the potential of individualized ravulizumab dosing to improve patient‐friendliness at reduced costs.
Lithium from breast‐milk inhibits thyroid iodine uptake and hormone production, which are remedied by maternal iodine supplementation
Authors: Ahmed Irfan , Ma Victor , Liu Yuanchao , Khan Muhammad Shehzad , Liu Zhenhui , Zhang Chi , Paidi Santosh Kumar , Manno Francis A. M. , Amjad Noreen , Manno Sinai H. C. , Ahmed Rafay , Law Alan W. L. , Ali Ahmed , Raza Faizan , Zhang Yanpeng , Cho William C. S , Barman Ishan , Alda Martin , Bergink Veerle , Lau Condon
Published: January 2021

Background

Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast‐feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well‐understood, affecting its usage and overall health implications.

Procedure

We developed a rat lithium and breast‐feeding model at human therapeutic levels to study the effects of lithium exposure through breast‐milk on pups’ thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups’ thyroid dysfunction.

Results

Pups exposed to lithium via breastmilk, even with the dam on a sub‐therapeutic level, experienced weight gain, reduced blood thyroxine (T4), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast‐feeding.

Conclusion

These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side‐effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast‐feed.
Introduction: The Politics of Open Access — Decolonizing Research or Corporate Capture?
Authors: Meagher Kate
Published: January 2021

This introductory article looks beyond the conventional framing of open access (OA) debates in terms of paywalls and copyrights, to examine the historical processes, institutional and digital infrastructures, and political dynamics shaping the effects of OA in development research. From a historical perspective, it focuses on tensions and crises in the relationship between scholarly and corporate publishing ecosystems. The spectrum of open access models is also examined, with a focus on green, gold, diamond and black, which tend to obscure the underlying scholarly publishing infrastructures that shape the parameters of openness and access. A closer look at distinctive for‐profit and non‐profit OA infrastructures reveals the inequitable and often neo‐colonial effects of for‐profit models on Southern researchers and the social sciences. Accounts of the politics of OA highlight processes of political capture of the OA agenda by Northern corporate and state interests and draw attention to alternative interest coalitions which are more suited to prioritizing the global public good over private profit. Reflecting on the requirements of OA in low‐resource environments, this article echoes calls for more equitable forms of openness and access in development research ecosystems, with a view to decolonizing as well as advancing OA.
Cerebral blood flow and acute episodes of Leigh syndrome in neurometabolic disorders
Authors: Loiselet Klervie , Ruzzenente Benedetta , Roux Charles‐Joris , Barcia Giulia , Pennisi Alessandra , Desguerre Isabelle , Rötig Agnès , Munnich Arnold , Boddaert Nathalie ,   Paediatric Radiology and Metabolics Group
Published: January 2021

Aim

To investigate cerebral blood flow (CBF) in acute episodes of Leigh syndrome compared with basal state in patients carrying pathogenic mitochondrial disease gene variants responsible for neurometabolic disorders.

Method

Arterial spin labelling (ASL) magnetic resonance imaging (MRI) sequences were used to measure CBF in 27 patients with mitochondrial respiratory chain enzyme deficiencies, ascribed to pathogenic variants of reported disease genes who were undergoing either urgent neuroimaging for acute episodes of Leigh syndrome (Group I: 15 MRI, seven females, eight males; mean age 7y; range 7mo–14y) or routine brain MRI (Group II: 15 MRI, eight females, seven males; mean age 5y 2mo; range 2mo–12y).

Results

Patients displayed markedly increased CBF in the striatum (2.8‐fold greater, p<0.001 [1.05–2.53]) during acute episodes of Leigh syndrome compared to basal conditions. Detection of elevated CBF preceded identification of structural MRI lesions in four out of 15 cases.

Interpretation

Our results suggest that increased CBF is an overt hallmark of Leigh syndrome episodes and ASL MRI sequences should facilitate early diagnosis of acute episodes of Leigh syndrome, especially during the first attack in young children, when structural MRI is insufficiently informative.
Linking range wide energetic tradeoffs to breeding performance in a long‐distance migrant
Authors: Carneiro Camilo , Gunnarsson Tómas G. , Méndez Verónica , Soares Amadeu M. V. M. , Alves José A.
Published: January 2021

Understanding how individual tradeoffs and carry‐over effects along the annual cycle influence fitness is fundamental to unravel population dynamics, but such data is particularly challenging to collect in long‐distance migrants. Here, with a full annual cycle perspective of Icelandic whimbrels Numenius phaeopus islandicus, we investigate tradeoffs across the entire distribution, assessing migration costs and wintering energetic balance experienced throughout the wintering range (from temperate to tropical regions), and link these to breeding parameters for two wintering regions.

We found that Icelandic whimbrels traded off higher costs of migration with more favourable wintering conditions, in terms of energetic balance. By migrating further, whimbrels experience lower thermoregulatory costs and higher net energetic intake rates, resulting in a more positive energetic balance during winter. However, these differences did not appear to carry‐over into the breeding season in terms of measurable effects on laying date (and, consequently, fledging success) or egg volume, suggesting that individual fitness is unlikely to be significantly influenced by previous wintering conditions, although effects on other traits may potentially occur. Nevertheless, Icelandic whimbrels seem to favour wintering locations where the conditions are more advantageous, as the abundance of individuals at the wintering sites reflects the variation in site quality.
An innovative interprofessional dental clinical learning environment using entrustable professional activities
Authors: Hissink Elske , Fokkinga Wietske A. , Leunissen Ronald R. M. , Lia Fluit C. R. M. G. , Loek Nieuwenhuis A. F. M. , Creugers Nico H. J.
Published: January 2021

Introduction

Changes in society, new public demands for dental care and contemporary educational insights have influenced dental education worldwide and demand a renewed perspective. Following this perspective, an innovative interprofessional dental Master curriculum was developed at Radboud University Nijmegen in the Netherlands.

Educational principles

The curriculum is based on five contemporary educational principles and the core of the curriculum consists of a Student Run Dental Clinic that is fully run by students under professional supervision.

The new curriculum

In the Student Run Dental Clinic, Master dental students and Bachelor oral hygiene students are responsible for the care of approximately 750 patients. The students work within the same clinic for 3 years and patients receive oral health care from the same students over a long period. The clinic is a longitudinal cross‐disciplinary clinic with different dental subdisciplines.

Entrustable professional activities (also known as EPAs), to our knowledge not yet widely used in dental education, were introduced to facilitate learning and assessment. Fourteen EPAs have been developed to stimulate interprofessional education and learning. Of these, five EPAs are identical for the dental and oral hygiene curriculum, leading to extended interprofessional education and learning in the Student Run Dental Clinic.

Discussion

Preliminary results show that EPAs are generally well received by supervisors and students.

Conclusion

To monitor and investigate the exact effect of the interventions and underlying mechanisms, a research programme on interprofessional learning, practice‐based learning and EPAs and entrustment in dental education was recently set up.
Parental relatedness and parasitoid sex ratios under local mate competition
Authors: Du Kai , Abdi Mohamed Khadar , Hardy Ian CW
Published: January 2021

Sex ratio theory predicts that, under local mate competition, a more female‐biased offspring sex ratio will be produced by females when their relatedness to their mates is closer. We assess how the sexual composition of broods responds to mother–mate relatedness using Goniozus legneri Gordh (Hymenoptera: Bethylidae), a parasitoid wasp that has biased sex ratios due to local mate competition. Relatedness was varied by providing virgin females with a mate that was either a sibling, a non‐sibling from the same strain, from a strain with geographically similar origin or from a strain with geographically distant origin. The sex ratios among broods produced by mothers that had mated with a sibling or a same‐strain male were similar and were more biased than broods produced by females mated with males from a different strain. Brood sex variances were higher after mating with different‐strain males. Previous evaluations of parasitoid sex ratio responses to mate relatedness have not found the patterns predicted, possibly because the species investigated can control progeny sex ratio but cannot discriminate kin. In contrast, female G. legneri appear to possess both these abilities and appears to respond to mate relatedness in qualitative agreement with theoretical predictions.
Shedding light on the link between the spatial distribution of eggs and survival in Northeast Arctic cod
Authors: Langangen Øystein , Stige Leif Christian
Published: January 2021

Spreading the offspring in space and time may offer bet‐hedging benefits by buffering environmental influences on parts of the offspring distribution. It has previously been shown that high mean age and size of spawners in the Northeast Arctic stock of Atlantic cod (Gadus morhua) is positively associated with high abundance and wide spatiotemporal distribution of eggs. However, little support has been found for a wide egg distribution acting as a buffer against environmental influences by leading to higher mean or less variable recruitment. The lacking relation between egg distribution and recruitment can be due to data limitation or alternatively that wide egg distributions may be of limited relevance for survival in later stages. To investigate these two alternatives, we analysed the output from a mechanistic coupled physical–biological drift model that projected the abundance of juvenile cod on the nursing grounds in the Barents Sea from empirically estimated egg distributions. The projections were performed with initial egg distributions reflecting the expected distributions at high and low mean weight of the spawners. We found that the extended distribution at the fringes only marginally contributed to recruitment, as a large proportion of the extra eggs at high mean age and size of spawners did not reach suitable nursing areas or failed to grow to a suitable size by the end of the season. In conclusion, our results suggest that the buffering effect of a geographically wide distribution of spawning products is insignificant compared to other effects on recruitment.
Purified Na2CrO4–H2SO4: A New Low‐Blank Medium for Re‐Os Dating of Black Shale
Authors: Li Xinwei , Li Chao , Pei Haoxiang , Zhou Limin , Qu Wenjun , Du Andao
Published: January 2021

The H2SO4–CrO3 method has been widely used in Re‐Os isotope dating of organic‐rich sedimentary rocks. However, the high Re blank of this method inhibits the collection of high‐precision Re‐Os data, especially for organic‐rich sedimentary rocks with low Re and Os mass fractions. Here, we report a new H2SO4–Na2CrO4 method in which the Re blank of the Na2CrO4 reagent can be greatly reduced after efficient purification by acetone. A proportion of 0.6 g Na2CrO4/8 ml H2SO4 was selected as the best digestion combination based on tests of black shales with different organic carbon contents in three digestion media (inverse aqua regia, H2SO4–CrO3, and H2SO4–Na2CrO4). The H2SO4–Na2CrO4 method has an ultra‐low total procedural blank of 1–2 pg for Re and 0.6–1 pg for Os, respectively, which is one order of magnitude lower than the H2SO4–CrO3 method and is comparable with to inverse aqua regia method. The new method was applied to reference material SBC‐1 and two series of black shale samples, and the results were consistent with those obtained via the inverse aqua regia method. These findings confirm the accuracy and feasibility of the H2SO4–Na2CrO4 method, and demonstrate its ability to accurately determine the depositional age of organic‐rich sedimentary rocks with low Re and Os mass fractions.
LincRNA‐EPS alleviates severe acute pancreatitis by suppressing HMGB1‐triggered inflammation in pancreatic macrophages
Authors: Chen Shengchuan , Zhu Jingfei , Sun Li‐Qiong , Liu Siying , Zhang Tan , Jin Yuepeng , Huang Chaohao , Li Dapei , Yao Haiping , Huang Jian , Qin Yanghua , Zhou Mengtao , Chen Gang , Zhang Qiyu , Ma Feng
Published: January 2021

Acute pancreatitis (AP), an inflammatory disorder of the pancreas with a high hospitalization rate, frequently leads to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). However, therapeutic targets for effective treatment and early intervention of AP are still urgently required to be identified. Here, we have observed that the expression of pancreatic lincRNA‐EPS, a long intergenic non‐coding RNA, is dynamically changed during both caerulein‐induced AP (Cer‐AP) and sodium taurocholate‐induced severe AP (NaTc‐SAP). The expression pattern of lincRNA‐EPS is negatively correlated with the typical inflammatory genes such as IL‐6, IL‐1β, CXCL1, and CXCL2. Further studies indicate that knockout of lincRNA‐EPS aggravates the pathological symptoms of AP including more induction of serum amylase and lipase, severe edema, inflammatory cells infiltration and acinar necrosis in both experimental AP mouse models. Besides these intrapancreatic effects, lincRNA‐EPS also protects against tissue damages in the extra‐pancreatic organs such as lung, liver, and gut in the NaTc‐SAP mouse model. In addition, we have observed more serum pro‐inflammatory cytokines TNF‐α and IL‐6 in the lincRNA‐EPS‐/‐ NaTc‐SAP mice and more extracellular HMGB1 around injured acinar cells in the pancreas from lincRNA‐EPS‐/‐ NaTc‐SAP mice, compared with their respective controls. Pharmacological inhibition of NF‐B activity by BAY11‐7082 significantly abolishes the suppressive effect of lincRNA‐EPS on TLR4 ligand‐induced inflammatory genes in macrophages. Our study has described a protective role of lincRNA‐EPS in alleviating AP and SAP, outlined a novel pathway that lincRNA‐EPS suppresses HMGB1‐NF‐B‐dependent inflammatory response in pancreatic macrophages and provided a potential therapeutic target for SAP.
Epitranscriptome machinery in Trypanosomatids: New players on the table?
Authors: Maran Suellen Rodrigues , de Lemos Padilha Pitta João Luiz , dos Santos Vasconcelos Crhisllane Rafaele , McDermott Suzanne M. , Rezende Antonio Mauro , Silvio Moretti Nilmar
Published: January 2021

Trypanosoma and Leishmania parasites cause devastating tropical diseases resulting in serious global health consequences. These organisms have complex life cycles with mammalian hosts and insect vectors. The parasites must, therefore, survive in different environments, demanding rapid physiological and metabolic changes. These responses depend upon regulation of gene expression, which primarily occurs posttranscriptionally. Altering the composition or conformation of RNA through nucleotide modifications is one posttranscriptional mechanism of regulating RNA fate and function, and modifications including N6‐methyladenosine (m6A), N1‐methyladenosine (m1A), N5‐methylcytidine (m5C), N4‐acetylcytidine (ac4C), and pseudouridine (Ψ), dynamically regulate RNA stability and translation in diverse organisms. Little is known about RNA modifications and their machinery in Trypanosomatids, but we hypothesize that they regulate parasite gene expression and are vital for survival. Here, we identified Trypanosomatid homologs for writers of m1A, m5C, ac4C, and Ψ and analyze their evolutionary relationships. We systematically review the evidence for their functions and assess their potential use as therapeutic targets. This work provides new insights into the roles of these proteins in Trypanosomatid parasite biology and treatment of the diseases they cause and illustrates that Trypanosomatids provide an excellent model system to study RNA modifications, their molecular, cellular, and biological consequences, and their regulation and interplay.
In favour of a Basque state. A paradigm shift?
Authors: Fullaondo Arkaitz , Zabalo Julen
Published: January 2021

There have been changes in how support is rallied for the secessionist process in the Basque Country this century. We can appreciate a new scheme based on factors relating to welfare along with the traditional scheme based, above all, on factors relating to identity. How important is each of them? By using the statistical technique of logistic regression, we have been able to look deeper into the variables that explain being favourably disposed to a Basque state, as well as those that explain a change in stance, based on a variety of dimensions. The results indicate, on the one hand, that there is currently no one factor to explain a favourable position towards a Basque state. What's more, in the future, the stances on a Basque state are likely to shift more easily, depending on the interests and sentiments at any given moment.
Systematic review of physical exercise for patients with idiopathic inflammatory myopathies
Authors: Zhang Huan , Liu Yuanfei , Ma Jingya , Li Zheng
Published: January 2021

Idiopathic inflammatory myopathies (IIM) are systemic autoimmune connective tissue diseases. The safety and effectiveness of exercise for patients with idiopathic inflammatory myopathies remains unclear. This study aimed to systematically review the evidence for physical exercise among patients with idiopathic inflammatory myopathies. Relevant experimental studies were identified through searching the PubMed, Cochrane, Embase, Scopus, and CINAHL databases, and studies involving any type of physical exercise for ≥1 month were considered. The primary outcome was muscle strength, and the secondary outcomes included aerobic fitness, functional performance, health status, quality of life, activities of daily living, pain, and fatigue. Eight randomized controlled trials and thirteen nonrandomized uncontrolled trials were reviewed. Physical exercise appeared safe, with several positive effects. However, selection or allocation biases and small sample sizes affected the certainty of the evidence. While physical exercise appeared safe for patients with idiopathic inflammatory myopathies with several positive effects, studies of a higher methodological quality and involving patients with active disease are needed. Furthermore, to design optimal exercise programs, consistent and sensitive outcome measures are needed to facilitate comparisons of results from different studies.