bluuebunny/crossref_metadata_2025_split huggingface dataset:
Artificial water fluoridation for dental health improvement: a review and meta-analysis of the evidence and implications of a possible association between water fluoride and IQ
Authors: Braithwaite Vickie S. , Valentine Ruth A. , Wareham Nicholas J. 
Published: March 2024

AbstractBackgroundGlobally, dental caries affects 60-90% of schoolchildren. Although artificial water fluoridation improves dental health and reduces dental health inequalities, there is concern that excessive fluoride exposure may lower cognition.We systematically reviewed and meta-analysed the association between water fluoride and intelligence quotient (IQ).MethodsA literature search of Medline and Web of Science and random-effects meta-analysis comparing mean IQ of children living in low/normal or higher water fluoride areas was investigated. Followed by exploration of possible dose effects among sub-groups, living in moderate (<1.5 ppm) high (1.5-3.0 ppm) or extremely high (>3ppm) water fluoride areas.ResultsTwenty-three observational studies (n=9539 children) were included. Overall, the higher water fluoride group had a lower mean IQ compared with the low water fluoride group (standardised mean difference (95% confidence interval): -0.43 (-0.63 to -0.24) p<0.0001, I2=94.2% p<0.0001). Sub-group analysis showed no association between water fluoride and mean IQ in studies of moderate fluoride concentrations (moderate: 0.04 (-0.08 to 0.15) p=0.53, I2=0.0% p=0.68). Mean IQ was lower in the higher water fluoride groups (high: - 0.52 (-0.92 to -0.12) p=0.01, I2=96.2% p<0.00001, extremely high: -0.60 (-0.87 to -0.33), p<0.0001, I2=84.6% p<0.0001).ConclusionsAt moderate levels (<1.5 ppm) there was no statistical or clinically meaningful association between water fluoride and IQ. This suggests that populations living in these areas could benefit from artificial water fluoridation without experiencing neurotoxicity. An association between lower mean IQ and high water fluoride observed suggests a need to prioritise removal of excess fluoride from drinking water in these regions.Key Message (3-5 bullet points in complete sentence)At low concentrations of water fluoride (<1.5 ppm) there was no detectable association between water fluoride and intelligence quotient (IQ);At high levels of water fluoride concentrations (>1.5 ppm) there was an inverse association between increasing fluoride concentration and decreasing mean IQ;In countries in which fluoridation of water is considered but kept within safe concentrations, the available evidence suggests that fluoridation has demonstrable benefits on public dental health without any clinically significant effect on IQ.In countries with excessive groundwater fluoride concentrations there is an imperative to promote water de-fluoridation schemes to protect the public from skeletal and dental fluorosis and from possible neurotoxicity.
H2inhalation therapy in patients with moderate Covid 19 (H2COVID): a prospective ascending-dose phase 1 clinical trial
Authors: Salomez-Ihl Cordélia , Giai Joris , Barbado Maud , Paris Adeline , Touati Saber , Alcaraz Jean- Pierre , Tanguy Stéphane , Leroy Corentin , Lehmann Audrey , Degano Bruno , Gavard Marylaure , Bedouch Pierrick , Pavese Patricia , Moreau-Gaudry Alexandre , Roustit Mathieu , Boucher François , Cinquin Philippe , Brion Jean-Paul 
Published: March 2024

AbstractIntroductionThe Covid-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for Covid-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy.MethodsThis Phase I study, characterized by an open-label, prospective, monocentric, and single ascending dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3+3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3).ResultsWe concluded that the Maximum Tolerated Duration is at least three days. Every patient showed clinical improvement and excellent tolerance to H2 therapy.Discussion/conclusionTo the best of our knowledge, this phase 1 clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized Covid-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials.QuestionWhat is the Maximum Tolerated Duration of inhalation for a gaseous mixture including 3.6% of molecular dihydrogen in moderate COVID-19 patients?FindingsThe Maximum Tolerated Duration is at least three days. All patients showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase 1 clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized Covid-19 patients.MeaningA gaseous mixture including 3.6% H2, considered in the literature to have promising anti-inflammatory potential, and presenting no risk of explosion, can be used in patients with moderate COVID 19 for at least three days.
The impact of Arctic environments on human cerebral blood flow
Authors: Liu Feifeng , Zheng Tianheng , Chen Jian , Liang Huazheng , Li Gang , Hao Junjie 
Published: March 2024

AbstractBackgroundThe Arctic environment represents an extreme living condition that has significant impact on life. But research on alterations of human cerebral blood flow (CBF) in a high-latitude and low-temperature environment in the Arctic is still lacking.MethodsMembers of the 12th Chinese National Arctic Research Expedition team who took the icebreaker R/VXuelong2 to the Arctic were recruited. Transcranial colour doppler (TCD) examination was performed at the beginning of the voyage (lower latitude and higher temperature, LLHT) and during the Arctic scientific expedition period (higher latitude and lower temperature, HLLT) respectively. The spectral pattern and parameters of cerebral arteries were compared.ResultsAmong 16 healthy individuals, 13 completed the TCD examination twice. They had a significantly lower mean velocity (Vm) (63.5 cm/s HLLT vs. 68.4cm/s LLHT;P=0.028) and peak systolic velocity (PSV) (94.6cm/s HLLT vs. 107.0cm/s LLHT;P=0.038) of the left middle cerebral artery (LMCA) and higher pulsatility index (PI) of the right middle cerebral artery (RMCA) (0.83 HLLT vs. 077 LLHT;P=0.011) in the HLLT environment compared to the LLHT one.ConclusionsChanges in human CBF may occur in higher-latitude and lower-temperature environments in the Arctic.
COVID-19-associated acute renal failure in critically ill patients correlates with microthrombosis and renal loss of thrombomodulin
Authors: Koskinen Matilda , Englund Elisabet , Korkut Gül Gizem , Schwarz Angelina , Jeansson Marie 
Published: March 2024

AbstractCritically ill COVID-19 patients have a high degree of acute kidney injury which develops in up to 85% of patients. We have previously shown that circulating levels of angiopoietin-2 increased in critically ill COVID-19 patients correlated to kidney injury, coagulopathy, and mortality. Furthermore, our experiments showed a causal effect on coagulopathy from angiopoietin-2 binding and inhibition of thrombomodulin mediated anticoagulation. In the current study we hypothesize that renal microthrombi may be a mechanism for reduced renal function in critically ill COVID-19 patients, and that local dysregulation of thrombomodulin and angiopoietin-2 may be involved.To investigate our hypothesis, we utilized postmortem kidney tissue from seven COVID-19 patients treated at the intensive care unit. We evaluated kidney function, thrombosis, tubular injury, fibrosis, glomerulosclerosis, glomerular size as well as renal expression of thrombomodulin and angiopoietin-2. Proximity ligation assay was utilized to evaluate the presence of angiopoietin-2 binding to thrombomodulin. Normal kidney tissue came from the healthy part of six nephrectomies due to cancer.Our experiments show renal thrombosis in 6/7 COVID-19 patients, on average 14.7 (6.9-22.5) thrombi per mm2. Most COVID-19 kidneys had extensive kidney injury, especially tubular necrosis, but also glomerular enlargement, glomerulosclerosis, and tubulointerstitial fibrosis which in some cases most likely resulted from underlying disease. Thrombomodulin expression was reduced in glomeruli and peritubular capillaries in kidneys from COVID-19 patients, whereas no change was found for angiopoietin-2.In summary, our study describes a high degree of acute renal failure, renal microthrombosis, and loss of thrombomodulin in postmortem tissue from critically ill COVID-19 patients.
The Impact of Cognitive Function on Health-Related Quality of Life in Persons with Post-COVID-19 Condition: A Randomized Controlled Trial on Vortioxetine
Authors: Kwan Angela T.H. , Lakhani Moiz , Le Gia Han , Singh Gurkaran , Teopiz Kayla M. , Guo Ziji , Manku Arshpreet Singh , Rosenblat Joshua D. , McIntyre Roger S. 
Published: March 2024

ABSTRACTBackgroundPost-Covid-19 Condition (PCC) manifests in persistent, debilitating symptoms that affect multiple cognitive domains. These symptoms can negatively impact an affected individual’s health-related quality of life (HRQoL). Herein, we investigate the effects of cognitive function on HRQoL in persons with PCC. Secondarily, we determine whether vortioxetine modulates cognitive function on HRQoL.MethodsParticipants aged 18-65 years were randomized to receive vortioxetine or placebo for 8 weeks. HRQoL was measured using the World Health organization Wellbeing Scale 5-item, cognition was measured using the Digit Symbol Substitution Test and the Trail-Making Test A/B. Generalized estimating equations were used to model the relationship of cognition to HRQoL for each treatment group.Results147 participants, 75.5% of which were female, were included in the analysis. At baseline, there was a statistically significant positive association between WHO-5 scores and combined DSST z-scores (β = 0.090, 95% CI [0.051, 0.129],p< 0.001), and a statistically significant negative association with TMT-A (β = −0.007, 95% CI [-0.011, −0.003],p< 0.001) and -B (β = −0.002, 95% CI [-0.003, 0.000],p= 0.024) scores, respectively. A significant treatment, time, and combined DSST z-score interaction on changes in overall WHO-5 total score (χ2= 15.481,p= 0.004) was reported. After adjusting for the type of cognitive test, there was a significant between-group difference (mean change = 1.77, SEM = 0.868,p= 0.042) favoring vortioxetine.ConclusionCognitive function is significantly associated with HRQoL in persons with PCC where enhanced cognitive functioning is associated with a better HRQoL. Vortioxetine is effective in improving HRQoL through enhancing cognitive function. Cognitive function in persons with PCC provides the impetus for future therapeutic targets for persons with PCC. Future studies should aim to investigate pro-cognitive therapeutic strategies.
Genomic insights on the potential role of the accessory genome in the emergence of a novel geographically restrictedK. pneumoniaelineage as a high-risk clone
Authors: Bighi Nathália , Freitas Fernanda , Morgado Sérgio , Cipriano Rosângela , Vicente Ana Carolina , Fonseca Érica L. 
Published: March 2024

ABSTRACTKlebsiella pneumoniaecauses life-threatening nosocomial infections and is featured by a remarkable propensity for multidrug resistance acquisition. Infections caused by multidrug- (MDR) and extensively drug-resistant (XDR) strains lead to a limitation of therapeutic options and an increase in persistent infections, and they are usually represented by high-risk lineages. Based on these features and their relevance to global public health, most of the studies focused on such high-risk clones, and little is known about the epidemiological and evolutionary dynamics of new/geographically restricted lineages. This study aimed to unveil the antimicrobial resistance and virulence genetic repertoire of a clinical XDRK. pneumoniae(Kp199) strain belonging to geographically-restricted ST, not linked to any known clonal complex. Its intrinsic (gyrA, parC, ramR, soxRandsoxSmutations) and acquired resistome agreed with the observed XDR phenotype. An extensive arsenal of both antibiotic and heavy metal resistance genes was observed, as well as genes involved with resistance to several antiseptics currently used in clinical settings. The co-occurrence ofblaKPC-2andblaNDM-1carbapenemase genes in Kp199 was an alarming finding since it could contribute to increased carbapenem resistance. Kp199 virulome was associated with bacterial survival and replication during infections. This study raises concern about a novel, geographically restrictedK. pneumoniaelineage harbouring a huge resistome and virulome, which may strongly contribute to its successful establishment as an epidemic lineage. Therefore, our findings underscore the importance of vigilant surveillance and control measures to mitigate the threat posed by the potential emergence of new high-risk pandemic clones.
Enhancing the Robustness of OPLS Modelling in Small Cohorts by Leveraging Permutation Analysis Prior to Variable Selection
Authors: Ström Marika , Wagner Nicole , Kolosenko Iryna , Wheelock Åsa M. 
Published: March 2024

AbstractThe R-workflow ropls-ViPerSNet (R orthogonalprojections oflatentstructures withVariablePermutationSelection and ElasticNet) facilitates variable selection, model optimization and significance testing using permutations of OPLS-DA models, with the scaled loadings (p[corr]) as the main metric of significance cutoff. Permutations including (over) the variable selection procedure, prior to (pre-), as well as post variable selection are performed. The resulting p-values for the correlation of the model (R2) and the cross-validated correlation of the model (Q2) pre-, post- and over-variable selection are provided as additional model statistics. These model statistics are useful for determining the true significance level of OPLS models, which otherwise have proven difficult to assess particularly for small sample sizes. Furthermore, a means for estimating the background noise level based on permuted false positive rates of R2and Q2is proposed. This novel metric is then used to calculate an adjusted Q2value. Using a publicly available metabolomics dataset, the advantage of performing permutations over variable selection was demonstrated for small sample sizes. Iteratively reducing the sample sizes resulted in overinflated models with increasing R2and Q2and permutations post variable selection indicated falsely significant models. In contrast, the adjusted Q2was marginally affected by sample size, and represents a robust estimate of model predictability, and permutations over variable selection showed true significance of the models. An additional Elastic Net variable selection option is included in the workflow for variable selection by coefficient value penalization using an iterative approach to reduce noise while avoiding overfitting.
Investigating the interactions of the cucumber mosaic virus 2b protein with the viral 1a replicase component and the cellular RNA silencing factor Argonaute 1
Authors: Crawshaw Sam , Murphy Alex M. , Rowling Pamela J. E. , Nietlispach Daniel , Itzhaki Laura S. , Carr John P. 
Published: March 2024

SUMMARYThe cucumber mosaic virus (CMV) 2b protein is a suppressor of plant defenses and a pathogenicity determinant. Amongst the 2b protein’s host targets is the RNA silencing factor Argonaute 1 (AGO1), which it binds to and inhibits. InArabidopsis thaliana, if 2b-induced inhibition of AGO1 is too efficient it induces reinforcement of antiviral silencing by AGO2, and triggers increased resistance against aphids, CMV’s insect vectors. These effects would be deleterious to CMV replication and transmission, respectively, but are moderated by the CMV 1a protein by sequestering sufficient 2b protein molecules into P-bodies to prevent excessive inhibition of AGO1. Mutant 2b protein variants were generated and red and green fluorescent protein fusions used to investigate subcellular colocalization with AGO1 and the 1a protein, and the effects of mutations on complex formation with the 1a protein and AGO1 were investigated using bimolecular fluorescence complementation and co-immunoprecipitation assays. Although we found that residues 56-60 influenced the 2b protein’s interactions with the 1a protein and AGO1, it appears unlikely that any single residue or sequence domain is solely responsible.In silicopredictions of intrinsic disorder within the 2b protein secondary structure were supported by circular dichroism (CD) but not by nuclear magnetic resonance (NMR) spectroscopy. Intrinsic disorder provides a plausible model to explain the 2b protein’s ability to interact with AGO1, the 1a protein and other factors. However, the reasons for the conflicting conclusions provided by CD and NMR must first be resolved.
Increased ‘selfness’ in the tumor emerges as a possible immune sculpting mechanism: A pan-cancer data analysis of 32 solid tumors in TCGA
Authors: Sakthivel Naren Chandran , Chinmayi Anoushka , Chandra Nagasuma 
Published: March 2024

AbstractTumors pose a unique challenge to the immune system since they straddle the boundary between ‘self’ and ‘non-self’. T-cells recognize tumors that contain ‘non-self’ neo-antigens. They can also recognize tumors that contain aberrantly expressed self-antigens, highlighting the importance of the central tolerance and the tuning of the T-cell repertoire in the thymus. Therefore, the similarity to the thymic expression profiles must have information in it to influence the T-cell repertoire and what self-peptides are recognized. We utilize this principle in a pan-cancer analysis and develop a thymus-like or ‘selfness’ score (TLS) based on the gene-expression similarity to thymi, indicative of recognizability of tumors by T-cells. We show that the TLS is indicative of patient survival in 8 different TCGA cohorts, indicating gene expression modulation to mimic that in thymi as a potential immune sculpting mechanism. Surprisingly, we also see an inverse relationship between TLS and the degree of immune infiltration.
New specimens ofBunaia woodwardi, Clarke 1919 (Euchelicerata): A new member of Offacolidae providing insight supporting the Arachnomorpha
Authors: Lustri Lorenzo , Antcliffe Jonathan B. , Gueriau Pierre , Daley Allison C. 
Published: March 2024

AbstractThe rapid early diversification of arthropods has made understanding internal relationships within the group fiendish. Particularly unresolved is the origin of Euchelicerata, a clade consisting of the Prosomapoda (comprising the extant Xiphosura and Arachnida and the extinct Chasmataspidida, Eurypterida and synziphosurines) and the extinct Offacolidae. Here we describe new material of the Silurian ‘synziphosurine’Bunaia woodwardithat reveals previously unknown features of its ventral anatomy: a pair of elongated chelicerae in the prosoma, followed posteriorly by five pairs of biramous appendages, a first pre-abdomen somite bearing a pair of paddle-like uniramous appendages (exopods), and a ventral pretelsonic process. Phylogenetic analyses retrieveB. woodwardias an Offacolidae closely related toSetapedites abundantisfrom the early Ordovician Fezouata Biota. An anatomical comparison of the pretelsonic process ofB. woodwardi, also present inSetapedites, with the posterior trunk morphologies of other Offacolidae, Habeliida and Vicissicaudata, suggests a possible homologous appendicular origin. This proposed apomorphic character supports a monophyletic Arachnomorpha, formed of Vicissicaudata, Habeliida and Euchelicerata. The establishment of this new homology could help to clarify the highly enigmatic phylogeny at the base of the euchelicerates as well as the sequence of character acquisition during their early evolution.
A Novel Tool for Multi-Omics Network Integration and Visualization: A Study of Glioma Heterogeneity
Authors: Coletti Roberta , Carrilho João , Martins Eduarda P. , Gonçalves Céline S. , Costa Bruno M. , Lopes Marta B. 
Published: March 2024

AbstractGliomas are highly heterogeneous tumors with generally poor prognoses. Leveraging multi-omics data and network analysis holds great promise in uncovering crucial signatures and molecular relationships that elucidate glioma heterogeneity. However, the complexity of the problem and the high dimensionality of the data increase the challenges of integrating information across various biological levels. In this study, we developed a framework comprising two steps for variable selection based on sparse network estimation from various omics. Subsequently, we introduced MINGLE (Multi-omics Integrated Network for GraphicaL Exploration), a novel methodology designed to merge distinct multi-omics information into a single network, enabling the identification of underlying relations through an innovative integrated visualization. Applying this method to glioma data, with patients grouped according to the newest glioma classification guidelines, led to the selection of variables as potential candidates for novel glioma-type-specific biomarkers.
A molecularly engineered lectin destroys EGFR and inhibits the growth of non-small cell lung cancer
Authors: Chan Susana M. , Raglow Zoe , Pal Anupama , Gitlin Scott D. , Legendre Maureen , Thomas Dafydd , Mehta Ranjit K , Tan Mingjia , Nyati Mukesh K. , Rehemtulla Alnawaz , Markovitz David M. 
Published: March 2024

AbstractSurvival rates for non-small cell lung cancer (NSCLC) remain low despite the advent of novel therapeutics. Tyrosine kinase inhibitors (TKIs) targeting mutant epidermal growth factor receptor (EGFR) in NSCLC have significantly improved mortality but are plagued with challenges--they can only be used in the small fraction of patients who have susceptible driver mutations, and resistance inevitably develops.Aberrant glycosylation on the surface of cancer cells is an attractive therapeutic target as these abnormal glycosylation patterns are typically specific to cancer cells and are not present on healthy cells. H84T BanLec (H84T), a lectin previously engineered by our group to separate its antiviral activity from its mitogenicity, exhibits precision binding of high mannose, an abnormal glycan present on the surface of many cancer cells, including NSCLC.Here, we show that H84T binds to and inhibits the growth of diverse NSCLC cell lines by inducing lysosomal degradation of EGFR and leading to cancer cell death through autophagy. This is a mechanism distinct from EGFR TKIs and is independent of EGFR mutation status; H84T inhibited proliferation of both cell lines expressing wild type EGFR and those expressing mutant EGFR that is resistant to all TKIs. Further, H84T binds strongly to multiple and diverse clinical samples of both pulmonary adenocarcinoma and squamous cell carcinoma. H84T is thus a promising potential therapeutic in NSCLC, with the ability to circumvent the challenges currently faced by EGFR TKIs.