bluuebunny/crossref_metadata_2025_split huggingface dataset:
Augmenting Transcranial Magnetic Stimulation Coil with Magnetic Material: An Optimization Approach
Authors: Lu Charles , Deng Zhi-De , Choa Fow-Sen 
Published: January 2022

AbstractTranscranial magnetic stimulation (TMS) is a neuromodulation technique that has been approved by the U.S. Food and Drug Administration for several neuropsychiatric disorders, including major depression and obsessive-compulsive disorder. However, the therapeutic efficacy of TMS treatment has been modest, despite decades of research. While there are many potential reasons as to why, one of the most obvious is the limitations of current technologies. One prominent example is the penetration depth–focality tradeoff of existing TMS coils. The most widely used figure-of-8 coils stimulate brain regions just superficially under the coil, missing deep brain regions known to be critically involved in psychiatric disorders; while ring-type coils can stimulate deep into the brain, but stimulate a large brain volume (lack of focality). A new coil design strategy is proposed: magnetic materials encompassing the human head are optimized to shape the electromagnetic field generated by the primary coil. Specifically, a mathematical model was developed to describe the physical problem; the magnetic materials were discretized into unit blocks; Newton’s gradient descent method was applied to iteratively optimize the spatial distribution of the unit blocks to achieve a desired electric field distribution inside a head model. Results reveal that the proposed design achieves a coil penetration depth equal to or better than state-of-the art commercial coils, while improving the depth–focality tradeoff by a factor of 2.2 to 2.7. As a proof-of-concept, a prototype coil and a spherical head model were constructed; the spatial distribution of the induced electric field inside the head model was mapped. Results validated the proposed coil design. TMS coils based on this novel design strategy could potentially lead to better therapeutic outcome.
The Epidemiology of Hundreds of Individuals Infected with Omicron BA.1 in Middle-Eastern Jordan
Authors: Hajjo Rima , AbuAlSamen Mahmoud M. , Alzoubi Hamed M. , Alqutob Raeda 
Published: January 2022

AbstractIn less than two months of its detection in Jordan, lineage B.1.1.529 recognized as Omicron, is constituting 55% of all confirmed coronavirus disease of 2019 (COVID-19) infections causing a rise in the daily cases in the country. Herein, we report on 500 cases, among the first identified Omicron infections in Jordan. We also report on the genomic diversity of 25 Omicron viruses identified in nasopharyngeal swabs from Jordan. Our results indicated that 96% of study participants were vaccinated who had asymptomatic, mild or moderate disease. One unvaccinated individual developed severe disease. The median age of Omicron cases was 30 years, and most frequent disease symptoms were: fever, coughing, sore throat, runny nose, general fatigue and muscle/joint pain. Viral genomic analysis results revealed that the BA.1 is the dominant Omicron sublineage in Jordan, with 45 to 58 total mutations. We identified a few amino acid modifications that could impact the accuracy of some polymerase chain reaction (PCR) tests. In summary, infections caused by BA.1 seem milder than earlier infections. However, it is unknown whether this change is due to alterations in the immunity landscape of the infected population or is the result of viral genetic mutations that reduced viral virulence. Hence, comparing similar studies from different countries is likely to give us a get a better understanding of this variant, its behavior and the impact on disease characteristics.
Association of Sleep Behaviors with Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean , Tsilidis Konstantinos K. , Ju Yo-El S , Govindan Ramaswamy , Puri Varun , Cao Yin 
Published: January 2022

ABSTRACTIMPORTANCEEsophageal cancer is among the most lethal type of cancers worldwide. However, risk factors contributing to more than tenfold increase in esophageal cancer in the last 50 years remain underexplored.OBJECTIVEThis study aimed to examine the associations between sleep behaviors and esophageal cancer overall, by histology, and according to genetic predispositions.DESIGNA prospective cohort study.SETTINGA population-based study.PARTICIPANTSA total of 410,428 participants aged 37-73 years at enrollment between 2006 and 2010 in the UK Biobank were followed up until March 31st, 2016 for England and Wales and October 31st, 2015 for Scotland.MAIN OUTCOME AND MEASUREThe risk of incident esophageal cancer.RESULTSDuring 2,799,342 person-years of follow-up, 410 incident esophageal cancer cases (294 adenocarcinomas) were diagnosed. Evening chronotype, sleep <6 or >9 h/day, daytime napping, and daytime sleepiness were significantly associated with increased risk of esophageal cancer in age-adjusted models and had aPlikelihood ratio test≤0.20 after multivariable adjustment. Compared with the group without these high-risk behaviors, participants with one high-risk behavior had a 41% (HR=1.41, 95%CI: 1.13, 1.77) increased risk of esophageal cancer, and those with two or more behaviors showed a 79% higher risk (HR=1.79, 95%CI: 1.32, 2.42) (Ptrend<0.001). These associations were largely driven by esophageal adenocarcinoma (Ptrend<0.001) but not squamous cell carcinoma (Ptrend=0.340). The elevated risks for esophageal adenocarcinoma were similar within strata of PRS quintiles (Pinteraction=0.791).CONCLUSION AND RELEVANCEUnhealthy sleep behaviors were associated with an increased risk of esophageal cancer, primarily adenocarcinoma, independent of genetic risk. Sleep behaviors may serve as modifiable factors for the prevention of esophageal cancer, particularly esophageal adenocarcinomas.Key PointsQuestionAre sleep behaviors associated with the risk of esophageal cancer?FindingsIn this prospective cohort study that included 410,428 participants in the UK Biobank, evening chronotype, sleep <6 or >9 h/day, daytime napping, and sleepiness were associated with increased risk of esophageal cancer. A greater number of these unhealthy sleep behaviors was associated with a higher risk of esophageal cancer. The elevated risks were primarily observed for esophageal adenocarcinoma and were independent of genetic risk.MeaningSleep behaviors may serve as modifiable factors for the esophageal cancer prevention, particularly esophageal adenocarcinoma, independent of genetic risk.
Multiplexed strain phenotyping defines consequences of genetic diversity in Mycobacterium tuberculosis for infection and vaccination outcomes
Authors: Carey Allison F. , Wang Xin , Cicchetti Nico , Spaulding Caitlin N. , Liu Qingyun , Hopkins Forrest , Brown Jessica , Sixsmith Jaimie , Ioerger Thomas R. , Fortune Sarah M. 
Published: January 2022

ABSTRACTThere is growing evidence that genetic diversity in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, contributes to the outcomes of infection and public health interventions, such as vaccination. Epidemiological studies suggest that among the phylogeographic lineages of Mtb, strains belonging to Lineage 2 (L2) are associated with concerning clinical features including hypervirulence, treatment failure, and vaccine escape. The global expansion and increasing prevalence of L2 has been attributed to the selective advantage conferred by these characteristics, yet confounding host and environmental factors make it difficult to identify the bacterial determinants driving these associations in human studies. Here, we developed a molecular barcoding strategy to facilitate high-throughput, experimental phenotyping of Mtb clinical isolates. This approach allowed us to characterize growth dynamics for a panel of genetically diverse Mtb strains during infection and after vaccination in the mouse model. We found that L2 strains exhibit distinct growth dynamics in vivo and are resistant to the immune protection conferred by Bacillus Calmette-Guerin (BCG) vaccination. The latter finding corroborates epidemiological observations and demonstrates that mycobacterial features contribute to vaccine efficacy. To investigate the genetic and biological basis of L2 strains’ distinctive phenotypes, we performed variant analysis, transcriptional studies, and genome-wide transposon sequencing. We identified functional genetic changes across multiple stress- and host-response pathways in a representative L2 strain that are associated with variants in regulatory genes. These adaptive changes may underlie the distinct clinical characteristics and epidemiological success of this lineage.
Probabilistic Learning of Treatment Trees in Cancer
Authors: Yao Tsung-Hung , Wu Zhenke , Bharath Karthik , Li Jinju , Baladandayuthapan Veerabhadran 
Published: January 2022

AbstractAccurate identification of synergistic treatment combinations and their underlying biological mechnisms is critical across many disease domains, especially cancer. In translational oncology research, preclinical systems such as patient-derived xenografts (PDX) have emerged as a unique study design evaluating multiple treatments administered to samples from the same human tumor implanted into genetically identical mice. In this paper, we propose a novel Bayesian probabilistic tree-based framework for PDX data to investigate the hierarchical relationships between treatments by inferring treatment cluster trees, referred to as treatment trees (Rx-tree). The framework motivates a new metric of mechanistic similarity between two or more treatments accounting for inherent uncertainty in tree estimation; treatments with a high estimated similarity have potentially high mechanistic synergy. Building upon Dirichlet Diffusion Trees, we derive a closed-form marginal likelihood encoding the tree structure, which facilitates computationally efficient posterior inference via a new two-stage algorithm. Simulation studies demonstrate superior performance of the proposed method in recovering the tree structure and treatment similarities. Our analyses of a recently collated PDX dataset produce treatment similarity estimates that show a high degree of concordance with known biological mechanisms across treatments in five different cancers. More importantly, we uncover new and potentially effective combination therapies that confer synergistic regulation of specific downstream biological pathways for future clinical investigations. Our accompanying code, data, and shiny application for visualization of results are available at: https://github.com/bayesrx/RxTree.
RNA-Targeting CRISPR/Cas13d System Eliminates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease
Authors: Morelli Kathryn H. , Wu Qian , Gosztyla Maya L. , Liu Hongshuai , Zhang Chuangchuang , Chen Jiaxu , Marina Ryan , Lee Kari , Jones Krysten L. , Duan Wenzhen , Yeo Gene W. 
Published: January 2022

AbstractHuntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a CAGEX RNA-eliminating CRISPR-Cas13d system (Cas13d/CAGEX) that binds and eliminates toxic CAGEX RNA in HD patient iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.
COVID-19 vaccines effectiveness against symptomatic SARS-CoV-2 during Delta variant surge: a population-based case-control study in St. Petersburg, Russia
Authors: Barchuk Anton , Bulina Anna , Cherkashin Mikhail , Berezina Natalia , Rakova Tatyana , Kuplevatskaya Darya , Stanevich Oksana , Skougarevskiy Dmitriy , Okhotin Artemiy 
Published: January 2022

BackgroundStudies of mRNA and vector-based vaccines used in different countries report acceptable levels of effectiveness against SARS-CoV-2 infection caused by the Delta variants of SARS-CoV-2. No studies estimated vaccine effectiveness (VE) of Gam-COVID-Vac and other vaccines used in Russia against symptomatic infection with Delta variant. In this population-based case-control study, we aimed to estimate the effectiveness of the Russian COVID-19 vaccines against symptomatic SARS-CoV-2 during the recent outbreak caused by the Delta VOC in October 2021 in St. Petersburg, Russia.MethodsIn a population-based case-control study with density sampling of controls, we acquired information on cases and controls from two independent studies conducted in St. Petersburg. Cases were symptomatic patients with confirmed SARS-CoV-2 (using polymerase chain reaction (PCR) test) referred to low-dose computed tomography (LDCT) triage in two outpatient centres between October 6 and 14, 2021 during the Delta variant outbreak. We recruited the controls during the representative survey of the seroprevalence study conducted during the same period in St. Petersburg using random digit dialling. In the primary analysis, we used logistic regression models to estimate the adjusted (age, gender, and history of confirmed COVID-19) VE against symptomatic SARS-CoV-2 resulted in a referral to triage centre for three vaccines used in Russia: Gam-COVID-Vac, EpiVacCorona, and CoviVac.FindingsWe included 1,254 cases and 2,747 controls recruited between the 6th and 14th of October in the final analysis. VE was 56% (95% CI: 48 to 63) for Gam-COVID-Vac (Sputnik V), 49% (95% CI: 29 to 63) for 1-dose Gam-COVID-Vac (Sputnik V) or Sputnik Light, -58% (95% CI: -225 to 23) for EpiVacCorona and 40% (95% CI: 3 to 63) for CoviVac. Without adjustment for the history of confirmed COVID-19 VE for all vaccines was lower, except for one-dose Gam-COVID-Vac (Sputnik Light). The adjusted VE was slightly lower in women — 51% (95% CI: 39 to 60) than men — 65% (95% CI: 5 to 73). It was also higher in younger age. However, in the analysis restricted to participants without a history of confirmed COVID-19, the differences in VE by age group were smaller.InterpretationIn contrast to other Russian vaccines, Gam-COVID-Vac is effective against symptomatic SARS-CoV-2 infection caused by Delta VOC. Effectiveness is likely higher than the estimated 56% due to bias arising from high prevalence of the past COVID-19 in St. Petersburg.FundingPopulation-based survey in St. Petersburg was funded by Polymetal International, plc.
Assembly and comparative analysis of the complete mitochondrial genome of three Macadamia species (M. integrifolia, M. ternifolia and M. tetraphylla)
Authors: Niu Yingfeng , Lu Yongjie , Song Weicai , He Xiyong , Liu Ziyan , Zheng Cheng , Wang Shuo , Shi Chao , Liu Jin 
Published: January 2022

AbstractBackgroundMacadamia is a true dicotyledonous plant that thrives in a mild, humid, low wind environment. It is cultivated and traded internationally due to its high-quality nuts thus, has significant development prospects and scientific research value. However, information on the genetic resources of Macadamia spp. remains scanty.ResultsThe mitochondria (mt) genomes of three economically important Macadamia species, Macadamia integrifolia, M. ternifolia and M. tetraphylla, were assembled through the Illumina sequencing platform. The results showed that each species has 71 genes, including 42 protein-coding genes, 26 tRNAs, and 3 rRNAs. Repeated sequence analysis, RNA editing site prediction, and analysis of genes migrating from chloroplast (cp) to mt were performed in the mt genomes of the three Macadamia species. Phylogenetic analysis based on the mt genome of the three Macadamia species and 35 other species was conducted to reveal the evolution and taxonomic status of Macadamia. Furthermore, the characteristics of the plant mt genome, including genome size and GC content, were studied through comparison with 36 other plant species. The final non-synonymous (Ka) and synonymous (Ks) substitution analysis showed that most of the protein-coding genes in the mt genome underwent negative selections, indicating their importance in the mt genome.ConclusionThe findings of this study provide a better understanding of the Macadamia genome and will inform future research on the genus.
Inversion of a topological domain leads to restricted changes in its gene expression and affects inter-domain communication
Authors: Galupa Rafael , Picard Christel , Servant Nicolas , Nora Elphège Pierre , Zhan Yinxiu , Bemmel Joke van , Marjou Fatima El , Johanneau Colin , Borensztein Maud , Ancelin Katia , Giorgetti Luca , Heard Edith 
Published: January 2022

AbstractThe interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors underlying genome topology, such as CTCF and cohesin, leads to modest alterations in gene expression, while genomic rearrangements involving boundaries of topologically associating domains (TADs) disrupt normal gene expression and can lead to pathological phenotypes. Here we inverted an almost entire TAD (245kb out of 300kb) within the X-inactivation centre (Xic), leaving its boundaries intact. This led to a significant rearrangement of topological contacts within the TAD, mostly in accordance to the orientation of underlying CTCF binding sites but suggesting heterogeneity in the “contact” potential of different CTCF sites. The inversion also led to increased contact insulation with the neighbouring TAD. Expression of most genes within the inverted TAD remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression in the neighbouring TAD of the noncoding transcript Xist, which controls X-chromosome inactivation, was ectopically upregulated. The same inversion in mouse embryos led to a bias in Xist expression, but X-inactivation choice ratios did not significantly deviate from wild type. Smaller deletions and inversions of specific clusters of CTCF sites within the TAD led to similar results: rearrangement of contacts, limited changes in local gene expression but significant changes in Xist expression. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighbouring TADs, highlighting the existence of mechanisms for inter-TAD communication.
Hippocampal fear engrams modulate ethanol-induced maladaptive contextual generalization in mice
Authors: Cincotta C. , Ruesch E. , Senne R. , Ramirez S. 
Published: January 2022

ABSTRACTThe compounding symptomatology of comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) gives rise to an interaction of maladaptive neurobiological processes, the etiology of which remains elusive. Here, we devised an optogenetic strategy aimed at rescuing maladaptive responses to fearful stimuli in male c57BL/6 mice following chronic ethanol administration and forced abstinence. In the first experiment, we confirmed that fear acquisition and maladaptive contextual generalization was potentiated in ethanol-exposed mice during fear conditioning and exposure to a novel environment, respectively. In the second experiment, using an activity-dependent tet-tag system, we labeled and artificially inhibited the neural ensemble selectively activated by contextual fear conditioning in the dorsal hippocampus to attenuate behavioral dysfunctions resulting from ethanol exposure. We found that acute optogenetic inhibition during exposure to a novel environment suppressed maladaptive generalization in ethanol-exposed mice. These results provide further evidence for a crucial link between ethanol exposure and impaired fear memory processing by providing cellular and behavioral insights into the neural circuitry underlying AUD and PTSD comorbidity.
The icon as a collaborative performance: non-standard solutions, invisible work and networks of trust in the construction of the Elbe Philharmonic Hall, Hamburg
Authors: Dimitrova Venetsiya , Grubbauer Monika 
Published: January 2022

PurposeThe main goal of this paper is to shift the focus from the symbolic and aesthetic features of iconic projects to the complex process of their actual materialisation. Hereby, the authors conceptualise iconic projects as the “collaborative performance” of a wide range of built environment professionals. The authors seek to unravel the complexity of organisational action, professional practices, knowledge and expertise, and the inter-firm networks required for the creation of iconic architecture.Design/methodology/approachThe analysis is based on an in-depth case study of the Elbe Philharmonic Hall, Hamburg's new icon. This included 26 semi-structured interviews with a broad range of interview partners, which were conducted by an interdisciplinary team.FindingsBesides by spectacular architectural design, iconic buildings are characterised by the meticulous execution of even the smallest details as well as of more hidden building elements unlikely to be seen by the public. Execution is usually contingent on the specific building processes and construction practices and requires the continuous engagement of project architects, as well as trusting collaborations with their partners in the construction industry. Yet the making of iconic projects is challenging and (financially) risky, and the interfaces between project partners cannot be easily translated into contractual agreements, which potentially compromises the collaboration between architects and construction firms.Originality/valueThis paper advances a cross-sectoral view on professional practices by providing in-depth insight into the work of less prominent project architects and their partners in the construction industry. This paper hereby bridges design and construction practices and provides a more holistic understanding of how iconic projects are constructed on the ground.