bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic signaling inhibits c-FLIP expression and promotes cancer cell survival during ECM-detachment
Authors: Tsegaye Matyas Abel , He Jianping , McGeehan Kyle , Murphy Ireland M. , Nemera Mati , Schafer Zachary T. 
Published: April 2021

AbstractInhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes the survival of ECM-detached cells and that c-FLIP overexpression in cancer cells restricts the viability of cancer cells grown in anchorage-independent conditions. Taken together, our study reveals an unexpected role for c-FLIP in constraining the viability of cancer cells during ECM-detachment and raises the idea that c-FLIP may have context-dependent pro- and anti-cell death roles during tumorigenesis.
Mutant alleles differentially shape cattle complex traits and fitness
Authors: Xiang Ruidong , Breen Ed J. , Bolormaa Sunduimijid , Vander Jagt Christy J. , Chamberlain Amanda J. , Macleod Iona M. , Goddard Michael E. 
Published: April 2021

AbstractClassical mutant alleles (MAs), with large effects on phenotype, tend to be deleterious to traits and fitness. Is this the case for mutations with small effects? We infer MAs for 8 million sequence variants in 113k cattle and quantify the effects of MA on 37 complex traits. Heterozygosity for variants at genomic sites conserved across 100 vertebrates increase fertility, stature, and milk production, positively associating these traits with fitness. MAs decrease stature and fat and protein concentration in milk, but increase gestation length and somatic cell count in milk (the latter indicative of mastitis). However, the allele frequency of MAs that decrease fat and protein concentration and stature and increase gestation length and somatic cell count is lower than the allele frequency of MAs with the opposite effect. These results suggest bias in the direction of effect of mutation (e.g. towards reduced protein in milk), but selection operating to reduce the frequency of these MAs. Taken together, our results imply two classes of genomic sites subject to long-term selection: sites conserved across vertebrates show hybrid vigour while sites subject to less long-term selection show a bias in mutation towards alleles that are selected against.
The Impact of a Dynamic Working Environment on Human Gut Microbiota
Authors: Ling Lu , Zhou Jun , Meng Qianlong , Zhang Ziran , Li Wenkun , Cui Zilu , Liu Kuiliang , Zeng Fanxin , Wu Jing , Wang Jing 
Published: April 2021

AbstractGut microbiota dysbiosis is associated with a variety of diseases, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), metabolic diseases, allergic diseases, neurodevelopmental disorders and cancer. The human gut microbiota can be influenced by a variety of factors, including geography, dietary habits, living environment, age and altered lifestyle etc. This study was conducted to explore the gut microbiota compositions in officials who are in a stable working environment and train drivers who are in a dynamic working environment. Microbiota communities in the feces of 80 officials and 88 train drivers were analyzed using Illumina MiSeq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene and ITS1 region of fungi. There were significant differences between the two groups in diversity and richness of gut microbiota, while the microbial community compositions of the two groups were similar. The relationship between gut microbiota and clinical characteristics was investigated. We found that more bacteria and fungi were positively correlated with clinical characteristics. Functional prediction analysis of the gut microbiota between the two groups by PICRUSt2 revealed significant differences between the official group and the train driver group. Elucidating these differences of the microbiome between the two groups will provide a foundation understanding of the impact of a dynamic environment on gut microbiota.
Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family
Authors: Brown Kevin M. , Xu Mai , Sargen Michael , Jang Hyunbum , Zhang Mingzhen , Zhang Tongwu , Zhu Bin , Jones Kristie , Kim Jung , Mendoza Laura , Hayward Nicholas K. , Tucker Margaret A. , Goldstein Alisa M. , Yang Xiaohong Rose , Stewart Douglas R. , Hicks Belynda , Consonni Dario , Pesatori Angela C. , Fargnoli Maria Concetta , Peris Ketty , Stratigos Alex , Menin Chiara , Ghiorzo Paola , Puig Susana , Nagore Eduardo ,   MelaNostrum Consortium, Andresson Thorkell , Nussinov Ruth , Calista Donato , Landi Maria Teresa 
Published: April 2021

AbstractWhile several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations, we identified a novel NRAS variant (c.170A>C, p.D57A) in a melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11 273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2+ binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A>C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
Effectiveness of the BNT162b2 vaccine in preventing COVID-19 in the working age population – first results from a cohort study in Southern Sweden
Authors: Björk Jonas , Inghammar Malin , Moghaddassi Mahnaz , Rasmussen Magnus , Malmqvist Ulf , Kahn Fredrik 
Published: April 2021

AbstractBackgroundVaccine effectiveness against COVID-19 needs to be assessed in diverse real-world population settings.MethodsA cohort study of 805 741 residents in Skåne county, Southern Sweden, aged 18-64 years, of whom 26 587 received at least one dose of the BNT162b2 vaccine. Incidence rates of COVID-19 were estimated in sex- and age-adjusted analysis and stratified in two-week periods with substantial community spread of the disease.ResultsThe estimated vaccine effectiveness in preventing infection ≥7 days after second dose was 86% (95% CI 72-94%) but only 42% (95% CI 14-63%) ≥14 days after a single dose. No difference in vaccine effectiveness was observed between females and males. Having a prior positive test was associated with 91% (95% CI 85 to 94%) effectiveness against new infection among the unvaccinated.ConclusionA satisfactory effectiveness of BNT162b2 after the second dose was suggested, but with possibly substantially lower effect before the second dose.
Children have similar RT-PCR cycle threshold for SARS-CoV-2 in comparison with adults
Authors: Polese-Bonatto Márcia , Sartor Ivaine Tais Sauthier , Varela Fernanda Hammes , Gianinni Gabriela Luchiari Tumioto , Azevedo Thaís Raupp , Kern Luciane Beatriz , Fernandes Ingrid Rodrigues , Zavaglia Gabriela Oliveira , de David Caroline Nespolo , de Almeida Walquiria Aparecida Ferreira , Porto Victor Bertollo Gomes , Scotta Marcelo Comerlato , Stein Renato T. ,   COVIDa study group
Published: April 2021

AbstractBackgroundThe viral dynamics and the role of children in the spread of SARS-CoV-2 are not completely understood. Our aim was to evaluate RT-PCR Ct values among children with confirmed SARS-CoV-2 compared with that of adult subjects.MethodsPatients (aged from 2 months to ≤18 years, and adults) with signs and symptoms of acute SARS-CoV-2 infection for less than 7 days, were prospectively enrolled in the study from May to November 2020. All participants performed RT-PCR assay for SARS-CoV-2 detection; Ct values of ORF1ab, N, and S gene-targets, and the average of all the three probes were used as surrogates of viral load.ResultsThere were 21 infants, 62 children and 293 adults of 376 participants with confirmed SARS-CoV-2 infections. RT-PCR Ct values of children under 18 were not significantly different from that of adults after adjusting for days of illness, as observed by the analyzed probes (namely ORF1ab, N, and S), and by the mean of all 3 gene-targets.ConclusionsCt values for children were comparable to that of adults. Days of illness are a major confounder for SARS-CoV-2 viral load and must be adjusted in any comparison. Although viral load is not the only determinant of SARS-CoV-2 transmission, children may play a significant role in the spread of in the community.
When can we safely return to normal? A novel method for identifying safe levels of NPIs in the context of COVID-19 vaccinations
Authors: Bianchin Gianluca , Dall’Anese Emiliano , Poveda Jorge I. , Buchwald Andrea G. 
Published: April 2021

AbstractOver the course of the COVID-19 pandemic, governing bodies and individuals have relied on a variety of non-pharmaceutical interventions (NPIs) to control the transmission of SARS-CoV-2, which posed an acute threat to individuals’ well-being and consistently impacted economic activities in many countries worldwide. NPIs have been implemented at varying levels of severity and in response to widely-divergent perspectives of risk tolerance. Now, concurrently with the introduction of multiple SARS-CoV-2 vaccines, the world looks optimistically to a “return to normality”. In this work, we propose a multi-disciplinary approach, combining transmission modeling with control and optimization theory, to examine how risk tolerance and vaccination rates will impact the safe return to normal behavior over the next few months. To this end, we consider a version of the Susceptible-Exposed-Infected-Recovered transmission model that accounts for hospitalizations, vaccinations, and loss of immunity. We then propose a novel control approach to calibrate the necessary level of NPIs at various geographical levels to guarantee that the number of hospitalizations does not exceed a given risk tolerance (i.e., a maximum allowable threshold). Our model and control objectives are calibrated and tailored for the state of Colorado, USA. Our results suggest that: (i) increasing risk tolerance can decrease the number of days required to discontinue all NPIs; (ii) increasing risk tolerance inherently increases COVID-19 deaths even in the context of vaccination; (iii) if the vaccination uptake in the population is 70% or less, then return to normal behavior within the next year may newly stress the healthcare system. Furthermore, by using a multi-region model accounting for travel, our simulations predict that: (iv) relaxation should take into account regional heterogeneity in transmission and travel; and (v) premature relaxation of NPIs, even if restricted only to low-density regions, will lead to exceeding hospitalization limits even when highly-populated regions implement full-closures. Although the simulations are performed for the state of Colorado, the proposed model of transmission and control methods are applicable to any area worldwide and can be utilized at any geographical granularity.
Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies
Authors: Krüger Johanna , Schubert Julian , Kegele Josua , Labalme Audrey , Mao Miaomiao , Heighway Jacqueline , Seebohm Guiscard , Yan Pu , Koko Mahmoud , Aslan Kezban , Caglayan Hande , Steinhoff Bernhard J. , Weber Yvonne G. , Keo-Kosal Pascale , Berkovic Samuel F. , Hildebrand Michael S. , Petrou Steven , Krause Roland , May Patrick , Lesca Gaetan , Maljevic Snezana , Lerche Holger 
Published: April 2021

ABSTRACTObjectiveDe novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms.Methods1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling.ResultsWe identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2- interaction, presumably in the non-conducting preopen-closed state.InterpretationOur study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5- expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.
Is it time to ACT? A qualitative study of the acceptability and feasibility
of Acceptance and Commitment Therapy for adolescents with Chronic Fatigue
Syndrome
Authors: Clery Philippa , Starbuck Jennifer , Laffan Amanda , Parslow Roxanne , Linney Catherine , Leveret Jamie , Crawley Esther 
Published: April 2021

Abstract

Background
Paediatric Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)
is disabling and relatively common. Although evidenced based treatments are
available, at least 15% of children remain symptomatic after one year of
treatment. Acceptance and Commitment Therapy (ACT) is an alternative therapy
option; however, little is known about whether it is an acceptable treatment
approach. Our aim was to find out if children who are still disabled by
CFS/ME after 12 months of treatment would find ACT acceptable, to inform a
randomised controlled trial (RCT) of ACT.

Methods
We recruited children (diagnosed with CFS/ME; not recovered after one
year of treatment; aged 11-17 years), their parent/carer, and healthcare
professionals (HCPs) from one specialist UK paediatric CFS/ME service. We
conducted semi-structured interviews to explore barriers to recovery; views
on current treatments; acceptability of ACT; and feasibility of using an RCT
to test effectiveness. Thematic analysis was used to identify patterns in
data.

Results
Twelve adolescents, eleven parents, and seven HCPs were interviewed. All
participants thought ACT was acceptable. Participants identified reasons why
ACT might be efficacious: pragmatism, acceptance and compassion are valued
in chronic illness; values-focussed treatment provides motivation and
direction; psychological and physical needs are addressed; normalising
difficulties is a useful life-skill. Some adolescents preferred ACT to
Cognitive Behavioural Therapy as it encouraged accepting (rather than
challenging) thoughts. Most adolescents would consent to an RCT of ACT but a
barrier to recruitment was reluctance to randomisation. All HCPs deemed ACT
feasible to deliver. Some were concerned patients might confuse ‘acceptance’
with ‘giving up’ and called for clear explanations. All participants thought
the timing of ACT should be individualised.

Conclusions
All adolescents with CFS/ME, parents, and HCPs thought ACT was
acceptable, and most adolescents were willing to try ACT. An RCT needs to
solve issues around randomisation and timing of the intervention.

BOX

What is known about the subject?

Not all young people with CFS/ME recover.

ACT is a possible alternative therapy for CFS/ME, which
focuses on improving functioning and quality of life rather
than symptom reduction.

ACT is efficacious in paediatric chronic pain, and
preliminary results show promising effects in adults with
CFS/ME.

What this study adds?

ACT is an acceptable therapy for young people with
CFS/ME.

Participants thought the ‘pragmatic’, ‘compassionate’
and ‘values-based’ focus of ACT would be helpful.

Adolescents, parents and healthcare professionals
support a randomised controlled trial of ACT.
DNA-based data storage via combinatorial assembly
Authors: Roquet Nathaniel , Bhatia Swapnil P , Flickinger Sarah A , Mihm Sean , Norsworthy Michael W , Leake Devin , Park Hyunjun 
Published: April 2021

AbstractPersistent data storage is the basis of all modern information systems. The long-term value and volume of data are growing at an accelerating rate and pushing extant storage systems to their limits. DNA offers exciting potential as a storage medium, but no practical scheme has been proposed to date that can scale beyond narrow-band write rates. Here, we demonstrate a combinatorial DNA data encoding scheme capable of megabits per second write speeds. The system relies on rapid, combinatorial assembly of multiple smaller DNA parts that are dispensed through inkjet printing. To demonstrate this approach, we wrote approximately 25 kB of information into DNA using our system and read the information back out with commercially available nanopore sequencing. Moreover, we demonstrate the ability to replicate and selectively access the information while it is in DNA, opening up the possibility of more sophisticated DNA computation.
High efficiency excitation energy transfer in biohybrid quantum dot–bacterial reaction center nanoconjugates
Authors: Amoruso Giordano , Liu Juntai , Polak Daniel W. , Tiwari Kavita , Jones Michael R. , Oliver Thomas A. A. 
Published: April 2021

AbstractReaction centers (RCs) are the pivotal component of natural photosystems, converting solar energy into the potential difference between separated electrons and holes that is used to power much of biology. RCs from anoxygenic purple photosynthetic bacteria such asRhodobacter sphaeroidesonly weakly absorb much of the visible region of the solar spectrum which limits their overall light-harvesting capacity. Forin vitroapplications such as bio-hybrid photodevices this deficiency can be addressed by effectively coupling RCs with synthetic lightharvesting materials. Here, we studied the time scale and efficiency of Förster resonance energy transfer (FRET) in a nanoconjugate assembled from a synthetic quantum dot (QD) antenna and a tailored RC engineered to be fluorescent. Time-correlated single photon counting spectroscopy of biohybrid conjugates enabled the direct determination of FRET from QDs to attached RCs on a time scale of 26.6 ± 0.1 ns and with a high efficiency of 0.75 ± 0.01.
Effects of CO2and RuBisCO concentration on cyanobacterial growth and carbon isotope fractionation
Authors: Garcia Amanda , Kedzior Mateusz , Taton Arnaud , Li Meng , Young Jodi , Kaçar Betül 
Published: April 2021

ABSTRACTCarbon isotope biosignatures preserved in the Precambrian geologic record are primarily interpreted to reflect ancient cyanobacterial carbon fixation catalyzed by Form I RuBisCO enzymes. The average range of isotopic biosignatures generally follows that produced by extant cyanobacteria. However, this observation is difficult to reconcile with several environmental (e.g., temperature, pH, and CO2concentrations), molecular, and physiological factors that likely would have differed during the Precambrian and can produce fractionation variability in contemporary organisms that meets or exceeds that observed in the geologic record. To test a range of genetic and environmental factors that may have impacted ancient carbon isotope biosignatures, we engineered a mutant strain of the model cyanobacteriumSynechococcus elongatusPCC 7942 that overexpresses RuBisCO and characterized the resultant physiological and isotope fractionation effects. We specifically investigated how both increased atmospheric CO2concentrations and RuBisCO regulation influence cell growth, oxygen evolution rate, and carbon isotope fractionation in cyanobacteria. We found that elevated CO2increases the growth rate of wild-type and mutant strains, and that the pool of active RuBisCO enzyme increases with increased expression. RuBisCO overexpression in our engineered strain does not significantly affect isotopic discrimination at all tested CO2concentrations, yielding cellular13C/12C isotope discrimination (εp) of ∼24‰ for both wild-type and mutant strains at elevated CO2. Understanding the environmental factors that impact gene regulation, physiology, and evolution is crucial for reconciling microbially driven carbon isotope fractionation with the geologic record carbon biosignatures.
Ultrastructure Expansion Microscopy inTrypanosoma brucei
Authors: Kalichava Ana , Ochsenreiter Torsten 
Published: April 2021

Abstract-IntroductionThe recently developed ultrastructure expansion microscopy (U-ExM) technique allows to increase the spatial resolution within a cell or tissue for microscopic imaging through the physical expansion of the sample. In this study we validate the use of U-ExM inTrypanosoma bruceiby visualizing the nucleus and kDNA as well as proteins of the cytoskeleton, the basal body, the mitochondrion and the ER.T. bruceiis a unicellular flagellated protozoan parasite and the causative agent of human African sleeping sickness and Nagana in cattle.The highly polarized parasite cell body is about 25 μm in length and is shaped by the subpellicular microtubule corset. Its single flagellum emanates from the posterior part of the cell and is attached along the entire cell body.T. bruceiThe cell contains all typical organelles of eukaryotic cells including ER, Golgi and mitochondrion. Interestingly, Golgi and mitochondrion are single unit organelles in this protozoan parasite. The signature feature of trypanosomes is the single unit mitochondrial genome, the kinetoplast DNA (kDNA) that is organized in a complex structure of interlocked mini- and maxicircles. The kDNA is segregated during cell division by the tripartite attachment complex (TAC) that connects it via the mitochondrial membranes to the base of the flagellum.