bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel map of human p53 response elements uncovers evidence of selection pressures and variants similar to Li-Fraumeni Syndrome mutations
Authors: Zhang Ping , Brown Katherine , Barnes David , Kitchen-Smith Isaac , Sims David , Flanagan Adrienne , De Noon Solange , Van Loo Peter , Hargreaves Steven , Cross Will , Pillay Nischalan , Jafri Mariam , Wallis Yvonne , Ucanok Deniz , Ntaoulas Sotirios , Manz Markus G , Tebaldi Toma , Inga Alberto ,   Genomics England Research Consortium, Grochola Lukasz F. , Bond Gareth 
Published: September 2022

AbstractBackgroundThe advent of functional genomic techniques and next generation sequencing has improved the characterization of the non-protein coding regions of the genome. However, the integration of these data into clinical practice is still in its infancy. Fifty percent of cancers mutate TP53, which promotes tumorigenesis, in part, by inhibiting its ability to bind to non-coding regions of the genome and function as a sequence-specific transcription factor. P53 is a tumour suppressor that inhibits cell survival through regulating transcription of anti-survival genes. However, p53 also regulates transcription of pro-survival genes and the target gene(s) responsible for p53 tumour suppression remains an open topic of research.MethodsIn this study, we integrate detailed genome-wide maps of p53 responsive elements (p53-RE), p53 occupancy, recently defined candidate cis-Regulatory Elements (cCREs) and whole genome sequencing for cancers to better define the regions of the genome that harbour functional p53 enhancers.ResultsWe determine that p53-REs are more likely to be closer to the consensus binding site, to be evolutionarily conserved and to be occupied by p53 in cellulo, when they reside in regions of the genome that have been noted to have accessible DNA and a regulatory epigenomic mark in at least one human cell even without obvious p53 activation signals (cCRE p53-REs). We offer evidence that it is only in cCRE p53-REs, where multiple signs of differential natural selection between pro-survival and anti-survival target genes can be noted. Using whole genome sequences of 38,377 individuals, we go on to demonstrate that carriers of rare germline mutations in cCRE p53-REs can have similar traits to carriers of rare p53 coding mutations that cause the Li-Fraumeni cancer predisposition syndrome.ConclusionsTogether, these observations suggest that functional p53 enhancers are enriched in cCREs and that germline mutations in them have the potential to improve current cancer risk management and screening strategies.
Seasonal Dynamics of Anopheles stephensi and its Implications for Mosquito Detection and Emergent Malaria Control in the Horn of Africa
Authors: Whittaker Charles , Hamlet Arran , Sherrard-Smith Ellie , Winskill Peter , Cuomo-Dannenburg Gina , Walker Patrick G.T. , Sinka Marianne , Pironon Samuel , Kumar Ashwani , Ghani Azra , Bhatt Samir , Churcher Thomas S. 
Published: September 2022

AbstractInvasion of the malaria vector Anopheles stephensi across the Horn of Africa threatens control efforts across the continent, particularly in urban settings where the vector is able to proliferate. Malaria transmission across Africa is primarily determined by the abundance of dominant vectors, which often varies seasonally with rainfall. However, it remains unclear how An.stephensi abundance changes throughout the year, despite this being a crucial input to surveillance and control activities. We collate longitudinal catch-data from across its endemic range to better understand the vector’s seasonal dynamics and explore the implications of this seasonality for malaria surveillance and control across the Horn of Africa. Our analyses reveal pronounced variation in seasonal dynamics, the timing and nature of which are poorly predicted by rainfall patterns. Instead, they are associated with temperature and patterns of land-use, with seasonality frequently differing between rural and urban settings. Our results show that timing entomological surveys to coincide with rainy periods is unlikely to improve the likelihood of detecting An.stephensi. Integrating these results into a model of malaria transmission, we show that timing indoor residual spraying campaigns to coincide with peak rainfall offers little improvement in reducing disease burden compared to starting in a random month. Our results suggest that unlike other major malaria vectors in Africa, rainfall may be a poor guide to predicting the timing of peaks in An.stephensi-driven malaria transmission. This highlights the urgent need for longitudinal entomological monitoring of the vector in its new environments given recent invasion and potential spread across the continent.
Exploring the Genetic and Genomic Connection Underlying Neurodegeneration with Brain Iron Accumulation and the Risk for Parkinson’s Disease
Authors: Jerez Pilar Álvarez , Alcantud Jose Luis , los Reyes-Ramírez Lucia de , Moore Anni , Ruz Clara , Montero Francisco Vives , Rodriguez-Losada Noela , Saini Prabhjyot , Gan-Or Ziv , Alvarado Chelsea , Makarious Mary B. , Billingsley Kimberley J. , Blauwendraat Cornelis , Noyce Alastair J , Singleton Andrew , Duran Raquel , Bandres-Ciga Sara 
Published: September 2022

AbstractBackgroundNeurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation and the presence of axonal spheroids in the brain. In Parkinson’s Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death.ObjectivesThe aim of this present study was to comprehensively explore the genetic and genomic connection between NBIA and PD etiology.MethodsWe screened the presence of known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4,481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons’ Disease Program and the UKBiobank. We further examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. To investigate the potential effect of NBIA gene expression on PD, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1,886 PD cases and 1,285 controls.ResultsOut of 28 previously reported NBIA screened coding variants, four missense were found to be associated with PD risk at a nominal p value < 0.05 (p.T402M-ATP13A2, p.T207M-FA2H, p.P60L-C19orf12, p.C422S-PANK2). No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested thatDCAF17is differentially expressed in blood from PD cases and controls.ConclusionsTaking into account the very low mutation occurrence in the datasets and the lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities, supporting the notion that the mechanisms underpinning iron accumulation in PD are likely not shared with NBIA. Elevated nigral iron levels may not contribute to PD etiology and may vary with anti-parkinsonian drugs used for treatment, environmental factors, or iron sequestration in tissue as a response to PD pathological change.
Differences in COVID-19 cyclicity and predictability among U.S. counties and states reflect the effectiveness of protective measures
Authors: Bozzuto Claudio , Ives Anthony R. 
Published: September 2022

AbstractData available for COVID-19 in the USA make it possible to assess the dynamics of disease spread with 20:20 hindsight. Here, we analyze archived data to explain variation among counties and states in the cyclicity and predictability (that is, the extent to which predictions are possible) of disease dynamics, using a combination of statistical and simulation models. For the period after the initial outbreak but before widespread vaccination (May 2020 – February 2021), we show that for half the counties and states the spread rate of COVID-19, r(t), was predictable at most 9 weeks and 8 weeks ahead, respectively, corresponding to at most 40% and 35% of an average cycle length of 23 weeks and 26 weeks. However, there were large differences among counties and states, and high predictability was associated with high cyclicity of r(t). Furthermore, predictability was negatively associated with R0 values from the pandemic’s onset. This suggests that a severe initial outbreak induced strong and sustained protective measures to lower disease transmission, and these protective measures in turn reduced both cyclicity and predictability. Thus, decreased predictability of disease spread should be viewed as a by-product of positive and sustained steps that people take to protect themselves and others.Significance statementDuring the COVID-19 pandemic, many quantitative approaches were employed to predict the course of disease spread. However, forecasting faces the challenge of inherently unpredictable spread dynamics, setting a limit to the accuracy of all models. For counties and states in the USA, we document very high variation in predictability after the initial outbreak and before widespread vaccination. Jurisdictions with high predictability were those that showed pronounced cyclic re-emergences (‘waves’). The variation in predictability can be explained by differences in the human responses to disease: jurisdictions in which individuals and authorities took strong and sustained protective measures against COVID-19 successfully curbed subsequent waves of disease spread, but at the same time unintentionally decreased its predictability.
Global proteome metastability response in isogenic animals to missense mutations and polyglutamine expansions in aging
Authors: Sui Xiaojing , Prado Miguel A. , Paulo Joao A. , Gygi Steven P. , Finley Daniel , Morimoto Richard I. 
Published: September 2022

ABSTRACTThe conformational stability of the proteome has tremendous implications for the health of the cell and its capacity to determine longevity or susceptibility to age-associated degenerative diseases. For humans, this question of proteome conformational stability has the additional complexity from non-synonymous mutations in thousands of protein coding genes challenging the capacity of the proteostasis network to properly fold, transport, assemble and degrade proteins. Here, we quantify the proteome-wide capacity to such challenges using the isogenic organism Caenorhabditis elegans by examining the dynamics of global proteome conformational stability in animals expressing different temperature-sensitive (ts) proteins or short polyglutamine (polyQ) expansions in the context of biological aging. Using limited proteolysis of native extracts together with tandem mass tag-based quantitative proteomics, we identify proteins that become metastable under these conditions and monitor the effects on proteome solubility and abundance. Expression of different mutant proteins in the same tissue identifies hundreds to a thousand proteins that become metastable affecting multiple compartments and processes in a cell autonomous and non-autonomous manner. Comparison of the network of metastable proteins, however, reveals only a small number of common proteins. The most dramatic effects on global proteome dynamics occur in aging with one-third of the proteome undergoing conformational changes in early adulthood. These age-dependent metastable proteins overlap substantially with ts proteins and polyQ; moreover, expression of polyQ accelerates the aging phenotype. Together, these results reveal that the proteome responds to misfolding one-at-a-time to generate a metastable sub-proteome network with features of a fingerprint for which aging is the dominant determinant of proteome metastability.
Rapid response of fly populations to gene dosage across development and generations
Authors: Li Xueying C. , Gandara Lautaro , Ekelöf Måns , Richter Kerstin , Alexandrov Theodore , Crocker Justin 
Published: September 2022

AbstractAlthough the effects of genetic and environmental perturbations on multicellular organisms are rarely restricted to single phenotypic layers, our current understanding of how developmental programs react to these challenges at a systems level remains limited. Here, we have examined the phenotypic consequences of disturbing the classicbicoidnetwork inDrosophila, which is essential for anterior-posterior patterning in the early embryo. This network can be synthetically perturbed by increasing the dosage ofbicoid, which causes a posterior shift of the network’s regulatory outputs and a decrease in fitness. To directly monitor network changes across populations and time with extra copies ofbicoid, we performed genome-wide EMS mutagenesis, followed by experimental evolution. After only 8-15 generations, experimental populations have normalized patterns of gene expression and increased survival. Using a phenomics approach, we find that populations were normalized through rapid increases in embryo size driven by maternal changes in metabolism and ovariole development. We extend our results to additional populations of flies, demonstrating predictability. Together, our results necessitate a broader view of regulatory network evolution at the systems level. In the future, such synthetic evolution approaches using animal models could provide a generalizable platform for studying the propagation of genetic perturbations across the many layers of complex multicellular systems.
Exosome-derived lncRNA HOXA-AS3 promotes castration resistance and progression of prostate cancer via the miR-29b-3p/Mcl-1/STAT3 axis
Authors: Teng Jie , Zhao Yan , Shang Limin , Li Yang , Zhang Jian , Zhu Liang , Chen Yegang , Li Gang , Liu Zhifei , Jia Mingfei , Kang Shaosan , Niu Haitao , Niu Yuanjie , Cai Qiliang 
Published: September 2022

AbstractProstate cancer is one of the leading causes of cancer-related deaths in men. While endocrine therapy is effective in the early stage of metastasis, significantly inhibits the progression of metastatic prostate cancer, most patients eventually develop CRPC. Tumor microenvironment are involved in the progression of prostate cancer as an “accomplice”, cancer cell–secreted exosomes were identified as crucial messengers can carry lncRNAs to participate in intercellular communication. we revealed PC-3-derived exosomes promote androgen resistance in LNCaP cells. HOXA-AS3 as a ceRNA of miRNA-29b-3p affects the proliferation and invasion ability of prostate cancer cells. A series of molecular experiments, cell experiments and clinical tissue verification experiments confirmed that HOXA-AS3 participates in the castration resistance and progression of prostate cancer through regulating the miR-29b-3p/Mcl-1/STAT3/Cytochrome C/caspases-9 pathway. Dysregulation of HOXA-AS3 is observed in many cancer types, and this study shows the importance of this lncRNA in controlling prostate cancer cell progression, thus highlighting it as a potential biomarker for inhibiting prostate cancer progression and a target for immunotherapy.
TGFβ-induced long non-coding RNA LINC00313 activates Wnt signalling and promotes cholangiocarcinoma
Authors: Papoutsoglou Panagiotis , Louis Corentin , Pineau Raphaël , L’Haridon Anaïs , Banales Jesus M. , Gilot David , Aubry Marc , Coulouarn Cédric 
Published: September 2022

AbstractCholangiocarcinoma (CCA) is a poor prognosis liver cancer characterized by high aggressiveness and resistance to therapy. Long non-coding RNAs (lncRNAs) and signals imposed by oncogenic pathways, such as transforming growth factor β (TGFβ), contribute to cholangiocarcinogenesis. Here, we identified LINC00313 lncRNA as a novel target of TGFβ signalling in CCA cells. TGFβ induced LINC00313 expression in a TβRI/Smad-dependent manner. Gene expression and genome-wide chromatin accessibility profiling revealed that nuclear LINC00313 transcriptionally regulated genes involved in Wnt signalling, such as TCF7. LINC00313 gain-of-function enhanced TCF/LEF-dependent transcription, promoted colony formation in vitro and accelerated tumour growth in vivo. Genes associated with LINC00313 over-expression in human CCA were characterized by KRAS and TP53 mutations and reduced patient’s overall survival. Mechanistically, actin-like 6A (ACTL6A), a subunit of SWI/SNF chromatin remodelling complex, interacted with LINC00313 and impacted on TCF7 and SULF2 transcription. We propose a model whereby TGFβ induces LINC00313 in order to regulate expression of hallmark Wnt pathway genes, in co-operation with SWI/SNF. By modulating key genes of the Wnt pathway, LINC00313 fine-tunes Wnt/TCF/LEF-dependent transcriptional responses and boosts cholangiocarcinogenesis.
DASH/Dam1 complex mutants stabilize ploidy by weakening kinetochore-microtubule attachments
Authors: Haase Max A. B. , Ólafsson Guðjón , Flores Rachel L. , Boakye-Ansah Emmanuel , Zelter Alex , Dickinson Miles Sasha , Lazar-Stefanita Luciana , Truong David M. , Asbury Charles L. , Davis Trisha N. , Boeke Jef D. 
Published: September 2022

SummaryForcing budding yeast to chromatinize their DNA with human histones manifests an abrupt fitness cost. We previously proposed chromosomal aneuploidy and missense mutations as two potential modes of adaptation to histone humanization. Here we show that aneuploidy in histone-humanized yeasts is specific to a subset of chromosomes, defined by their centromeric evolutionary origins, however, they are not adaptive. Instead we show that a set of missense mutations in outer kineto-chore proteins drive adaptation to human histones. Further, we characterize the molecular mechanism of two mutants of the outer kinetochore DASH/Dam1 complex, which reduce aneuploidy by suppression of chromosome instability. Molecular modeling and biochemical experiments show that these two mutants likely disrupt a conserved oligomerization interface thereby weakening microtubule attachments. Lastly, we show that one mutant, DAD1E50D, while suppressing chromosome instability in mitosis, leads to gross defects in meiosis. In sum, our data show how a set of point mutations evolved in the histone-humanized yeasts to counterbalance human histone induced chromosomal instability through weakening microtubule interactions, eventually promoting a return to euploidy.
HSV-1 infection induces a downstream shift of promoter-proximal pausing for most host genes
Authors: Weiß Elena , Hennig Thomas , Graßl Pilar , Djakovic Lara , Whisnant Adam W. , Jürges Christopher S. , Koller Franziska , Kluge Michael , Erhard Florian , Dölken Lars , Friedel Caroline C. 
Published: September 2022

AbstractHerpes simplex virus 1 (HSV-1) infection exerts a profound shut-off of host gene expression at multiple levels. Recently, HSV-1 infection was reported to also impact promoter-proximal RNA Polymerase II (Pol II) pausing, a key step in the eukaryotic transcription cycle, with decreased and increased Pol II pausing observed for activated and repressed genes, respectively. Here, we demonstrate that HSV-1 infection induces more complex alterations in promoter-proximal pausing than previously suspected for the vast majority of cellular genes. While pausing is generally retained, it is shifted to more downstream and less well-positioned sites for most host genes. We exclude that this is an artefact of alternativede novotranscription initiation at downstream sites or read-in transcription originating from disruption of transcription termination for upstream genes. Use of downstream 2ndpause sites associated with +1 nucleosomes was previously observed upon NELF depletion. However, downstream shifts of Pol II pausing upon HSV-1 infection are much more pronounced than observed upon NELF depletion. Thus, our study reveals a novel aspect in which HSV-1 infection fundamentally reshapes host transcriptional processes with implications for our understanding of maintenance of promoter-proximal Pol II pausing in eukaryotic cells.
Treatment of Hydrocephalus by Decreasing Inflammatory Cytokine Response Using GIT 27
Authors: Zaranek Mira , Harris Carolyn 
Published: September 2022

AbstractBackgroundSurgical insertion of a ventricular shunt initiates a cytokine response shown to play a role in shunt failure caused by obstruction. These pro-inflammatory and anti-inflammatory cytokines cause astrocytes, amongst others, to enter an activated state which causes an increase in attachment. 4,5-Dihydro-3-phenyl-5-isoxazoleacetic acid (GIT 27) is a reagent with immunomodulatory properties which acts by blocking the main signaling protein on astrocytes and microglia called toll-like receptor 4 (TLR-4).MethodsIn this experiment, we tested the effect of GIT 27 on astrocytes when used as a pre-treatment, simultaneous treatment, and post-treatment relative to shunt insertion represented by the introduction of IL-1β or IL-10. Control, DMSO vehicle control, and GIT 27 treated sample groups were assayed for cell counts and cytokine concentration data.ResultsExposure of astrocytes to suspended GIT 27 in a DMSO vehicle caused a decrease in cell attachment and a significant decrease in the concentration of the majority of cytokines. Comparisons of GIT 27 exposure times, represented by pre-, simultaneous, and post-treatment groups, showed that pre-treatment with GIT 27 is most effective at decreasing cellular attachment where post-treatment was generally the most effective at decreasing pro-inflammatory cytokine concentrations. In future practice, this could be embodied by pharmacologic dosing prior to shunting and/or slow release from the shunt surface.ConclusionsGIT 27 is most effective at decreasing cell counts and cytokines when in-suspension compared to when attached to the shunt surface. Our data show that GIT 27 has the potential to be used as an effective way to modulate the cytokine response associated with shunt insertion.
Parallel evolution and cryptic diversification in the common and widespread Amazonian tree, Protium subserratum
Authors: Misiewicz Tracy M. , Simmons Tracey , Carter Benjamin E. , Fine Paul V. A. , Moore Abigail J. 
Published: September 2022

AbstractThe lowland Amazon rainforest houses some of the greatest tree diversity on earth. While the vast majority of these species are rare, a small number are common and widespread and thus considered to play a disproportionate role in many of the global ecosystem services provided by the Amazon. However, the extent to which dominant Amazonian tree species actually include multiple clades, each on their own unique evolutionary trajectory, is unknown. Here we investigate the extent to which lineage divergence may be occurring within Protium subserratum (Burseraceae), a common and widespread tree species that is monophyletic with populations exhibiting genotypic and phenotypic differences associated with soil and geography. Utilizing a combination of phylogenomic and population genomic methods with sampling from across the range, we found that P. subserratum contains at least eight distinct clades. Specialization onto white-sand soils has evolved independently at least two times within the species; however, phenotype is not correlated with soil type. Finally, cryptic diversity at the base of the Andes is associated with elevational shifts. Together these results lend support to the hypothesis that common and widespread Amazon tree species may not represent evolutionary cohesive units. Instead, these dominant species may more commonly represent species complexes, undergoing evolutionary transitions on a trajectory to become multiple range restricted, specialist species.