bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional burst kinetics are linked to short term transcriptional memory
Authors: Senecal Adrien , Singer Robert , Coleman Robert 
Published: November 2021

SUMMARYTranscriptional bursting is thought to be a stochastic process that allows the dynamic regulation of most genes. The random telegraph model assumes the existence of two states, ON and OFF. However recent studies indicate the presence of additional ON states, suggesting that bursting kinetics and their regulation can be quite complex. We have developed a system to study transcriptional bursting in the context of p53 biology using the endogenous p21 gene tagged with MS2 in human cells. Remarkably, we find that transcriptional bursts from the p21 gene contain multiple ON and OFF states that can be regulated by elevation of p53 levels. Distinct ON states are characterized by differences in burst duration, classified as Short and Long, with long bursts associated with higher Pol II initiation rates. Importantly, the different ON states display memory effects that allow us to predict the likelihood of properties of future bursting events. Long bursting events result in faster re-activation, longer subsequent bursts and higher transcriptional output in the future compared to short bursts. Bursting memory persists up to 2 hours suggesting a stable inheritable promoter architecture. Bursting memory at the p21 gene is the strongest under basal conditions and is suppressed by UV and inhibition of H3K9me1/2, which also increase transcriptional noise. Stabilization of p53 by Nutlin-3a partially reverses suppression of bursting memory suggesting that higher p53 levels may be a key in enforcing memory under conditions of cellular stress. Overall our data uncover a new found bursting property termed Short-Term Transcriptional Memory (STTM) that has the potential to fine-tune transcriptional output at the p21 gene.
The contribution of common regulatory and protein-coding TYR variants in the genetic architecture of albinism
Authors: Michaud Vincent , Lasseaux Eulalie , Green David J. , Gerrard Dave T. , Plaisant Claudio ,   UK Biobank Eye and Vision Consortium, Fitzgerald Tomas , Birney Ewan , Arveiler Benoît , Black Graeme C. , Sergouniotis Panagiotis I. 
Published: November 2021

ABSTRACTGenetic diseases have been historically segregated into rare Mendelian and common complex conditions.1,2 Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits.3–8 Aiming to gain insights into the genetic architecture of rare recessive disorders, we studied a cohort of 1,313 individuals with albinism, an archetypal Mendelian condition. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.-301C>T [rs4547091], modulates the penetrance of a prevalent, disease-associated missense change, TYR c.1205G>A [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[-301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants increases diagnostic yield and informs genetic counselling in families with albinism.
Emergence and spread of a sub-lineage of SARS-CoV-2 Alpha variant B.1.1.7 in Europe, and with further evolution of spike mutation accumulations shared with the Beta and Gamma variants
Authors: Stadtmüller Marlena , Laubner Alexa , Rost Fabian , Winkler Sylke , Patrasová Eva , Šimůnková Lenka , Reinhardt Susanne , Beil Johanna , Dalpke Alexander H. , Yi Buqing 
Published: November 2021

AbstractSARS-CoV-2 evolution plays a significant role in shaping the dynamics of the COVD-19 pandemic. To monitor the evolution of SARS-CoV-2 variants,through international collaborations, we performed genomic epidemiology analyses on a weekly basis with SARS-CoV-2 samples collected from a border region between Germany, Poland and the Czech Republic in a global background. For identified virus mutant variants, active viruses were isolated and functional evaluations were performed to test their replication fitness and neutralization sensitivity against vaccine elicited serum neutralizing antibodies. Thereby we identified a new B.1.1.7 sub-lineage carrying additional mutations of nucleoprotein G204P and open-reading-frame-8 K68stop. Of note, this B.1.1.7 sub-lineage is the predominant B.1.1.7 variant in several European countries, such as Czech Republic, Austria and Slovakia. The earliest samples belonging to this sub-lineage were detected in November 2020 in a few countries in the European continent, but not in the UK. We have also detected its further evolution with extra spike mutations D138Y and A701V, which are signature mutations shared with the Beta and Gamma variants, respectively. Antibody neutralization assay of virus variant isolations has revealed that the variant with extra spike mutations is 3.2-fold less sensitive to vaccine-elicited antibodies as compared to other B.1.1.7 variants tested, indicating potential for immune evasion, but it also exhibited reduced replication fitness. The wide spread of this B.1.1.7 sub-lineage was related to the pandemic waves in early 2021 in various European countries. These findings about the emergence, spread, evolution, infection and transmission abilities of this B.1.1.7 sub-lineage add to our understanding about the pandemic development in Europe, and could possibly help to prevent similar scenarios in future.
Patient ABO blood type is a major predictor of a positive DAT following a transfusion reaction
Authors: Schnieders Eric , Leon Judith , Knudson C. Michael 
Published: November 2021

ABSTRACTBackgroundA direct antiglobulin test (DAT) checks for antibody or complement on the surface of RBCs and is often done following a transfusion reaction. While passive anti-A and anti-B antibodies are known to cause positive DATs, the extent this occurs following transfusion is unknown.Study Design and methodsDAT results, ABO type and blood product information was recorded on 1097 transfusion reactions at a large academic hospital over 8 years. The effect of patient blood type, product type and plasma compatibility of blood product transfused on DAT results were determined. Statistical significance was determined using Chi-squared testing.ResultsPlasma compatibility of the product was a strong predictor of a positive DAT with plasma compatible transfusions having a 9.4% positive rate while plasma incompatible transfusions were positive 44% of the time (P<0.0001). Patient ABO blood type was a strong predictor of a positive DAT with Type O patients having 6.6% positive rate and non-O patients having a positive rate of 20.6% (P <0.0001). These results were significant for individual blood types as well. Type A, B or AB patients had higher DAT positive rates even when plasma incompatible transfusions were excluded from the analysis (P<0.0001). Platelets were significantly more likely to be associated with a positive DAT when compared to RBC transfusions.ConclusionsThese results show plasma compatibility and ABO types are strong predictors of positive DAT results following a transfusion reaction. Anti-A and anti-B antibodies are estimated to account for about 50% of positive DATs in this study.
Cell-Free Tumor DNA Dominant Clone Allele Frequency (DCAF) Is Associated With Poor Outcomes In Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy
Authors: Uson Junior Pedro Luiz Serrano , Majeed Umair , Yin Jun , Botrus Gehan , Sonbol Mohamad Bassam , Ahn Daniel H. , Starr Jason S. , Jones Jeremy C , Babiker Hani , Inabinett Samantha R , Wylie Natasha , Boyle Ashton WR , Bekaii-Saab Tanios S. , Gores Gregory J , Smoot Rory , Barrett Michael , Nagalo Bolni , Meurice Nathalie , Elliott Natalie , Petit Joachim , Zhou Yumei , Arora Mansi , Dumbauld Chelsae , Barro Oumar , Baker Alexander , Bogenberger James , Buetow Kenneth , Mansfield Aaron , Mody Kabir , Borad Mitesh J. 
Published: November 2021

ABSTRACTPURPOSEThis investigation sough to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment.METHODSWe performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF) as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS).RESULTSThe median age of patients was 67 years (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancers. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20 or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11 and IDH1 were the genes with highest frequency as DCAF. Median DCAF was 3% (0-97%). DCAF >3% was associated with worse OS (median OS: 10.8 vs. 18.8 months, p=0.032). Stratifying DCAF in quartiles, DCAF>10% was significantly related to worse PFS (median PFS: 3 months, p=0.014) and worse OS (median OS: 7.0 months, p=0.001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9.CONCLUSIONDCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decrease survival probabilities.
A new gene family diagnostic for intracellular biomineralization of amorphous Ca-carbonates by cyanobacteria
Authors: Karim Benzerara , Elodie Duprat , Tristan Bitard-Feildel , Géraldine Caumes , Corinne Cassier-Chauvat , Franck Chauvat , Manuela Dezi , Issa Diop Seydina , Geoffroy Gaschignard , Sigrid Görgen , Muriel Gugger , Purificación López-García , Fériel Skouri-Panet , David Moreira , Isabelle Callebaut 
Published: November 2021

ABSTRACTCyanobacteria have massively contributed to carbonate deposit formation over the geological history. They are traditionally thought to biomineralize CaCO3extracellularly as an indirect byproduct of photosynthesis. However, the recent discovery of freshwater cyanobacteria forming intracellular amorphous calcium carbonates (iACC) challenges this view. Despite the geochemical interest of such a biomineralization process, its molecular mechanisms and evolutionary history remain elusive. Here, using comparative genomics, we identify a new gene (ccyA) and protein (calcyanin) family specifically associated with cyanobacterial iACC biomineralization. Calcyanin is composed of a conserved C-terminal domain, which likely adopts an original fold, and a variable N-terminal domain whose structure allows differentiating 4 major types among the 35 known calcyanin homologues. Calcyanin lacks detectable full-length homologs with known function. Yet, genetic and comparative genomic analyses suggest a possible involvement in Ca homeostasis, making this gene family a particularly interesting target for future functional studies. Whatever its function, this new gene family appears as a gene diagnostic of intracellular calcification in cyanobacteria. By searching forccyAin publicly available genomes, we identified 13 additional cyanobacterial strains forming iACC. This significantly extends our knowledge about the phylogenetic and environmental distribution of cyanobacterial iACC biomineralization, especially with the detection of multicellular genera as well as a marine species. Phylogenetic analyses indicate that iACC biomineralization is ancient, with independent losses in various lineages and some HGT cases that resulted in the broad but patchy distribution of calcyanin across modern cyanobacteria. Overall, iACC biomineralization emerges as a new case of genetically controlled biomineralization in bacteria.Significance statementFew freshwater species of Cyanobacteria have been known to mineralize amorphous CaCO3 (ACC) intracellularly. Despite the geochemical interest of this biomineralization, its evolutionary history and molecular mechanism remain poorly known. Here, we report the discovery of a new gene family that has no homolog with known function, which proves to be a good diagnostic marker of this process. It allowed to find cyanobacteria in several phyla and environments such as seawater, where ACC biomineralization had not been reported before. Moreover, this gene is ancient and was independently lost in various lineages with some later horizontal transfers, resulting in a broad and patchy phylogenetic distribution in modern cyanobacteria.
Flexible Circuit Mechanisms for Context-Dependent Song Sequencing
Authors: Roemschied Frederic A. , Pacheco Diego A. , Ireland Elise C. , Li Xinping , Aragon Max J. , Pang Rich , Murthy Mala 
Published: November 2021

ABSTRACTMany sequenced behaviors, including locomotion, reaching, and vocalization, are patterned differently in different contexts, enabling animals to adjust to their current environments. However, how contextual information shapes neural activity to flexibly alter the patterning of actions is not yet understood. Prior work indicates such flexibility could be achieved via parallel motor circuits, with differing sensitivities to sensory context [1, 2, 3]; instead we demonstrate here how a single neural pathway operates in two different regimes dependent on recent sensory history. We leverage the Drosophila song production system [4] to investigate the neural mechanisms that support male song sequence generation in two contexts: near versus far from the female. While previous studies identified several song production neurons[5, 6, 7, 8], how these neurons are organized to mediate song patterning was unknown. We find that male flies sing ‘simple’ trains of only one syllable or mode far from the female but complex song sequences consisting of alternations between modes when near to her. We characterize the male song circuit from the brain to the ventral nerve cord (VNC), and find that the VNC song pre-motor circuit is shaped by two key computations: mutual inhibition and rebound excitability [9] between nodes driving the two modes of song. Weak sensory input to a direct brain-to-VNC excitatory pathway (via pC2 brain and pIP10 descending neurons) drives simple song far from the female. Strong sensory input to the same pathway enables complex song production via simultaneous recruitment of P1a neuron-mediated disinhibition of the VNC song pre-motor circuit. Thus, proximity to the female effectively unlocks motor circuit dynamics in the correct sensory context. We construct a compact circuit model to demonstrate that these few computations are sufficient to replicate natural context-dependent song dynamics. These results have broad implications for neural population-level models of context-dependent behavior [10] and highlight that canonical circuit motifs [11, 12, 13] can be combined in novel ways to enable circuit flexibility required for dynamic communication.
The mitochondrial gene CMPK2 functions as a rheostat for macrophage homeostasis in inflammation
Authors: Arumugam Prabhakar , Chauhan Meghna , Rajeev Thejaswitha , Chakraborty Rahul , Shankaran Deepthi , Ramalingam Sivaprakash , Gandotra Sheetal , Rao Vivek 
Published: November 2021

AbstractIn addition to their role in cellular energy production, mitochondria are increasingly recognized as regulators of the innate immune response of phagocytes. Here, we demonstrate that altering expression levels of the mitochondria associated enzyme, cytidine monophosphate kinase 2 (CMPK2), disrupts mitochondrial physiology and significantly de-regulates the resting immune homeostasis of macrophages. Both CMPK2 silenced as well as constitutively over expressing macrophage lines portray mitochondrial stress with marked depolarization of their membrane potential, enhanced ROS and disturbed architecture culminating in the enhanced expression of the pro-inflammatory genes-IL1β, TNFα and IL8. Interestingly, the long-term modulation of CMPK2 expression resulted in an increased glycolytic flux of macrophages akin to the altered physiological state of activated M1 macrophages. While infection induced inflammation for restricting pathogens is regulated, our observation of a total dysregulation of basal inflammation by bidirectional alteration of CMPK2 expression, only highlights a critical role of this gene in mitochondria mediated control of inflammation.
Computational simulations reveal that Abl activity controls cohesiveness of actin networks in growth cones
Authors: Chandrasekaran Aravind , Clarke Akanni , McQueen Philip , Fang Hsiao Yu , Papoian Garegin A. , Giniger Edward 
Published: November 2021

AbstractExtensive studies of growing axons have revealed many individual components and protein interactions that guide neuronal morphogenesis. Despite this, however, we lack any clear picture of the emergent mechanism by which this nanometer-scale biochemistry generates the multi-micron scale morphology and cell biology of axon growth and guidance in vivo. To address this, we studied the downstream effects of the Abl signaling pathway using a computer simulation software (MEDYAN) that accounts for mechanochemical dynamics of active polymers. Previous studies implicate two Abl effectors, Arp2/3 and Enabled, in Abl-dependent axon guidance decisions. We now find that Abl alters actin architecture primarily by activating Arp2/3, while Enabled plays a more limited role. Our simulations show that simulations mimicking modest levels of Abl activity bear striking similarity to actin profiles obtained experimentally from live-imaging of actin in wild type axons in vivo. Using a graph-theoretical filament-filament contact analysis, moreover, we find that networks mimicking hyperactivity of Abl (enhanced Arp2/3) are fragmented into smaller domains of actin that interact weakly with each other, consistent with the pattern of actin fragmentation observed upon Abl overexpression in vivo. Two perturbative simulations further confirm that high Arp2/3 actin networks are mechanically disconnected and fail to mount a cohesive response to perturbation. Taken together, these data provide a molecular-level picture of how the large-scale organization of the axonal cytoskeleton arises from the biophysics of actin networks.Highlight summaryHow do single-molecule dynamics produce multi-micron scale changes in actin organization in an extending axon? Comparison of computational simulations to in vivo data suggests that Abl kinase and Arp2/3 expand actomyosin networks by fragmenting into multiple domains, thus toggling the axon between states of local vs global internal connectivity.
A universal, single primer amplification protocol (R-SPA) to perform whole genome sequencing of segmented dsRNA reoviruses
Authors: Chrzastek Klaudia , Sellers Holly S. , Kapczynski Darrell R. 
Published: November 2021

AbstractBackgroundThe Reoviridae family represents the largest family of double-stranded RNA (dsRNA) viruses, and the members have been isolated from a wide range of mammals, birds, reptiles, fishes, insects, plants. Orthoreoviruses, one of the 15 recognized genera in the Reoviridae family, can infect humans and nearly all mammals, and birds. Genomic characterization of reoviruses has not been adopted on a large-scale due to the complexity of obtaining sequences for all 10 segments.ResultsIn this study, we developed a time-efficient, and practical method to enrich reovirus sequencing reads from isolates that allowed for full genome recovery using single-primer amplification method coupled with next generation sequencing. We refer to this protocol as reovirus-Single Primer Amplification (R-SPA). Our results demonstrated that most of the genes were covered with at least 500 reads per base space. Furthermore, R-SPA covered both 5’ and 3’ end of each reovirus genes.ConclusionA universal and fast amplification protocol that yields double-stranded cDNA in sufficient abundance and facilitates and expedites the whole genome sequencing of reoviruses was presented in this study.
Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function
Authors: Bygrave Alexei M , Sengupta Ayesha , Jackert Ella P , Ahmed Mehroz , Adenuga Beloved , Nelson Erik , Goldschmidt Hana L , Johnson Richard C , Zhong Haining , Yeh Felix L , Sheng Morgan , Huganir Richard L 
Published: November 2021

SUMMARYSynapses in the brain exhibit cell-type-specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell-type-specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron-specific synapse-enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd-95. Intriguingly, we show that Btbd11 can undergo liquid-liquid phase separation when expressed with Psd-95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin-positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell-type-specific protein that supports glutamatergic synapse function in inhibitory interneurons—with implication for circuit function and animal behavior.
A metagenomic analysis of the wrackbed microbiome indicates a phylogeographic break along the North Sea - Baltic Sea transition zone
Authors: Berdan Emma L. , Roger Fabian , Kinnby Alexandra , Cervin Gunnar , Pereyra Ricardo , Töpel Mats , Wellenreuther Maren , Johannesson Kerstin , Butlin Roger K. , André Carl 
Published: November 2021

AbstractSandy beaches are biogeochemical hotspots that bridge marine and terrestrial ecosystems via the transfer of marine organic matter, such as seaweed (termed wrack). A keystone of this unique ecosystem is the microbial community, which helps to degrade wrack and re-mineralize nutrients. However, little is known about the wrackbed microbiome, its composition, trophic ecology, or how it varies over time and space. Here we characterize the wrackbed microbiome as well as the microbiome of a primary consumer, the seaweed fly Coelopa frigida, and examine how they change along one of the most studied ecological gradients in the world, the transition from the marine North Sea to the brackish Baltic Sea. We found that polysaccharide degraders dominated both the wrackbed and seaweed fly microbiomes but there were still consistent differences between wrackbed and fly samples. Furthermore, we observed a shift in both microbial communities and functionality between the North and Baltic Sea. These shifts were mostly due to changes in the frequency of different groups of known polysaccharide degraders (Proteobacteria and Bacteroidota). We hypothesize that microbes were selected for their abilities to degrade different polysaccharides corresponding to a shift in polysaccharide content in the seaweed communities of the North vs. Baltic Sea. Our results reveal the complexities of both the wracked microbial community, with different groups specialized to different roles, and the cascading trophic consequences of shifts in the near shore algal community.